|
1952 The
Nobel Medicine Prize to Waksman
^top^
for his discovery of streptomycin, the
first antibiotic effective against tuberculosis
Nobel
Lecture.
Shortly after the discovery
of the tubercle bacillus by Robert Koch in 1882 a search
was made for an effective therapeutic agent against this
germ. Eight years later Koch announced that he had succeeded
in isolating a substance from tubercle-bacilli medium which
he had found to be effective against tuberculous diseases.
This substance is now known as tuberculin. Physicians throughout
the world were most optimistic about this latest discovery
by Koch, but this early optimism was soon dispelled when
it was found that Koch's results could not be reproduced
by other workers, and some of these workers found that tuberculin
was dangerous when used in large doses.
A similar picture has occurred
with all subsequent anti-tuberculous remedies. I will recall
the short-lived triumph of sanocrysin and the sulpha compounds,
promin, promizol, and diazone which were used in the States
during the War and which were received at first with great
enthusiasm. It is therefore quite natural for physicians
to be sceptical when they heard that a new anti-tuberculous
remedy called «streptomycin» had been produced in the United
States in 1943. A decade has almost passed since this discovery
and experiences from the whole world has proven that we have
at last the first effective remedy against tuberculosis.
In contrast to the discovery
of penicillin by Professor Fleming which was largely due
to a matter of chance, the isolation of streptomycin has
been the result of a long-term, systematic and assiduous
research by a large group of workers. The initiator and leader
of this group was Dr. Waksman. Dr. Waksman is the microbiologist
at the Agricultural Department of Rutger's University in
New Brunswick, New Jersey, and has been actively engaged
on research work on soil microbes for many years, including
their synergistic and antagonistic fight for existence. In
1939, i.e. one year before the rediscovery of penicillin
by Florey and Chain, Dr. Waksman started an extensive programme
of study which was aimed at determining the nature of the
substance by which the various soil microbes destroyed each
other. He had been interested in the actinomycetes for a
quarter of a century, and it was only natural that he should
first turn his attention to these microbes. In 1915 Dr. Waksman
and one of his assistants had isolated from the soil a strain
of actinomycete which they called Actinomyces griseus. This
name was changed to Streptomyces griseus in 1943 and under
this name it has now become world renowned. It is from a
strain of this species that streptomycin is produced. Dr.
Waksman had shown that of the microbes, Streptomyces was
best able to survive when the living conditions in the soil
became unsatisfactory, and this was an additional reason
for commencing with the Streptomyces.
It has been known for a long
time that the tubercle bacillus is rapidly destroyed in the
soil. In 1932 Dr. Waksman was entrusted by the American National
Association against Tuberculosis to make an investigation
into this matter. He was able to confirm earlier observations
and concluded that the disappearance of the tubercle bacilli
in the soil was probably due to the influence of other antagonistic
microbes. At that time the word antibiotic had not been coined.
It was Dr. Waksman who introduced the new word «antibiotic»,
and it represents an antibacterial substance, produced by
a microbe which is antagonstic in action to another.
In 1940 Dr.Waksman and his
collaborator had succeeded in isolating the first antibiotic,
which was called «actinomycin» and it was very toxic. In
1942 another antibiotic was detected and studied, called
«streptothricin». This had a high degree of activity against
many bacteria and also against the tubercle bacillus. Further
studies revealed that streptothricin was too toxic. During
the streptothricin studies Dr. Waksman and his collaborators
developed a series of test-methods, which turned out to be
very useful in the isolation of streptomycin in 1943.
Encouraged by the discovery
of streptothricin and stimulated by the triumphal development
of penicillin treatment, the research team headed by Dr.Waksman
continued their untiring search for new antibiotic-producing
microbes. Before the discovery of streptomycin no less than
10'000 different soil microbes had been studied for their
antibiotic activity. Dr. Waksman directed this work and distributed
the various lines of research among his young assistants.
One of these was Albert Schatz, who had previously worked
with Dr. Waksman for 2 months and in June 1943 returned to
the laboratory. Dr. Waksman gave him the task of isolating
new species of Actinomyces. After a few months he isolated
two strains of Actinomyces which were shown to be identical
with Streptomyces griseus, discovered by Dr. Waksman in 1915.
In contrast to the previous one the rediscovered microbe
was shown to have antibiotic activity. To this antibiotic
Dr. Waksman gave the name «streptomycin». He studied the
antibiotic effect of streptomycin with Schatz and Bugie and
found that it was active against several bacteria including
the tubercle bacillus. These preliminary studies were completed
in a relatively short time, thanks to the clear principles
which had been set out previously by Dr. Waksman for the
study of streptothricin.
