An Interview with Professor Manuel Varela: Paul Ehrlich and the “Magic Bullet”

Aug 27, 2018 by

Michael F Shaughnessy –

1) Professor Varela, some scientists are almost inextricably linked with one discovery or invention. Why is Paul Ehrlich linked with this “magic bullet concept”?

Dr. Paul Ehrlich was a scientist of many, amazing, astonishing discoveries. One such discovery is the concept of the so-called “magic bullet.” At the turn of the 20th century, Dr. Ehrlich was the first scientific investigator to coin the expression and consequently to conduct an intensive search for the magic bullet in a systematic way.

The idea of the magic bullet holds that there must exist a chemical agent (i.e., the “bullet”) that can go through a patient to selectively inhibit or kill an invading microbial pathogen without harming the patient (i.e., the “magic”) to produce fewer side effects. The magic chemical bullet seeks and harms the microbe without profoundly affecting the normal physiology, cell biology, and biochemistry of the patient who has an infectious disease. Both the modern literature and scientific textbooks that deal with microbes, immunology, and chemotherapy frequently start their discourses with mention of Dr. Ehrlich’s magic bullet.

2) Why is this an important idea or construct in science?

As a result of clearly devising and communicating his magic bullet idea, Dr. Ehrlich initiated what is now considered modern chemotherapy for infectious diseases and later, development of such chemical therapy for cancer. His systematic searches and discovery of a candidate magic bullet led other investigators to search other, perhaps better, magical bullets in their own laboratories.  These later searches by other scientists led, for instance, to further discoveries of novel chemicals with antibacterial activities, such as the antibiotics. Due to Ehrlich’s tremendous efforts, we now enjoy actual medicines that can treat a variety of infectious diseases and cancer.

This magic bullet construct of Ehrlich’s is still of major relevance today. One of the major reasons for this persistence of Ehrlich’s magical bullet idea is that both microbes and cancers continually find new ways to evolve and fight back against virtually all of the magic bullet substances in our medical arsenals.

Consequently, microbes and cancers develop resistance to modern chemotherapeutics, making them less useful in treating these maladies. Thus, the push for newer and better magic bullets is important today more than ever. In fact, one can envisage this battle between future putative bullets directed against infectious microbes and cancers with no end in sight. Thus, magic bullet searches will be a continual proves of never-ending battles. It is anticipated that the search for the magic bullets, i.e., chemotherapeutics, will no doubt continue for the duration of humanity.

3) What does it mean to the average scientist?

Ehrlich’s magic bullet conception has relevance to scientists of many fields. For instance, chemists invoke the magic bullet concept by finding new chemical agents and in modifying them to create new derivatives, each of which may have better antimicrobial and anti-cancer activities, perhaps even with fewer side effects.

To the biochemists, Ehrlich’s concept means that such scientists are in place to evaluate the effects of extant and future chemotherapeutics upon their intended targets, namely, dangerous microbes and cancers. They would want to know, for example, to what extent are the microbes and cancers inhibited or even eliminated by novel therapies. They are interested in understanding the effects of the therapies on the biochemistry of the body.

The biochemists like to know also whether the human body will alter the structures or the activities of the magic bullets. Perhaps an inactive chemical can be made active by the body’s biochemical machinery.  Whatever the case may be, knowing such information is vital!

To the cell biologists, they may be interested in understanding the targeting of the new magic bullets to the particular cell type, tissue, or organ systems and in how these living systems and components each may be affected. Cell biologists may also like to know first how magic bullets work in cell or tissue culture systems and in animal models in order to evaluate both the safety and the efficacy in human patients.

To the microbiologists and oncologists, they may like to know precise dosage levels that are needed to attain proper antimicrobial and anticancer activities.  They may like to understand also the particular mode of magic bullet action towards the pathogenic microbes and cancers in the living body of the host. This is important in helping to reduce side effects.

To the immunologists, the advent of the successful chemotherapeutic permits the systems they study to let the immune system now take over once the microbes and the cancer cells are reduced to manageable levels by the magic bullets. The immune system can then purge microbes and cancers from the patient and then remember the next encounter to provide immunity. Perhaps the immunologist can tweak these immunities artificially by producing new vaccines. Ehrlich’s Nobel Prize-winning diphtheria antiserum work was a key avenue towards this latter endeavor.

These types of scientific work represent a tremendous amount of effort on the part of many thousands of investigators worldwide.

4) What is Salvarsan and why do we need to learn about it?

