Professor Jörgen Lehmann was a doctor and researcher who discovered two of the most important medications of the twentieth century within the course of only a few years. He is widely regarded as the most deserving candidate for the first Nobel Prize awarded to a Gothenburg scientist. Professor Anders Lehmann talks about his grandfather’s discovery of para-aminosalicylic acid (PAS) and antiprothrombin (AP) dicumarol.
Tuberculosis and thromboses accounted for many deaths and enormous suffering as late as the early 1940s. Professor Lehmann, who was affiliated with Sahlgrenska University Hospital, discovered two revolutionary medications within the course of a few years: PAS for tuberculosis and AP dicumarol for thromboses. A widespread view is that he deserved to share the 1952 Nobel Prize in Physiology or Medicine for his discovery of PAS. Three locations in Gothenburg honor his name: a display case about his research at the Museum of Medical History on Östra Hamngatan, Jörgen Lehmann’s Gångväg at Guldheden, and the Jörgen Lehmann conference room at Medicinareberget. But his accomplishments cannot be encapsulated by showcases or street names.
Professor Lehmann was born in Copenhagen in 1898 and died in Gothenburg in 1989. Research ran in the family. His father Edward, an historian of religion, was well-known for his wit and rhetorical skills. His grandfather Heinrich received a PhD in ophthalmology in 1848, and his great grandfather Martin Gottlieb wrote a doctoral thesis on the external sensory organs of insects in 1798 . His father held various European chairs—the last in Lund, where his son studied medicine and began his postgraduate work. His supervisor was the legendary Professor Torsten Thunberg at the Department of Physiology. He wrote his doctoral thesis in 1930 about redox potentials and competitive inhibition in the citric acid cycle.
After pursuing research for a couple of years in Lund, he did his postdoc with Professor Herbert Gasser, a future Nobel Laureate, at the Rockefeller Institute in New York. He studied the physiology of the peripheral nervous system and was listed as the sole author of the works published by the institute. Hoping to obtain an appointment upon his return to Sweden, he padded his résumé in this manner. Apparently Professor Gasser was not only a great scientist but a humanitarian as well. Shortly after arriving back in Lund, Dr. Lehmann was appointed to a new chair in biochemistry in Århus in 1937. Not much later, Sven Johansson, Professor of Surgery at Sahlgrenska University Hospital (known as “Sven with the Nail” for his discovery of a method for treating fractures) asked him to set up a leading-edge clinical chemistry lab. Though accepting the appointment, Professor Lehmann was not satisfied with establishing a routine lab but set his sights on research as well. Professor Johansson passed away in 1959—suitably enough, Sven Johansson’s Backe is adjacent to Jörgen Lehmann’s Gångväg in the southern part of Guldheden. Their tombstones at Stampen Cemetery are close enough to wink at each other every now and then.
Moldy white sweet clover kills livestock: Discovery of dicumarol for thromboses
Postoperative thromboembolisms were a major clinical dilemma in the 1940s. Professor Lehmann’s very first scientific article in 1922 dealt with the effect of divalent cations on coagulation. In his capacity of clinical chemist, he developed a micro-method for neonatal prothrombin determination. The risk of neonatal Vitamin K deficiency that reduced prothrombin levels was well-known. An American by the name of Edward A. Doisy identified the structure of Vitamin K a couple of years later and shared the 1944 Nobel Prize in Physiology or Medicine with Henrik Dam (Denmark) for research in the area. While conducting prothrombin research in 1940, Professor Lehmann read an article about sweet clover disease in Canada and the northern United States. The symptoms were severe, occasionally life-threatening, bleeding during polling and castration of livestock that had eaten moldy white sweet clover (Melilotus alba). Quickly realizing that the molds form one or more anticoagulants, he set out to isolate the active compounds. He took a hospital gardener and an intern by the name of Johan Mårtensson to Hisingen to obtain Melilotus alba, which he left to mold in the basement of the clinical chemistry lab. The incident attracted widespread interest and more than one researcher scratched their head in wonderment about what the eccentric Dane was up to.
