Mr President, Count Bernadotte, ladies and gentlemen.
I am extremely happy to be here this morning
and to tell you something about this fantastic new development known as the antibiotics.
This period, covering the last 3 decades, is known, will remain known in the history of medical science and medical application
as the golden age of chemotherapy.
Many people refer to it as the atomic age, the communications age;
I prefer, and fortunately many of my colleagues prefer, to call it the antibiotic age.
Because at no period previously in the history of the human race
have been such blessings conferred upon mankind as during the last 3 decades.
It all began about 1939/1940, when almost simultaneously there were announced 3 new substances isolated from bacteria,
one of which was discussed a few minutes ago by our eminent college under the name gramicidin S.
Actually, it was known as tyrothricin of which one of the components was gramicidin.
A second one was penicillin, which, although named and discovered 10 years before,
was actually proven to be effective in 1939/1940 at Oxford University.
And finally actinomycin, isolated from this group of actinomycetes in my laboratory.
It was known before that various groups of microorganisms are capable of producing substances.
And I want you to remember that the word antibiotic has been introduced only in 1941, also nearly 3 decades ago.
It was known under a variety of names, mostly as microbial toxins –
actually as far back as 1895, a precursor or a substance similar to penicillin was isolated from a green mould.
Numerous other observers, including Professor Gratia in Belgium, observed prior to Fleming
the ability of certain fungi to produce chemical substances, which have a growth-inhibiting
or even a destructive effect upon various microorganisms, including numerous pathogenic forms.
Bacteria products have also been isolated prior to tyrothricin.
Professor Ernst Pringsheim, working not far from here, demonstrated that certain bacteria,
especially spore-forming aerobic bacteria of the Bacillus mycoides-type, not very distant from Bacillus brevis,
are capable of producing substances that have an inhibiting effect upon various bacteria.
And even actinomycetes were shown capable of inhibiting the growth of various bacteria.
But again, I begin this period only in 1939/1940,
because we might call it the beginning of the antibiotic era because of those 3 discoveries.
Purification, actually the substances were purified
and their effect was tested on animals and in humans and found to be extremely important.
Now my own, as the Chairman so ably presented: I began to work as a soil microbiologist.
As you know microbes are concerned with the causation of disease.
Microbes used in industry are primarily effective in pure culture.
In the soil, however, as well as in sewage or on compost, manures, they are living in mixed populations.
In other words, there are millions upon millions of different kinds of microbes living side by side in these natural substrates.
And it was only logical to ask the question, how not only would these microbes ruin the soil,
not only how they affect plant growth and soil transformations, but especially how do they affect one another?
And in my own case, to my greatest surprise, I found that some of them have a greatly stimulating affect upon other microbes,
while others have a greatly injurious affect upon other microbes.
So much so that actually in January 1937 I published a comprehensive review
which I called 'Associated and antagonistic interrelationships among microbes'.
And it is very simple to prove that.
As Professor Fleming said time and again, if he had worked in a clean laboratory
perhaps he would never have observed a mould contaminating a plate, and producing a substance which he called penicillin.
In my own case, as many soil microbiologists do,
they dilute the soil sample to a very high dilution, 1 to a million, whereby isolated colonies appear on the plate.
But occasionally either I made a mistake or the assistant whom I asked to carry out the analysis made a mistake,
and instead of using a million dilution of soil, we used a thousand or 10,000 dilution.
And to my great surprise, while the plate was covered with numerous colonies,
some colonies existed at very sharp destructive affect - in other words inhibiting affect rather - upon others.
And therefore the question was first of all, how do they do it?
Why do they do it?
And what use can we make of this particular observation?
And further, another phenomenon must be emphasised here.
Since my very early work on soil microbes in 1915, I concentrated primarily upon one group that is known as the actinomycetes.
These are the so-called ray fungi.
The microbiologists refer to them as fungi as the very name indicates.
While the bacteriologists call them higher bacteria.
Really to clear up that point: at the present time they are classified among the bacteria,
but as a very special group of higher bacteria.
And while it was known that they occur in large numbers in the soil, they were all given one generic name: actinomyces.