The story of the Salvarsan discovery is one of epic proportions! The search for it was of great effort. Salvarsan is the first of the so-called magic bullets to be propounded by Dr. Ehrlich. The story starts first with Ehrlich’s studies of chemical dyes, made by chemists, which Ehrlich noticed stained various microbes and specific cell types when exposed to these chemical agents. Dr. Ehrlich has been credited with the discovery of the mast cells, which he had speculated had a catabolism-based metabolic role during their feeding behaviors.  Ehrlich noticed that in laboratory animals, many of these chemical dyes, while specifically targeting only certain cells and tissues, were nevertheless relatively harmless to higher organisms, at least on a general level.

At about this time, Ehrlich moved to the laboratory of the famous Robert Koch, whom you will recall was key to the elucidation of the Koch’s postulates, for which one invokes in order to associate a microbe as a causative agent of an infectious disease. In Koch’s lab, Emil von Behring had just discovered the diphtheria antitoxin at about the time of Ehrlich’s arrival to the laboratory.  Ehrlich began studies in which he worked out a method for development and mass production of the diphtheria antitoxin in Koch’s lab. 

Ehrlich then postulated a hypothesis to explain the nature of the toxin-antitoxin association. It was called the side-chain theory. The theory said that immune cells contained an assortment of different receptors, called side chains, each receptor with a different specificity for a microbe or some other non-self-antigen.

According to the theory, each individual immune cell would harbor many different receptor types on its cell surface. The side-chain model predicted that an antigenic microbe with its corresponding specificity for one of the cellular side chains would bind that particular side chain of the many types of receptors available on a given immune cell. The binding between an immune cell’s specific side-chain and the microbe would then trigger the synthesis of the specific side chain receptor and release it into the cellular external milieu, according to Ehrlich’s hypothesis. 

While we now know that the side-chain theory of Ehrlich is not accurate, it provided a foundation for further work. It turns out that, rather than a given cell possessing many types of receptors for the various antigens, as incorrectly postulated by Ehrlich, each cell instead has only one specific receptor type for a given antigen. Each immune cell is, therefore, unique to an antigen, and all side chain copies on a cell’s surface are identical, representing the specificity that’s geared for that one antigen.

Therefore, antigen binding to such a cell with its one specific receptor, will now trigger that cell to become a clone, a concept known as clonal selection, with each of the many daughter clone cells all having the same specificity as the original immune cell that had been bound by the microbial antigen in the first place.

These receptors with their side chains are what we now consider in modern times to be the antibody, sometimes called a B-lymphocyte receptor. When Ehrlich proposed his magic bullet theory, he had in fact believed that that the antibody, then known as an antitoxin (i.e., likely representing Ehrlich’s side chain receptors) was the magic bullet. However, technologies of the day made it difficult to apply the antibody as a practical magic bullet. Therefore, he continued his search for other candidates as suitable magic bullets.

Ehrlich’s findings that the chemical dyes were non-toxic plus microbial-, cell-, and tissue-specific, led him to postulate the notion of the magic bullet for these agents. Thus, he set out to systematically search for magic bullets among the chemical dyes.

First, using mice, he studied a microbial infection disease model, now called American trypanosomiasis, African sleeping sickness, or Chagas’ disease, using its causative agent protozoans, called trypanosomes in Ehrlich’s time, one modern scientific name for the microbe being Trypanosoma cruzi.

Ehrlich and his colleague, Kiyoshi Shiga, a famous Japanese bacteriologist and medical doctor, commenced the magic bullet search.  Incidentally, Dr. Shiga is famous for having discovered the causative agent of the notorious bacterially conferred dysentery, a microbe now called Shigella dysenteriae.

Drs. Ehrlich and Shiga tested hundreds of chemical dyes against the trypanosomes in mice. With profound numbers of chemical dyes having failed to work in their animal infection model, they finally came upon compound numbered 418, which was later shown to be composed of the chemical called arsnophenylglycine. This compound, no. 418, as Dr. Ehrlich called it, showed good anti-protozoan activity in their trypanosomiasis-mouse infection models. 

With this work published and now behind him, Dr. Ehrlich then collaborated in 1910 with another Japanese bacteriologist by the name of Sahachiro Hata, who had invented another animal infection model, this one being for the syphilis disease. The causative agent is a bacterium called at the time Spirochete pallidum, now called Treponema pallidum, and Dr. Hata was able to infect the skin of mice and rabbits with the bacteria, causing visible lesions that could be measured.

