Paul Ehrlich: the man behind the ‘magic bullet’
The ‘Father of Chemotherapy’ made lasting contributions to immunology and hematology.
Unwavering reliance on the scientific method marked the career of Paul Ehrlich. From graduate work with aniline dyes to the discovery of Salvarsan, one of the first consistently effective treatments for syphilis, he dedicated his life to the progress of medical science.
Even cursory examination of Ehrlichs life reveals that he was a remarkable man, both personally and professionally. From his university days until his death, he smoked an average of 25 cigars a day. He diagnosed his own tuberculosis infection using a method that he had developed just months before. His magic bullet theory, which was known as the side-chain theory at the time, led to contributions in immunology that resonate today. Later in his career, he applied the same theory to the study of tumor cells and effectively invented the field of chemotherapy, a word which he coined.
He accomplished most of this after a falling out with Emil von Behring, who was in his own right, one of the more distinguished scientists of his time. Had the two men continued their collaboration, the contributions to medicine may have been exponentially more influential. As it stands, Ehrlichs work has provided successive generations with more than enough to build upon.
Source: National Library of Medicine
The first notable contribution Ehrlich made to science was in the field of hematology when he was a student at the University of Leipzig in 1878. Working from the observation that the uptake of different dyes varied in different tissues, Ehrlich proposed that a true chemical reaction occurred in the staining of cells. In his doctoral thesis he identified mast cells, created the field of differential staining of blood cells, and defined neutrophils, eosinophils, basophils, lymphocytes, erythrocytes and reticulocytes based on a predilection toward acidic or basic dyes. He was 24.
After graduation in 1878, Ehrlich took a position at the Charité Hospital in Berlin and continued his dogged laboratory investigations. Just six weeks after Robert Koch published results on the cause of tuberculosis, Ehrlich wrote a paper outlining the acid-fast method of staining the tubercle bacillus.
Shortly thereafter, Ehrlichs life and work dovetailed when he discovered the acid-fast bacillus in his own sputum. He had contracted the infection in his laboratory. He went to southern Europe and ultimately to Egypt with his wife, Hedwig Pinkus, to recuperate for two years. Upon his return to Berlin, Ehrlich began working in a small private laboratory that was funded by his father-in-law, and later he took an unpaid position at the Institute for Infectious Diseases, which had been built by Koch.
Focus on immunology
The first major development to come from the institute was a therapeutic antiserum to combat diphtheria. Ehrlich quantified and standardized an antiserum that had been developed in animals by von Behring and Shibasaburo Kitasato in 1892. It was Ehrlichs work that made the antiserum marketable.
Ehrlich moved his research to an abandoned bakery that he converted into a laboratory. It was at this time that the split between Ehrlich and von Behring occurred because von Behring failed to include Ehrlich in a commercial contract to produce the diphtheria antiserum.
Ehrlich continued his work alone, and in 1897 published his revolutionary side-chain theory. He described the process as being similar to key fitting a lock that, in modern terms, would involve cells having receptors for antigens. Upon contact with the antigen, the receptors are shed into the bloodstream as antitoxins. The theory included Ehrlichs first use of the term "magic bullet": the concept that chemicals could be designed to bind to and kill specific microbes or tumor cells.
The proposition was ridiculed by many contemporary scientists, and Ehrlich had to wait several years before being awarded the Nobel Prize for this work. Even in spite of the award, the theory did not become a cornerstone of immunology for almost 60 years. Many modern scientists believe that it was simply too advanced for its time. The ridicule and denial of the Nobel Prize appears not to have fazed Ehrlich. He continued with his research and eventually turned his attention to other endeavors.
The advent of chemotherapy
In 1899, Ehrlich was offered the position of director of the Royal Prussian Institute for Experimental Therapy in Frankfurt. This opportunity provided him the resources to conduct more rigorous research. The strength of his reputation gave him access to the best products of the synthetic chemical industry and a multidisciplinary team of scientists. It was here that he reapplied the magic bullet theory in pursuit of a treatment for syphilis.
Ehrlich continued to defy conventional thought with the belief that it was possible to synthesize a compound that negatively impacted the parasite with little damage to healthy body tissue. When the microbe causing syphilis is found, I must be prepared, he said.
August Wasserman discovered the reaction for the diagnosis of syphilis in 1906. It took four years and 605 failed attempts for Ehrlich and his colleagues to arrive at arsphenamine, a form of organic arsenic. It was initially called compound 606, but then marketed under the name Salvarsan. In fact, the compound had been dismissed and shelved after an evident failure in 1907. However, a pupil of Kitasato later tested the discarded compound on rabbits that were infected with syphilis and found it to be effective.
In 1910, Ehrlich published results demonstrating the clinical efficacy of Salvarsan. Hochst Chemical Works immediately began manufacturing the drug, distributing more than 65,000 free doses for use in clinical trials.
Life and death
Despite such rigorous laboratory work, it has been said that Ehrlich always had his eye on the clinic. His ideas were revolutionary, but his results were practically applicable. There is a story from his schoolboy days about a teacher who assigned the class an essay on "Life as a Dream." Rather than tackling the assignment as the other children did, Ehrlich wrote at length about life being dependent on normal oxidation processes and that nerve activity is an example of one such process. A dream, therefore, is a form of oxidation resulting in the phosphorescence of the brain.
Ehrlich attempted to apply the insight of his dreams to his lifework. The hope of eradicating syphilis fueled his efforts in supervising the distribution of Salvarsan after the drugs debut in 1910. However, it is rumored that he was distressed by the outbreak of the First World War, and in 1914 he suffered a minor stroke that temporarily curtailed his capabilities. He recovered but not fully, and on Aug. 20, 1915, a second stroke ended his life.
Apart from the Nobel Prize, Ehrlich received the Prize of Honour at the XVth International Congress of Medicine at Lisbon in 1906, the Liebig Medal of the German Chemical Society in 1911 and the Cameron Prize of Edinburgh in 1914. He was awarded honorary doctorates or membership to more than 80 universities and medical societies from Chicago to Rio de Janeiro.
Although histologic staining and the birth of the idea of chemotherapy are considered Ehrlichs greatest accomplishments, his contributions to medicine number many more. by Rob Volansky
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