by King-Thom Chung, Department of Biology, The University of Memphis

Paul Ehrlich, as described by his secretary, was a man who was lost in his scientific thought all the time. He paid little attention to his clothes and appearance. He smoked twenty-five cigars daily and was chronically covered with cigar ashes. He would write notes all over his sleeves, his shirts, on the floor, and on everywhere or everything he could touch. He was a "microbe hunter" when he said, "We must learn to shoot microbes with magic bullets." For this, others laughed at him. People cartooned him under the name "Doctor Phantasus".

Paul Ehrlich was born in Strehlen, Silesia in Germany on March 14, 1854. He was the first and only son (after many sisters) of a well-to-do Jewish innkeeper. He was interested in Latin, chemistry and biology in his youth but did poorly in German composition. When he was a young schoolboy, his thoughts were different from ordinary youths. One time his teacher wanted him to write an essay on the topic "Life is a dream" in his literature class. He wrote, "Life rests on normal oxidation, dreams are an activity of brain and the activities of the brain are only oxidations. Dreams are sort of phosphorescence of the Brain." His thought was full of scientific notions; however his teacher did not understand anything he wrote and gave him a bad grade. His interest in drug experiments dates back to when he was very young. He requested the pharmacist in town to prepare his cough drops based on his own formula.

Ehrlich started medical school at Breslan and later attended three different medical schools before he graduated. He transferred to Strasbourg later then transferred to and graduated from Leipzig University in 1878. In medical school, he was not an ordinary medical student. He was a revolutionist, with a record of refusing to memorize the medical terminology that he was required of a medical student. When working on an autopsy, instead of learning the human anatomy, he was more interested in histology stains. He spent extra hours performing tissue staining and began to investigate the properties of aniline dyes. He wrote his doctoral thesis, Contribution to the theory and Practice of Histological Stain. He studied the staining of white blood cells and called these "mast cells." Mast cells today are known as basophils; these migrate into the tissues during injury or infection. They release histamine and heparin. Histamine causes vasodilation and initiates the inflammatory response. Heparin's function mainly inhibits blood clotting. Ehrlich improved the method of preparing a dye discovered by William Perkins from coal-tar distillates for staining. This was the first "coal-tar" or aniline dye. In 1875, Ehrlich's methyl violet was used to stain bacteria by Weigert and Koch and still is the best staining method used today. In 1884, a different stain, the most useful in microbiology even today, was developed by a Danish scholar, Gram. Ehrlich's methyl violet solution was adopted by Gram for the staining of the Gram-positive bacteria. The Gram-negative bacteria did not retain this dye after an alcohol wash. They can be counter-stained by a different color dye, safranin.

After graduation from medical school in 1878, he worked at Chariete Hospital in Berlin as a house staff physician under Professor Von Fredrichs. His first laboratory was only equipped with a Bunsen burner, a water tap and a laboratory bench. Today, we think a research laboratory needs all kinds of apparatus, modern equipment, chemicals, computers, etc. Under these simple conditions, he continued to work on his dye. He developed some techniques and methods of staining the tubercule bacillus. In 1882, Ehrlich began to work for Robert Koch, a tuberculosis specialist and a famous scientist at that time. Unfortunately, Ehrlich was infected by tuberculosis in 1887. He went to Egypt where the dry climate was better for recovery from the disease. He recovered after two years and returned to Berlin. Ehrlich rejoined Robert Koch and worked together with von Behring and Kitasato. They teamed together and attempted to search for the cure for diphtheria. Ehrlich was the experimenter who did most of the work involved. He worked out the detailed dosage and techniques for dosages. In 1892, diphtheria antitoxin was successfully produced. Behring was awarded a Nobel Prize for his discovery because it was Behring's idea to make use of immunology theory in forming the serum therapy concept. Ehrlich left the Institute due to an argument with von Behring. In 1896, Ehrlich took a position as the director of the Institute for serum research and serum testing in a suburb of Berlin in Steglitz. The position was appointed by Dr. Althoff, the director of the Prussian Ministry of Education and Medical Affairs because of his expertise in diphtheria toxin. The early facility of the serum control center was very poor and the state's research budget was slim, but Paul Ehrlich's work continued. He focused on the theoretical problems of immunity. He suggested a theory to explain antibody function in response to the chemical substance in the foreign cell. At the same time, he worked out the technicalities of standardizing and testing. He even tried to establish an International Unit to standardize the antitoxin in using assay techniques. In 1896, his International Unit concern was reinforced by the report of the Lancet's commission in the article "Relative strengths of Diphtheria anti-toxin serums."

