An Interview with Professor Manuel Varela: Who was Emil von Behring and what does he have to do with Diphtheria?

Sep 13, 2018 by

Emil von Behring

Michael F Shaughnessy –

1) First of all Professor Varela, what is diphtheria and what are its SXS (Signs and Symptoms)?

Diphtheria is a serious toxin-mediated infectious disease that is caused by the Gram-positive bacterial species named Corynebacterium diphtheriae. In general, there are two forms of the illness. The first form is referred to as the respiratory type of the diphtherial disease. The second is called the cutaneous form of the diphtheria.

The particular type of diphtheria that is acquired by an individual depends largely upon the nature of the infected site of the patient (i.e., respiration into the airway or contact with broken skin), the levels of immune defenses possessed by the individual, and the virulence strength possessed by the diphtheria-causing microbe. Further, the severity of the diphtheria in a patient can vary from mild to severe, or it can even be lethal in its eventual outcome.

The signs and symptoms of the respiratory diphtheria include the following in their clinical presentation.  First, the patient experiences an abrupt arrival of a discomforting uneasiness feeling (called malaise). The patient also has a sore throat, an inflammation of the throat accompanied by excess fluid (called exudative pharyngitis), a mild fever, and the development of a so-called pseudomembrane structure that originates from the exudate and resides on the tissue surface of the throat, such as on the tonsils, palate, or the uvula of the patient.

The diphtherial pseudomembrane can consist of a mixture of dead host and bacterial cells, living plasma cells, white blood cells, fibrin material, and living Corynebacterium diphtheriae bacteria. This pseudomembrane structure is often securely attached to the host throat area and is difficult to remove, sometimes resulting in release of blood when attempts are made to remove it from the surface of host’s throat region. The pseudomembrane eventually releases itself from the throat after about a week, and the patient will ultimately cough out the peripheral pseudomembranous structure, thus expunging it from the body.

The patient eventually convalesces without complications. If complications do occur, however, such as seen in patients with severe respiratory diphtheria, the patient may then suffer systemic heart and nerve dysfunctions.

The signs and symptoms of the cutaneous diphtheria include the following type of patient presentation.  First, a papule lesion emerges on the skin of the patient. The papule may be raised and either smooth or rough in its texture. Next, the papule develops into a long lasting ulcer on the skin surface. A similar type of pseudomembrane such as that seen in the respiratory diphtheria, often appearing grayish in color, may cover this chronic ulcer lesion in the cutaneous diphtheria.

Complications of the cutaneous diphtheria can also occur. Such clinical difficulties during convalescence may include secondary infection of the ulcer lesion with Streptococcus or Staphylococcus bacteria.

2) Now who was Emil von Behring and what did he discover??

Emil Adolf von Behring (Emil Behring) was a German bacteriologist and immunologist who is considered by many historians of science to be the first expert microbiologist to have earned the coveted Nobel Prize, in 1901.  In fact, Dr. Behring was the very first individual ever to earn the Nobel in the category of physiology or medicine. Among his many scientific discoveries, he is perhaps most famous for his discovery of the serum mode of therapy against the terrible disease diphtheria, and it is precisely because of this innovation for which the Nobel to Dr. Behring had been bestowed.  

Dr. Behring is further credited with being an early pioneer in the historic breakthrough of the blood serum component called the antibody, an element he had denoted as the antitoxin. He showed that his antitoxin was directed against the dreaded diphtheria disease. The antitoxin work was later demonstrated to be an excellent example of passive immunization when it had been applied as a treatment in humans.

Dr. Behring was also key to the development of the so-called toxin-antitoxin mixture for vaccination.  This latter work was thus important in conferring active immunity in individuals who were immunized with the toxin-antitoxin combination. His work was key to the advancement of a medical treatment for diphtheria. Because the major targets of the diphtheria were young children, and his work led to an effective serum treatment against the ailment, Dr. Behring became known as the “savior of the children.”

Furthermore, Dr. Behring’s collaborative work with Dr. Shibasaburo Kitasato led to the development of an antitoxin for the severe disease called tetanus. Their tetanus work has been hailed as an early pioneering example of effective passive immunization and prophylactic prevention of toxin-mediated infectious disease.

Dr. Behring also worked tirelessly to develop an antitoxin type of vaccine for human tuberculosis, but was largely unsuccessful in doing do.  However, his tuberculosis work did lead to an effective vaccination regimen for bovine TB, and it led the way for Drs. Camille Guérin and Albert Calmette to develop ultimately a human-based tuberculosis immunization agent known as the Bacillus Calmette-Guérin (BCG) vaccine.

