7.31 Serum Therapy in Therapeutics and Medical Science
Emil von Behring
Nobel Lecture
Nobel Lecture, December 12, 1901
Serum therapy in the form in
which it finds application in the treatment of diphtheria patients is an
antitoxic or detoxicating curative method. It is based on the view, held by
Löffler in
When the diphtheria poison is
rendered harmless within the human organism, then the diphtheria bacilli behave
like the innumerable micro-organisms which we absorb without suffering harm
every day and like those micro-organisms which correspond morphologically with
the diphtheria bacilli, but, from the outset, have no capacity to produce
poisons (pseudo-diphtheria bacilli). The poison excreted by the bacilli is the
diphtheria bacilli's dangerous weapon against the human being, without which
weapon they would be delivered over helplessly to the natural prophylactic
power of the living human organism.
The way in which the diphtheria
bacilli, after penetrating into the human body, release then poison and how
this poison develops its destructive activity has been the subject of many
interesting investigations, the result of which can be summed up briefly as
follows: In a typical clinical picture of diphtheria in human beings, as
summarized for the first time 80 years ago by the Frenchman Bretonneau, the diphtheria
bacilli are first localized in the pharyngeal amygdala, which, in all
probability, they reach principally via the breath, but also in substances
which we take in by way of nourishment. In the niches and small cavities of the
amygdala the diphtheria bacilli can multiply as though in an artificial
incubator and excrete their poisons. In animals, the organ, called
"amygdala" tonsils) on account of its shape (L. "amygdala"
= almond), is missing and this is probably the reason why epidemics of
diphtheria are the tragic privilege of human beings. The diphtheria poison gets
into the blood stream by way of the lymphatic vessels and starts up
inflammatory processes from there in the various organs. The inflammatory
symptoms are outwardly visible chiefly in the proximity of the site of
production, on the pharyngeal mucous membrane and in the larynx.
If we now introduce the
diphtheria serum as an antitoxin into the blood by injecting it under the skin,
this antitoxin will reach all parts of the body to which the blood has access.
If the injection takes place at a time when the diphtheria bacilli have not yet
begun their destructive activity, then the secondary inflammatory phenomena of
diphtheria toxicity will not arise. We speak then of immunization or of preventative
or prophylactic serum therapy. If, on the other hand, the toxic process has
already begun, then the already existing inflammatory processes will follow
their natural course, for the anti-toxin exerts no influence, either useful or
harmful, on the substrata of the inflammation, on the cells and organs.
In this case, all that can influence the already existing disease is firstly
to render harmless the poison which has already reached the body fluids, and secondly
to prevent the entry of fresh supplies of active poison into the blood stream.
It is easily understandable that the diphtheria serum has an abortive
action, but it is not the disease which is cut off but the creation of
new disease-engendering substances.
It will be seen from this how
important early use of diphtheria serum is. The longer one delays the
injection after the start of the illness, the more existing focal points of
inflammation and the more disturbances of vital functions will threaten health
and life.
In addition, a certain time must
elapse from the injection of the serum until its antitoxic and healing activity
in the affected parts of the body can develop. Also, serum injected under the
skin does not pass straight into the blood vessels but first into the lymphatic
vessels. From here it takes several hours before passing gradually into the
blood stream and further time still is needed before it is diffused, not only
everywhere in the blood stream, but also into the extra-vascular
poison-containing fluids. This interval between injection and detoxification
can mean the difference between life and death for the threatened individual
and I have asked myself whether, in the interest of the patient, this interval
could not be shortened. It can indeed be done if the serum is injected directly
into the blood stream instead of under the skin. According to experimental
investigations carried out by my erstwhile collaborators, Dr. Knorr and Dr.
Ransom, about 8 hours can be saved in this way. Furthermore, it is possible to
have a local effect on the poison-producing localities by using dilute serum
solution as a mouth wash to rinse the poisoned pharyngeal organs. So that we
may recognize the position which serum therapeutics have gained in the
treatment of diseases, as compared with other methods in medicine, I hope you
will allow me to use one or two technical terms, not only because these have,
during the course of time, come to embody a well-known and generally respected
concept, but also because these technical expressions, taken from Latin and
Greek, are more suited to international understanding than more modern
expressions which we might use in their place.
