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A Nobel Prize for a humble soil bacterium

by on 2015/10/13

The Nobel Prize announcements are in full swing. The prizes are awarded in the name of Alfred Nobel to those who bestow ‘the greatest benefit on mankind’. The prizes in physics, chemistry, literature, peace and physiology or medicine always create excitement, and no more so than in the scientific community – they are somewhere between the Oscars and the World Cup of Science.

I’m a practicing biologist and I always eagerly await the announcement of the prizes. Discussions on social media and blogs running up to the announcement was that the award in medicine or physiology would go to the insights gained from the human microbiome, or the discovery of the CRISPR ‘bacterial immune system’ proteins, that are now being exploited to edit human genes.

On Monday morning, the announcement came, and in all my years of avidly following the prize, it has never been awarded so close to my own work – which was a delight.

The Nobel Prize for physiology or medicine 2015 was shared between Satoshi Omura and  William Campbell “for their discoveries concerning a novel therapy against infections caused by roundworm parasites” and Youyou Tu “for her discoveries concerning a novel therapy against Malaria”. I will focus on the work of Omura and Campbell from now on for its truly remarkable impact.

My own research is focused on a group of bacteria called Streptomyces, which is a amazing group of soil bacteria that are prolific producers of medically useful metabolites such as antibiotics, anti-cancer, immunosuppressive molecules and anti-helminthics (de-worming drugs). It is these anti-helminthics drugs that won Omura and Campbell their prize!

In the early 1970’s Satoshi Omura was a post-doctoral scientist working in the USA, interested in isolating soil bacteria that were able to produce useful molecules that may be developed as human medicines. Before he moved back to the Kitasato Institute in Japan, he established a collaboration with the drug company Merck, Sharp, Dohme to collaborate on drug discovery. Omura’s work focused on isolating bacteria using innovative ways of culturing bacteria from soil, enriching for those that may produce useful chemicals that could be exploited as drugs. This work involved the testing of lots of samples of soil collected from all over the world. Omura could not have anticipated the gold-mine that was so close to home. A soil sample collected from a seaside golf course at Kawana, Ito City, in Japan yielded a strain of bacteria that was remarkable in the chemicals it was able to produce – it was able to kill worms! This bacterium was named Streptomyces avermitilis. Almost 25 years later the group of Dr Ōmura mapped the genes encoding the biosynthetic machinery for production of the anti-helminthic compound (now called Avermectin) and in 2001 sequenced the complete genome of S. avermitilis.

This strain of bacteria was one of 54 strains sent to Merck by Omura for further study as part of the ongoing collaboration. Dr Campbell continued to study the anti-helminthic (worm-killing) properties of the new compound in a mouse infection model using a nematode worm. The new compound, Avermectin was found to prevent shedding of eggs and worms in mouse faeces (blocking the re-infection routes) and the elimination of worms from the guts of infected mice with little or no side effects to the mouse. The team also showed that it had great activity against lots of different parasites. Campbell set about purifying and characterizing the chemical, which turned out to be a mixture of closely related chemicals, one of which dihydro-avermectin was particularly active and this was given the name Ivermectin.

Given its safety and efficacy, Ivermectin was introduced as a veterinary anti-parasitic drug in 1981 and within two years it was the market leader – and still maintains that position with around US$1 billion sales per annum. Within five years of its introduction, 320 million cattle, 151 million sheep and 21 million horse were being treated in over 40 countries. Ivermectin is still the global leading anti-parasitic drug in animal health and has increased animal health and welfare immeasurably, increasing productivity in farm animals (especially in the developing world) and has had a massive socio-economic impact on human farming and wider communities globally. Testament to the success of Ivermectin in horses is the almost total eradication of the Horse worm (Onchocerca cervicalis). Given the successes of Ivermectin in treating the Horse worm, Dr Campbell hypothesised that Ivermectin may be useful in treating the closely related worm species Onchocerca volvulus, that causes the debilitating illness River Blindness (or Onchocerciasis) in humans. River Blindness is a major global health problem. Adult worms can live for up to 15 years and produce millions of microscopic microfilariae (larvae) that migrate throughout the body causing many of the symptoms. The larvae are spread by the bite of the Black Fly (Simulium sp.) and it is the death of the microfilariae in the host that causes the visual impairment associated with the disease.

To really understand the impact of Omura and Campbell’s work it is worth examining the river blindness infection rates – there are an estimated 18 million infections annually, 6.5 million people suffering symptoms including blindness, and it has been estimated that one million disability-adjusted life years are lost annually through these infections that occur in 28 countries in tropical Africa and with small isolated pockets in the middle east and Latin America. Until Ivermectin was available, the previous treatments often made the symptoms worse and by the 1970s these treatments were suspended. While Ivermectin does not kill adult parasites, a single annual dose eradicates the larvae of the worms and prevents disease progression. Ivermectin is now one of the World Health Organisation’s (WHO)Essential Medicines’.

Ivermectin was registered in 1987 as a drug for human use – and as a result of an innovative public/private partnership between Kitasato Institute, Merck Sharp Dohme and the WHO it was immediately donated free of charge for use in the treatment of River Blindness. As a result of this unique partnership, by 2012 around 99 million people were receiving Ivermectin annually to treat River Blindness (around 75% of those at risk) and around 105 million were receiving Ivermectin to treat Lymphatic Filariasis (Elephantiasis; 24% of those at risk) as part of the Lymphatic Filariasis Elimination campaign. In 2013, 168 and 167 million doses of Ivermectin were approved for River Blindness and Lymphatic Filariasis treatment respectively. Since the introduction of both campaigns almost 2.3 billion doses of Ivermectin have been donated. It is estimated that with current rates continuing, both diseases are on course for total eradication by 2020. This level of success from a drug is unprecedented in human health.

Very few drugs impact on human and animal health and socio-economic well-being to the extent of Ivermectin – and seldom does this occur on a global scale – changing the lives of hundreds of millions of people and approaching a billion farm and companion animals. Moreover, the work of these scientists, via a ground-breaking and innovative public/private partnership paved the way for this ‘wonder-drug’ to be supplied free of charge to the people who needed it most. Seldom do winners of the Nobel Prize for physiology or medicine have such direct impact from their work, touching the lives of so many. And all from a humble soil bacterium!

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