Satoshi Ōmura - Nobel Lecture: A splendid gift from the Earth: The origins & impact of Avermectin

That's why you're introducing the spikes first Satoshi Omura Satoshi Omura received a PhD in pharmaceutical sciences. in 1968 from the University of Tokyo, Japan, and a PhD in chemistry in 1970 from Tokyo University of Science. He initiated his research at the Kitazato Institute in Tokyo. Japan in 1965. He moved to Wesleyan University in 1971 as a postdoctoral fellow. Subsequently, he became a professor at Kitazato University in 1975. And Omura is currently professor emeritus at Kitazato University. Please join me in welcoming Dr. Omura, who will deliver his Nobel lecture under the title A Splendid Gift from the earth. The origin and impact of A.V. Please. Thank you for that extremely kind Introduction. It is a very great personal pleasure for to be in this wonderful hall today and to be able to share with you some of the joy and the result of my research. Firstly, I would like to thank the Nobel Committee and all those responsible for identifying me work as being of both major importance and a significant benefit to humanity and worthy of a Nobel Prize. It gave me the greatest pleasure and the deepest honor to share this prestigious award, and I do so with the awareness that I I am here presenting a large and diverse group of individuals and agencies all who deserve to share in the recognition of a highly successful story in human health. I have made my appearance through a collaboration between the Mark Pharmaceutical Company and my research group and to start with, I would like to explain a little about our work at Kitasato. My research on microbial metabolites began In 1965 at the Kitasato Institute. I began with the structural analysis of the clinically used antibiotics leucomycin and other antibiotics discovered at the institute. Soon afterward I decided to focus on research novel naturally occurring substances that possess biological activity, particularly those produced by microorganisms. Ever since I have been involved in developing new methods to isolate microbes from samples taken from nature, culturing them and creating and exploiting novel highly specific screening systems to detect interesting chemicals These are the steps in our research. We isolate more than 2,000 microbes each year from among the hundreds of thousands that exist in the small sample. We then cultivate and grow them on different media. They are then passed through a variety of screening systems to Identify any interesting bioactivity. Those producing Promising biochemicals are identified and preserved for use by us or by other scientists. Promising chemicals or microorganisms proceed to further research and development. This of course is expensive, and R&D usually requires a commercial partner. This was the initial pathway that eventually led to the appearance of ivermectin. This is an example of the diversity of microorganisms that have been isolated from the soil as opposed to the plant root. There is a distinct, a divergent and extensive variety between the two. We have been able to discover many new organisms as well as chemicals with interesting bioactivity. You can begin to visualize the as yet undiscovered potential that microbes hold possess. Our research has resulted in the discovery of an an average of 10 novel compounds per year over a period of almost 50 years. Among them, 26 compounds have been widely used as medicine in human and animal health and as a biological reagent. Among the compounds we discovered, over 100 have become target for the synthesis in organic chemistry, meaning that our compounds have also contributed substantially to worldwide advancement in organic chemistry and biochemistry, including making a contribution to other Nobel Prize-winning research. This is an overview of the microbial metabolites we have. discovered so far. Now I'd like to focus on ivermectin. story. Fortunately, in the early 1970s, Professor Michael Tischler of Western University, former president of the ACS, and former the president of Mark Sharpe and Ohm Research Laboratory introduced me to Mark. This enabled me to initiate a Nobel International collaboration with Mark Company. It represented the world's first major public sector-private sector partnership at times, which I am sure that most of you are now familiar with. Professor Tischler invited me to work with him at Western University in 1971, and we became close friends. He played a central and key role in establishing up the collaboration with Mark. At this point, I have emphasized that scientific research cannot be done in isolation. It is not an individual effort. I have been able to work with some wonderful scientists and colleagues from many disciplines and from many countries. Ivermectin originated in Japanese soil, but it would not have seen that light of the day were it not for the excellent teams of scientists at Mark Company. You see some of the key personnel involved here, and I would like to draw attention to the a very special role played by Max. Today, scientific progress is increasingly being achieved by a group of multidisciplinary professionals scientists. Ivermectin was a pioneer in this regard. As you can see from this selected sample of product, our joint research discovered many biologically and structurally interesting metabolites. For example, luminamycin and rastromycin are antimicrobial, active against anaerobic bacteria. Elastinin It is the first human elastase inhibitor of microbial origin. Thetamycin is a VATB inhibitor, and this compound is very