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The advent of ivermectin: people, partnerships, and principles

2014; Elsevier BV; Volume: 30; Issue: 9 Linguagem: Inglês

10.1016/j.pt.2014.07.001

1471-5007

Andy Crump,

Helminth infection and control

The 2014 Gairdner Global Health Award has been given for the discovery of the microorganism and industry partnership that resulted in the appearance of ivermectin, possibly the world's most successful human health tool. The chemist responsible for the discovery, Satoshi Ōmura, also found many other microbial metabolites which have been the origin of novel, impactful drugs. The award emphasizes that multidisciplinary and equitable partnerships, often international in scope, are the key to advances in virtually all branches of science in the modern era. The 2014 Gairdner Global Health Award has been given for the discovery of the microorganism and industry partnership that resulted in the appearance of ivermectin, possibly the world's most successful human health tool. The chemist responsible for the discovery, Satoshi Ōmura, also found many other microbial metabolites which have been the origin of novel, impactful drugs. The award emphasizes that multidisciplinary and equitable partnerships, often international in scope, are the key to advances in virtually all branches of science in the modern era. Growing up in the basic, resource-poor Japanese countryside in the late 1930s, Satoshi Ōmura began to realize that Nature holds all the things that we need for us to lead happy, healthy, and productive lives. Almost 50 years later, while traveling in Africa to witness first-hand the beneficial impact of ivermectin, one of the many medicaments developed from his discoveries, he experienced the same conditions as in his youth. Nevertheless, the sight of some of the hundreds of millions of Africans whose lives and welfare had improved immeasurably as a result of his work provided immense satisfaction that his vision, philosophy, and effort over a 45 year career had achieved his intended goal. The origins of everything lay in a small scoop of Japanese soil.Canada's 2014 Gairdner Global Health Award has been given to Ōmura for his key role in the discovery of the avermectins and the derivative ivermectin. The highly prestigious award was made for the discovery of the microorganism Streptomyces avermitilis (avermectinius) (Figure 1) and its bioactivity that eventually led to the discovery of the unprecedented antiparasitic endectocidal avermectins. This, in turn, resulted in the development of ivermectin, an unparalleled and immensely successful treatment for many parasitic diseases, especially for several that had plagued for centuries the lives of remote and underserved rural communities throughout the tropics. Ivermectin is commonly referred to as a ‘wonder drug’ [1Geary T.G. Ivermectin 20 years on: maturation of a wonder drug.Trends Parasitol. 2005; 21: 530-553Abstract Full Text Full Text PDF PubMed Scopus (200) Google Scholar]. Today millions of people in both developing and developed countries, including Japan, take it regularly to combat a wide range of diseases, and new uses for the compound are continually being discovered.Satoshi Ōmura has long been regarded as one of the leading exponents worldwide of discovering useful chemicals from naturally occurring sources, primarily soil-dwelling microorganisms [2Crump A. Otoguro K. Satoshi Ōmura: in pursuit of nature's bounty.Trends Parasitol. 2005; 21: 126-312Abstract Full Text Full Text PDF PubMed Scopus (15) Google Scholar]. His career began in the mid-1960s when he started his lifelong association with the world-renowned Kitasato Institute in Tokyo. Shortly thereafter, in 1967, he discovered his first new compound produced by a soil fungus. Cerulenin is an antifungal antibiotic that inhibits fatty acid biosynthesis. Other researchers later found that targeting fatty acid synthase by cerulenin-related drugs could become a possible treatment for breast cancer [3Menendez J.A. et al.Inhibition of fatty acid synthase (FAS) suppresses HER2/neu (erbB-2) oncogene overexpression in cancer cells.Proc. Natl. Acad. Sci. U.S.A. 2004; 101: 10715-10720Crossref PubMed Scopus (281) Google Scholar]. This represented the first of many such biomedical ‘breakthoughs’ propagated and facilitated by some of the 476 compounds that Ōmura has discovered to date. Another example is his discovery of staurosporine, the first protein kinase inhibitor identified, that possess antifungal and antihypertensive characteristics, and which proved to be the forerunner of many of today's novel anticancer agents, such as imatinib (Gleevec®) and geftinib (Iressa®) [4Nakano H. Ōmura S. Chemical biology of natural indolocarbazole products: 30 years since the discovery of staurosporine.J. Antibiot. (Tokyo). 