The enormity of their investigative study was profound. Drs. Ehrlich and Hata studied over 600 compounds. The effort was also extremely labor-intensive, just as it had been with the arsnophenylglycine work and the trypanosomiasis studies. Finally arriving at compound no. 606, a now very famous chemical, Ehrlich and Hata found that the agent, now called Salvarsan, showed good anti-bacterial activity against the syphilis-causing bacteria in the laboratory rabbits. Compound 606 was named Salvarsan because it provided salvation from the syphilis, and it was an arsenic-containing chemical. The chemical name of the active ingredient contained within Salvarsan was termed arsphenamine.

While the Salvarsan provided an effective treatment in the laboratory animals and in some human test subjects, certain events conspired against its practical use in a widespread fashion.  First, Ehrlich died, in 1915. Thus, the main push for further studies was thwarted. 

Further, church officials were not too pleased about the possibility for a treatment of the syphilis, and such a treatment they had regarded as needlessly encouraging immoral behavior. Syphilis is a sexually transmitted ailment. As such, church officials apparently felt that such immoral sexual behavior should be punishable by ailment instead of rewarded by treatment.

Another reason for the Salvarsan treatments being problematic was its arsenic toxicity, which brought about serious side effects.  To make matters worse, the Salvarsan treatment was shown to be only temporary, requiring repeated administration over 18 months and even requiring combination therapy with other agents, like bismuth.

Attempts to synthesize chemically less toxic derivatives were performed, producing, for instance, a derivative, compound no. 914, called Neosalvarsan.  While certainly less toxic and conferring less serious side effects, the Neosalvarsan nonetheless produced certain other serious side effects, like vomiting and nausea, which also seemed to be too much for patients to endure.

Probably the straw that broke the logistics back of the Salvarsan and Neosalvarsan agents for practical usage as good magic bullets, was World War I.  The Great War made it logistically too formidable to acquire arsenical platform molecules in order to produce the magic bullets for widespread distribution. 

During this time, a controversy arose regarding the structural nature of the so-called active principle, the arsphenamine. Ehrlich’s preparations had apparently consisted of mixtures of non-essential compounds, mixed in with the active arsphenamine principle. The purity of the compound was required.

Taken together, these various complications all served to erode further enthusiasm for the Salvarsan and related arsphenamine compounds. It did set in motion, however, new searches for other additional magic bullet chemicals.

5) Now, what exactly is diphtheria? How prevalent is it and is there an antiserum?

Diphtheria is a serious infectious disease caused by the bacterium called Corynebacterium diphtheriae.  The diphtheria illness is characterized by a respiratory or a skin involvement, depending on the site of the bacterial infection (lungs versus skin), the degree of immunity of the patient, and the level of virulence of the infection-causing Corynebacterium diphtheriae microbe.

In the respiratory diphtheria, the patient may experience a sudden onset of discomfort (malaise), mild fever, a sore throat, and a so-called exudative pharyngitis condition that can lead in some cases to the production of a thick pseudomembrane in various locations of the upper airway. The pseudomembrane binds tightly to the tissue and is difficult to remove. After about a week, the pseudomembrane dislodges and is expelled by the patient.

In the cutaneous diphtheria, the patient suffers a papule lesion on the skin and sinks to the deeper underlying skin tissues, producing a long-lasting ulcerative lesion that is often covered by a grayish-colored membrane. In some patients, complications can occur, such as bacterial infection of the damaged skin tissue with the Staphylococcus aureus or with the Streptococcus pyogenes, both bacterial microbes of which can lead to serious conditions in their own right.

Diphtheria has become extremely rare in the U.S., with scattered epidemics occurring in locations abroad where proper immunization is lacking. Since diphtheria is no longer a reportable disease with the Centers for Disease Control and Prevention, the true number of diphtheria cases is actually not well known.

In the mid-1880s, Drs. Friedrich Loeffler and Robert Koch studied the bacterial microbe, Corynebacterium diphtheriae, that caused the dreaded diphtheria, a serious disease that had historically wiped out hundreds of thousands of children on a worldwide scale. In the late 1880s, Drs. Émile Roux and Andre Yersin were successful in purifying the toxin agent from the bacteria and in demonstrating that their purified toxin could induce the diphtheria illness in laboratory animals. In 1889, Drs. Emil Adolf von Behring and Shibasaburo Kitasato invented the diphtheria and tetanus antisera, also called antitoxins.