important. biochemical reagent and alpha-chain RNA inhibitor. Of all the metabolites we found, ivermectin, co-discovered with William Campbell's team, was the most unique and the most important. It was the world's first endicticide, a completely new class of drug capable of killing organisms inside and outside the body. Ivermectin was modified by Mark's chemistry group into a safer, more effective compound, a dihydroderivative, Ivermectin. Among the first 50 promising organisms I sent to Mark for testing, this one had the most Potent cell. It produced several interesting metabolites. Campbell's team found that it had good antiemetic activity. Based on In our genetic study, we named it Streptomyces avarymyctinus. It was later renamed Streptomyces avarymyctinus. Despite decades of searching around the world, the single organism we discovered in Japanese soil remained the only source for industrial production of Ivermectin has been discovered. Ivermectin blocks nerve impulse transmission. in glutamate-gated anion channels, causing paralysis and death in parasites. In 1981, products containing ivermectin were commercialized for animal health, and it proved extremely safe and effective for human use. Mark's scientists, working with a collaboration with the World Health Organization and disease-affected communities in Africa, soon discovered that Ivermectin was the ideal tool to combat a disease that had plagued tropical regions for centuries. Onchocerciasis is also known as river blindness. It causes skin disease, blindness, and sometimes death. It also prevents socioeconomic development in all endemic areas. In the late 1980s, Well over 120 million of the poorest people in Africa and Latin America had no access to a suitable solution for the disease. No safe, effective The drug was available until Ivermectin appeared. Massive clinical trials with Ivermectin were conducted in tropical Africa by WHO, TDR, and other organizations. They showed that a single annual dose of ivermectin to 200 micrograms per kilogram of body weight eradicated microflora worms from the eye and skin after one month, and that patients remained free of mature worms for up to 12 months. Ivermectin was registered for human use in 1987. Mark, under the direction of Dr. Roy Vagelos immediately launched a unique donation program under the Brand name Mekuchizan. Ivermectin was to be provided free of charge. treatment of liver blindness in humans with the Kitasato Intensive Abandoning Loyalty. The donation was for as much drug as needed, for as as long as needed. This created the world's largest, longest-running, and the most successful drug donation program. Using this Mekuchizan tablet, a formulation of Ivermectin for human use, continued community-directed mass treatment with villagers. The distribution The tablet is now used throughout Africa and in other endemic countries. in Latin America and in Yemen. Donation does not mean that it reaches the people who need it most. especially if they are in the poorest and most remote communities around the world. Here you see some of the key members of truly international partnerships that have enabled ivermectin to reach those in need, no matter where they are. MAC, TDR, APOC, and of course, the affected communities themselves. Everything works well together to achieve the outstanding result we are witnessing. Today. In 2004, I went to Africa to see the real impact that Ivermectin has Having. I went to a vendor where in the 1970s, many of the adults villagers had been blinded by onchocerciasis. The blind farmer, You see here, taking Mekuchizan tablets every year, the skin itching has has been dramatically reduced, although blindness cannot be reversed. However, by taking Ivermectin, the infection will not be transmitted. Since 1987, alone some 37 million African children have been saved from the threat of onchocerciasis through ivermectin. Lymphatic filariasis also results from infection with parasitic worms. Filarial worms transmitted by mosquitoes. Infection causes filarial fever, elephantiasis, and genital damage. and social stigma. This was the situation in 2000. More than 1.3 billion people are at risk. This number is nearly 20% of the world's population. 120 million people are already infected, and this disease affects 83 countries. In the year 2000, the drug donation programs were extended to Cover this disease where it coexists with onchocerciasis. Today, these numbers are dramatically decreasing primarily due to to Ivermectin. Since the donation program began in 1987, 2.6 billion doses of Ivermectin Treatments have been approved. RACET data show that approximately 227 million people are taking donated Ivermectin annually. Today, no child in Africa will face the prospect of being blinded. due to onchocerciasis. The health and socioeconomic well-being of millions of families in Africa and Latin America are being saved from the dangers of both liver blindness and elephantiasis. Thanks to a single soil organism, united scientific minds and collaborative efforts. Within the decade, two of the world's most diverging and despairing diseases should soon be eliminated as public health concerns problems, lymphatic filariasis by 2020 and onchocerciasis by 2025, or even sooner. None of these children will be affected by either illness. No child born in Africa after 1987 will face the threat of blindness or disfigurement, thanks mainly to ivermectin. That my work helped activate this is a reward beyond measure. But the success does not stop there. Around the world, commercial formulations of Ivermectin are also