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1945 The
Nobel Medicine Prize to Sir Alexander Fleming, Ernst Boris
Chain, and Sir Howard Walter Florey .
^top^
“for the discovery of penicillin and
its curative effect in various infectious diseases”
Attempts have been made to reach
the goal of medical art - the prevention and cure of disease
- by many different paths. New and reliable ones have become
practicable as our knowledge of the nature of the different
diseases has widened. Thus the successful combating of certain
disturbances in the activities of the organs of internal
secretion, as also of the deficiency diseases, or avitaminoses,
has been a direct result of the increase in our knowledge
of the nature of these afflictions. When, thanks to the research
work of Louis Pasteur and Robert Koch, the nature of the
infectious diseases was laid bare, and the connection between
them and the invasion of the body by bacteria and other micro-organisms
was elucidated, fully a generation ago, this was an enormous
advance, both for the prevention and the treatment of this
important group of diseases. This was so much the more important
as the group included a number of the worst scourges of humanity,
which had slain whole peoples, and at times had laid waste
wide areas. But now possibilities were revealed which have
not yet been by any means fully utilized. In rapid succession,
different forms of vaccination were evolved, and subsequently
also serum treatment, for the introduction of which the first
Nobel Prize for Physiology or Medicine was given 44 years
ago today. In these cases advantage was taken of the capacity
of the human and animal bodies themselves to produce protective
substances in the fight against the invaders, and to do so
in great abundance.
But it is by no means the
higher organisms only that are able to produce such substances.
In cooperation with Joubert (1877), Pasteur himself observed
that anthrax bacilli cultivated outside the body were destroyed
if bacteria from the air were admitted, and with prophetic
acumen he realized that it was justifiable to attach great
hopes to this observation in the treatment of infectious
diseases. Nevertheless more than two decades passed before
an attempt was made to profit by the struggle for existence
which goes on between different species of micro-organisms.
Experiments carried out by Emmerich and Loew (1899) did not
give such favourable results, however, that any great interest
was aroused, nor did success attend the later efforts of
Gratia and Dath and others. It was reserved to this year's
Nobel Prize winners to realize Pasteur's idea.
The observation made by Professor
Alexander Fleming which led to the discovery of penicillin,
is now almost classical. In 1928, in the course of experiments
with pyogenic bacteria of the staphylococcus group, he noticed
that, around a spot of mould which had chanced to contaminate
one of his cultures, the colonies of bacteria had been killed
and had dissolved away. Fleming had earlier made a study
of different substances which prevent the growth of bacteria
and, inter alia, had come upon one in lacrimal fluid and
saliva, the so-called lysozyme. As he points out himself,
he was therefore always on the look-out for fresh substances
which checked bacteria, and he became sufficiently interested
in his latest find to make a closer investigation of the
phenomenon. The mould was therefore cultivated and subsequently
transferred to broth, where it grew on the surface in the
form of a felted green mass. When the latter was filtered
off a week later, it was found that the broth had such a
strongly checking effect on bacteria that even when diluted
500-800 times it completely prevented the growth of staphylococci;
consequently an extremely active substance had passed to
the broth from the mould. This proved to belong to the Penicillium
group or brush moulds, and therefore first the broth, and
later the substance itself, was called «penicillin».
It was soon realized that
most of the species of Penicillium did not form it at all,
and a closer scrutiny showed that the species which polluted
Fleming's culture was Penicillium notatum. It had been described
for the first time by Richard Westling, in the thesis which
he defended in the autumn of 1911 at the University of Stockholm
for the degree of Doctor of Philosophy - an illustration
of the international nature of science, but also of the suddenly
increased importance which sometimes accrues to sound work
as a result of further developments. Fleming also showed
that penicillin was extremely effective against cultures
of many different kinds of bacteria, above all against those
belonging to the coccus group, among them those that usually
give rise to suppuration, pneumonia and cerebral meningitis,
but also against certain other types, such as diphtheria,
anthrax, and gas gangrene bacteria. But as numerous other
species, among them the influenza, coli, typhoid and tuberculosis
bacilli, grew even if they were exposed to moderate quantities
of penicillin, Fleming was able to work out a method for
isolating out from a mixture of bacteria those which were
insensitive to penicillin. He found, further, that the white
blood corpuscles, which are usually so sensitive, were not
affected by penicillin. When injected into mice, too, it
was fairly harmless. In this respect penicillin differs decisively
from other substances which had been produced earlier from
micro-organisms, and which were certainly found to be noxious
to bacteria, but at the same time at least equally noxious
to the cells of the higher animals. The possibility that
penicillin might be used as a remedy was therefore within
reach, and Fleming tested its effect on infected wounds,
in some cases with moderate success. Three years after Fleming's
discovery, the English biochemists Clutterbuck, Lovell, and
Raistrick, endeavoured to obtain penicillin in the pure form,
but without success. They established, inter alia, that it
was a sensitive substance which easily lost its antibacterial
effect during the purifying process, and this was soon confirmed
in other quarters. Penicillin would undoubtedly still have
remained a fairly unknown substance, interesting to the bacteriologist
but of no great practical importance, if it had not been
taken up at the Pathological Institute at the venerable University
of Oxford.
