Paul Ehrlich (1854-1915): man with the magic bullet

Tags: Ehrlich, Paul Ehrlich, University of Hawaii, dye molecules, mast cells, John A Burns School of Medicine, Professor of Medicine, research ideas, Grimes S, laboratory walls, Elie Metchnikoff, Emil Fisher, chemical structure, DU NIGER PRIX NOBEL DE MEDECINE, lifelong habit, side chain theory, side chains, magic bullets, Kiyoshi Shiga, magic bullet, Ziehl-Neelsen stain
Content: Singapore Med J 2010; 51(1 1) : 842
Medicine in Stamps Paul Ehrlich (1854-1915): man with the magic bullet Tan S Y, MD, JD and Grimes S, MS* Professor of Medicine, John A Burns School of Medicine, University of Hawaii *Research carried out during 2nd year Medical School at the John A Burns School of Medicine, University of Hawaii.
"It is because we are not exact that we fail." - Paul his ideas. In his frantic enthusiasm, he would scribble
Ehrlich
on any available surface: laboratory walls, tablecloths,
the bottom of his shoes and the shirts of colleagues.
Let's paint a picture of a man fascinated by Colour allowed Ehrlich to better understand the chemical
colours and chemistry, whose imagination underpinnings of biology. This obsession led to a few
enabled the deduction of theories and cures peculiarities: his pocket overflowed with sharpened
years beyond his contemporaries. Add to coloured pencils, his laboratory brimmed with vibrantly
this an unyielding enthusiasm and perseverance, and we coloured test tubes, and his research ideas were preserved
have Paul Ehrlich, Nobel laureate for contributions in on large coloured note cards.
adaptive and acquired immunity. Born on March 14, 1854 in Strehlen, Germany, to wealthy German -Jew parents, TUBERCULOSIS Ehrlich's most "gripping experience"
Ehrlich studied medicine at Breslau, and was a mediocre was his realisation, at a lecture by Koch, that he had
student who refused to memorise the ten thousand and seen the tuberculosis organism while staining a diseased
fifty medical terms necessary to graduate. He earned his liver. That night, he rushed to his laboratory to improve
MD in 1878 and began his career in
the acid-fast staining method
thE Department of internal medicine at Charite Hospital in Berlin under Friedrich, a liberal whose motto was
---)104
for mycobacterium, he demonstrated to Koch the next day.
which Robert Today,
"only free birds sing, those in captivity
the Ziehl-Neelsen stain for
don't." At Charite, Ehrlich showcased
acid -fast bacteria is a direct
a lifelong habit of unrelenting work and smoking strong black cigars. He exercised little and drank much,
DU NIGER PRIX NOBEL DE MEDECINE 1908
REP UBLI QUE
200f
descendant of his method. That year, 1882, marked the start of a lifelong friendship and
frequently with colleagues in order to
mutual intellectual admiration
engage them in lively discussions of his favourite topic, between these two pioneers of medicine. In 1885, Ehrlich
chemistry. His self-depreciating humour earned him discovered, to his chagrin, the presence of mycobacteria
many friends, often men in high places.
in his own sputum. As was the standard cure at that
time, he went to Egypt for two years to rest his lungs.
HISTOLOGY Early in his career, the chemist in Meanwhile, Koch thought he had found a cure, and
Ehrlich took note of Carl Weitgert's use of aniline dyes administered it to his friend. Fortunately, Ehrlich survived
as biological stains, which caused him to ponder on the despite Koch's ineffective and dangerous treatment.
link between a dye's chemical structure and its selectivity for certain tissues. At 23, he published his first paper,
IMMUNOLOGY In 1885, Ehrlich published a paper
"Contributions to the Theory and Practice of Histological on the requirement of the organism for oxygen, which
Staining", which advanced the novel argument that both proposed that cells have a multitude of specific receptors
the colouring of fabrics and the staining of cells were that enable them to take up necessary molecular nutrients.