Isolating biologically active fractions in the molds was an exhausting effort. The molds were evaluated by means of experiments with laboratory animals but generally yielded negative results. Professor Lehmann consulted Gothenburg botanists, who gave him access to the species of molds that can cause bleeding. That was when he started to chart up successes. When Göte Turesson, his brother-in-law and professor of botanical genetics at Uppsala University, told him that Melilotus alba forms various coumarin derivatives, he knew that he was headed in the right direction. He compared the structure of the compounds with Vitamin K and found that they were closely related. That could hardly have been a coincidence, so he assumed that the compounds in the mold formed Vitamin K antagonists. Around the same time, an American professor by the name of Karl P. Link identified an active substance that he called 3,3-methylene-bis(4-hydroxycoumarin)—dicumarol for short. While it was a key discovery, Professor Lehmann did not have access to the chemical expertise required to take that step.
Right after Professor Link published his findings, Professor Lehmann contacted the Ferrosan pharmaceutical company in Malmö and asked them to synthesize dicumarol. Before long the anticoagulant properties of the substance had been verified in rabbits. Elisabeth, the first subject, lived out her days as the mascot of the laboratory. Her body was stuffed and mounted at the Museum of Medical History.
Drug discovery and development are strictly regulated these days, subject to extensive toxicological testing. Phase I trials on healthy volunteers use very low doses to start off with in order to detect any potential adverse effects. The rules were a lot more lenient in the 1940s, allowing Professor Lehmann to experiment on himself by titrating doses of dicumarol. To his great satisfaction, his prothrombin levels declined as expected. Aware of the risks, he noted his blood type in his reports just in case he started hemorrhaging and needed a transfusion. Totally acceptable and a bit heroic back in those days, such methods would be grounds for dismissal in the contemporary world.
Encouraged by the results, Professor Lehmann told a surgeon at Sahlgrenska University Hospital about his findings. The colleague was more than willing to let Professor Lehmann experiment on a patient with a huge leg thrombosis. Four weeks later, the patient’s prothrombin levels had declined substantially and his symptoms were much better. The project had succeeded. Nowadays it can easily take three years once a drug candidate has been synthesized to proceed to Phase II trials. Professor Lehmann performed the first animal experiments in June 1941 and reached that point only four months later. Pharmaceutical researchers must be envious, if not wryly amused, when they look back on such events.
Professors Lehmann and Link independently came up with identical ideas across the Atlantic
As a veterinarian, Professor Link may not have fully realized the enormous clinical potential that dicumarol had to offer. But a team at Mayo Clinic was quick to jump onboard, announcing simultaneously with Professor Lehmann the efficacy of dicumarol in treating thromboses, along with oral presentations in late 1941 and articles in early 1942. World War II was raging and scientific communication was unreliable at best. Professors Lehmann and Link independently came up with identical ideas across the Atlantic divide. Scholarly contact was so capricious that Professor Lehmann was unaware that Science and The Lancet had published the articles he submitted for review until Professor Link notified him.
Professor Link had access to medicinal chemists, who synthesized a number of dicumarol derivatives. The effort eventually produced warfarin, which has the same mode of action as dicumarol with greater potency and bioavailability. Warfarin has become a leading antithrombotic. That it is just as popular as rat poison serves as a telling example of the maxim that toxicology is often nothing more than high-dose pharmacology.
Professor Link had Professor Lehmann—whom he met later—to thank for the discovery of PAS, which most likely saved his life.
Stimulating the tubercle bacillus: the discovery of PAS
Tuberculosis has been a scourge on humanity and mowed down millions of lives since time immemorial. The discovery of penicillin and sulfa preparations, the first effective antibiotics, in the 1930s spurred the quest for a chemotherapeutic to treat tuberculosis. The monumental nature of the task shattered the initial optimism, and anyone who claimed to have found a new cure in the early 1940s was met with cynicism and skepticism.
Professor Lehmann came up with the idea for PAS in 1940 while reading a Science article by Frederick Bernheim of Duke University. The article showed that salicylic acid substantially activates the metabolism of the tubercle bacillus. With the subject of his doctoral thesis in the back of his mind, Professor Lehmann was immediately struck by the idea that a structural analog of salicylic acid could inhibit the metabolism of Mycobacterium tuberculosis and thereby produce a bacteriostatic effect. He had been applying the exact same principle to his dicumarol research. Without a moment to spare, he had no choice but to put his new insights on the back burner for the time being.