3) Tell us about Emil Von Behring and his education and experience.

Behring was born on the 15th day of March, in 1854, to parents Georg August Behring, a schoolteacher, and Augustine Behrir Zech, his mother, in a town known then as Hansdorf, Germany, Western Prussia, now known as Ławice, in modern Poland.

As a child, he had gained the attention of his parents and, importantly, of their family priest, a vicar, all of whom recognized young Emil as being extremely intelligent. Unfortunately, his family had suffered through a harsh economic standing, too poor to enroll young Emil in school. However, the story is told that their parish priest, Fr. Leipolz, helped to ensure that Emil gained admission into the Hohenstein Gymnasium, a high school, in Eastern Prussia, where he had shaped an interest in pursuing medicine as a career. 

However, because Emil Behring’s parents could not afford to send him to medical school, they encouraged him to become a vicar, instead. Thus, Behring enrolled in university courses at Konigsberg, focusing on theology. Another story is told that Fr. Leipolz managed to pull some strings with his nephew, a one Dr. Blumensaht, who in turn somehow pulled strings of his own, perhaps monetarily, to ensure that 20-year old Behring acquire admission, in 1874, to the prestigious military academy called Kaiser Friedrich Wilhelm Institute, located at Berlin, Germany. Thus, Behring subsequently earned his medical doctorate, in 1878, from the University of Berlin.

Dr. Behring first became a military surgeon while stationed at Posen, having acquired an interest in wound infections and in their treatment. At first, in 1882, he had considered the chemical called iodoform as a potential wound antiseptic agent, but found that the iodoform chemical was toxic to the affected surgical tissue. 

In 1885, Dr. Behring was promoted to Captain, and in 1888, he became a staff surgeon and lecturer at the Army Medical Corp College, housed in Berlin, where he published his first scientific paper dealing with his antiseptic studies of the iodoform.

In 1889, Dr. Behring moved to the Koch Institute of Hygiene, which later became the Koch Institute of Infectious Diseases, also at Berlin, where he discovered his antitoxins for diphtheria and tetanus, the latter antitoxin work of which he had collaborated with Dr. Kitasato, publishing the work in 1890. During this timeframe, Dr. Behring had also worked in collaboration with Dr. Paul Ehrlich to develop a treatment for humans against the diphtheria, using the antitoxin approach.

In 1894, Dr. Behring moved to Halle University (now known as Martin Luther University of Halle-Wittenberg), Germany, where he took a post as professor of hygiene. Then, in 1895, Dr. Behring moved to the University of Marburg, Germany, where he became its director of the Institute for Hygiene and stayed for the duration of his scientific career, having developed his toxin-antitoxin mixture work.

In late 1896, he married Else Spinola (born on the 30th day of August, in 1876), who was said to be 22 years younger than Behring had been at that time. Together, the couple had six children, all of them males.  Interestingly, it is reported that Dr. Émile Roux was godfather to their eldest son, and Dr. Elie Metchnikoff was godfather to their fifth son.

On the 31st day of March, in 1917, Dr. Behring died in Marburg, Germany, at the age of 63 years, from complications associated with a surgical infection, which had occurred after repair of a bone fracture of femur in his left leg, a condition that he had suffered during an accident.

4) He apparently developed an antitoxin – tough question but what exactly is an antitoxin and how exactly does it work?

Dr. Behring discovered the antitoxins that were directed against the bacterial toxins produced by Clostridium tetani, the causative agent of tetanus, and by the Corynebacterium diphtheriae, the causative agent of diphtheria. In the laboratory, Dr. Behring and colleagues had repeatedly injected animals with broth preparations of these bacilli bacteria, in which these microbes had been killed. Each injection contained increasing amounts of the killed bacteria broth preparations. He then obtained blood sera samples from the immunized animals and showed that the anti-sera (harboring antitoxins) countermanded the detrimental effects of the two bacterial tetanus and diphtheria toxins. He also showed that the immunized animals were recalcitrant to the two bacterial pathogens. Lastly, Dr. Behring demonstrated that when test animals had obtained the tetanus and diphtheria diseases, rapid treatment with antitoxins (serum therapy) showed clinical improvements of their ailments.

We now know the antitoxins to be the antibody, the modern term for Dr. Behring’s antitoxin. The antibodies are proteins that are made by the body in response to the exposure of foreign antigens, like bacteria or their toxins, for instance. The antibodies are quite specific on a molecular level to the particular antigenic agents that they are directed against. The antibodies will then seek and bind to the toxins, bacteria, etc., and neutralize them, initiate their destruction, or eliminate them from the body, depending on the particular nature of the invading microbial antigen.

