From the industrial production of the dipherium to the industrial production four years, the success of the new remedy was resounding.
125 years ago, on December 4, 1890, the Berlin medical officer Emil Behring and the Japanese bacteriologist Shibasaburo Kitasato published theirs in the German Medical Weekly groundbreaking essay "On the Coming of Diphtheria Immunity and Tetanus Immunity in Animals". In the article, which was only two pages long, not only was the discovery of the antitoxin in the blood of sick animals known, but also its possible transferability in principle: A novel immunization method for the treatment of infectious diseases was discovered. It only took four years from publication to industrial production of the diphtheria healing serum, and the success of the new remedy was resounding.
Diphtheria, highly contagious infectious disease whose pathogen Corynebacterium diphtheriae was discovered by Friedrich Löffler (1852–1915) in 1884, hardly occurs in Germany today thanks to vaccination in children. The vaccination protection for toddlers and preschool children is 97 percent thanks to the combination vaccination in the first year of life.
High child mortality
That was not always the case. From 1881 to 1886, an average of 25,000 babies and toddlers aged up to three years died as result of the infection in Prussia. Diphtheria was the leading cause of death in children aged three to five years. Child mortality was population and health problem that needed solutions to be addressed by city and state authorities. The institutions first tried to record the extent of the spread by compiling disease and death statistics; However, research into pathogens and the development of remedies was in the hands of state and university research institutes, such as the Berlin Institute for Infectious Diseases founded in 1891, which was directly subordinate to the Prussian state and was headed by the bacteriologist Robert Koch (1843–1910).
The Koch Institute, located near the Charité, had special position within the research institutes, as it was established outside university and without any obligation to teach.
From the industrial production of the dipherium to the industrial production four years, the success of the new remedy was resounding.
125 years ago, on December 4, 1890, the Berlin medical officer Emil Behring and the Japanese bacteriologist Shibasaburo Kitasato published theirs in the German Medical Weekly groundbreaking essay "On the Coming of Diphtheria Immunity and Tetanus Immunity in Animals". In the article, which was only two pages long, not only was the discovery of the antitoxin in the blood of sick animals known, but also its possible transferability in principle: A novel immunization method for the treatment of infectious diseases was discovered. It only took four years from publication to industrial production of the diphtheria healing serum, and the success of the new remedy was resounding.
Diphtheria, highly contagious infectious disease whose pathogen Corynebacterium diphtheriae was discovered by Friedrich Löffler (1852–1915) in 1884, hardly occurs in Germany today thanks to vaccination in children. The vaccination protection for toddlers and preschool children is 97 percent thanks to the combination vaccination in the first year of life.
High child mortality
That was not always the case. From 1881 to 1886, an average of 25,000 babies and toddlers aged up to three years died as result of the infection in Prussia. Diphtheria was the leading cause of death in children aged three to five years. Child mortality was population and health problem that needed solutions to be addressed by city and state authorities. The institutions first tried to record the extent of the spread by compiling disease and death statistics; However, research into pathogens and the development of remedies was in the hands of state and university research institutes, such as the Berlin Institute for Infectious Diseases founded in 1891, which was directly subordinate to the Prussian state and was headed by the bacteriologist Robert Koch (1843–1910).
The Koch Institute, located near the Charité, had special position within the research institutes, as it was established outside university and without any obligation to teach.The state had invested 370,000 marks and it was completed after an exceptionally short construction period of just seven months. With the subdivision into "Experimental" and "Clinical Department", it combined research and patient care under one roof in terms of personnel and space, thus enabling the study of pathogens and the treatment of infectious diseases in one house. The scientific staff subordinate to Robert Koch was manageably small, the committed employees - including Paul Ehrlich (1854–1915), Shibasaburo Kitasato (1853–1931), Richard Pfeiffer (1858–1945), August von Wassermann (1866–1925) and Emil Behring (1854–1917) - should soon make name for himself in the scientific world.
Evidence in animal experiments
One of the institute's most important researches was work on immunity. Emil Behring and the Japanese guest scientist Kitasato had already dealt with the question of immunization for long time at Koch's Hygienic Institute at Berlin University. The theoretical background was formed by the observation that when epidemics occurred, there were always individuals in whom the disease did not break out or only in weakened form; they were immune to this. Through the work of Émile Roux (1853–1915) and Alexandre Yersin (1863–1943) at the Pasteur Institute in Paris, it was known since 1888 that it was not the diphtheria bacterium but the toxin produced by the bacterium that triggered the symptoms of the disease. In the autumn of 1890, the Berlin researchers succeeded in curing rats, guinea pigs, rabbits and mice already infected with diphtheria or tetanus, or in pretreating healthy animals in such way that they no longer fell ill later. The most important result they found was that the immunity of those animals that were immunized against tetanus is based on the ability of the blood serum to “render the toxic substances that the tetanus bacilli produce harmless”.