first-line drugs for various diseases, including thrombosis and scabies As you can see here, evidence is also accumulating that providing Ivermectin to entire communities improves all sorts of health issues and socio-economic factors, not just overcoming onchocerciasis and lymphatic failure We are currently funding a project to quantify the complete Impact of long-term Ivermectin consumption in communities in Nigeria We have also donated bicycles and mobile phones to help make The job of a volunteer village-based Ivermectin distributor Distribution much easier. Research is also showing that Ivermectin has a significant impact against a variety of neglected tropical diseases. We have established a research collaboration with Oswaldo Institute in Brazil to test Ivermectin against a number of other neglected tropical diseases, and have already obtained some encouraging results regarding schistosomiasis. I would like to indicate that the Japanese community also benefited from our discovery. The loyalty we earn from sales of animal products has been used to fund continuing research, as well as to cover the costs of construction of this 440-bed district hospital, nursing college, dormitory for nurses, and vaccine production facilities. Today, in addition to inpatients, over 1,000 outpatients Pay per day to visit the hospital. Ivermectin is, without any doubt, a splendid gift. from the earth Now, I'd like to talk briefly about our genetic research. on the ivermectin producer. To understand and exploit the way microbes produce metabolites, we performed complete genome analysis of the organism, which, as I mentioned, It is the only source ever found for ivermectin. We first reported our findings, which covered 99.5% of the total genome in 2001, and completed the analysis of the entire genome in 2003. This is the issue of Nature Biotechnology in which our paper is published. in the entire genome analysis appeared, with an electron micrograph of the organism we discovered on the cover. The information obtained, which represented the first genome analysis of an industrially important bacteriomyces, triggers intensive research on the secondary metabolites of microorganisms worldwide. These slides show the outline of the genome. There are more than 9 megabases, highlighting the gene clusters involved in the biosynthesis of metabolites Italicized abbreviations beneath each molecular structure indicate the biosynthetic genes, whose location is indicated by arrows in the linear chromatography. Underlined italic abbreviations indicate that the products were identified in the fermentation process of this strain. For example, in addition to Ivermectin, oligomycin, pentaene macrolide squalene, and carotene. Fortunately and astonishingly, No ivermectin resistance has been reported. in humans, despite more than 30 years of monotherapy. But we are continuing to create a new analog through genetic manipulation to help offset Any problem that should arise, resistance must be developed. as it has done in animals. The upper figure is the gene cluster. for ivermectin biosynthesis. These four genes have one to four products. A multifunctional protein that catalyzes the formation of the rapton skeleton. Please take a look at the elegant work of organisms in the ivermectin-producing process. The elongation and the rapton-forming modification And to this rapton, the oleander was synthesized. from glucose and linked to the 13 positions. Thanks to our genetic research, we can now control and manipulate this process, opening up the prospect of greater potency and more multi-purpose compounds. At this point, I would like to briefly explain. my basic research philosophies I should perhaps emphasize that I have always been convinced that Nature holds the answer to all our needs. and problems. As you can see, my thinking has been that Microorganisms are a limited resource. capable of meeting our requirements. I said this in the early 1970s. They have proven through 50 years of research. I've been lucky enough to find ivermectin. and a number of other extremely useful chemicals such as staurosporine, the world's first protein kinase inhibitor of microbial origin, and raptacystin, the world's first proteasome inhibitor of microbial origin And I shall continue to search for more and more compounds that can bring health and socioeconomic benefits to communities around the world and encourage new generations of scientists to do the same all in the hope of discovering new Ivermectin or, a bit more Such a wonder drug. For 50 years, I have worked alongside specialized researchers in the fields of such as biochemistry, molecular biology microbiology and clinical medicine My approach has always been influenced by the Tenet, One Encounter, One Chance. It conveys a profound respect that is an essential part of the tea ceremony, Tea ceremony. Chanoyu is held in the highest esteem. in Japanese culture as well as the fact that under exactly the same circumstances at any point in time It will never happen again. I believe it is important to seize the opportunity when they appear and to maintain profound respect and consideration To all my colleagues as well as for microorganisms I work with. Such sentiments form the foundation of all good scientific research and discovery. To conclude, I would like to once again express my sincere gratitude To all concerned for being chosen as the recipient of the Nobel Prize in Physiology or Medicine. I humbly accept the award on behalf of all those who have helped me at every step of the wonderful journey of discovery Thank you very much.