Mr. President, Count Bernadotte, ladies and gentlemen, I'm 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 three 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, as the communications age. I prefer, and fortunately many of my colleagues prefer to call it the antibiotic age, because

that no period previously in the history of the human race have been such blessings conferred upon mankind as during the last three decades. The war began about 1939, 1940, when almost simultaneously there were announced three

new substances isolated from bacteria, one of which was discussed a few minutes ago by an eminent colleague under the name Gramicidin S. Actually, it was known as tyrotricin,

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 three 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 mold. Numerous other observers, including Professor Grazia 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. Bacterial products have also been isolated prior to tyrotricin.

Professor Ernest Springstein, working not far from here, demonstrated that certain bacteria, especially spore-forming aerobic bacteria of the bacillus microlithis type, not very

far 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 three discoveries. Purification, actually the substances were purified and their effect was tested in animals

and in humans and found to be extremely important. Now my own, as the chairman, Sir Ably, presented, I began to work as a soil microbiologist. As you know, microbes concerned with the causation of disease, microbes used in industry

are primarily affected in pure culture. In the soil, however, as well as in sewage or on compost of 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 were these microbes do in 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 effect upon other microbes, while others have a greatly injurious effect

upon other microbes. So much so that in 19, 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 mold 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, one 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 dilutions of soil, we used a thousand or 10,000 dilutions. And to my great surprise, while the plate was covered with numerous colonies, some colonies exerted a very sharp destructive effect, in other words, inhibiting effect, 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 emphasized 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 array fungi. The mycologists refer to them as fungi, as the very name indicates, while the bacteriologists

call them hyobacteria. Nearly to clear up that point, at the present time they are classified among the bacteria, but as a very special group of hyobacteria. And while it was known that they occur in large numbers in the soil, they were all

given one generic name, actinomycetes. Actually, the oldest two names to this group of organisms were given right here in Germany. Professor Ferdinand Korn at Wresslauer University called them in 1872, streptotrix, and Professor

Haas and Berlin called it in 1879, actinomycetes. And these two names are very important from the point of view of the naming, of the nomenclature of these antibiotics. And it is therefore quite understandable why I should have concentrated upon the antibiotics

of this group of organisms. And it is fortunately that I did so. Because while the bacteria have contributed a large number of antibiotics, only two or three of them have found practical application.

I need only mention tyrotricin, bacitracin, and palimixin, other one or two others that are used occasionally. The fungi originally made such a tremendous impression because of the discovery of their ability to produce penicillin, have also contributed for practical use only four

or five compounds, such as griseofulvin, such as cephalosporin, and one or two 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 I'm 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,

their sale to other 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 millions of dollars of production a year throughout the world. And among these antibiotics, the actinomycetes probably moved in a thousand compounds

of preparation that 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 foodstuffs, such as feeding of certain animals, and so on.

The important thing is to remember that, first of all, that 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 Erlich, Paul Erlich, isolated Salvar San, not very long ago, as history goes, but as far as the chemotherapy, a long time ago.

And Erlich himself prophesied that it will not take very long before chemical compounds will be found that will do for bacterial infections what Salvar San did for syphilis. But it took a quarter of a century before Dormac, again in this country,

demonstrated the capacity of these sulfur 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 life-saving drugs,

but to the greatest astonishment primarily of the chemical profession came the antibiotics. And the story is told that when, and I hope you will forgive me, I do not have any particular inclination to throw reflection upon any particular group,

but the story must be told here that when the German soldiers in the African core in North Africa found among the dead American soldiers packages of penicillin, and they were told that these chemical substances

were isolated from mold 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 earlier 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 and 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 was 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 chemo-therapeutic point of view, it offers no promise whatsoever, and we put it aside. Now remember, the word actinomycin was derived from Hartz's first word,

actinomyces, that he attached to this group of organisms. Then two years later, between 1940 and 1942, 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 Hawkeye, we concentrated in my laboratory upon the isolation of substances

that would be active against gram-negative bacteria. And within two years, we isolated streptotrycin. Now first the name, as you will recognize, was derived from Ferdinand Kohn's first name, streptotrix, 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 streptotrycin, and I can most assure you that streptotrycin was the precursor of streptomycin. If it had not been for the isolation six months later of streptomycin,

streptotrycin would have been a therapeutic drug at the present time. Streptotrycin had all the desirable properties of a therapeutic agent. It was water-soluble, it was active, it was heat-stable, it was active in 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 streptotrycin

began to die off a week or two 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 streptotrycin, 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 actinomycetes had the capacity to produce all types of compounds similar,

and some of them which might be better than streptotrycin. All our methods were developed in the study of streptotrycin. And within six months, the isolated streptomycin, which although possessed very similar properties to streptotrycin, still it had much less toxicity than streptotrycin,

and therefore it became much more desirable. And merely to distract you for a minute, you may have heard of the expression of the word screening programs. There have been two approaches in the study of these antibiotics.