This time a start was again
made from what is usually called basic research. Professor
Howard Florey, who devoted his attention to the body's own
natural protective powers against infectious diseases, together
with his co-workers, had studied the lysozyme referred to
above, the nature of which they succeeded in elucidating.
Dr. Ernst Boris Chain, a chemist, took part in the final
stage of these investigations, and during 1938 the two researchers
jointly decided to investigate other antibacterial substances
which are formed by micro-organisms, and in that connection
they fortunately thought first of penicillin. It was certainly
obvious that the preparation of the substance in a pure form
must involve great difficulties, but on the other hand its
powerful effect against many bacteria gave some promise of
success. The work was planned by Chain and Florey, who, however,
owing to the vastness of the task, associated with themselves
a number of enthusiastic co-workers, among whom mention should
be made especially of Abraham, Fletcher, Gardner, Heatley,
Jennings, Orr-Ewing, Sanders and Lady Florey. Heatley worked
out a convenient method of determining the relative strength
of a fluid with a penicillin content, by means of a comparison
under standard conditions of its antibacterial effect with
that of a penicillin solution prepared at the laboratory.
The amount of penicillin found in one cc. of the latter was
called an Oxford unit. In the purifying experiments then
made, the mould was cultivated in a special nutritive fluid
in vessels, to which air could only gain access after it
had been filtered through cotton wool. After about a week
the penicillin content reached its highest value, and extraction
followed. In this connection advantage was taken of the observation
that the free penicillin is an acid which is more easily
dissolved in certain organic solvents than in water, while
its salts with alkali are more readily dissolved in water.
The culture fluid was therefore shaken with acidified ether
or amyl acetate. As, however, the penicillin was easily broken
up in water solution, the operation was performed at a low
temperature. Thus the penicillin could be returned to the
water solution after the degree of acidity had been reduced
to almost neutral reaction. In this way numerous impurities
could be removed, and after the solution had been evaporated
at a low temperature it was possible to obtain a stable dry
preparation. The strength of this was up to 40-50 units per
mg and it prevented the growth of staphylococci in a dilution
of at least 1 per 1 million - thus the active substance had
been successfully concentrated very considerably. It was
therefore quite reasonable that it was thought that almost
pure penicillin had been obtained - in a similar manner,
in their work with strongly biologically active substances,
many earlier researchers had thought that they were near
to producing the pure substance.
The further experiments, which
were made subsequently with the help of the magnificent resources
of modern biochemistry proved, however, that such was not
the case. In reality the preparation just mentioned contained
only a small percentage of penicillin. Now when it has become
possible to produce pure penicillin in a crystalline form,
it has been found that one mg contains about 1,650 Oxford
units. It is also known that penicillin is met with in some
different forms, which possibly have somewhat different effects.
The chemical composition of penicillin has also been elucidated
in recent years, and in this work Chain and Abraham have
successfully taken part. The Oxford school was able to confirm
Fleming's observation that penicillin was only slightly toxic,
and they found that its effect was not weakened to any extent
worth mentioning in the presence of blood or pus. It is readily
destroyed in the digestive apparatus, but after injection
under the skin or into the muscles, it is quickly absorbed
into the body, to be rapidly excreted again by way of the
kidneys. If it is to have an effect on sick persons or animals,
it should therefore be supplied uninterruptedly or by means
of closely repeated injections - some more recent experiments
indicate that gradually perhaps it will be possible to overcome
the difficulties in connection with taking the preparation
by mouth. Experiments on mice infected with large doses of
pyogenic or gas gangrene bacteria, which are sensitive to
penicillin, proved convincingly that it had a favourable
effect. While over 90% of the animals treated with penicillin
recovered, all the untreated control animals died. Experiments
on animals play an immense role for modern medicine; indeed
it would certainly be catastrophic if we ventured to test
remedies on healthy or sick persons, without having first
convinced ourselves by experiments on animals that the toxic
effect is not too great, and that at the same time there
is reason to anticipate a beneficial result.