Since earliest times, in that
sphere of medicine which is responsible for the analysis of the symptoms of
disease, their cause and natural or artificially induced conquest, namely
pathology, humoral and solidistic pathologists have been in opposition to one
another. In the last century the solidistic pathologists won the upper hand and
the form which Virchow has given to the solidistic pathology by the foundation
of cellular pathology is now so firmly established that the old humoral
pathology can probably be regarded as having been finally laid to rest. With
the victory of solidistic pathology, however, there has now arrived,
pari passu, in the teaching hospitals a solidistic and cellular therapy
of which one cannot speak so highly as in the case of the cellular pathology.
In the treatment of wounds,
solidistic trend in therapy expressed itself more in salves, balsams,
alteratives, which were supposed to influence the diseased body elements in
ill-looking wounds to new and different activity. As you know, this aspect of
solidistic therapy has vanished from medicine since Lister, with epoch-making
success, laid down the principle, which he taught us to follow down to the
smallest detail: "Keep fingers away from wounds, leave the cells as much
as possible undisturbed, but take care that noxious agents from outside
are kept away from wounds and cells".
In internal medicine, however,
solidistic therapy remained "faute de mieux". New remedies were
constantly coming on to the market and into use in practice which were supposed
to curb, with anti-febrins, the vigorous activity of the cells aroused by
fever, encourage the will to live and alter the misdirected cell activity. I do
not need to quote instances when I maintain that we were all reared in the
solidistic- and cellular-therapy dogma according to which the morbid
manifestations of life are and must remain the subject of internal therapy. A glance
at any Government-sanctioned Pharmacopoeia will show that even now medicaments
are classified against a background of this viewpoint.
The detoxicating, or as it is
also called, the antitoxic serum therapy, is, on the other hand, humoral
therapy. Just as little as it has any direct influence on the diphtheria
bacilli, is it able to have any direct action, whatever, on the living body
elements of the patient who either has, or is threatened with, diphtheria. The
detoxicating process acts exclusively in the body fluids, in the blood,
in the lymphs and in the pericellular lymphatic areas. I must emphasize this
especially, because many authors take the view that the diphtheria anti-toxin
can also neutralize the poison which has penetrated into the body cells and
become established there. My own experience runs entirely contrary to such a
view.
Serum therapy in the treatment
of diphtheria is, therefore, humoral therapy in the strictest sense of the
word. It leads us back to the supposedly long-abandoned crasis theory which
attributed an important role in the development and overcoming of disease to
the peculiarities of the mixing of the substances solved in the body fluids. As
long as there is active diphtheria poison in the body fluids, then a dyscrasia
exists. After inactivation of the diphtheria poison, or in other words after
the detoxication of the body fluids by the addition of diphtheria antitoxin,
the dyscrasia is overcome; in its place appears, so to say, a eucrasia.
I do not object if someone tells me that the process of disease does not
consist in a faulty mixture of fluids, but in the abnormal functioning of
living body elements, the solids of the whole organism. In this sense, there
can, in fact, only be solidistic pathology or cellular pathology,
and never humoral pathology since, indeed the lifeless, inert body fluids
cannot be attacked by any 
or illness. In so far, however, as
the diseased function of the living body elements is, in the main, conditioned
by the incorrect mixture of body fluids, I find the linguistic inconsistency of
the use of the word humoral pathology no worse than if one speaks of pathological
anatomy, although the subject matter of this discipline concerns cadaver
anatomy and cannot really be attributed to
cadavers. However this may be, no one doubts any more of the existence of a
humoral therapy since antitoxic diphtheria therapy has found an assured
place for itself in medicine.
