Ehrlich, Paul WORLD OF MICROBIOLOGY AND IMMUNOLOGY178•
ored with an appointment as Extraordinary Professor at the
University of Berlin. In 1891, Ehrlich accepted Robert Koch’s
invitation to join him at the Institute for Infectious Diseases,
newly created for Koch by the Prussian government. At the
institute, Koch began his immunological research by demon-
strating that mice fed or injected with the toxins ricin and abrin
developed antitoxins. He also proved that antibodies were
passed from mother to offspring through breast milk. Ehrlich
joined forces with Koch and Emil Adolf von Behringto find a
cure for diphtheria, a deadly childhood disease. Although von
Behring had identified the antibodies to diphtheria, he still
faced great difficulties transforming the discovery into a
potent yet safe cure for humans. Using blood drawn from
horses and goats infected with the disease, the scientists
worked together to concentrate and purify an effective anti-
toxin. Ehrlich’s particular contribution to the cure was his
method of measuring an effective dose.
The commercialization of a diphtheria antitoxin began
in 1892 and was manufactured by Höchst Chemical Works.
Royalties from the drug profits promised to make Ehrlich and
von Behring wealthy men. But Ehrlich, possibly at von
Behring’s urging, accepted a government position in 1885 to
monitor the production of the diphtheria serum. Conflict-of-
interest clauses obligated Ehrlich to withdraw from his profit-
sharing agreement. Forced to stand by as the diphtheria
antitoxin made von Behring a wealthy man, he and von
Behring quarreled and eventually parted. Although it is
unclear whether bitterness over the royalty agreement sparked
the quarrel, it certainly couldn’t have helped a relationship that
was often tumultuous. Although the two scientists continued
to exchange news in letters, both scientific and personal, the
two scientists never met again.
In June of 1896, the Prussian government invited
Ehrlich to direct its newly created Royal Institute for Serum
Research and Testing in Steglitz, a suburb of Berlin. For the
first time, Ehrlich had his own institute. In 1896, Ehrlich was
invited by Franz Adickes, the mayor of Frankfurt, and by
Friedrich Althoff, the Prussian Minister of Educational and
Medical Affairs, to move his research to Frankfurt. Ehrlich
accepted and the Royal Institute for Experimental Therapy
opened on November 8, 1899. Ehrlich was to remain as its
director until his death sixteen years later. The years
in Frankfurt would prove to be among Ehrlich’s most
productive.
In his speech at the opening of the Institute for
Experimental Therapy, Ehrlich seized the opportunity to
describe in detail his “side-chain theory” of how antibodies
worked. “Side-chain” is the name given to the appendages on
benzene molecules that allow it to react with other chemicals.
Ehrlich believed all molecules had similar side-chains that
allowed them to link with molecules, nutrients, infectious tox-
ins and other substances. Although Ehrlich’s theory is false,
his efforts to prove it led to a host of new discoveries and
guided much of his future research.
The move to Frankfurt marked the dawn of chemother-
apyas Ehrlich erected various chemical agents against a host
of dangerous microorganisms. In 1903, scientists had discov-
ered that the cause of sleeping sickness, a deadly diseaseprevalent in Africa, was a species of trypanosomes (parasitic
protozoans). With help from Japanese scientist Kiyoshi Shiga,
Ehrlich worked to find a dye that destroyed trypanosomes in
infected mice. In 1904, he discovered such a dye, which was
dubbed “trypan red.”
Success with trypan red spurred Ehrlich to begin testing
other chemicals against disease. To conduct his methodical
and painstaking experiments with an enormous range of
chemicals, Ehrlich relied heavily on his assistants. To direct
their work, he made up a series of instructions on colored
cards in the evening and handed them out each morning.
Although such a management strategy did not endear him to
his lab associates, and did not allow them opportunity for their
own research, Ehrlich’s approach was often successful. In one
famous instance, Ehrlich ordered his staff to disregard the
accepted notion of the chemical structure of atoxyl and to
instead proceed in their work based on his specifications of the
chemical. Two of the three medical scientists working with
Ehrlich were appalled at his scientific heresy and ended their
employment at the laboratory. Ehrlich’s hypothesis concerning
atoxyl turned out to have been correct and would eventually
lead to the discovery of a chemical cure for syphilis.
In September of 1906, Ehrlich’s laboratory became a
division of the new Georg Speyer Haus for Chemotherapeu-
tical Research. The research institute, endowed by the
wealthy widow of Georg Speyer for the exclusive purpose of
continuing Ehrlich’s work in chemotherapy, was built next to
Ehrlich’s existing laboratory. In a speech at the opening of the
new institute, Ehrlich used the phrase “magic bullets” to illus-
trate his hope of finding chemical compounds that would
enter the body, attack only the offending microorganisms or
malignant cells, and leave healthy tissue untouched. In 1908,
Ehrlich’s work on immunity, particularly his contribution to
the diphtheria antitoxin, was honored with the Nobel Prize in
medicine or physiology. He shared the prize with Russian
bacteriologist Élie Metchnikoff.
By the time Ehrlich’s lab formally joined the Speyer
Haus, he had already tested over 300 chemical compounds
against trypanosomes and the syphilis spirochete (distin-
guished as slender and spirally undulating bacteria). With each
test given a laboratory number, Ehrlich was testing com-
pounds numbering in the nine hundreds before realizing that
“compound 606” was a highly potent drug effective against
relapsing fever and syphilis. Due to an assistant’s error, the
potential of compound 606 had been overlooked for nearly
two years until Ehrlich’s associate, Sahashiro Hata, experi-
mented with it again. On June 10, 1909, Ehrlich and Hata filed
a patent for 606 for its use against relapsing fever.
The first favorable results of 606 against syphilis were
announced at the Congress for Internal Medicine held at
Wiesbaden in April 1910. Although Ehrlich emphasized he
was reporting only preliminary results, news of a cure for the
devastating and widespread disease swept through the
European and American medical communities and Ehrlich
was besieged with requests for the drug. Physicians and vic-
tims of the disease clamored at his doors. Ehrlich, painfully
aware that mishandled dosages could blind or even kill
patients, begged physicians to wait until he could test 606 onwomi_E 5/6/03 2:12 PM Page 178