Fish provide insight into the evolution of the immune system

New research from the University of East Anglia (UEA), UK, and Dalhousie University, Canada, reveals how immune systems can evolve resistance to parasites.

A study, published today in Nature Communications, solves the enigma of how species can adapt and change their immune system to cope with new parasitic threats – whilst at the same time showing little or no evolutionary change in critical immune function over millions of years.

The findings help to explain why we humans have some immune genes that are almost identical to those of chimpanzees.

Scientists from UEA and Dalhousie University studied how Guppy fish (Poecilia reticulata) adapt to survive by studying their immune genes, known as the Major Histocompatibility Complex or MHC genes.

They found that guppies fine-tune these genes in each location, enabling them to adapt and survive in many different and extreme environments. Despite this adaptation, genes maintained critical function of tens of millions of years.

The discovery could improve scientists’ understanding of how related species can adapt and change their immune system to cope with new threats from parasites while simultaneously sharing similar function.

Dr Jackie Lighten from UEA led the study. He said: “Guppies are a small, colourful fish native to South America, Trinidad and Tobago. They are a fantastic model for researching the ecology and evolution of vertebrates.

“MHC genes are an important line of defence in the immune system in vertebrates, including humans. Because parasites evolve quicker than their vertebrate hosts, immune genes need to be highly diverse to keep up with parasites and prevent infections.

“MHC genes produce protein structures that are on the external surface of cells. These genes are diverse and so produce an array of proteins, each of which presents a specific part of a parasite or pathogen that has attempted to infect the body. The specific shape of the protein dictates which parasites it can recognize, and signals to the immune system to prevent infection.”

The study looked at MHC genetic variation in 59 guppy populations across Trinidad, Tobago, Barbados, and Hawaii. The authors found hundreds of different immune variants, but these so called ‘alleles’ appear to be clustered in a smaller number of functional groups or ‘supertypes’.

Prof van Oosterhout, also from UEA’s School of Environmental Sciences, said: “Each supertype protects the host against a specific group of parasites, and these supertypes were common across populations, and species, irrespective of the location.

“However, the alleles that make up a supertype track the rapid evolution of the parasites, and they too are evolving rapidly. These alleles are largely specific to each population, and they help in the ‘fine-tuning’ of the immune response to the specific (local) parasites that attack the host in that population.”

Before this study, scientists debated how these immune genes can evolve rapidly (which is necessary to keep up with the fast-evolving parasites), whilst also showing little or no evolutionary change in their function over millions of years, as observed between humans and chimpanzees. This study resolves that debate.

Prof Bentzen from Dalhousie University said: “Although this study focused on MHC genes in vertebrates, the evolutionary dynamics described in it likely apply to other gene families, for example resistance genes and those which prevent self-fertilization in plants (self-incompatibility loci) that are caught up in their own evolutionary races.”

Dr Lighten added: “It is an important step forward in understanding the evolutionary genetics of the immune system, and can help explain some of the puzzling observations observed in previous studies of many other organisms.”

The research was funded by the British Ecological Society, Natural Sciences and Engineering Research Council of Canada (NSERC) and the Biotechnology and Biological Sciences Research Council (BBSRC).

‘Evolutionary genetics of immunological supertypes reveals two faces of the Red Queen’ is published in the journal Nature Communications on November 3, 2017.

Item from UEA News webpage.

NRP biotech spin-out Iceni Diagnostics wins Business Award

NRP based biotech company, Iceni Diagnostics, which is a spin-out from John Innes Centre and University of East Anglia has won a prestigious award that celebrates the best businesses in the region.

The long standing EDP Business Awards recognised the achievements of the Norwich Research Park based company with the Knowledge Catalyst award.

It was one of thirteen awards handed out to businesses from all over the county.

The theme of the 2017 awards was “Innovation”, a quality demonstrated by winners from diverse areas including artificial intelligence and medical diagnostics, through to tourism and construction.

Iceni Diagnostic are developing a device designed to detect microbial and viral pathogens. It is hoped that this simple colour-change test will allow rapid diagnosis, improve decision making, and potentially reduce the unnecessary prescription of antibiotics.

Professor Rob Field, co-founder and CEO of Iceni Diagnostics and a project leader at the John Innes Centre said, “It’s great to be recognised for doing something that we’re passionate about. We work to take fundamental scientific understanding and apply it to real world problems, in this case reducing our dependence on antibiotics.”

