William C. Campbell - Nobel Lecture: Ivermectin: A reflection on simplicity

Williams Campo received a BA from Trinity College University of Dublin in Ireland 1952 and a PhD from University of Wisconsin Madison Wisconsin in the United States in 1957 it was with the Merck Institute for therapeutic research from 1957 and in 1984 he became the senior scientist and director for sa research and development Kapil is currently a research fellow emeritus Drew University Madison New Year's Eve USA please join me in welcoming dr. Campbell who will present his Nobel lecture under the title either macton a reflection on simplicity your excellencies ladies and gentlemen you see from my title I intend to talk about simplicity simplicity in the context of science and in talking about simplicity I do not mean to suggest that science itself is simple nor will I suggest that the discovery and development of the drug ivermectin was an exercise in simplicity I want rather to call attention to the element of simplicity within science and I want to do that by pointing out the prominence of simplicity in the genesis of ivermectin it has of course long been acknowledged and recognized that simplicity has an intrinsic appeal to scientists as it does to others and indeed simplicity is widely celebrated in science as a matter of beauty but I want to talk about simplicity not as a matter of beauty but as a matter of practical utility consider a real-life actual event on a particular day the 9th of May 1975 there was a mouse in a mouse box in a laboratory it had been purposely infected with worms but not enough to cause illness and on that particular day the mouse's diet was altered it was altered by having some liquid stirred into its regular food and it ate that food for almost a week and then this regular diet was restored and almost a week after that its worms were gone the mouse had been cured of its warming and from that moment there was a train of events set in motion that would lead to an advance in medicine both human medicine and veterinary medicine and that advanced in the basic science would in turn lead to practical changes in the management of diseases so to a very large extent the drug ivermectin was brought about by simple science it is not conventional science it was not obvious science but it was simple science I I want to make a slight digression here in relation to another question I have often been asked in recent weeks how it felt when I heard that I had won the prize and I can say without hesitation that my mind was instantly flooded with two emotions one of the motion of joy and gratitude and the other emotion one of sadness and the sadness because I knew instantly that all the people who contributed to this drug and made it a success could not be named individually and so I am a representative of the American company research team and in that capacity I am grateful and honored beyond imagining so what was in that liquid that was added to the regular food of that Mouse on the 9th of May it was a liquid in which a microbe a bacterium had been allowed to multiply breaking down the surrounding nutrients and producing all kinds of byproducts metabolites of various kinds in other words the liquids added to the diet had been fermented by a bacterium and that bacterium had been isolated and sent murk and company and by dr. Satoshi amaura whom you have just heard and who shares with me the prize that has brought us here together today and many years later I had the pleasure of visiting him in Tokyo microbes do not all look alike or actual like but the carousel of Institute and Merck both of them were interested in finding microbes that stand out from the crowd microbiologist get tired of finding microorganisms that have already been found professor emeritus microbes that were unfamiliar in general to microbiologists and we found that one of those unfamiliar microbes produced an unfamiliar substance and that that substance had very potent activity against worm parasites and also against some other parasites but that is a story for another time is the mouse that I mentioned was a single mouse I do not mean that the mouse was unmarried I mean I mean only that that that special diet had been tested in only one month usually things are tested in groups of mice experimental groups but that was tested in just one single Mouse other individual mice got other diets altered by other liquids in which other bacteria had flourished but only one Mouse only one of those liquids ended in the cure of worms excuse me for moments but that test method which might strike you as unusual was developed in the parasitology department of american company by dr. john egerton and that is also in the same department dr. dan Ostend had pioneered the reduction of experimental group size to a singleton simplicity in the history of ivermectin was just a beginning from then on there was complexity many years of basic complex research and many years of complex developmental research pharmaceutical development is the epitome not of simplicity but of complexity and many scientists and many disciplines were involved in the development of this drug and I will mention perhaps one or two perhaps biased towards personal logical matters but I will have I trust in the written written version of this talk opportunities to acknowledge my colleagues and family and friends more generously many things were going on at once at this time the microbiologist microbiologist to describe the bacterium as a new species of streptomyces the fermentation chemists and biologists isolated the mystery substance that killed worms and they persuaded the microorganism to puce that substance more abundantly and analytical analytical chemists determined this chemical structure it's actually a set of closely related molecules that we named aver mengdan the synthetic chemists found how to make an even better version of it and so I will show you the structure this is picture I took if dr. immoral in 1990 and you can see that he has not changed at all this is the original stuff a ver mikta nor even Becton b1a this simplified slide there's a lot of detail left out of this it's also known as album actin so that's the original stuff on modified but organic friends in chemistry they acknowledge that microorganisms can make molecules that humans cannot but they also seem to believe that only a chemist can make it properly and so they they tweak these things and modified and so what they did was to make a better version of it which is shown here now I trust you all have noticed the difference but just in case you haven't just focus on the upper right hand corner where you see here and here the 2223 bond between those carbon atoms each of them has been and it has been given another hydrogen so this was accomplished by hydrogenation of a verme actin to make ivermectin and so this ivermectin is 2223 dye hydro a permanent B 1 a B 1 a just been one of these closely related