2009; 62: 17-26Crossref PubMed Scopus (145) Google Scholar]. Via the application of innovative methods of isolating useful microorganisms, Ōmura has identified 13 novel genera, such as the Kitasatosporia, Longispora, and Arbophoma, and 42 new species, resulting in the discovery of almost 500 new compounds, including several novel or first-in-class antibiotics.Of all the biopharmaceutical products ever produced, ivermectin has a solid claim to be the most beneficial. Ivermectin is globally one of the most important animal and human endectocidal antiparasitic medicines ever produced, one of the foremost public health interventions ever in the developing world, and rivals penicillin for its beneficial impact on global health – with well over 300 million people using the compound annually.Increasingly, advances in science result from team efforts rather than from individuals, as embodied in the rapidly increasing number of authors per scientific paper – the past decade has witnessed publications with over 2000 named authors [5King C. Multiauthor papers: onward and upward.ScienceWatch Newsletter. July 2012; (Thompson Reuters)http://archive.sciencewatch.com/newsletter/2012/201207/Google Scholar]. Ōmura is the first to admit that, although individuals are the sole agents of change, scientific progress, especially in the biomedical field, is almost always the result of the efforts of a committed and talented group of people. Mutual respect, tolerance, consideration, and understanding are essential for optimal success of such teams, irrespective of each member's expertise. Ivermectin may well be heralded as one of the greatest successes in the field of global public health, but he recognizes that it was a synergistic combination of people, partnerships, and principles, coupled with a touch of serendipity, that was behind the unmatched success of the compound and its positive impact on public health improvements worldwide.Ivermectin arose through a unique and unprecedented international partnership that Ōmura entered into with the US-based pharmaceutical giant, Merck Sharp & Dohme (MSD) in 1973. The enterprise was facilitated and orchestrated by the world-renowned American chemist Max Tishler, who was head of the MSD Research Laboratories before being succeeded by his protégé, Lewis Sarrett. Tishler left MSD to start a Chemistry department at Wesleyan University and recruited Ōmura to work alongside him, the two later becoming close and deeply respectful friends. When Ōmura was recalled back to Japan to head the Microbial Chemistry research program at the Kitasato Institute he sought a US-based collaborative partner to ensure that the fruits of research could be quickly exploited for the benefit of global society. This philosophy embodied the approaches of both Merck and the Kitasato Institute, which appeared to be a perfect match. The Kitasato Institute philosophy, established in 1878 by the founder Shibasaburo Kitasato, the Father of Serotherapy, was that ‘the basis of medicine should be the prevention of disease and that achievements obtained by medical research should be actively applied and widely used to improve public health.’ Merck's mission statement was ‘to provide society with superior products and services’ [6Vagelos R. Galambos L. The Moral Corporation. Cambridge University Press, 2006Crossref Google Scholar], with George W. Merck's avowed approach being ‘we try never to forget that medicine is for the people. It is not for the profits’ [7Vagelos R. Galambos L. Medicine, Science and Merck. Cambridge University Press, 2004Crossref Google Scholar].Both Tishler and Sarrett recognized the world-leading research being carried out in Japan at the time [8Sarrett L.H. Research and Innovation.Proc. Natl. Acad. Sci. U.S.A. 1983; 80: 4572-4574Crossref PubMed Scopus (4) Google Scholar]. Tishler, especially, recognized that Hamao Umezawa, discoverer of 30 antibiotics and anticancer compounds, had found more antibiotics from natural sources than even Tishler's own hitherto ‘best living scientist of the soil’, Selman Waksman. Tishler and Sarrett had previously established a productive fermentation program in MSD animal health product research. Already fully aware of Ōmura's capabilities and vision, Tishler advised his friend and ex-colleague Sarrett that Ōmura's group would be an excellent source of novel and highly promising fermentation broths to put through existing and novel screens at the MSD research facilities [9Sarrett L.H. Roche C. Max Tishler.Biographical Memoirs. Vol. 66. National Academies Press, 1995: 352-369Google Scholar]. Consequently, the research collaboration between Merck and Kitasato was established and extended. Working together with his counterpart in the Merck New Jersey laboratories, E.O. Stapley, and alongside the Merck project coordinator in Tokyo, Boyd Woodruff, Ōmura's group sent specially selected microorganisms that they had isolated and identified as having significant bioactive promise for assay in MSD screens. One fermentation broth proved to be remarkably efficient at ridding mice of worms in an experimental model using infection with a helminth parasitic worm, Nematospiroides dubius, as has been well documented elsewhere, especially by William Campbell who oversaw much of the work that discovered the remarkable antiparasitic properties of the avermectins [10Campbell W.C. Ivermectin and Abamectin. Springer-Verlag, 1989Crossref Google Scholar, 11Campbell W.C. The genesis of the antiparasitic drug, ivermectin.in: Weber R.J. Perkins D.N. Inventive Minds: Creativity in Technology. Oxford University Press, 1992: 194-214Google Scholar]. Ōmura and a Japanese colleague, Ruiko