The EDP Business Awards are aimed at ambitious businesses and organisations that are underpinned by the acquisition, implementation, and exchange of knowledge.

The judges look for a sustained commitment to acquiring and embedding new ideas within their business planning and structure.

From JIC News pages.

Landmark discovery turns marathon of evolution into a sprint

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.

Norwich Science Festival 2017

The Annual Norwich Science Festival is being held over school half-term from 21st to 29th October based mainly at The Forum in Norwich.  It features an exciting mixture of over 125 events, interactive exhibits, stalls and demonstrations from scientists based in Norwich and across the UK.  Researchers from the Norwich Research Park’s partners will be engaging with the Norwich public on a wide range of topics including astronomy, food, physics and chemistry.

Further information can be found on the festival’s website and the programme downloaded through this link.

Anglers’ delight as algal blooms breakthrough highlights innovative science

Millions of fish-deaths caused by toxic Prymnesium algal blooms could be prevented with the application of a household chemical best known for bleaching hair, breakthrough research has revealed.

Trials carried out in the Norfolk and Suffolk Broads National Park have shown that at controlled concentrations hydrogen peroxide (H2O2) is deadly to Prymnesium parvum, the golden algae.

The discovery follows research led by a team of scientists at the John Innes Centre and the University of East Anglia, aimed at finding a cost-effective solution to a persistent problem that threatens the £100m angling economy of the Broads.



In 2015, following an outbreak of toxic Prymnesium blooms, the Environment Agency supported by angling clubs, rescued almost three quarters of a million fish from Hickling Broad and Somerton. The fish were released back into safer parts of the River Thurne, Norfolk, over the course of six weeks in one of the largest rescues of its kind. The operation cost just under £40,000 and involved 561 hours of staff time.

Prymnesium trials Whispering Reeds Boatyard

Major rescue operations of this sort are on the verge of becoming a thing of the past following successful trials at Whispering Reeds Boatyard on Hickling Broad. “We wanted to come up with an easy, cheap chemical treatment so that when the Prymnesium bloom does happen there’s a way to control it that prevents fish deaths,” explained Ben Wagstaff, PhD student at the John Innes Centre who took part in the trials.

“Our lab and literature research came up with hydrogen peroxide as a potential chemical treatment. We developed a system in the lab where you could use low enough concentrations that would kill algae but wouldn’t affect any fish or macro invertebrates. Then we took our lab understanding and sprayed a very small section of a broad which had been affected by blooms and it worked brilliantly.”

He added: “We are really grateful to Norfolk Wildlife Trust and Whispering Reeds Boatyard for their help to facilitate this exciting work”.

Prymnesium, unlike other algae, does not produce obviously visible blooms; the first indication is often the death of fish or large masses of fish frantically trying to escape the source of toxicity.

Blooms happen regularly in slightly salty or brackish waters such as the coastal parts Norfolk and Suffolk Broads, although not all of them are deadly. Under certain environmental conditions still being researched, Prymnesium can produce toxins, very quickly turning water toxic for fish within a matter of days, sometimes even hours.

Previous research by the John Innes Centre team revealed the existence of a virus which is believed to cause Prymnesium to release toxins into the water.

The research was hailed as a “life-saver” by John Currie General Secretary of the Pike Angling Club of Great Britain: “It’s hard to put into words how important this is for us. Thanks to this research from the John Innes Centre we can save fish rather than observe them dying.”

“At one time before the first Prymnesium wipe out in 1969 this area had the British pike record, so was one of the most important pike fisheries in Europe. With this success we hope that in the next six years we will see growth rates coming back to pre-1969 levels, that’s completely feasible.”

He added: “In 2015, during the Prymnesium incident we had over a million fish in a small area. If we were in that situation again we would be able to use hydrogen peroxide…so it’s a life-saver.”

Hydrogen peroxide is already used by the Environment Agency during pollution incidents to raise oxygen levels for fish and stop them from effectively suffocating. Peroxide can also help where large numbers of fish can become trapped in small areas of water and need extra aeration to help them survive. It is extremely effective – much more effective than other aeration methods. Only slightly higher doses are needed to go from being useful for water aeration to being a safe chemical to kill off Prymnesium and, after a short period, it breaks down into water and oxygen which makes it very safe when applied.

Field Trial – Dr Jenny Pratscher UEA School of Environmental Science

The versatile chemical compound is perhaps best known as a hair bleaching agent. It also has a string of other useful functions such as an antiseptic mouthwash, teeth-whitener, acne treatment, stain-remover and laundry whitener.