I must add another important
epithet to the word serum therapy in order to characterize its position
in medicine. It is aetiological therapy in contrast to the symptomatic
therapy just described. As in the case of the Lister treatment of localized
wound infections, serum therapy also, in the treatment of general infections,
holds to the principle "leave the cells in peace and simply take care that
noxious agents from outside are kept out, or, if they once get into the body,
are removed". The internal anti-infectious therapy would appear to have
the more difficult task, and as long as it was thought that anti-infectious
activity could only be carried out by killing the living disease germs, the
pessimists appeared to be justified in making the discouraging statement that
"internal disinfection would always remain impossible". If now
an internal disinfection has, nevertheless, been achieved, this is not thanks
to speculation or change of doctrine, but thanks to the fact that Nature
herself has been taken as a guide. I doubt whether it will ever be possible to
establish artificially the antitoxic principle of serum therapy in diphtheria,
without the aid of vital organization and secretion faculties. It is one of the
most wonderful things imaginable to see how the supply of poison becomes the
prerequisite for the appearance of the antidote in the poisoned living
organism, how then the antidote in the blood reaches a state of almost
unbelievable antitoxic energy through the systematic increase of the poison
supply, how the bearers of this energy, the albumins and globulins of the
blood, show no sign of any chemical change whatever, how the newly-won energy
is so elective that we have no other means of proving its existence than solely
by the diphtheria poison.
An attempt has been made to
make a comparison between the method of action of the antitoxic serum albumin
on the poison molecules with other compensating and inactivating processes. In
my first work, I myself used the non-prejudicial expression "rendering the
poison harmless", replacing it later, following Ehrlich*, with the better sounding expression "poison
destroying". But I gave up this expression as well when I realized that I
was being credited, on account of it, with the assumption that the poison
molecule would be, to a certain extent, demolished and so become non-poisonous.
I began then to speak of "neutralization", but right from the start I
secured myself against the opinion that the antitoxic and the toxic protein
combine in a way which resembles the formation of salts from acid and alkali.
Now I prefer to use the word "detoxication" which makes no reference
to the method of action. But if I want to indicate roughly how I imagine this
detoxicating process, then I speak of "inactivation". I imagine, in
fact, that, as regards chemical analysis, the antitoxic and the toxic protein
stay exactly the same after detoxication as before; what changes
is simply the activated condition; in the same way as the conductors of
positive and negative electricity, before and after compensation of their
active conditions, remain the same substances in terms of chemical analysis.
Perhaps, at some later date, work in the physico-chemical border territory
which you here see represented by such illustrious names as van't Hoff and Arrhenius will bring us to the point where we can refer to
active protein without the need of talking in parables!
With this example of antitoxic
diphtheria therapy, I have attempted to enumerate for you the chief
characteristics of serum therapy as a novum in therapeutics and as a
progressive step in medicine.
It is a humoral therapy,
because its activity develops only within the fluid and solved components of
the individual who is ill or threatened with illness. It has an anti-infectious
action brought about by internal disinfection, but is, in this respect, in
contrast to the anti-bacterial disinfectant treatment methods which, for
example, can be carried out in laboratory experiments with the aid of the R.
Pfeiffer's bacteriolysin; because its activity is only detoxication, we call it
antitoxic. Because it does not influence the substrata of the diseased
manifestations, the cells and organs, but only the cause of the disease,
I call it aetiological therapy, which comes to approximately the same thing as
the therapeutic endeavours which are referred to in other quarters as causal,
radical, abortive, etc.
Now I must speak on a special
subject in which serum therapy takes its place with those methods of combating
infectious diseases such as Jenner's smallpox vaccination, Pasteur's anthrax
prevention, Pasteur's hydrophobia treatment, and Koch's tuberculin therapy.
These kinds of treatment can be
indicated as isotherapeutic methods because they treat the infectious diseases
with media which are of the same kind as the disease-causing, infective
substances. Briefly expressed, serum therapy works through anti-bodies,
iso-therapy through iso-bodies.