The subsequent testing of
streptomycin as an anti-tuberculosis remedy was entrusted
to two physicians, Feldman and Hinshaw, at the Mayo Clinic
in Rochester. From experiences with sulpha compounds they
had developed a reliable research technique. As a result
of very promising work with experimental tuberculosis in
guinea pigs, Feldman and Hinshaw considered it appropriate
to try its activity in human tuberculosis. They selected
a series of cases in which spontaneous recovery was regarded
as hopeless. The most surprising result was the apparent
curative action of streptomycin in two extremely severe cases
of tuberculous diseases, viz. tuberculous meningitis and
miliary [= like millet seeds] tuberculosis. Encouraged
by this experience they ventured to treat more benign and
recent cases of tuberculosis and these were improved considerably.
In the meantime Dr. Waksman
and his associates continued with their researches. They
found that different strains of Streptomyces griseus varied
in their capacity to produce antibiotic substances. Out of
all isolated strains of this microbe, only four were adapted
for the production of streptomycin on a large scale. Streptomyces
griseus grows on many different media, but streptomycin can
only be produced under certain conditions. Dr. Waksman and
his co-workers made preliminary chemical studies in order
to determine the formula of streptomycin. The great work
of Folkers and Wintersteiner in this field of research gave
us the chemical formula, which led to the isolation of streptomycin
in pure form.
The activity of streptomycin
is principally bacteriostatic, i.e. it checks the bacterial
growth and is in some degree also bacteriolytic, i.e. it
destroys the tubercle bacillus. The mechanism of this important
antibacterial effect is not yet known.
At the present time streptomycin
has had such a widespread and a long trial throughout the
world that it is now possible to form a fair opinion of its
therapeutic value. The most sensational effect is seen in
the treatment of miliary tuberculosis and tuberculous meningitis.
The former had previously had a fatal outcome with few exceptions
and meningitis has always been fatal. Nowadays the prognosis
is far better, thanks to streptomycin. The immediate result
with streptomycin treatment of tuberculous meningitis can
be dramatic; patients that are unconscious and have a high
fever may improve rapidly after administering the drug. The
ultimate result in such severe cases is not so satisfactory.
The earlier the streptomycin treatment is started the greater
the chance of recovery. The outcome of streptomycin treatment
is therefore dependent on an early diagnosis of the tuberculous
disease. This circumstance can explain the great difference
in the reported results by different workers, ranging from
75% recoveries in the most favourable cases to 20% in the
more severe. Miliary tuberculosis is more amenable to streptomycin
treatment than meningitis. According to recent experiences
one can reckon with a definite healing in about 80%.
Early cases of pulmonary tuberculosis
may be successfully treated with streptomycin. In cases of
pulmonary tuberculosis suitable for surgery, streptomycin
has proved a very valuable supplement. By means of streptomycin
it has been possible to transform patients into a suitable
condition for operation, which before streptomycin treatment
would have been considered impossible. In the treatment of
tuberculosis of the genito-urinary tract and in bone and
joint tuberculosis, streptomycin has been of considerable
value. Thanks to the possibility of pre- and postoperative
chemotherapy, new and more conservative principles for the
surgical treatment have been applied with success.
Streptomycin is not altogether
a harmless remedy, but with greater experience with this
antibiotic, methods have been devised to minimize this effect.
The untoward effects that have been reported previously,
viz. damage to the vestibular and auditory nerves, have been
greatly reduced or abolished by using purified streptomycin,
smaller doses and shorter periods of treatment. These side-effects
cannot be regarded nowadays as a contraindication to streptomycin
treatment.
Another complication is the
development of strains of bacteria that become more and more
resistant to streptomycin. This very important question has
been studied in many centres, and different ways have been
tried to prevent the development of streptomycin-resistant
bacteria. It has been shown that in combination with other
anti-tuberculous compounds, especially PAS, the chemotherapeutic
remedy detected by the Swedish biochemist Lehmann, the development
of streptomycin resistance is delayed.
This summany has dealt almost
exclusively on streptomycin as an anti-tuberculous remedy,
because it is this which has earned the Nobel Prize. However,
streptomycin has a much more extensive antibacterial action
and has been successfully used against a large number of
the common pathogenic bacteria, including several not affected
by penicillin. The value of streptomycin as a remedy against
infectious diseases in humans is therefore much greater than
may appear from this presentation of its antituberculous
effect.
By the discovery of streptomycin
Dr. Waksman and his collaborators have made a very important
contribution to the history of medicine. Even if streptomycin
is not the perfect anti-tuberculous remedy, its introduction
nevertheless signifies a gigantic step forward. Above all,
its isolation has suggested procedures for future investigations
that may guarantee fundamental results. One may hope that
this approach will lead in the near future to the eagerly
expected goal, viz. a remedy that will make possible the
eradication of tuberculous disease.
The Caroline Medical Institute
has awarded to Professor Selman Waksman the 1952 Nobel Prize
for Physiology or Medicine, for his ingenious, systematic
and successful studies of the soil microbes that have led
to the discovery of streptomycin, the first antibiotic remedy
against tuberculosis. Neither is he a physiologist nor a
physician, but still his contribution to the advancement
of medicine has been of paramount importance. Streptomycin
has already saved thousands of human lives. Physicians regard
Waksman as one of the greatest benefactors to mankind.
|