Concentrated in Berlin Behring and Kitasato set out to artificially establish immunity and to find the antidote to bacterial toxins in animal experiments, which was suspected to be the anti-toxin in the blood serum of sick animals. On November 23, 1890, Behring was able to note in his laboratory diary: “Is the blood of immune animals able to neutralize the poisonous effect? Yes! ”- The blood serum was discovered as remedy.
Just eleven days later, on December 4, 1890, the influential German Medical Weekly published summary of the experiments carried out by Behring and Kitasato.The state had invested 370,000 marks and it was completed after an exceptionally short construction period of just seven months. With the subdivision into "Experimental" and "Clinical Department", it combined research and patient care under one roof in terms of personnel and space, thus enabling the study of pathogens and the treatment of infectious diseases in one house. The scientific staff subordinate to Robert Koch was manageably small, the committed employees - including Paul Ehrlich (1854–1915), Shibasaburo Kitasato (1853–1931), Richard Pfeiffer (1858–1945), August von Wassermann (1866–1925) and Emil Behring (1854–1917) - should soon make name for himself in the scientific world.
Evidence in animal experiments
One of the institute's most important researches was work on immunity. Emil Behring and the Japanese guest scientist Kitasato had already dealt with the question of immunization for long time at Koch's Hygienic Institute at Berlin University. The theoretical background was formed by the observation that when epidemics occurred, there were always individuals in whom the disease did not break out or only in weakened form; they were immune to this. Through the work of Émile Roux (1853–1915) and Alexandre Yersin (1863–1943) at the Pasteur Institute in Paris, it was known since 1888 that it was not the diphtheria bacterium but the toxin produced by the bacterium that triggered the symptoms of the disease. In the autumn of 1890, the Berlin researchers succeeded in curing rats, guinea pigs, rabbits and mice already infected with diphtheria or tetanus, or in pretreating healthy animals in such way that they no longer fell ill later. The most important result they found was that the immunity of those animals that were immunized against tetanus is based on the ability of the blood serum to “render the toxic substances that the tetanus bacilli produce harmless”.
Concentrated in Berlin Behring and Kitasato set out to artificially establish immunity and to find the antidote to bacterial toxins in animal experiments, which was suspected to be the anti-toxin in the blood serum of sick animals. On November 23, 1890, Behring was able to note in his laboratory diary: “Is the blood of immune animals able to neutralize the poisonous effect? Yes! ”- The blood serum was discovered as remedy.
Just eleven days later, on December 4, 1890, the influential German Medical Weekly published summary of the experiments carried out by Behring and Kitasato.The scientists here explained their thesis that the blood fluid of immune animals can "render harmless" the toxic substances produced by the bacteria. In addition, the poison-destroying properties of the blood serum are firstly permanent and secondly, although heterologous, also effective in the body of other living beings. Both points were essential, as they opened up the possibility of using the animal blood containing antitoxin for therapeutic purposes, i.e. also for the treatment of sick people, according to the principle of passive immunization.
From animal experiments to therapeutic use on However, humans still had some obstacles to overcome. First of all, blood suppliers had to be found with larger blood volume than that of the small laboratory animals. The producers of the blood containing antitoxin were initially dogs, sheep and goats. At the end of 1891 the serum was first tested on child patients in the Berlin Surgical University Clinic, where tracheotomies were performed against the threat of suffocation caused by the pseudomembranes produced by the diphtheria toxin. However, these first deployments were not convincing because the amounts of active ingredient used were still too small. As result, surgical and children's clinics outside of Berlin also used healing serums that were made available free of charge to vaccinate those suffering from diphtheria.
Consistently positive results in the treatment of the disease could only be recorded when the problem of the dosage of the Antitoxins had been clarified - task that Koch's then employee Paul Ehrlich successfully took on. Finally, on September 7th, 1894, the pediatrician Otto Heubner, who had been receiving diphtheria healing serum from Behring since November 1892, reported in public lecture at the International Hygiene Congress in Budapest about his practical experiences “at the bedside” - experiences that he initially shared Leipzig and then in the Charité in Berlin with the use of the diphtheria remedy had been able to collect.
Worthwhile investment
The remedy developed by Behring, referred to by Heubner as "Behring's gold" , replaced the classic treatment by incision of the trachea and, in contrast to the short-term relief of one symptom, namely the difficulty swallowing and the shortness of breath, led to the healing of the disease. As Heubner emphasized in his lecture, the serum is harmless and thus corresponds to the medical motto primum non nocere, it does not cause any serious side effects, but it helps immediately. The “Behring’s gold” was “worth gold”.