Tests on human beings may,
however, involve many disappointments, even if the results
of experiments on animals appear to be clear. At first this
seemed to be the case with penicillin, in that the preparation
gave rise to fever. Fortunately this was only due to an impurity,
and with better preparations it has subsequently been possible
to avoid this unpleasant effect. The first experiments in
which penicillin was given to sick persons were published
in August 1941 and appeared promising, but owing to the insufficient
supplies of the drug, the treatment in some cases had to
be discontinued prematurely. However, Florey succeeded in
arousing the interest of the authorities in the United States
in the new substance, and with the cooperation of numerous
research workers it was soon possible, by means of intensive
work, to obtain materially improved results there and to
carry on the preparation in pure form to the crystallization
stage just mentioned. Large quantities of penicillin could
be made available, and numerous tests were made above all
in the field, but to a certain extent also in the treatment
of civilians. Many cases were reported of patients who had
been considered doomed or had suffered from illness for a
long period without improvement, although all the resources
of modern medicine had been tried, but in which the penicillin
treatment had led to recoveries which not infrequently seemed
miraculous.
Naturally such testimony from
experienced doctors must not be underestimated, but on the
other hand we must bear in mind the great difficulties in
judging the course of a disease. «Experience is deceptive,
judgment difficult», is one of Hippocrates' famous aphorisms.
Therefore it is important that a remedy should be tested
on a large material and in such a way that comparison can
be made with cases which have not been given the remedy but
had otherwise received exactly the same treatment. There
are now many reports of such investigations. The extraordinarily
good effects of penicillin have been established in a number
of important infectious illnesses, such as general blood
poisoning, cerebral meningitis, gas gangrene, pneumonia,
syphilis, gonorrhea and many others. It is of special importance
that even sick persons who are not favourably affected by
the modern sulfa drugs are not infrequently cured with penicillin.
The effect naturally depends on the remedy being given in
a suitable manner and in sufficient doses. On the other hand,
experience has confirmed what might have been surmised, namely
that penicillin is not effective in cases of, e.g. tuberculosis,
typhoid fever, poliomyelitis, and a number of other infectious
diseases. Consequently penicillin is not a universal remedy,
but it is of the highest value for certain diseases. And
it appears not improbable that, with the guidance of experience
with penicillin, it will be possible to produce new remedies
which can compete with or perhaps surpass it in certain respects.
Four years is a short time
in which to arrive at definite conclusions as to the value
of a remedy. But during these last few years experiences
of penicillin have been assembled which, under ordinary conditions,
would have required decades. And therefore there is no doubt
at the present time that the discovery of penicillin and
its curative properties in the case of various infection
diseases for which this year's Nobel Prize is awarded, is
of the greatest importance for medical science. Sir Alexander
Fleming, Doctor Chain, and Sir Howard Florey. The story of
penicillin is well-known throughout the world. It affords
a splendid example of different scientific methods cooperating
for a great common purpose. Once again it has shown us the
fundamental importance of basic research. The starting-point
was a purely academic investigation, which led to a so-called
accidental observation. This gave the nucleus, around which
one of the most efficient remedies ever known could be crystallized.
This difficult process was made possible with the aid of
modern biochemistry, bacteriology, and clinical research.
To overcome the numerous obstacles, all this work demanded
not only assistance from many different quarters, but also
an unusual amount of scientific enthusiasm, and a firm belief
in an idea. In a time when annihilation and destruction through
the inventions of man have been greater than ever before
in history, the introduction of penicillin is a brilliant
demonstration that human genius is just as well able to save
life and combat disease.
Alexander
Fleming gana el Premio Nobel de Medicina.
Sir Alexander Fleming
Biography
Nobel
Lecture
Ernst Boris Chain
Biography
Nobel
Lecture
Sir Howard Walter Florey
Biography
Nobel
Lecture
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