Oiwa, played a significant role in the 37 member multidisciplinary team responsible for the identification of the avermectins and for the downstream work that led to the development of ivermectin [12Stapley E.O. Woodruff H.B. Avermectins, antiparasitic lactones produced by Streptomyces avermitilis isolated from a soil in Japan.in: Umezawa H. Trends in Antibiotic Research: Genetics, Biosyntheses, Actions and New Substances. Japan Antibiotic Research Association, 1982: 154-170Google Scholar], which was introduced to massive commercial success onto the Animal Health market in 1981. Subsequently, other key Merck staff, such as Campbell, Ralph Hirschmann, Mohammed Aziz, Ken Brown, and Roy Vagelos, played pivotal roles resulting in ivermectin being donated for human use in globally coordinated programs to control or eliminate diseases that had previously been virtually ignored – but which plagued millions in the world's poorest communities least able to combat them.In addition, Merck were able to work collaboratively with several key United Nations agencies, including the World Health Organization (WHO), the Special Programme for Research and Training in Tropical Diseases (TDR), the Onchocerciasis Control Programme in West Africa (OCP), the World Bank, and others, to prove that ivermectin was an extremely safe and effective anthelmintic agent for large-scale human use. Subsequent partnerships with international donors, governments, various non-governmental organizations, and communities actually afflicted with the diseases, who took it upon themselves to implement and pay for an unprecedented and unique system of community-directed distribution of ivermectin, emphasized the crucial roles that multifaceted, multidisciplinary, deeply committed partnerships played in the success of ivermectin.It is envisaged that two of the most disfiguring, debilitating, stigmatizing, and socioeconomically harmful diseases worldwide – onchocerciasis (river blindness) and lymphatic filariasis (elephantiasis) (Figure 2) – will be eliminated as public health problems within a decade [13WHO Sustaining the Drive to Overcome the Global Impact of Neglected Tropical Diseases (2nd WHO Report on Neglected Tropical Diseases). World Health Organization, 2013Google Scholar]. Ivermectin will be either the sole or primary medical tool responsible for those goals being reached, provided that no drug resistance appears in the near future. Despite continuous searching around the world, the S. avermectinius organism discovered by Ōmura and coworkers remains the only avermectin-producing organism ever found.Figure 2African man disfigured by river blindness and elephantiasis (WHO/TDR/Andy Crump].View Large Image Figure ViewerDownload (PPT)The Gairdner Global Health Award is given to a scientist, from any discipline, whose discoveries or advances have, or will potentially have, a significant impact on health outcomes in the developing world. The vision of the Gairdner Foundation to select a bioorganic chemist most responsible for unearthing the avermectins and all that followed is extremely worthy and very well merited. It will also reinforce the notion that scientists from any discipline can play a significant role in improving the lives and wellbeing of millions of people worldwide, and encourage scientists around the world, young and old, to strive to achieve that goal. Growing up in the basic, resource-poor Japanese countryside in the late 1930s, Satoshi Ōmura began to realize that Nature holds all the things that we need for us to lead happy, healthy, and productive lives. Almost 50 years later, while traveling in Africa to witness first-hand the beneficial impact of ivermectin, one of the many medicaments developed from his discoveries, he experienced the same conditions as in his youth. Nevertheless, the sight of some of the hundreds of millions of Africans whose lives and welfare had improved immeasurably as a result of his work provided immense satisfaction that his vision, philosophy, and effort over a 45 year career had achieved his intended goal. The origins of everything lay in a small scoop of Japanese soil. Canada's 2014 Gairdner Global Health Award has been given to Ōmura for his key role in the discovery of the avermectins and the derivative ivermectin. The highly prestigious award was made for the discovery of the microorganism Streptomyces avermitilis (avermectinius) (Figure 1) and its bioactivity that eventually led to the discovery of the unprecedented antiparasitic endectocidal avermectins. This, in turn, resulted in the development of ivermectin, an unparalleled and immensely successful treatment for many parasitic diseases, especially for several that had plagued for centuries the lives of remote and underserved rural communities throughout the tropics. Ivermectin is commonly referred to as a ‘wonder drug’ [1Geary T.G. Ivermectin 20 years on: maturation of a wonder drug.Trends Parasitol. 2005; 21: 530-553Abstract Full Text Full Text PDF PubMed Scopus (200) Google Scholar]. Today millions of people in both developing and developed countries, including Japan, take it regularly to combat a wide range of diseases, and new uses for the compound are continually being discovered. Satoshi Ōmura has long been regarded as one of the leading exponents worldwide of discovering useful chemicals from naturally occurring sources, primarily soil-dwelling microorganisms [2Crump A. Otoguro K. Satoshi Ōmura: in pursuit of nature's bounty.Trends Parasitol. 