molecules so they had made this change by adding hydrogen so they thought not surprisingly that they would like to call this stuff another Abram actin but ivermectin because it's been hydrogen had been added but it was pointed out to them and that in some language hayver means testicle and so that's how ivermectin became ivermectin despite being unique in its origin ivermectin not as many relatives many of them are on in on the market in animal health and there's a whole whole family of these related compounds called macro cyclic lactones and there is a vast literature on those meanwhile the parasitologists had found out which worms it would kill and the biochemists found out how it would kill or rather how it would paralyze them because with peril with with parasitic worms paralyzing them is just as good or from the worms point if you just as bad as killing them the body itself will get rid of paralyzed burns with this flood of information that was being gathered the project was given developmental status so even more disciplines more scientists became involved and I will just mention one as an example of many very different scientific disciplines and I want to mention for a moment the Veterinary parasitologists we had many very parasitologists not only from our own country but from from Vetri schools all over the world and they were brought into this project and they had an astonishing brett's and depth of knowledge of parasites and they set up trials to assess the efficacy of ivermectin against many different kinds of parasites in many different kinds of host animals in many different lands and I think their expertise was actually essential to the success of ivermectin and animal health where it became the dominant anti-parasitic agent sometimes things that one are thought of as bad turn out to be good if a broad-spectrum anti-parasitic agent fails to be active against some particular important pathogen that Julie oblivion for that drug candidate if it misses some very important parasite but not necessarily so in the case of dog heartworm the the significant pathogen is the adult worm stage and ivermectin is not active against adult heartworms taraf alaria images in dogs however in the routine treatment of dogs to get rid of their worms and emphasizing the routine treatment that goes on all the time it is actually dangerous to kill that adult worm killing the worm the adult worm is quite likely to end in the death of the dogs can be fatal to dogs it can be fatal to the reputation of the veterinarian and so that is not a good thing to do so ivermectin turns out to be ineffective exactly where you would like it to be ineffective SIL ivermectin is used all the time to control heartworm disease in dogs it's used as a preventative agent and as it happened before the discovery of ivermectin I had instituted a program of her heartworm research at Merck and Linda Blair and I had set up the life cycle in the lab mosquito to dog life cycle and we had that going just when we needed it to test ivermectin against heartworm and we found that it's active against a pre adult phase so we were able to do the research that led to the development of a once-a-month treatment the first once-a-month treatment for the prevention of heartworm in dogs the potential value of ivermectin was in humans was was never overlooked I had always insisted that our written objectives include the development of drugs for the control of parasites of people and when my colleagues John Edgerton and Linda Blair found that ivermectin was active against the larvae of the parasite uncus circuit Kahless in the skin of horses then I knew it was time to take further action and my chief dr. Jerry Birnbaum enthusiastically approves my proposal to invite dr. Bruce cokeman and Australia to do a trial against another uncle circle species uncle circle got to Rosa in cattle and we gave him funds to support that research which he did and he's an expert on it and again he found that ivermectin was effective so at that time we had information suggesting that ivermectin might be useful in humans against a variety of parasitic worms including hookworm for example but it was clear when one would evaluate the situation that the best way to meet an unmet need in human medicine would be to have it used against river blindness which is caused by yet another species among kazakh on Costa Rica volvulus so dr. Burma dr. Birnbaum and I took that message to the top level of research management at Merck and company it was an exciting moment for both of us we made our pitch and at that time the head of research at Merck was dr. Roy evangelist who himself was a physician and the chemist and they listened very intently to our story and they approved a trial of ivermectin in humans a very cautious trial in patients that had the very early stages of river blindness long before there was any actual blindness they would have the infection that causes river blindness but they would have light early infections so this was a very cautious trial at the beginning and this was one of a series of trials that were set up and directed by dr. Muhammad as is who was one of Merck clinical directors and he was in charge of doing this and he set up this trial in Senegal and it was undertaken by dr. as is and dr. died a low of the university of takara and dr. lariviere of university of paris and there are colleagues and they showed that ivermectin was active against the microscopic larvae the baby worms in the skin of people and that was of course thought to be exactly what is needed the trial had to be very cautious because there had been some precedent that it was dangerous to kill those microscopic worms but this turned out not to be dangerous and in fact to be very safe and do you understand why the activity of that against those larvae is important it's necessary to understand that in river blindness unlike the situation was dog heartworm it is the offspring these microscopic progeny is that caused the damage to the skin and to the eye and eventually leads to blindness as well as skin disease and serious itching and so killing those those larvae can prevent the onset of disease you can block it before it gets going and that's what I've imagined does in 1987 dr. valueless was then CEO president of American company and he announced that the company would donate the drug for the use against river blindness and this led to an unprecedented donation of the Medus an unprecedent translation of this donation of the drug into the actual distribution of the drug and that was a very complicated business and it was undertaken by many groups I will just mention a couple of them you've heard of some of them already but I mentioned the World Health Organization and mercs own Mectizan donation program which was set up from the very beginning to make sure that it was properly used and the Carter Center in Atlanta Georgia but our many many other agencies involved in this