Having finally found time to focus on tuberculosis, Professor Lehmann wrote to the research director at Ferrosan in 1943 and proposed synthesis of two different salicylic acid derivatives. He left no doubt that he preferred the PAS molecule. And sure enough, it turned out to be the most active of the many molecules that were subsequently tested.
Its simple structure notwithstanding, PAS proved to be a daunting challenge to synthesize, and Ferrosan did not send Professor Lehmann the compound (13 grams) until December 1943. While historians have frequently neglected to give the medicinal chemists due credit, Professor Lehmann never missed an opportunity to honor K.G. Rosdahl for his extraordinary feat in synthesizing PAS. He wrote to Ferrosan on New Year’s Eve to announce that PAS substantially inhibited the growth of M. tuberculosis in vitro. He wasn’t going to let a mere holiday blunt his scientific enthusiasm.
Events took on a life of their own. Toxicological studies on rodents began in 1944 along with pharmacological efficacy experiments on guinea pigs. Meanwhile, Professor Lehmann developed a method for measuring the concentration of PAS in the blood and established the concept of the relationship between a compound’s pharmacokinetic and pharmacodynamic properties (PKPD). Even before the experiments had generated favorable results, Professor Lehmann wanted to treat tuberculous fistulas locally based on the observation that PAS had negligible toxicity. These initial clinical studies of PAS gave rise to great optimism, and the first patient received an oral dose in October 1944.
Clinical trials proceeded slowly due to the complex nature of PAS synthesis. The manufacturing process was so costly that the director at Ferrosan wanted to abandon the entire project. He changed his mind when Professor Lehmann announced that he would apply for grants from various foundations. The event was reminiscent of the history of omeprazole (Losec®), another epoch-making Swedish discovery (see article in Akademiliv). Astra management wanted to drop the project but Ivan Östholm, the zealous research director at Hässle (now AstraZeneca R&D Mölndal), scrounged up the funds to continue for a period of time. Professor Lehmann, Ferrosan and Gylfe Vallentin (senior consultant at the Renström Sanatorium in Gothenburg) had an agreement not to publish their initial clinical studies until they had obtained convincing evidence. And so two years transpired between Professor Lehmann’s first positive in vitro discovery and an article about PAS in The Lancet in January 1946. All that time he kept a large quantity of data showing the efficacy of PAS both in vitro and in vivo close to his chest. First marketed in 1948, PAS enjoyed its glory days in the 1950s and 1960s. Though still used in special cases, it has eventually been outstripped by more effective drugs.
PAS and streptomycin: fraternal twins
Selman Waksman, a professor of microbiology at Rutgers University, discovered streptomycin (SM). He became the 1952 Nobel Laureate in Physiology or Medicine on the claim that SM was the first effective drug for tuberculosis. But was it?
Let’s start off by comparing PAS and SM. Each has its particular benefits and risks. SM is generally regarded as more effective but can cause deafness, an uncommon but serious adverse effect. Moreover, it turned out that the tubercle bacillus often developed resistance to SM such that many patients suffered a relapse after initial improvement. Though not unheard-of, resistance to PAS was less pronounced. While serious adverse effects from PAS were rare enough, many patients experienced gastrointestinal discomfort. Researchers realized a little too late that PAS reduced resistance to SM so effectively that consistent use of combination treatment could have significantly improved tuberculosis care.
The two drugs met with very different receptions at the national level. Whereas SM made a rapid breakthrough in the United States, skepticism and criticism on the part of many leading doctors delayed the launch of PAS in the Swedish market. A number of prominent physicians were highly dubious about PAS when it was first presented at the 13th annual Nordic Tuberculosis Conference in Gothenburg in June 1946. They eventually ate their words, and the events reflected core differences between Swedish and American attitudes. Jesus said “No prophet is acceptable in his own country,” but the American propensity to worship success, particularly when achieved by a compatriot, tends to dilute the validity of that timeless axiom.