They had injected laboratory animals with toxoid versions of the toxins produced by the microbes that caused the diphtheria and tetanus diseases. The inoculated animals then mounted an immune response to the injected antigens, thus producing antitoxins, or what we now called antibodies, today.  They then isolated the respective antisera from the inoculated animals. They had shown that their antiserum could provide protection from the diphtheria toxin. One problem they encountered had to do with quality control during their antisera production processes.

It is at this point in the investigative effort, where Dr. Ehrlich then entered the story and became involved in the ongoing antitoxin work. He was key to attaining an efficient production process for the diphtheria antitoxin, establishing standardized protocols for immunizing individuals, in choosing horses for inoculation, and in large-scale antiserum production. Dr. Ehrlich’s studied showed that the mass-produced diphtheria antitoxin had to be administered almost immediately upon the onset of clinical disease. 

He also found that if the diphtheria disease was diagnosed while in its later stages, that correspondingly higher doses of the antitoxin had to be administered. Due to Ehrlich’s efforts, the mass-production method of the antitoxin was now standardized and, thus, used in a widespread manner.  The result of the newly mass-produced antitoxin was an amazing success, saving countless millions of children from the potentially lethal effects of the diphtheria.

6) What do we know about this person’s life and personality?

Paul Ehrlich was born on the 14th day of March, in 1854, in the small town called Strehlen in Prussia, which is presently Sztrelin, Poland. His parents were Ismar Ehrlich and Rosa Weigert Ehrlich. The child Ehrlich attended grade school in Breslau (now Wroclaw) at St. Maria Magdalen School, where a classmate of his was Albert Neisser, now famous for his discovery of the causative agent of gonorrhea. Early accounts of young Ehrlich’s personality point to his having somewhat of a “Type A” demeanor, with an impatient and nervous disposition, often associated with rapidly speaking to others, as if he were often in a hurry. His speech later in life has been described as being quite animated, especially when discussing science or novel ideas. He has also been characterized by countless individuals who knew him well and worked with him as being quite an amicable person, a characteristic that stayed with him apparently for many years.

After high school, Ehrlich first went to the university that was housed in Breslau, where found that the biological sciences, and especially histology, had greatly interested him. It is reported that Ehrlich had had an acumen in the study of organic chemistry. 

Nevertheless, he then moved to the University of Strasbourg, where he worked under Prof. Heinrich Waldeyer and gained an appreciation of the utility of the chemical dyes, such as aniline-based chemicals, which he used to stain histological tissues.

Next, Ehrlich returned to the University of Breslau to work under Prof. Julius Cohnheim in his laboratory, where he was reportedly introduced to the great Prof. Robert Koch, a visiting physician also working in Cohnheim’s research laboratory. After finishing his academic and research studies with high honors at Breslau, Ehrlich then moved to the University of Leipzig to attend medical school. While in medical school, Ehrlich focused his thesis studies on the aniline dyes and histological staining methods. In 1878, Dr. Ehrlich earned his medical degree from Leipzig.

Afterwards, Dr. Ehrlich moved to Berlin, Germany where he became a physician at the Charité Hospital, working under the supervision of Dr. Friedrich von Frerichs. Spending about nine years at the Charité Hospital, Dr. Ehrlich was known to have studied a variety of medical fields, including those pertaining to pernicious anemia, the typhoid fever, and the great consumption, the latter of which is known today as tuberculosis.

During this time, Ehrlich did not get along well with his new chief, Dr. Carl Gerhardt, who took over after his good friend and supervisor Dr. von Frerichs had died unexpectedly. It was also during this period in 1883 that he married Hedwig Pinkus; the couple had had two children, Stephanie and Marianne.

Interestingly, it is reported that when Ehrlich himself acquired the tuberculosis in 1888, he was able to clinically diagnose himself using his expertise to do so. In order to convalesce and, importantly, to avoid the new work policies of Dr. Gerhardt at Berlin, Dr. Ehrlich consequently moved to Egypt for a brief while. He fully recovered from the tuberculosis in 1890 and returned to his old position at Berlin, forming a newly independent laboratory funded primarily by his father-in-law.

Dr. Ehrlich had become a professor in 1884 and began teaching at the University of Berlin, in 1887. Then, in 1891, Dr. Ehrlich moved to a new position at the Berlin Institute for Infectious Diseases.  In 1896, he later worked to establish, at Steglitz, the so-called Institute for Serum Research & Testing, becoming its first director. In the period between 1897 and 1906, Dr. Ehrlich had moved to Frankfurt, Germany to become head of the Georg Speyer House (Speyerhaus), a research foundation funded by the generous benefactor Frau Franziska Speyer.