Behring's numerous publications also aroused the interest of the industry.The scientists here explained their thesis that the blood fluid of immune animals can "render harmless" the toxic substances produced by the bacteria. In addition, the poison-destroying properties of the blood serum are firstly permanent and secondly, although heterologous, also effective in the body of other living beings. Both points were essential, as they opened up the possibility of using the animal blood containing antitoxin for therapeutic purposes, i.e. also for the treatment of sick people, according to the principle of passive immunization.
From animal experiments to therapeutic use on However, humans still had some obstacles to overcome. First of all, blood suppliers had to be found with larger blood volume than that of the small laboratory animals. The producers of the blood containing antitoxin were initially dogs, sheep and goats. At the end of 1891 the serum was first tested on child patients in the Berlin Surgical University Clinic, where tracheotomies were performed against the threat of suffocation caused by the pseudomembranes produced by the diphtheria toxin. However, these first deployments were not convincing because the amounts of active ingredient used were still too small. As result, surgical and children's clinics outside of Berlin also used healing serums that were made available free of charge to vaccinate those suffering from diphtheria.
Consistently positive results in the treatment of the disease could only be recorded when the problem of the dosage of the Antitoxins had been clarified - task that Koch's then employee Paul Ehrlich successfully took on. Finally, on September 7th, 1894, the pediatrician Otto Heubner, who had been receiving diphtheria healing serum from Behring since November 1892, reported in public lecture at the International Hygiene Congress in Budapest about his practical experiences “at the bedside” - experiences that he initially shared Leipzig and then in the Charité in Berlin with the use of the diphtheria remedy had been able to collect.
Worthwhile investment
The remedy developed by Behring, referred to by Heubner as "Behring's gold" , replaced the classic treatment by incision of the trachea and, in contrast to the short-term relief of one symptom, namely the difficulty swallowing and the shortness of breath, led to the healing of the disease. As Heubner emphasized in his lecture, the serum is harmless and thus corresponds to the medical motto primum non nocere, it does not cause any serious side effects, but it helps immediately. The “Behring’s gold” was “worth gold”.
Behring's numerous publications also aroused the interest of the industry.In May 1892 there was meeting with August Laubenheimer (1848–1909), member of the board of the Farbwerke Höchst, who offered Behring the factory-made production of diphtheria healing serum - at financially very favorable conditions for him. Laubenheimer, chemist with doctorate, recognized the therapeutic - and economic - importance of diphtheria healing serum. For the Farbwerke, founded in 1863, almost thirty years earlier, the investment in an organic-based remedy meant profitable expansion of sales Sheep and horses, which are considerably more expensive to buy and maintain, also had to be bought in expert knowledge, which Behring made available to Paul Ehrlich. Ehrlich had dealt intensively with the determination of the value of medicinal products and determined and numerically described the progressive degree of immunity using sophisticated measuring and testing procedures. Ehrlich's research had made it possible to calculate dosage of the serum appropriate to the weight and age of the children, and thanks to it, the Farbwerke were finally able to offer graduated doses of the remedy adapted to the degree of illness and to enable the remedy to be standardized .
Already in his first year of contract, 1892, Behring received 3,000 marks for immunization material from the Farbwerke for his services; for the following year (1893) he was granted 10,000 marks for experiments. In addition, in 1896 the Farbwerke set up private serum research institute for the scientist who had been teaching at Marburg University since 1895, for which he received 40,000 marks year for maintenance. In return, Behring undertook to make future research results and product improvements available.
In the summer of 1894, production began in Höchst in specially built serum system and, from August 1894, sales, the official inauguration in the presence of Robert Koch, Emil Behring and others took place on November 24, 1894. 57 horses were being treated and by the end of the year over 75,000 vials of the serum had already been sold. Immediately after the introduction of serum therapy, the mortality rate from diphtheria fell to fifth of the 1893 figure.
Although numerous researchers from Koch's scientific environment were involved in the development of the diphtheria healing serum, it was Behring who was ultimately recognized in many ways and was decorated, nationally through the ennoblement and internationally through the Nobel Prize for Medicine, first awarded in 1901.
Already in his first year of contract, 1892, Behring received 3,000 marks for immunization material from the Farbwerke for his services; for the following year (1893) he was granted 10,000 marks for experiments. In addition, in 1896 the Farbwerke set up private serum research institute for the scientist who had been teaching at Marburg University since 1895, for which he received 40,000 marks year for maintenance. In return, Behring undertook to make future research results and product improvements available.