Today, we know a great deal about the antibody (Behring’s antitoxin).  We know that the antibody is a protein-based molecule.  Dr. Behring’s immunization work made it possible for vaccines to promote protective antibodies, for preventing diseases, like tetanus or diphtheria and many other diseases. Dr. Behring’s antibody is produced in a direct response to non-self antigens encountered in the body.

The newly made antibody works by first binding to its specific target, the toxins, microbes, microbial elements or just about any large complex substance that’s foreign to the body and possibly detrimental to the individual. After the antibody has bound to the antigens, they may be readily neutralized by simply preventing their toxigenic or pathogenic activities.

Alternatively, the antibody might precipitate an agglutination process, forming large insoluble complexes that thwart the antigens. Interestingly, the agglutinating activities of specific antibodies permit clinicians and scientists to detect microbes and cancer cells, for the purpose of diagnosis. The antibody is even known for possessing oxidative activities, which can destroy the antigens outright.

The antibody is known also for recruiting innate immune defenses by provoking, for example, the complement system, first described by Dr. Jules Bordet, to lyse bacteria, to induce inflammation, or to coat antigens with opsonic factors in order to target the antigens for their destruction by phagocytes. The antibody may even incur cellular entry of certain self-death factors to initiate a self-destructive process, called apoptosis, also referred to as programmed cell death. Antibodies can even recruit so-called natural killer cells to target specifically cancerous cells to mediate their killing, in a process referred to as antibody-dependent cellular cytotoxicity. 

5) Why was this such a breakthrough discovery?

As a direct result of Dr. Behring’s pioneering antitoxin and antitoxin-toxin work for preventing diseases like tetanus and diphtheria, we now enjoy many newer vaccines for the express prevention of many other harmful diseases. His groundbreaking studies paved the way for further establishing preventive measures against serious diseases like pertussis, meningitis, pneumonia, and influenza.

Today, entire scientific disciplines are devoted to the study of toxoid vaccines, thanks to the historic research of Dr. Behring.  Scientific textbooks dealing with the fields of microbiology, immunology, and medical pathology readily incorporate the antitoxin and sera therapies into them, such chapters are considered required reading by scientists and clinicians alike.

Entire chapters are devoted to the study of antibody structure, their genetics, and to their effector functions. These areas are widely considered to be of monumental importance for infectious disease and cancer.

6) What have I forgotten to ask about this man of science?

Dr. Behring had been involved in several scientific disputes. Chief among these were his arguments with Dr. Robert Koch, himself. Apparently, they first engaged in a conflict that dealt with a patent priority for the method for developing the tuberculin test, a system that both investigators had been eagerly pursuing. The court battle was decided in favor of Dr. Behring. 

Next, Drs. Behring and Koch clashed over their respective work with the bovine TB vaccine. While Dr. Behring succeeded in providing a decent bovine TB vaccine, based on his antitoxin theories, it is Dr. Koch who triumphed with his human-based TB vaccine.

The two prominent scientists also differed on their opinion regarding the particular mode of infectious transmission for tuberculosis.  Dr. Behring believed inaccurately that contaminated milk was the prime source of human infection while Dr. Koch believe correctly that the tuberculosis was largely a respiratory disease, transmitted by an airborne mode. While TB can indeed be transmitted via contaminated milk, the primary TB transmission mode in humans is via the airborne route. In the end, however, it was Dr. Koch, who, though he was correct about the TB-airborne connection, was, nonetheless, humiliated over his mistaken notion that milk did not require pasteurization. Milk did indeed command that it undergo the pasteurization, not only for preventing TB transmission to humans, but also for preventing transmission of a variety of other serious microbial pathogens.

On a personal level, Dr. Behring had suffered from seemingly lifelong bouts of depression, and occasionally progress with his work would consequently be delayed.  In fact, one biographer has maintained that Dr. Behring was never to experience true happiness during his lifetime, referring to him as an individual tormented by unfulfilled ambition, despite the impressive quality of his life’s scientific work.

It is reported also that Dr. Behring was sensitive to any perceived slights or of errors pertaining to scientific credit for his discoveries. One related incident involved his good friend Dr. Émile Roux, who French journalists had given sole credit for the development of the antitoxin, to the chagrin of Behring, who had heard firsthand of these accounts in the news reports. Fortunately, Dr. Roux was reported to have quickly corrected the inaccuracy.  In fact, when an award was to be bestowed to him, Dr. Roux refused to accept it unless Dr. Behring was also given the accolade.  Both scientists thus received the Knight’s Cross, from their Legion of Honor. 

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