In 1908, Dr. Ehrlich received the Nobel Prize, in the fields of Physiology or Medicine, for his contribution to the burgeoning field of humoral immunity and his work with serum therapy, sharing the prize with Illy (Élie) Illyich Metchnikoff (Mechnikov), who discovered the phagocytes. 

The Nobel having gone to both Drs. Ehrlich and Metchnikoff had the effect of settling the controversy regarding whether immunity had an antitoxin humoral basis (Ehrlich) versus a cellular basis (Metchnikoff). 

The humoral versus cellular explanation for immunity had been a serious point of contention for many years, with each side firmly holding on to their own philosophies.  In the end, both sides had been correct. Today, both humoral and cellular immunity, plus innate immunity, are all taught to students of immunology.

In 1909, Drs. Ehrlich and Hata discovered the now famous Salvarsan, a chemical treatment for syphilis, publishing the work in 1910 and ushering the new era of modern chemotherapy.

In 1914, the Great War started, and the stress of the conflict may have been a factor in Dr. Ehrlich suffering a mild stroke, from which he was able to recover shortly thereafter. On the 20th day of August, in 1915, however, he experienced another stroke, this time dying from it at the age of 61 years, in Bad Homburg, Germany.

7) What have I neglected to ask about this famous scientist?

Overall, Dr. Ehrlich’s body of scientific work was prolific. His investigative career spanned almost three decades and delved into various fields of study, like bacteriology, chemistry, biochemistry, virology, chemotherapy, physiology, and immunology.

Dr. Ehrlich made his first discovery of note starting in 1882, when he observed that the tuberculosis bacterium was acid-fast in its staining properties, improving the staining technique of Dr. Koch and paving the way for Drs. Franz Ziehl and Friedrich Neelsen to establish their so-called Ziehl-Neelsen method in 1883 for the staining of the acid-fast Mycobacterium tuberculosis microbe.

In 1885, while studying tissues that he stained with chemical dyes, Dr. Ehrlich suggested that such agents, like the aniline dyes, might also be good candidates for antisepsis. Interestingly, many other investigators followed up on Ehrlich’s idea, ushering in new advancements for the field of modern chemotherapy.

Prontosil, a red dye studied in the late 1930s by Dr. Gerhard Domagk, comes to mind, as this chemical dye was shown to be effective against certain pathogenic Gram-positive bacteria, like the Staphylococcus aureus, in living septic patients.

In 1889, Dr. Ehrlich had an interest in a certain chemical, called para- dimethylaminobenzaldehyde, for its use in detecting a breakdown product of the amino acid tryptophan, called indole, in clinical urine samples. Other investigators followed up on Ehrlich’s indole work to study bacteria, and after modifying the method, it later became known as the indole test. Today, students of microbiology laboratory courses will routinely conduct the indole test, in order to examine, for instance, tryptophan metabolism and to aid in identifying the species of individual bacterial isolates.

In 1895, Dr. Ehrlich coined a new term “complement” to describe alexin (alexine), a heat-sensitive serum factor that worked together with a heat-resistant serum factor, now known as the antibody, to provide an immune response to the cholera bacteria.

The term alexine had been devised by Prof. Hans Buchner, and later Dr. Jules Bordet invoked the alexin name to describe the antibody-helping serum factor during cholera disease. Dr. Ehrlich decided to change the name alexin to the new term complement, as he felt that the alexin was complementing the effect of the antibody. Today, the complement system is still a focus of intense research study and is treated as its own academic field within the scope of immunology.

In 1901, Ehrlich speculated that because the immune system produced a variety of cell types that were directed against a variety of antigens, then autoimmune specific cell types would be prevented from acting against an individual’s own self-antigens. Dr. Ehrlich invoked the term “horror autotoxicus” to denote a fear of self-intoxication or self-poisoning—the body certainly wouldn’t allow itself to activate substances that might harm itself, such as would be seen in an autoimmune condition. 

Unfortunately, these sentiments were largely misunderstood to incorrectly mean that autoimmunity simply was not possible, thus, setting back the course of progress with the field of autoimmune diseases. Today, it is understood that there are a constellation of autoimmune diseases, like Hashimoto’s thyroiditis. The current list of autoimmune diseases is extensive.

Dr. Ehrlich’s foundational scientific works led to great discoveries by many other investigators throughout the 20th century and well into the 21st century. It is anticipated that his work will no doubt continue to influence biomedical sciences and microbiology for a great many years.

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