In the summer of 1894, production began in Höchst in specially built serum system and, from August 1894, sales, the official inauguration in the presence of Robert Koch, Emil Behring and others took place on November 24, 1894. 57 horses were being treated and by the end of the year over 75,000 vials of the serum had already been sold. Immediately after the introduction of serum therapy, the mortality rate from diphtheria fell to fifth of the 1893 figure.
Although numerous researchers from Koch's scientific environment were involved in the development of the diphtheria healing serum, it was Behring who was ultimately recognized in many ways and was decorated, nationally through the ennoblement and internationally through the Nobel Prize for Medicine, first awarded in 1901.
Thanks to the discoverer
The vaccine sent all over the world from Höchst bore Behring's name. The product was so closely linked to the inventor that grateful parents kept sending letters to the Behring Villa in Marburg, which usually described the severity of the disease and expressed relief from the life-saving effect of the blood serum.
The letters were not only accompanied by group photos of the flock of children rescued by the vaccination, but also by Behring's food or portraits, which were to be signed and returned by the honored "Privy Councilor". The personality cult went so far that on the occasion of the 60th birthday the Berliner Illustrirte Zeitung ordered reporters and photographers to Marburg, who were supposed to report on the researcher's life and places of work in the manner of home story under the heading “Benefactors of Mankind”. Poems were written in honor of the vanquisher of diphtheria, and prominent banker, whose daughter was healed, vividly summed up that, thanks to Behring's highly ingenious invention, the “scourge of children. . . lost the sting ”.
In 1913, Behring presented the diphtheria protection agent TA (= toxin-antitoxin) for active immunization (protective vaccination) to the medical public after trials in Magdeburg and Marburg at the Congress for Internal Medicine. Despite the inclusion in production at the Behring works in Marburg and Bremen, it was unable to establish itself due to its high rate of side effects. It was only with the development of toxoid vaccine by the French Gaston Ramon (1886–1963) in 1923 that prophylactic vaccination could be carried out safely. The antitoxin as immune serum from horses is still used today in the immediate specific therapy of diphtheria; rapid administration of the antitoxin neutralizes the toxin that is not yet bound to the cell. In addition, the antibiotic therapy initiated at the same time destroys the toxin-producing germs.
The WHO is currently trying to eradicate diphtheria in Europe as part of its "Expanded Program of Immunization". However, around 50 percent of adults in Germany do not have adequate vaccination protection because they missed booster vaccinations.
Dr. phil. Ulrike Enke Emil von Behring Library Office for the History of Medicine Philipps University of Marburg ulrike.enke @ staff.uni-marburg.November 1890: “Is the blood of immune animals able to neutralize the poisonous effect? - Yes- yes! “
Thanks to the discoverer
The vaccine sent all over the world from Höchst bore Behring's name. The product was so closely linked to the inventor that grateful parents kept sending letters to the Behring Villa in Marburg, which usually described the severity of the disease and expressed relief from the life-saving effect of the blood serum.
The letters were not only accompanied by group photos of the flock of children rescued by the vaccination, but also by Behring's food or portraits, which were to be signed and returned by the honored "Privy Councilor". The personality cult went so far that on the occasion of the 60th birthday the Berliner Illustrirte Zeitung ordered reporters and photographers to Marburg, who were supposed to report on the researcher's life and places of work in the manner of home story under the heading “Benefactors of Mankind”. Poems were written in honor of the vanquisher of diphtheria, and prominent banker, whose daughter was healed, vividly summed up that, thanks to Behring's highly ingenious invention, the “scourge of children. . . lost the sting ”.
In 1913, Behring presented the diphtheria protection agent TA (= toxin-antitoxin) for active immunization (protective vaccination) to the medical public after trials in Magdeburg and Marburg at the Congress for Internal Medicine. Despite the inclusion in production at the Behring works in Marburg and Bremen, it was unable to establish itself due to its high rate of side effects. It was only with the development of toxoid vaccine by the French Gaston Ramon (1886–1963) in 1923 that prophylactic vaccination could be carried out safely. The antitoxin as immune serum from horses is still used today in the immediate specific therapy of diphtheria; rapid administration of the antitoxin neutralizes the toxin that is not yet bound to the cell. In addition, the antibiotic therapy initiated at the same time destroys the toxin-producing germs.
The WHO is currently trying to eradicate diphtheria in Europe as part of its "Expanded Program of Immunization". However, around 50 percent of adults in Germany do not have adequate vaccination protection because they missed booster vaccinations.
Dr. phil. Ulrike Enke Emil von Behring Library Office for the History of Medicine Philipps University of Marburg ulrike.enke @ staff.uni-marburg.de
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