A research collaboration has discovered a new way of rapidly generating a swathe of medically significant natural products after discovering a ground-breaking technique that turns the marathon of evolution into a sprint.
The surprise discovery came when the research team inadvertently replicated a process that bacteria use to evolve their machinery for making natural products.
Now the team, which includes scientists at the John Innes Centre, plan to harness this process to generate "libraries" of valuable compounds created from the technique which they have named Accelerated Evolution.
"For 20 years we have been using rational bioengineering to modify the chemical structures of clinically important natural products - using genetics to make a new molecule in a process that parallels medicinal chemistry - and that's what we were doing when we stumbled upon this," said Professor Barrie Wilkinson from the John Innes Centre.
"We have discovered a completely new way of doing things, one that will also teach us how to better bioengineer systems in a rational manner."
The collaboration was led by Isomerase Therapeutics Ltd, and included the University of Cambridge, Pfizer, Roche and DSTL.
The team were involved in lab work to produce new versions of rapamycin, a commercially successful natural compound produced by bacteria, used to prevent organ transplant rejection and treat certain cancers.
Rapamycin belongs to a medically and agriculturally important class of compounds called Polyketides. Fungi and bacteria produce these compounds to give them a survival advantage, for example to defend against pathogen attack and secure resources in the environment.
As part of their experiment, the team inserted a temperature sensitive replicon into the genome of the host strain, the soil bacteria Streptomyces rapamycinicus.
But instead of the expected result - a new Streptomyces rapamycinicus strain producing a specific new version of rapamycin - they isolated a wide range of new strains that each produced unexpected new molecules. These strains could be further modified leading to hundreds of new, structurally diverse compounds.
The team believe that, by inserting the replicon into the genes responsible for making rapamycin, they inadvertently introduced a genetic instability which activated a DNA repair process called homologous replication.
This caused the host bacteria to "spit" out the replicon from the genome, causing a rearrangement of the rapamycin biosynthetic genes.
Professor Wilkinson explains: "We think this process mimics and accelerates the processes that are prevalent during natural polyketide evolution."
By setting up a drug discovery development platform to harness the Accelerated Evolution platform, the team believes it is at the beginning of a new age in natural product drug discovery.
Dr Matthew Gregory, a corresponding author of the paper and CEO of Isomerase Therapeutics Ltd, said: "The work described in this paper has important ramifications for the natural products field and synthetic biology generally."
The discovery is outlined in the journal Nature Communications in a paper called: Diversity oriented biosynthesis via accelerated evolution of modular gene clusters. http://www.
The full report: link to paper etc
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About the John Innes Centre
The John Innes Centre is an independent, international centre of excellence in plant science and microbiology.
Our mission is to generate knowledge of plants and microbes through innovative research, to train scientists for the future, to apply our knowledge of nature's diversity to benefit agriculture, the environment, human health, and wellbeing, and engage with policy makers and the public.
To achieve these goals we establish pioneering long-term research objectives in plant and microbial science, with a focus on genetics. These objectives include promoting the translation of research through partnerships to develop improved crops and to make new products from microbes and plants for human health and other applications. We also create new approaches, technologies and resources that enable research advances and help industry to make new products. The knowledge, resources and trained researchers we generate help global societies address important challenges including providing sufficient and affordable food, making new products for human health and industrial applications, and developing sustainable bio-based manufacturing.
This provides a fertile environment for training the next generation of plant and microbial scientists, many of whom go on to careers in industry and academia, around the world.
The John Innes Centre is strategically funded by the Biotechnology and Biological Sciences Research Council (BBSRC). In 2015-2016 the John Innes Centre received a total of £30.1 million from the BBSRC.
The John Innes Centre is also supported by the John Innes Foundation through provision of research accommodation and long-term support of the Rotation PhD programme.
The John Innes Centre is the winner of the BBSRC's 2013 - 2016 Excellence with Impact award.
For more information about the John Innes Centre visit our website http://www.
About the BBSRC
The Biotechnology and Biological Sciences Research Council (BBSRC) invests in world-class bioscience research and training on behalf of the UK public. Our aim is to further scientific knowledge, to promote economic growth, wealth and job creation and to improve quality of life in the UK and beyond.
Funded by Government, BBSRC invested over £473M in world-class bioscience in 2015-16. We support research and training in universities and strategically funded institutes. BBSRC research and the people we fund are helping society to meet major challenges, including food security, green energy and healthier, longer lives. Our investments underpin important UK economic sectors, such as farming, food, industrial biotechnology and pharmaceuticals.
For more information about BBSRC, our science and our impact see: http://www.
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