process and also there were many leaders involved in this process many directors of the various components and I will just mention one of them and I feel I must mention one because he is Swedish he is dr. Buren he Lafourche and I am honored that he is here for the activities of this week I will now show that a few more slides this is a sculptural representation of a well-known iconic scene in endemic areas where you have endemic areas that are endemic for river blindness where you have adult people who are blind have been led by children and often connected with the sticks sometimes three or four or five people all connected to one child and this is a well-known thing and this is where the river blindness program comes in and the impact of ivermectin and river blindness in terms of the extents of that impact which has now been developing over many years is something that is now a well documented and well established and not for me to discuss here I just want to show a few pictures of the some of the very early treatments that I was an observer for in the early program this is dr. Mohammed Aziz America a clinical director who was responsible and who chose the place to do the first trial chose the place did people to do it with and made sure that all was done according to proper protocol I'll show another side of people there's three people here of great significance my wife and I are talking to two of the people beer on the left and I don't need to say why my wife is important you already know that but the two people on the right are of tremendous importance one is Jimmy Carter the head of the Carter Center former presidents of the United States and he because of his past position was in a position to be very influential in helping the distribution program and then standing next to him second from the left second from the right and this picture is dr. Roy Vangelis and he was the one who had to make the decision whether what to do with this drug and he was the one who decided it would be donated and there is no point really in talking about various people who have suggested it in various parts of the world at various times because the important thing is who who considered it who were in a position to do something about it if you have to be accountable for it then it becomes a big decision to make and that's why Roy evangelist made such an important decision now I would like to not talk further about how great an impact this was but rather I want to get back to that Mouse assay the test system with which I began the operation of that assay was simple as I have explained the operation was simple but so was the principle of it sinking it up was a different matter that was innovative thinking on the part of my colleagues but the underlying principle was simple it was bizarre but it was simple and I have described it this way you line up a series of infected mice you treat each Mouse with an unknown amount of an unknown substance that might not be there and then you check to see if it works on the face of it it seems to find in the face of what we are taught about science with a dwell regulated system and its emphasis on measurement but we need to understand that this too is well regulated to science the empirical research based on observation and trial and error screening of substances has been the foundation of the discovery of anti-parasitic drugs but in recent decades that screening approach has been beaten into disrepute and deaths weighted and his many played in many places being abandoned and when it is abandoned we cannot know what price has been paid in non discovery I have recently made a proposal I'm sorry before I get to that proposal let me just show these last few sides I had a chance to observe the early trials this is in a remote village in northern Togo where I saw the first community-based trials in remote places like this where villagers would gather together in a school yard under the tree for treatment you see on the left a girl standing on the bathroom scale to be measured because at this stage very detailed records were kept it turned out later that that bathroom scale was a unnecessary expenditure of a high-tech instrumentation and it was long since replaced by a measuring stick which is much easier to use much more efficient children were given a tiny pill which they could easily swallow and have a drink of water and open their mouths to show that they had swallowed it this is a village elder but when you in the one of these gathering situations where the treatment was being given when dursa would see people like this blind elder who had that leopard skin caused over many many years of infection with river blindness and had been preceded by really excruciating itching unfortunately in those situations you would also see a man like this a blind man for whom treatment had come too late because ivermectin will prevent blindness it will not cure it but what the good part of those collection to visit under three under the tree or in schoolyard were seen collections of children who would now be safe and we'd no longer grow up under the threat of the skin disease and the itching and the eventual blankness I recently made a proposal for more broadly searching the world for my natural products especially microorganisms as a means of finding new molecules for development as chemotherapeutic agents that might be useful to supplement to some of the mass treatment programs that are currently underway to treat various diseases but nevertheless Kemah therapeutics control should not be seen as the ultimate objective unnatural measures are likely to have unforeseen natural consequences and the broader the activity spectrum of biodynamic substance the more we must guard against the hazards of indiscriminate use and since we cannot count on discriminate use we should try to control the disease without recourse to chemical agents there are very few acceptable antiparasite vaccines but we might yet learn how to make better ones and more of them and we also might be able to devise public health measures to subvert parasite life cycles more subtly than in the past in late afternoon I often climb a nearby hill not a mountain it's just a grassy half-mile hill called half-mile hill and from the top there is a marvelous vista of woodland and lake and the sky often tinted with color as evening falls and it is a moment of uplifting tranquility but when realizes of course that not everybody lives amidst such natural beauty and in conditions of peace and around the world there are many people making heroic efforts to redress that terrible imbalance then one of their objectives is to improve global health and as we bring science to bear on such problems I hope we will keep in mind that solutions are sometimes to be found in science that is simple thank you

Channel: Nobel Prize

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Length: 30min 56sec (1856 seconds)

Published: Tue Dec 08 2015