On the one hand, the cursory observation, similar to the one of Fleming and Grazia and others, who observed a culture of a mold or bacterium that had a destructive effect upon,

or a growth inhibiting effect 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 program, 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 and thousands of laboratories throughout the world, and of particular importance, the industrial laboratories,

which I will mention in a minute. And you might say that ontogeny repeats phylogeny. And namely, in most of these screening programs, the first substance that had been usually isolated in various laboratories, no matter whether it was in the United States or in Great Britain

or in the Soviet Union, was actinomycin. And the second one was streptomycin. 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 two or three years

after we found many antibiotics active upon bacteria, immediately the idea occurred, how about viruses? And we started to apply the screening program 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 the form of actinomycin. We call that form, ouractinomycin, actinomycin A. Within five or six years, an industrial laboratory

in our own state of New Jersey, Hafmalaros, isolated another form of actinomycin, what they called B. But again, there was no excitement, there was no hope, there was nothing to follow. Until six years later, right here again in Germany, our old friend Domach, whom we miss here today,

although I had the great pleasure of being with him at this meeting six years ago, Domach and his colleagues isolated a new form of actinomycin, which they called actinomycin C. And upon superficial, I'm 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.

And I received those papers early in 1953 at the time of the microbiological congress in Rome. And I happened to be the chairman of a session on actinomycin. And in my presidential address, I said that the story of these antibiotics

has not come to an end. There are tremendous potentialities, and that is their effectiveness upon cancer. And I illustrated that with the work of the Domach 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, we came out with 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's 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 practical use and stories of that nature. But the most interesting thing was when I came home, in 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. There are a group there and buyers syndicated that claim to have that effect, and if you wanted, go in contact with them.

No, no, no, he said, I want you. What do you say about it? I say, 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. See, 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 a check. And I got it next week. And we immediately initiated a program 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 Brotman at Grittingen, 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.

When we initiated that program, what we were looking for is for a form of actinomycin that might be less toxic than our original form, A, and secondly, particularly because of Brotman'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 shield struck a flock. 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 rhabdasachcoma. 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, that 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 and 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, to work the losses, the streptomycin played such an important role.

So much so, perhaps a story or two here might be in place when I dedicated the first streptomycin plant built in India outside of Bombay. I had the fortune of addressing a large audience side by side with Mr. Nehru.

At that time, the great premier of India. Mr. Nehru said to me, why do you bring us such drugs? We have too many people. You bring us drugs to save many upon whose death we counted to keep our population under control. I said to him, Mr. Nehru, that is your problem.

My problem is to help save the lives that are already on this world. And of course, he had nothing further to add, and I'm sure that they will solve it sociologically, rather to prevent the progress of medicine.

Now, streptomycin had certain limitations. On the one hand, it possessed a certain limited toxicity. And hearing, auto-toxicity, and under motion, the motion controlled by the nervous system,

or rather the eighth nerve effect. And 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 bacterium, to the bacterium tuberculosis,

mycobacterium tuberculosis, to develop resistance. And many people felt so unhappy about these two 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 the infection in the animal and in humans. And certainly it could not be the last one. And it certainly could not be the best one.

And very fortunately, before very long, Professor Lohman from Gotterberg in Sweden demonstrated, established that a certain chemical synthetic compound, pyraminocellulosilic acid, taken by mouth,

streptomycin had to be injected, by mouth will have a destructive effect upon tuberculosis. And by combining streptomycin with PAS, pyraminocellulosilic 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, soon within two weeks,

perhaps a week after I received the Nobel Prize in Sweden, I had to fulfill another engagement, which was around the world on the other side, and that was in Tokyo. Since I undertook six 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, and 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, and it took 52 hours and one plane,

which brought us there to fulfill our earlier engagement. And 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 is very important historical 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 December 1952,

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 he liked 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, other self, 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 masked very frequently,

how about virus diseases? How about cancer diseases? Do kin antibiotics or do antibiotics offer any hope for their control? And you must remember that we are dealing in the case of these two groups of diseases in a totally different fashion

from infectious diseases called by microbial systems. In the case of, let us say, typhoid or pneumonia or tuberculosis, we deal with a microbe that grows, that metabolizes, that multiplies.

In the case of viruses, they do not grow. They do not metabolize. They do not multiply per se. When I mean multiply, I mean the white. In other words, there are nothing but chemical agents that stimulate the cell to produce substances like them.

And therefore, any end I have, 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. Now, 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 recognize

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 their problem. And I can assure you that on my part, that was the greatest waste of time and money, because we accomplished practically nothing. And the same is true for virus research, I mean for antiviral, the search for antiviral agents throughout the world.

Although at the present time, there are known compounds that may affect viruses in tissue culture and the test tube, but not in the human or animal body. Now, 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, saccharomycin, and I suppose one of you who has recently read

or heard about this compound, what is it called, rifampicin, or the derivative of rifamycin, a typical antibiotic, that there might be certain chemical derivatives

of some antibiotics, and incidentally, I hardly mention 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 penicillin, 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 penicillin 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 tetracyclines, 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 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 have 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 owe you a chart with several leveling-off periods. And unfortunately, one of the leveling-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'm 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, and certain others, there is the government or the Food and Dog Administration

of the Health Service in the United States has become extremely demanding upon the chemical industry or antibiotic industry for their 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. 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 peritoneal tract and the carditis, and the carditis particularly.

But in the case of endocarditis, you have to use a great 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. Here I have a culture, and you find out for me

how much penicillin, how much streptomycin, how much other drugs I've got to use. Sometimes he has to act immediately. And therefore, these combinations of antibiotics were life-saving to him, and I'm 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 knew 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.