You know that by treating horses
with an iso-body, the diphtheria poison, we obtain the curative anti-body. In
explaining the nature of isotherapy, I would like, however, to start with an
example where, for me, the isotherapy is not just a means to an end, but an end
in itself. This is the case in the experiments which I have been carrying out
for a number of years in
As you know, tuberculosis in
cattle is one of the most damaging infectious diseases to affect agriculture. It
causes premature death in affected animals, damages nutrition and milk
production and is the cause of inferior meat. Furthermore, it is feared as
being a carrier of tuberculosis to humans, although admittedly R. Koch recently
disputed this.
In different countries, or in
different regions of the same country, the disease does not always strike with
the same violence and frequency. Thanks to the support of Count Zedlitz, the
Lord-Lieutenant of Hesse-Nassau, I have been in a position to ascertain some
remarkable statistical facts in this connection. As a result of many thousands
of tuberculin inoculations in two areas of the
When making these observations,
attention was also paid to whether, in those areas which had been pointed out
to us by the authorities as being suspected breeding grounds for human
tuberculosis, an especially large number of cases of bovine tuberculosis was
present. But such a coincidence was definitely not found to exist.
One could feel inclined to use
this observation (which I passed on to the Lord-Lieutenant at the beginning of
this year in an official report) as corroborative evidence for the view
expressed by R. Koch that the tubercle bacilli are different in humans and in
cattle. My own observations, however, point more to the view that spontaneously
occurring cases of cattle tuberculosis are no more caused by passing contact
than is the case with humans, but that rather cohabitation of long duration is
required if infection leading to tuberculosis is to be passed from individual
to individual.
In my experience cattle are on
a relatively low susceptibility plane with regard to tuberculosis infection. In
a series of cases, I introduced tuberculosis virus, from pearl nodules
containing tubercle bacillus, under the skin direct from animal to animal,
achieving in this way nothing more than a local tuberculosis with extensive
proliferation of bacilli, which after existing for months completely
disappeared. After intravenous injection of the emulsified pearl nodules I
observed a general feverish condition lasting for weeks, but which also cleared
up spontaneously. Many of these spontaneously cured cattle I later infected
together with fresh control cattle in such a way that the latter died of acute
miliary tuberculosis in 4-6 weeks, whereas those which had recovered earlier
were quite healthy again after a short indisposition.
If there is to be any certainty
of cattle dying after a single, arbitrary infection with tuberculosis virus, it
is essential that consideration be given to the following main factors:
(1) origin and special composition of the virus;
(2) method of application;
(3) dosage.
I can confirm absolutely Koch's
statement that many tubercle-bacilli cultures of human origin are no more
dangerous to cattle than Arloing's homogeneous bacilli culture is to
guinea-pigs.
In my own experiments with
tubercle bacilli of human origin which were avirulent to cattle, cultures were
always used which had been cultivated for years in the laboratory. If, however,
I used human cultures for cattle infection which had only recently been
cultivated from tubercular sputum, they proved by no means unharmful. In the
same way, those human bacilli which had become avirulent to cattle through
long-continued culture in the laboratory can act again with considerable
virulence in cattle if they are first used to infect goats and then, after the
death of the animals, are cultivated from the carcases. I have a strain of
human-goat tubercle bacilli which, after culture, is probably the most virulent
of all to cattle.
There is more probability that
cattle-virulent cultures can be obtained without first being passed through
goats if the culture stock is obtained from the body of the cattle. Even
here, however, I have gained the impression that a long period of cultivation
on artificial nutrient medium curtails the disease-causing activity in cattle.
It is very noteworthy here that
one must certainly not conclude that the loss of disease-causing activity for
cattle necessarily means a decrease in virulence for other animals. The Pasteur
Anthrax studies establish, in fact, that there is a definite scale for
the decline in virulence. A weakened anthrax strain no longer fatal to mice is
not fatal to any other kind of animal either, and one which is virulent for rabbits
proves always extra virulent for guinea-pigs and mice. It would be very
surprising indeed and would strain credulity if anyone were to report an
anthrax strain which is virulent for rabbits, but not for mice and guinea-pigs.
There is a firm scale here in accordance with which all anthrax strains,
wherever and however they may be obtained, act with greater disease-causing
energy in mice than in guinea-pigs, and with greater energy in guinea-pigs than
in rabbits.