2005; 21: 126-312Abstract Full Text Full Text PDF PubMed Scopus (15) Google Scholar]. His career began in the mid-1960s when he started his lifelong association with the world-renowned Kitasato Institute in Tokyo. Shortly thereafter, in 1967, he discovered his first new compound produced by a soil fungus. Cerulenin is an antifungal antibiotic that inhibits fatty acid biosynthesis. Other researchers later found that targeting fatty acid synthase by cerulenin-related drugs could become a possible treatment for breast cancer [3Menendez J.A. et al.Inhibition of fatty acid synthase (FAS) suppresses HER2/neu (erbB-2) oncogene overexpression in cancer cells.Proc. Natl. Acad. Sci. U.S.A. 2004; 101: 10715-10720Crossref PubMed Scopus (281) Google Scholar]. This represented the first of many such biomedical ‘breakthoughs’ propagated and facilitated by some of the 476 compounds that Ōmura has discovered to date. Another example is his discovery of staurosporine, the first protein kinase inhibitor identified, that possess antifungal and antihypertensive characteristics, and which proved to be the forerunner of many of today's novel anticancer agents, such as imatinib (Gleevec®) and geftinib (Iressa®) [4Nakano H. Ōmura S. Chemical biology of natural indolocarbazole products: 30 years since the discovery of staurosporine.J. Antibiot. (Tokyo). 2009; 62: 17-26Crossref PubMed Scopus (145) Google Scholar]. Via the application of innovative methods of isolating useful microorganisms, Ōmura has identified 13 novel genera, such as the Kitasatosporia, Longispora, and Arbophoma, and 42 new species, resulting in the discovery of almost 500 new compounds, including several novel or first-in-class antibiotics. Of all the biopharmaceutical products ever produced, ivermectin has a solid claim to be the most beneficial. Ivermectin is globally one of the most important animal and human endectocidal antiparasitic medicines ever produced, one of the foremost public health interventions ever in the developing world, and rivals penicillin for its beneficial impact on global health – with well over 300 million people using the compound annually. Increasingly, advances in science result from team efforts rather than from individuals, as embodied in the rapidly increasing number of authors per scientific paper – the past decade has witnessed publications with over 2000 named authors [5King C. Multiauthor papers: onward and upward.ScienceWatch Newsletter. July 2012; (Thompson Reuters)http://archive.sciencewatch.com/newsletter/2012/201207/Google Scholar]. Ōmura is the first to admit that, although individuals are the sole agents of change, scientific progress, especially in the biomedical field, is almost always the result of the efforts of a committed and talented group of people. Mutual respect, tolerance, consideration, and understanding are essential for optimal success of such teams, irrespective of each member's expertise. Ivermectin may well be heralded as one of the greatest successes in the field of global public health, but he recognizes that it was a synergistic combination of people, partnerships, and principles, coupled with a touch of serendipity, that was behind the unmatched success of the compound and its positive impact on public health improvements worldwide. Ivermectin arose through a unique and unprecedented international partnership that Ōmura entered into with the US-based pharmaceutical giant, Merck Sharp & Dohme (MSD) in 1973. The enterprise was facilitated and orchestrated by the world-renowned American chemist Max Tishler, who was head of the MSD Research Laboratories before being succeeded by his protégé, Lewis Sarrett. Tishler left MSD to start a Chemistry department at Wesleyan University and recruited Ōmura to work alongside him, the two later becoming close and deeply respectful friends. When Ōmura was recalled back to Japan to head the Microbial Chemistry research program at the Kitasato Institute he sought a US-based collaborative partner to ensure that the fruits of research could be quickly exploited for the benefit of global society. This philosophy embodied the approaches of both Merck and the Kitasato Institute, which appeared to be a perfect match. The Kitasato Institute philosophy, established in 1878 by the founder Shibasaburo Kitasato, the Father of Serotherapy, was that ‘the basis of medicine should be the prevention of disease and that achievements obtained by medical research should be actively applied and widely used to improve public health.’ Merck's mission statement was ‘to provide society with superior products and services’ [6Vagelos R. Galambos L. The Moral Corporation. Cambridge University Press, 2006Crossref Google Scholar], with George W. Merck's avowed approach being ‘we try never to forget that medicine is for the people. It is not for the profits’ [7Vagelos R. Galambos L. Medicine, Science and Merck. Cambridge University Press, 2004Crossref Google Scholar]. Both Tishler and Sarrett recognized the world-leading research being carried out in Japan at the time [8Sarrett L.H. Research and Innovation.Proc. Natl. Acad. Sci. U.S.A. 1983; 80: 4572-4574Crossref PubMed Scopus (4) Google Scholar]. Tishler, especially, recognized that Hamao Umezawa, discoverer of 30 antibiotics and anticancer compounds, had found more antibiotics from natural sources than even Tishler's own hitherto ‘best living scientist of the soil’, Selman Waksman. Tishler and Sarrett had previously established a productive fermentation program in MSD animal health product research. Already fully aware of Ōmura's capabilities and vision, Tishler advised his friend and ex-colleague Sarrett that Ōmura's group would be an excellent source of novel and highly promising fermentation broths to put through existing and novel screens at the MSD research facilities [9Sarrett L.H. Roche C. Max Tishler.Biographical Memoirs. Vol. 66. National Academies Press, 1995: 352-369Google Scholar]. Consequently, the research collaboration between Merck and Kitasato was established and extended. Working together with his counterpart in the Merck New Jersey laboratories, E.O. Stapley, and alongside the Merck project coordinator in Tokyo, Boyd Woodruff, Ōmura's group sent specially selected microorganisms that they had isolated and identified as having significant bioactive promise for assay in MSD screens. One fermentation broth proved to be remarkably efficient at ridding mice of worms in an experimental model using infection with a helminth parasitic worm, Nematospiroides dubius, as has been well documented elsewhere, especially by William Campbell who oversaw much of the work that discovered the remarkable antiparasitic properties of the avermectins [10Campbell W.C. Ivermectin and Abamectin. Springer-Verlag, 1989Crossref Google Scholar, 11Campbell W.C. The genesis of the antiparasitic drug, ivermectin.in: Weber R.J. Perkins D.N. Inventive Minds: Creativity in Technology. Oxford University Press, 1992: 194-214Google Scholar]. Ōmura and a Japanese colleague, Ruiko Oiwa, played a significant role in the 37 member multidisciplinary team responsible for the identification of the avermectins and for the downstream work that led to the development of ivermectin [12Stapley E.O. Woodruff H.B. Avermectins, antiparasitic lactones produced by Streptomyces avermitilis isolated from a soil in Japan.in: Umezawa H. Trends in Antibiotic Research: Genetics, Biosyntheses, Actions and New Substances. Japan Antibiotic Research Association, 1982: 154-170Google Scholar], which was introduced to massive commercial success onto the Animal Health market in 1981. Subsequently, other key Merck staff, such as Campbell, Ralph Hirschmann, Mohammed Aziz, Ken Brown, and Roy Vagelos, played pivotal roles resulting in ivermectin being donated for human use in globally coordinated programs to control or eliminate diseases that had previously been virtually ignored – but which plagued millions in the world's poorest communities least able to combat them. In addition, Merck were able to work collaboratively with several key United Nations agencies, including the World Health Organization (WHO), the Special Programme for Research and Training in Tropical Diseases (TDR), the Onchocerciasis Control Programme in West Africa (OCP), the World Bank, and others, to prove that ivermectin was an extremely safe and effective anthelmintic agent for large-scale human use. Subsequent partnerships with international donors, governments, various non-governmental organizations, and communities actually afflicted with the diseases, who took it upon themselves to implement and pay for an unprecedented and unique system of community-directed distribution of ivermectin, emphasized the crucial roles that multifaceted, multidisciplinary, deeply committed partnerships played in the success of ivermectin. It is envisaged that two of the most disfiguring, debilitating, stigmatizing, and socioeconomically harmful diseases worldwide – onchocerciasis (river blindness) and lymphatic filariasis (elephantiasis) (Figure 2) – will be eliminated as public health problems within a decade [13WHO Sustaining the Drive to Overcome the Global Impact of Neglected Tropical Diseases (2nd WHO Report on Neglected Tropical Diseases). World Health Organization, 2013Google Scholar]. Ivermectin will be either the sole or primary medical tool responsible for those goals being reached, provided that no drug resistance appears in the near future. Despite continuous searching around the world, the S. avermectinius organism discovered by Ōmura and coworkers remains the only avermectin-producing organism ever found. The Gairdner Global Health Award is given to a scientist, from any discipline, whose discoveries or advances have, or will potentially have, a significant impact on health outcomes in the developing world. The vision of the Gairdner Foundation to select a bioorganic chemist most responsible for unearthing the avermectins and all that followed is extremely worthy and very well merited. It will also reinforce the notion that scientists from any discipline can play a significant role in improving the lives and wellbeing of millions of people worldwide, and encourage scientists around the world, young and old, to strive to achieve that goal.