Paul Ehrlich’s “Magic Bullet”
One of the most critical concepts in any therapeutic measure is the concept of selective toxicity. Many treatments for infectious and non-infectious disease will involve the use of compounds that can cause some measure of damage to the human body. It is the hope of the health care provider that the compound is more damaging to the agent causing the disease. We must therefore weigh and balance any potential benefits to the patient to the risks that may be incurred by the treatment.
Paul Erhlich (1854-1915) was one of the giants of microbiology, during the period of time when the biological sciences were transitioning from observational studies to experimental (hypothesis-driven) studies. This shift in the way science was conducted had immediate benefits to society, and resulted in an almost miraculous increase in the ability to combat infectious disease. People believed at the time that virtually all diseases would soon be eradicated, through the power of medical research.
Erhlich’s early training was as a histologist and microscopist. Like Hans Gram, he was interested in using chemicals to increase the contrast and specificity of microscopic samples. He was interested in the ability of chemicals to bind to tissues, and found that the body responded in an immunologic manner to introduced chemicals. Erhlich felt that the specificity that certain chemical dyes had for different kinds of cells (for example, the way that Gram positive and Gram negative cells react in the Gram’s stain) was the principle behind the specificity that immune responses show for a given infectious agent. This idea was formally proposed as the “side-chain theory,” and Erhlich’s early work in immunology resulted in his sharing the Nobel Prize in Medicine with Ilya Mechnikov in 1908.
The side chain theory was an interesting way to think about the way that pathogens react with the immune system, but ultimately is only a very rudimentary framework to think about the way the immune system recognizes foreign materials. He correctly intuited that the immune system recognizes the shapes of foreign materials, but did not recognize that the immune system is able to accomplish this feat without the direct use of our cells.
In 1909, Erhlich and his students began to study the synthesis of a number of arsenic-containing compounds. Long time readers will be aware of my interest in arsenic! His team was interested in a very toxic drug called atoxyl, which appeared to have promise in treating parasitic diseases such as African Sleeping Sickness. However, the correct dosage of atoxyl was extremely difficult to achieve, and it very frequently led to irreversible damage to the optic nerve, and caused other systemic damage. Erhlich had the very clever idea of imagining that perhaps another arsenic-containing compound might continue to have anti-microbial effects, but have fewer toxic side effects in the human body. So the approach the lab perused was to chemically synthesize many varieties of related compounds, test each of them for their antimicrobial efficacy, and to then see what kind of side effects each had in the body. Compound #606, or Salvorsan, showed the most promise. Modern pharmaceutical research uses exactly this assembly line approach in the quest to identify novel drugs.
Compound 606 proved to be amazingly effective, and very rapidly became the preferred treatment for syphilis until it was replaced by penicillin in the 1940’s. Drugs like compound 606 were described by Erhlich as “magic bullets,” in that the compounds would specifically target the pathogen cell, and leave the patient’s cells alone. This premise came about again from his training as a chemist, where he was using chemicals to differentially stain bacteria for microscopic observation. Erhlich also coined the term “chemotherapy,” or the use of chemicals as therapeutic agents in the treatment of various diseases. Erhlich’s dream of a truly magic bullet, or a compound that will hone in on a foreign object and leave the host completely alone, was realized with the development of monoclonal antibodies in the 1970’s.
The concept of selective toxicity, therefore comes out of this idea: can we find compounds of therapeutic merit that have minimal side effects? Note that we don’t require compounds to have no side effects, but we do want the side effects to be less than the potential benefits to the patient. Strategies to accomplish this will typically look for something that is present in the pathogen (and therefore a target for the drug) that is absent in the patient. An example of this at work is the fact that microorganisms grow at a significantly higher rate than our cells, therefore an arsenic-containing compound such as Compound 606 will affect the microorganism much more quickly than our cells, simply because they grow more rapidly.
BONUS: In the comments, suggest a potential microbial target for a selectively toxic compound, and explain why you think it would be selectively toxic.