In the case of tuberculosis
things are different. I have studied with special care in this direction three
tubercle bacilli modifications: tubercle bacilli from human beings (Tb-Hu),
tubercle bacilli from cattle (Tb-Ca) and tubercle bacilli weakened according to
Arloing (Tb-Arl). Tb-Hu and Tb-Ca remain, with great obstinacy, virulent to
guinea-pigs and rabbits, but behave differently, in so far as Tb-Hu loses its
Ca-virulence more quickly than Tb-Ca. Tb-Arl are harmless to human beings; in
rabbits and horses, when injected intravenously, they cause severe illness
which can quite soon end in death with symptoms of pneumonia.
For my tuberculosis strains,
therefore, I have a quite different virulence scale, according to the kind of
animal which is being taken as standard. The reaction of horses is quite
exceptionally striking. In these animals the tubercle bacilli obtained from
cattle show the lowest degree of virulence.
As regards my methods, I test
the disease-causing energy in cattle in three ways: through infection from the
subcutaneous tissue, through intravenous injection of the emulsified
tuberculosis virus, and through intra-ocular infection. With my assistant, Dr.
Römer, I have found that intra-ocular infection is the most effective. I was
led to this method of infection by a study of the work of Professor Baumgarten
of Tübingen and I now use the intra-ocular infection method to determine the
degree of artificially achieved tuberculosis immunity in my cattle. Next I use
intravenous infection and lastly subcutaneous infection.
Even when using the tubercle
bacilli most virulent to cattle, the culture dose must not be too small
in the case of intravenous infection if it is required to cause an illness
severe enough to lead to the death of the animal. As an average dose for this
purpose, I take 0.04 g from a culture not more than 6 weeks old. The quantity
of bacilli contained in this dose corresponds approximately to 2 cm3
of tuberculosis bouillon culture. With intra-ocular infection, a much stronger
action is achieved with a much smaller quantity of bacilli. Here the
propagation rate in the eye itself is very considerable.
After observing several cases
of spontaneous recovery in tuberculosis-infected cattle, the thought occurred
to me that the tubercle-bacilli modifications which were only slightly active
in the case of cattle behaved in the same way as the vaccines to the
destructive virus. I then undertook an experiment aimed at systematically
rendering young cattle immune to tuberculosis with living tubercle bacilli. An
exact description of these immunization experiments, with detailed records and
temperature curves, will most probably follow in March of next year in my
"Beitrage zur experimentellen Therapie". At this point, I should like
to emphasize the following results: in the case of cattle, I forego the
subcutaneous preliminary treatment and use instead exclusively the intravenous
injection. As immunization vaccine I use a little Ca-virulent Tb-Hu (3267),
then go over to Tb-Ca (Nocard) and, finally, I use nothing stronger in the way
of tuberculosis virus than a goat-passage culture.
I have also made experiments
using an originally strong tuberculosis virus which has then been dried under
vacuum conditions at room temperature and left standing for a long time,
whereby its disease-causing potential is greatly reduced. Where pure cultures
on artificial nutrient media were concerned, I was not very satisfied with the
results; the experiments with dried pearl nodules and tubercular organs from
cattle turned out better.
If, on account of the
preliminary treatment, a cow became immune to Ca-virulent Tb-(cultures), then
there was also an immunity against Ca-virulent Tb-Hu (goat-passage) and vice
versa. This does not appear to confirm that Tb-Hu and Tb-Ca are different in
kind.
After my
I need hardly add that the
fight against cattle tuberculosis only marks a stage on the road which leads
finally to the effective protection of human beings against the disease. Here,
however, it has been my intention to report on facts, not hopes. And it is as a
fact that I think I am able to report the immunization of cattle against
tuberculosis to you.
*As far as I can
ascertain, the expression "poison destruction" appears for the first
time in the Abrin study by Ehrlich in the year 1891 (Deut. Med. Wochschr.
1891).
From Nobel Lectures, Physiology or Medicine 1901-1921,
Elsevier Publishing Company,
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