PAS and SM were discovered and developed alongside each other in 1943-1945. While PAS was always a couple of months ahead, the Americans took a more aggressive approach and published their clinical data four months ahead of the article in The Lancet. Gösta Birath, the first Swedish professor of pulmonary medicine, wrote many years ago that PAS and SM were fraternal twins. Let me add that if they had been viewed that way from a pharmacotherapeutic point of view at their inception, many deaths and a great deal of suffering might have been avoided.
One member of the committee was a powerful opponent of Professor Lehmann and may have been motivated by their rivalry in the field of coagulation research
Assuming that tuberculosis research would be hailed by the 1952 Nobel Prize in Physiology or Medicine, Professor Waksman and most other observers expected that the discoverers of PAS and SM would share it. When Professor Waksman turned out to be the sole recipient, many people were astonished and even indignant. Since there is no doubt that SM was not the first effective drug for tuberculosis, the reasoning of the Nobel Committee remains fairly incomprehensible. However, one member of the committee was a powerful opponent of Professor Lehmann and may have been motivated by their rivalry in the field of coagulation research. It is certainly possible that he was unable to bear the thought that a researcher with limited resources and the responsibility of directing and expanding a clinical chemistry lab in a city that had no university at the time would have chalked up two groundbreaking achievements within the course of a few years. Minutes of the Nobel Committee at Karolinska Institutet are classified for 50 years and may be released after that time only when germane to current research. So the 1952 discussions are still being kept under wraps.
He had no airs about him and could corner the first passerby in the hallway to discuss his latest findings
I would like to conclude with a few personal observations about my grandfather. He was a vibrant person whose personality made a deep impression on everyone he met. He liked to boast that he was the second worst student in his class in Lund, but his curiosity, imagination, determination and unshakable faith in his ideas were decisive to his success. He lived in an era when medical researchers could still roam from one field to another instead of being confined to a particular specialty. He was a worthy interlocutor no matter what branch of biomedicine you brought up. After retiring in 1963, he started to research the role of tryptophan deficiency in comas caused by midgut carcinoids, which his favorite sister had died of. By an odd twist of fate, he wound up at the Department of Pharmacology, where Professor Arvid Carlsson subsequently became the first researcher at Gothenburg University to become a Nobel Laureate (2000). After embarking on my doctoral studies at the Department of Histology in 1981, I found myself sitting adjacent to my grandfather’s office. Every now and then he would drop in to mull over his research. He had no airs about him and could corner the first passerby in the hallway to discuss his latest findings with his unique blend of Danish and Swedish. Just before he threw in the towel for good, a colleague at the department told me that she had been talking to a mechanic when my grandfather happened to walk by. The mechanic said, “Look, here comes Grandpa,” and my colleague asked him how he had found out that we were related. The mechanic replied, “I had no idea, that’s just what everyone calls him.” People who were unaware of his unique contributions to medical progress in the 1940s and succeeding decades felt a kinship with him well into his later years.
British physician Frank Ryan offered the most vivid description of my grandfather’s personality in Tuberculosis: the Greatest Story Never Told (1992):
No medical scientist of the twentieth century was ever more unorthodox, more impulsively creative than this charming Scandinavian doctor, Jörgen Lehmann. Gifted with a deductive ability and speed that in his own lifetime became legendary, yet nevertheless handsome and witty in so many aspects of his life and personality, Lehmann seemed the very embodiment in real life of Conan Doyle’s fictitious genius Sherlock Holmes… His genius inhabited a wild spirit, untamable with the mundane academic conventions. Rebellious, eccentric, brilliant, he didn’t care a jot for the hierarchical posturing of his more conventional colleagues. [He had] a stubborn independence… a fantastic imagination, which was apparent even as a child. Later on he would joke about his over-developed imagination, realizing how vital a part it would play in his life.
Anders Lehmann, Professor
Institute of Neuroscience and Physiology, Sahlgrenska Academy
Thanks to Johan Wennerberg, Malmö, for his editing services and Thomas Gütebier, Gothenburg, for the photos
P.S.: Associate Professor Johan Wennerberg is currently authoring a biography of Jörgen Lehmann