Actually, all the names to this group of organisms were given right here in Germany.
Professor Ferdinand Cohn at Bratislava University called them in 1872 streptothrix;
and Professor Harz in Berlin called it in 1879 actinomyces.
These 2 names are very important from the point of view of the naming, of the nomenclature of these antibiotics.
It is therefore quite understandable why I should have concentrated upon the antibiotics of this group of organisms,
and it is fortunate that I did so, because while the bacteria have contributed a large number of antibiotics,
only 2 or 3 of them have found practical application.
I need only mention tyrothricin, bacitracin and polymyxin.
There are 1 or 2 others that I used occasionally.
The fungi, who originally made such a tremendous impression because of the discovery of their ability to produce penicillin,
have also contributed for practical use only 4 or 5 compounds, such as griseofulvin, such as cephalosporin and 1 or 2 others.
But it is the actinomycetes that have contributed the greatest number of antibiotics,
and the greatest number of which have found practical application.
While at the beginning of the period that I am speaking of there were hardly any antibiotics used for practical purposes –
I mean if a person financially inclined would have enumerated what we call now antibiotics,
the sales throughout the world would not have amounted to more than a few hundred dollars;
while at the present time we can actually calculate it in terms of billions of dollars of production a year throughout the world.
And among these antibiotics the actinomycetes:
probably more than a thousand compounds of preparations have been isolated since 1939 from this group of organisms.
And practically 80, between 50 and 80 depending upon the particular use, are now used
for practical control of infectious diseases of man, animals and plants.
Some of them have found other applications which I will not dwell upon this morning,
such as preservation of food stuffs, such as feeding of certain animals and so on.
The important thing is to remember that first of all these antibiotics are now produced in such a scale
that nobody would have ever dreamt of.
I just want to remind you that again it was in this country that Paul Ehrlich isolated Salvarsan –
not very long ago as history goes, but as far as the chemotherapy a long time ago.
And Ehrlich himself prophesied that it will not take very long before chemical compounds will be found,
that will do for bacterial infections what Salvarsan did for syphilis.
But it took a quarter of a century before Domagk, again in this country, demonstrated the capacity of these sulpha drugs
to inhibit bacterial growth - not only in the test tube but also in the living animal.
Again, it seemed that only chemical industry will contribute these lifesaving drugs,
but to the greatest astonishment, primarily of the chemical profession came to antibiotics.
And the story is told that when - and I hope you will forgive me: I do not have any particular inclination to draw reflection
upon any particular group, but the story must be told here that when the German soldiers in the African corps,
in North Africa found among the dead American soldiers packages of penicillin,
and they were told that these chemical substances were isolated from mould cultures, they said this is another American bluff.
But fortunately this bluff turned out a great saving of the human race.
As I said, I began early observations since my early work on the actinomycetes, beginning in 1915.
But it was in 1939 that I began to concentrate upon the actual isolation of these chemical compounds
from various cultures of actinomycetes.
And the first culture that we isolated in 1940, in a pure crystalline state, we called actinomycin.
And this substance alone is worth a great story - an extensive discussion for which I have no time.
Later, if I do, I will mention it again.
But actinomycin proved to be so extremely toxic that it would kill the animals which were treated with it
as quickly as it would kill the bacteria that were infecting the animal.
And therefore, after a certain amount of experimentation,
we came to the conclusion that from a chemotherapeutic point of view it offers no promise whatsoever, and we put it aside.
Now remember the word 'actinomycin' was derived from Harz’s first word 'actinomyces' that he attached to this group of organisms.
Then 2 years later, between 1940 and ’42, penicillin became a reality.
It’s important to remember the historical dates.
And therefore I saw that the important substances that we are trying to isolate
should have an activity which is not possessed by penicillin.
And since penicillin was primarily active against gram-positive bacteria and certain gram-negative cocci,
we concentrated, in my laboratory, upon the isolation of substances that would be active against gram-negative bacteria.
And within 2 years we isolated streptothricin.