In 1899 the Institution for the serum research and serum testing was renamed the Royal Institute for Experimental Therapy--Frankfurt Institute, and transferred to the city of Frankfurt. It was state supported and well funded. Under the direction of Paul Ehrlich, Frankfurt Institute served three major functions: 1) to test all government's control serum and vaccines; 2) to serve as a hygiene and bacteriological laboratory (like the state boards of health of today); and 3) to perform active research in immunology. Ehrlich's work at the Institute was productive and fulfilling.

In 1902, a second Institute called the Georg Speyer House started next to the Frankfurt Institute. It was under construction and opened in 1906. The function of the House was a privately endowed organization funded by the wealthy Speyer's family in memory of Georg Speyer upon his death. It was dedicated for research in chemotherapy. Ehrlich became director of both Institutions. His goal in the new Georg Speyer House was to produce a specific synthetic chemical that can target specific pathogen in the body. In the dedication of the Georg Speyer House, Ehrlich stated in his opening speech that: "The task of the new Institute will be a specific chemotherapy of infectious disease. It is easy to see that this line of approach, by its very nature, must be a much more difficult one than that of serum therapy. Magic substances like antibodies, which affect exclusively the harmful agent, will not be so easily found in the series of artificially produced substances. It must be regarded as in the highest degree probable that substances of this kind, foreign to the body, will be attacked also by the organs, and that, since we shall be dealing with a range of different substances, all with pronounced activities, these are not unlikely to injure the organism as a whole, or some part of it. This point of view has been specially justified when a chemical therapy has been tried on the common infections by pathogenic bacteria. Sublimate in aqueous solution, even in high dilutions, will kill anthrax bacilli. If, however, as was shown by our veteran master Koch, one injects a considerably greater quantity of sublimate into an anthrax-infected animal, its death is in no way retarded, but is, in fact, accelerated; he bacteria themselves suffer no harm whatsoever."

It was difficult to apply test tube experiments to life models, but he found it challenging to do so. His ambition for the new institute was to find new curative drugs for deadly infectious disease. He explains, "The concepts which have thus been developed indicate the direction which must be followed in the construction

of new organotropic medicaments. It will, therefore, be one of the main tasks of the new Institute to preserve along this path; and this entails, in the first instance, the discovery of substances and chemical groups that have affinity for particular organs. The organotropic substances must then be furnished with pharmacophore groups that will bring about a therapeutic and pharmacological activity. We intend, as it were to use certain chemical complex as vehicles to carry appropriate pharmacophore groups to the desired type of cells."

Ehrlich's chemotherapeutic agent development dated back to his earlier studies of methylene blue dye in 1891. The striking affinity of the dye for the nervous system stimulated his later developments. He attempted to use the dye for his future drug work. Methylene blue would later become an antipyretic agent in 1893.

Starting in 1902, he and his staff worked extensively on the chemical involved with trypanosomes, a spirochete that caused a sleeping sickness. His work involved the synthesis of hundreds of chemicals, and he (and his staff) gave each chemical a number. They tried many different chemicals on laboratory animals, compound 418 arsenophenyl glycine (trypan red) was found effective against trypanosomes. Other derivatives of this chemical had also been tried. The combination of a dose of arsenic acid followed by trypan red after two days were found to be more effective against trypanosomes. He and his associates kept trying to find better drugs. They tried all arsenic-containing compounds that they could synthesize. In 1907 they found dihydroxydianioarseno-

benzene hydrochloride (arsphenanine)---chemical number 606. It did not work very well against trypanosomes at the time.

In 1908, Ehrlich was awarded as shared Nobel Prize with Metchnikoff in medicine and physiology for his work on immunity and serum therapy. Happy endings did not stop Ehrlich from continuing research. A year later, his new Japanese associate Sahachiro Hata chose compound 606 again and found that was very effective against the spirochetes. And, it was still effective against trypanosomes. More than that, chemical number 606, to be known as Salvarsan or Arsphenamine, turned out to be a remarkably effective killer for another spirochete microorganism, Treponema pallidum (syphilis). Many people were infected by the deadly syphilis. In 1910, Salvarsan was announced to the world. It was one of the scientific breakthroughs in microbiology and chemotherapy history. Despite some problems, for 40 years, Salvarsan remained the most effective drug for the treatment of Syphilis until the discovery of Penicillin by Scottish physician, Alexander Fleming. After Salvarsan, chemical number 914, Neosalvarsan, a water-soluble Salvarsan was introduced. Chemotherapy research still went on, but Ehrlich's health was declining. He died in August 1915 from failing health at age 61.

It should be noted that syphilis is still a killer. Many antibiotic resistant strains have developed. The germ has also learned to "hide" in body tissues, like a virus, and later spread.