fundamentally the result of a true chemical reaction. His Harmful compounds could mimic nutrients and bind
expertise in histology and meticulous work ethic led to to these receptors. Despite a few missing details, his
the eventual description of the various granulocytes and bold hypothesis gradually evolved; both living cells
mast cells. Ehrlich used drawings and colour to present and dye molecules possess side chains that define their
Singapore Med J 2010; 51(1 1) : 843
properties and interactions. In 1900, Ehrlich described his famous side chain theory of antibody formation, proposing that antigens bind to pre-existing side chains on the cell surface, stimulating the synthesis of additional side chains that are then secreted into the extracellular fluid to neutralise the instigating antigen. He described these antibodies as "magic bullets" in search of toxins. Ehrlich drew his inspiration from Emil Fisher, who had proposed that enzymes fit their substrates like a lock and key. Ehrlich went further, adding that cells were capable of producing receptors prior to, not after, contact with foreign proteins, although later studies showed that the full spectrum of receptors is not present on every cell. Unfortunately, Ehrlich's colleagues did not always understand his detailed diagrams and erratic explanations, and some openly mocked him. Convinced that mathematics governed toxin-antitoxin reactions, he searched for simple formulas, but lapsed into complex and complicated explanations. Despite these shortcomings, the core idea of his side chain theory firmly laid the foundation for modern-day truisms governing immunity. In 1908, he shared the Nobel Prize with Elie Metchnikoff. MAGIC BULLETS In 1896, Germany established the Institute for Serum Research and Serum Testing. There, Ehrlich worked with colleagues Emil von Behring, Nobel winner for diphtheria therapy, and Shibasaburo Kitasato, who isolated the tetanus bacterium. Ehrlich's insistence on precision led to the quantifying and standardising of the antisera for diphtheria and tetanus, and optimised their immunisation regimen. In 1901, with the help of bacteriologist Kiyoshi Shiga, Ehrlich tested hundreds of dyes on mice, in search of the magic bullet to target the large trypanosome that causes sleeping sickness. Earlier efforts by Alphonse Laveran with subcutaneous injections of arsenic had failed. After two years of frustrating work, Ehrlich and Shiga finally created a red dye modified with sulfo-groups, verified its effectiveness, and subsequently released it as Trypan Red in 1904 as a cure for sleeping sickness. In 1906, Ehrlich, now the director of the GeorgSpeyer-Haus, turned his attention to malaria. Together with Bertheim, the resident chief chemist, he developed hundreds of derivatives of Atoxyl, a toxic drug that caused blindness, before discovering a gold powder, code -named Compound 606. He had found another magic bullet, one capable of killing the malaria organism without corresponding host toxicity. In 1909, Ehrlich tested Compound 606 on a syphilis -infected rabbit,
and demonstrated the killing of the spirochaetes with a single dose. At the time, the standard therapy for syphilis was a two -to-four-year regimen of mercury injections. His experimental success led to Clinical Trials with Compound 606; terminal patients with dementia began to improve and early stage patients with infected sores recovered. 400,000 doses were distributed in approved clinics before Compound 606 was publicly released as Salvarsan in 1910. Unfortunately, adverse neurological side effects, including convulsions and death, led to harsh criticisms. Further toiling in the laboratory yielded -a the 914th compound less toxic, albeit less effective alternative to Salvarsan named Neosalvarsan, which was released in 1913. These remained the most effective syphilis treatments until antibiotics were available in the 1940s. DEATH AT 61 Ehrlich eventually developed diabetes and suffered two strokes - the second causing his death on August 20, 1915. He was buried in Frankfurt, where the citizens named a street in his honour. Von Behring, who became an adversary after allegedly failing to honour a commercial contract for antiserum production, had these words of farewell: "If we have hurt you, forgive us." Paul Ehrlich, the average student who resisted the learning of medical terms, had unlocked the secrets of magic bullets and vindicated himself with words of his own making such as hapten, toxin, complement and chemotherapy. BIBLIOGRAPHY Bowden ME, Crow AB, Sullivan T. Paul Ehrlich. In: Pharmaceutical Achievers - The human face of pharmaceutical research. Philadelphia: Chemical Heritage Press, 2003. Clendening L. source book of Medical History. New York: DOVER PUBLICATIONS Inc, 1960. de Kruif, Paul. Microbe Hunters. New York: Blue Ribbon Books, 1954. Gensini GF, Conti AA, Lippi D. The contributions of Paul Ehrlich to infectious disease. J Infection 2007; 54:221-4. Harrison LW. Ehrlich versus syphilis as it appeared to LW Harrison. Br J Vener Dis 1954; 30:2-6. Kaufmann S. Immunology's foundation: the 100 -year anniversary of the Nobel Prize to Paul Ehrlich and Elie Metchnikoff. Nat Immunol 2008; 9:705-12. Schwartz RS. Paul Ehrlich's Magic Bullets. New Engl J Med 2004; 350:1079-80. Simmons JG. Doctors and Discoveries - Lives That Created Today's Medicine. Boston: Houghton Mifflin Company, 2002: 186-98. Thorburn AL. Paul Ehrlich: a pioneer of chemotherapy and cure by arsenic (1854-1915). Br J Vener Dis 1983; 59:404-5. Turk JL. Paul Ehrlich - the dawn of immunology. J R Soc Med 1994; 87:314-5. Winau F, Westphal 0, Winau R. Paul Ehrlich - in search of the magic bullet. Microbes and Infection 2004; 6:786-9.

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