Now first, the name, as you will recognise, was derived from Ferdinand Cohn’s first name streptothrix;
and it was logical that we should use for our second antibiotic the second name given to a member of the group of these organisms.
But streptothricin - and I must assure you that streptothricin was the precursor of streptomycin.
If it had not been for the isolation 6 months later of streptomycin,
streptothricin would have been a therapeutic drug at the present time.
Streptothricin had all the desirable properties of a therapeutic agent: it was water-soluble; it was active; it was heat-stable;
it was active on a wide range of bacteria, both among gram-positive and among gram-negative bacteria.
We could save various experimental animals infected with a variety of pathogenic bacteria,
but unfortunately the animals that we saved by the use of streptothricin began to die off a week or 2 later.
In other words it possessed not as strong a toxicity as actinomycin,
but it possessed a delayed toxicity which certainly had to be taken into immediate consideration.
And streptothricin, in spite of its great desirability –
we knew already at that time that it does not represent an isolated type of compound,
but the various actinomyces had the capacity to produce all types of compounds similar,
and some of them which might be better than streptothricin.
All our methods were developed in the study of streptothricin.
And within 6 months we isolated streptomycin which, although it possessed very similar properties to streptothricin,
still had much less toxicity than streptothricin and therefore became much more desirable.
And merely to distract you for a minute: you may have heard of the expression or the word 'screening programmes'.
There have been 2 approaches in the study of these antibiotics.
On the one hand the cursory observation, similar to the one of Fleming and Gratia and others, who observed a culture of a mould
or a bacterium that had a destructive affect upon our growth, inhibiting affect upon other microorganisms.
On the other hand there was - and this was the system that I followed and perhaps even helped to develop –
the systematic search for chemical substances produced by different microorganisms
that have the capacity of inhibiting the growth of others, which we called antibiotics.
And now this screening programme, namely the testing of numerous organisms - systematically, of course.
Because we did not have to actually isolate them, we developed techniques that gave us, in a preliminary fashion,
what organisms are desirable and which ones are not desirable.
But this system was immediately followed in thousands of laboratories throughout the world,
and of particular importance the industrial laboratories which I will mention in a minute.
You might say that ontogeny repeats phylogeny.
And namely in most of these screening programmes, the first substance that had been usually isolated in various laboratories –
not my laboratory, that was in the United States or in Great Britain or in the Soviet Union –
was actinomycin; and the second one was streptothricin.
And the third one might have been streptomycin or might have been something else.
As a matter of fact, actinomycin at the present time... perhaps a word about actinomycin:
As I said, because it has a tremendous importance at the present time,
actinomycin which has a tremendous activity upon numerous bacteria, but it also possesses a very high toxicity.
But we observed: because within 2 or 3 years after we found many antibiotics active upon bacteria,
immediately the idea occurred, how about viruses?
And we started to apply the screening programme to viruses.
And we failed miserably, as I will explain in a few minutes later why.
But the only type of compound that we found had some definite activity was a form of actinomycin;
we called that form, our actinomycin, actinomycin A.
Within 5 or 6 years an industrial laboratory in our own state of New Jersey,
Hoffmann La Roche, isolated another form of actinomycin that they called B.
But again: there was no excitement; there was no hope; there was nothing to follow.
Until 6 years later, right here again in Germany, our old friend Domagk whom we miss here today –
although I had the great pleasure of being with him at this meeting 6 years ago –
Domagk and his colleagues isolated a new form of actinomycin, which they called actinomycin C.
And upon superficial, I am sorry to say, study, they claimed or they believed
that it possesses a great effectiveness upon a certain form of cancer, known as Hodgkin’s disease.
And they published quite a group of papers, that actinomycin C is active upon Hodgkin’s disease.
I received those papers early in 1953 at the time of the Microbiological Congress in Rome.
I happened to be the chairman of a session on actinomyces, and in my presidential address I said
that the story of these antibiotics has not come to an end,
that there are tremendous potentialities, and that was the effectiveness upon cancer.
And I illustrated that with the work of the Domagk group.
And to my great misfortune there was a reporter in the audience who understood only one word of what I said
and that word was 'cancer'.
And since I received the Nobel Prize a year earlier, it came out at a large announcement in the front pages
of all the newspapers of the world: Nobel Prize winner announces a cure for cancer - and I can assure you that I had hell to pay.
I would receive telegrams; I can just cite to you from one of the Kings of Africa
who said he is prepared to come with his daughter who suffers from Hodgkin’s disease,
that I should treat her, and I can have every Arab horse that has ever found a practical use - and stories of that nature.
But the most interesting thing was when I came home.
Within a day I received a telephone call from a very wealthy American industrialist.
And he said, what do I hear, that you discovered a cure for Hodgkin’s disease?
I said, oh that’s a lot of nonsense.
First of all I didn’t discover it.
They’re a group there and bias indicate that claim to have that effect.
And if you wanted, go and contact with them.
No, no, no he said, I want you.
What do you say about it?
I said, we don’t know, we have to study it further.
And he said, do you need any money to enlarge your activities?
I said, I could use some (laughter); even a Nobel Prize winner does not have all the money at his disposal for research.
And he said, and I mentioned quite a substantial sum, he said very well, next week you shall get the cheque.
And I got it next week.
And we immediately initiated a programme in search for - by that time we knew that there are numerous forms of actinomycin;
as a matter of fact one of the most brilliant chemists in this country, Professor Brockmann at Göttingen,
actually separated these actinomycin into dozens and dozens of different forms
for which he used every letter of the Greek alphabet and every number of both the Arab and the Roman numerals.
Then we initiated that programme.
What we were looking for was for a form of actinomycin that might be less toxic than our original form A.
And secondly, particularly because of Brockmann's difficulties in separating the actinomycin,
which is a mixture of different chemical identities, a single form.
And within a year we succeeded in isolating such a compound; and logically we called it actinomycin D.
And by a sheer stroke of luck it was found that this actinomycin D actually has an effect upon certain forms of cancer,
but unfortunately not the very common ones, such as Wilms cancer or kidney cancer in children;
such as a certain form of throat cancer known as rhabdosarcoma.
But much more important than that, actinomycin, and especially the D form, has become in recent years
one of the greatest biochemical tools that have been introduced into the laboratory in recent years.
It actually - if I may say so in spite of any molecular so-called biologists that may be in this room –
it helped to solve the riddle, the genetic code of the DNA/RNA transformation;
and it is being used at the present time in numerous laboratories in such studies.
Now, as I said, to come back to streptomycin.
Streptomycin was not necessarily an ideal drug.
As the chairman said, it has eliminated numerous infectious diseases.
Practically every infectious disease afflicting the human race - I am speaking of the infectious disease,
incidentally exclusive of the viruses, to which I will come in a minute - can be controlled in a more or less definite fashion;
and notably with tuberculosis streptomycin played such an important role.
So much so - perhaps a story or 2 here might be in place.
When I dedicated the first streptomycin plant built in India, outside of Bombay, I had the good fortune
of addressing a large audience, side by side with Mister Nehru – at that time the premier, the great premier of India.
And Mister Nehru said to me, why will you bring us such drugs?
We have too many people.
You bring us drugs to save many upon whose deaths we counted to keep our population under control.
I said to him, Mister Nehru, that is your problem.
My problem is to help save the lives that are already in this world.
And, of course, he had nothing further to add;
and I am sure that they will solve it sociologically rather than prevent the progress of medicine.
Streptomycin had certain limitations: on the one hand it possessed a certain limited toxicity on hearing ototoxicity,
and under motion, the motion control by the nervous system, rather the 8th nerve effect; and the second limitation was
that since, in the case of tuberculosis particularly, it had to be used for a long time in order to control the disease,
it gave every opportunity to the mycobacterium tuberculosis to develop resistance.
And many people felt so unhappy about these 2 phenomena,
that they thought that before very long tuberculosis will come back again to where it was before.
Fortunately, and I said that time and again, streptomycin was the first drug that was shown to be effective against tuberculosis –
not only against the organism in the test tube but also against infection in the animal and in humans.
Certainly it could not be the last one, and it certainly could not be the best one.
And fortunately before very long, Professor Lehmann from Gothenburg in Sweden demonstrated, established
that a certain chemical synthetic compound, para-aminosalicylic acid, taken by mouth - streptomycin had to be injected - by mouth
will have a destructive effect upon tuberculosis.
And by combining streptomycin with PAS, para-aminosalicylic acid, not only were you able to reduce the toxicity of streptomycin
or the amount that was required; but by distributing the dose at lesser frequency,
you were able to reduce greatly the toxic effect.
And more fortunate - and here comes another story:
In 1952 - within 2 weeks, perhaps a week after I received the Nobel Prize in Sweden –
I had to fulfil another engagement which was around the world, on the other side, and that was in Tokyo.
Since I undertook 6 months earlier to deliver a series of important addresses in that country,
and the Nobel Prize ceremonies finished on the 10th of December - as you well remember.
On the 13th of December I had to deliver my general address, and on the 14th I had a plane that took us directly to Tokyo.
It took 52 hours in one plane.
It brought us there to fulfil our earlier engagement.
I was invited by the Emperor of Japan to come and pay him a visit.
He was very gracious.
He asked me a series of questions, and one of the questions - it’s very important historically here.
He said, when the war broke out, we had in Japan every year 300 deaths from tuberculosis,
annually 300 deaths from tuberculosis, in 1940/41.
Last year, which was 1952, and I was speaking to him at the end of January ’52 – I mean the end of December ’52
or early in January, I believe it was early in January ’53; we stayed in Japan about a month.
And he said, last year, which was ‘51/’52, the deaths from tuberculosis fell to 90 out of 300 that we used to have before.
And we'd like to ascribe that reduction to the use of streptomycin.
But the question, he said, I want to ask you, what fate do these 90 have?
Do they have any hope of surviving?
And I said to him, you must remember that Streptomycin was the first drug and, as I said a minute ago,
you can hardly think that it will be the only one.
Others will forthcome which might even replace it and certainly may combine with it.
And as I was talking with him, isoniazid, the third great important anti-tuberculosis drug,
was being discovered in the United States and elsewhere.
And I was very happy to read another 10 years later that the mortality in Japan from tuberculosis
went down to less than 30 a year.
So that at the present time, as the chairman said, tuberculosis is practically under complete control.
I need not go into this subject further.
But before I leave, I want to discuss, because I am asked very frequently, how about virus diseases?
How about cancer diseases?
Can antibiotics or do antibiotics offer any hope for their control?
And you must remember that we are dealing in the case of these 2 groups of diseases
in a totally different fashion from infectious diseases caused by microbial systems.
In the case of, let us say, typhoid or pneumonia or tuberculosis,
we deal with a microbe that grows, that metabolises, that multiplies.
In the case of viruses they do not grow, they do not metabolise, they do not multiply per se - I said multiple, I mean: divide.
In other words they are nothing but chemical agents that stimulate the cell to produce substances like them.
And therefore any... the time does not permit me to discuss the mode of action of these antibiotics.
Because that is extremely important to know: how do they act upon these sensitive bacteria?
Some affect the growth; others affect their metabolism; still others affect their multiplication in one form or another.
Since the viruses do not have these properties, the antibiotics will automatically not act upon viruses.
And I can assure you that as soon as we recognise the importance of streptomycin,
as soon as we receive the first funds to enlarge upon our work –
we built a special building for the study of viruses, of which I knew very little.
But we obtained the help of virologists and other experts in the field, and we immediately attacked the problem.
And I can assure you that on my part it was the greatest waste of time and money, because we accomplished practically nothing.
And the same is true for virus research, I mean for anti-viral, the search for anti-viral agents throughout the world.
Although at the present time there are known compounds that may affect viruses in tissue culture and in the test tube,
but not in the human or animal body.
Fortunately for cancer phenomena or neoplastic diseases, the situation is not as bad.
Because in the case of neoplastic diseases, where we have certain cells get out of control
and begin to multiply independent of the control of the human or animal body, we can affect the rate of growth of these cells.
And therefore substances have been found and at the present moment quite a few of them –
as I said beginning with actinomycin and ending with a number of compounds that have been isolated primarily in Japan, sacromycin.
I suppose one of you who has recently read or heard about this compound Rifampicin,
or the derivative of rifamycin, a typical antibiotic, that there might be certain chemical derivatives of some antibiotics.
And incidentally I hardly mentioned the fact that in the case of antibiotics, numerous attempts have been made
to modify them chemically, possibly in the hope to change their activity.
As you know no doubt, that penicillin has made tremendous progress in this direction only in very recent years.
Where they have found the so-called semi-synthetic penicillins.
The natural penicillin, that means the penicillin produced by the microbe, can be split by an enzyme
and then rebuilt by adding other chemical compounds.
And these semi-synthetic penicillins prove to enlarge greatly the effectiveness of the penicillin group of compounds.
Unfortunately, in the case of streptomycin that proved to be impossible.
Although originally a compound called dihydrostreptomycin was prepared from streptomycin synthetically,
that compound proved to have no more desirable properties than streptomycin itself.
On the other hand, there are numerous other antibiotics that have been isolated after streptomycin –
notably the chloramphenicol first of all and then the tetracyclins, and then numerous others,
as I have mentioned, rifamycin and so on - which lend themselves to chemical modifications.
There are dozens of tetracyclines at the present time, both in the laboratory and in practical use.
And in the case of chloramphenicol we have the active and the inactive form;
so much so that that is practically the only antibiotic now that is produced synthetically.
So while it is still an antibiotic, because originally it was isolated from a culture of a microbe,
at the present time it is largely produced synthetically.
Therefore our hope is great.
And the first compound that uncovers the potentialities of some of these microbial products that we call antibiotics,
perhaps their names will be different, and prove to be effective against viruses or against neoplasms,
the whole field will open up tremendously.
Now, I’ve been asked time and again, where do the antibiotics stand at the present moment?
If I had the time to examine to you the progress of these compounds and their practical use,
I would draw you a chart with several levelling-off periods;
and unfortunately one of the levelling-off periods came from a compound, isolated again in this country, and that was thalidomide.
The discovery of thalidomide and its use everywhere, especially in the United States,
rendered a terrific blow to the further search for new antibiotics.
I need not dwell upon that in detail; I am sure that most of you are familiar with that.
And at the present time, in the United States particularly, because of the toxic effects of certain antibiotics,
especially Chloramphenicol again, in certain orders, there is the government or the Food and Drug Administration
of the Health Service in the United States has become extremely demanding upon the chemical industry or antibiotic industry
for the practical evaluation before introducing them or allowing their introduction into practical use.
Just one illustration: for example when streptomycin was discovered
and when its potentialities against gram-negative bacteria was demonstrated,
the logical question was in the case of mixed infections, why not use penicillin and streptomycin?
And as a result of that there have been introduced numerous combinations,
only the first of which I think was called combiotic - that means a combination of antibiotics.
And it has been used since probably ’44, ’45 until this year.
But now even this old combination is being questioned by the government agencies.
Because they say, the best use of this combination is in the case of certain mixed infections of the ... (inaudible 42.16) tract,
endocarditis particularly.
But in the case of endocarditis you have to use a large dose of penicillin.
And if you use combiotic you are thereby introducing a large quantity of streptomycin,
which is more than necessary and which actually may prove to be toxic to the body.
And therefore: why not use individual antibiotics and then combine them in different concentrations as they are required?
But, unfortunately, the doctor, the practitioner does not have a very extensive laboratory at his disposal
that could answer his questions.
I have a culture and you find out for me how much penicillin, how much streptomycin, how many other drugs I’ve got to use.
Sometimes he has to act immediately.
And therefore this combination of antibiotics are lifesaving to him; and I am sure they saved many lives.
And therefore the question is, what is going to happen now?
And the result is that in very recent years only very few new antibiotics.
And therefore the question, have we reached the end of antibiotic development
or have we isolated enough compounds to take care of all our needs?
Well, only time will tell.
Thank you.
Applause.