The John Innes Centre/University of East Anglia team tested a range of concentrations – working out that the optimum levels to kill the Prymnesium while remaining harmless to fish and other wildlife.

The team believe that preventatively treating localised areas with hydrogen peroxide could help create safe refuges during periods in which a build-up of Prymnesium threatens a toxic bloom.

Jamie Fairfull, Senior Environmental Officer for the Environment Agency said: “Prymnesium is one of the biggest risks to the fish population in the Broads. Being able to use hydrogen peroxide is a major breakthrough because for us the current options are so labour intensive. The Environment Agency usually recharges polluters for the cost of dealing with pollution incidents – but with Prymnesium of course there is no-one to invoice.”

Prymnesium, when stressed is able to produce a toxin that kills off its competition as well as fish, but the tests showed that the peroxide completely broke the Prymnesium and its toxin down without adverse effects.

Follow up trials, said Mr. Fairfull, are necessary for us to fully understand how the peroxide mixes and disperses so that it can be used effectively and safely. It will then be used and implemented along with a range of other methods in combating Prymnesium.

“This will allow us to protect the fish population for the benefit of the environment, anglers and the economy of Norfolk,” he added.

Andrea Kelly, Senior Ecologist for the Broads Authority said: “This research has given us a new way to protect fish stocks and angling in the Broads and we continue to support the John Innes Centre and the University of East Anglia in developing knowledge for managing the fishery of the National Park. Although Prymnesium only occurs in a small area, the Broadland rivers are connected and what effects fish in one area of the Broads impacts on the whole system.”

Prymnesium Fish Kill

Prymnesium – factfile

Prymnesium parvum, also known as the golden algae, has caused problems on the Norfolk Broads since the mid-1960s.

It is of concern to anglers and aquaculture industry because of its ability to produce the toxin prymnesin. Unlike some other algal blooms it is not harmful to humans or cattle, but can turn waters deadly for fish in a matter of hours.

Current research, carried out by the John Innes Centre and University of East Anglia, is investigating the virus which is responsible for causing the alga to spill its toxic contents into the water. This happens when the virus kills the algal population causing cell lysis – the bursting of algal cells, which releases toxins into the water.

It is believed that if the virus is not present the algae will die off more slowly and there are insufficient toxins in the water to cause major fish death episodes.

Prymnesium kills millions of fish worldwide – in brackish systems like the Norfolk and Suffolk Broads, also in fish farms with major incidents reported in the United States, Israel and Scotland.

Steve Lane, Fisheries Technical Specialist from the Environment Agency said the trials carried out by the John Innes Centre team represented a “massive step forward,” adding: “Transferring thousands of fish to other parts of the system is a last resort as it is stressful to the fish and very disruptive. While we may still need to rescue fish in the future, being able to use peroxide to create safe refuges would be a major step forward. The John Innes Centre’s work on peroxide shows how we can work together to translate research into a real-world situation in which angling, tourism, the economy and the environment all benefit.”

The John Innes Centre and UEA are working with the Environment Agency and a range of partners to manage the risks of Prymnesium in the Upper Thurne system. Partners include the Broads Angling Strategy Group, the Pike Anglers Club, the Broads IDB, the Earlham Institute, the Angling Trust, the Water Management Alliance, Natural England, Fishtrack and the Broads Authority.

Broads and Angling – Factfile
Angling influences direct expenditure of £100m a year in the Norfolk & Suffolk Broads.
One in five visitors to the Broads come to fish.
More than 40 per cent of the Broads’ hire boat industry is influenced by angling.
According to one of the largest holiday companies operating within the Broads, 75 per cent of water-facing accommodation is let to anglers and their families.
The rescue of almost 750,000 fish from a Prymnesium outbreak in 2015 was one of the largest fish rescue operations ever undertaken by the Environment Agency, and accounted for 94% of the total fish rescued by the Environment Agency in that year.

This media release was published on the John Innes Centre website and appeared in the press.

ELSA welcomes a new Independent Research Fellow Dr Laura Lehtovirta-Morley

Dr Laura Lehtovirta-Morley who has been recently awarded a Dorothy Hodgkin Royal Society Fellowship joins us from the University of Aberdeen and brings new expertise on Archaea to the Norwich Research Park. She is based in the School of Biological Sciences at UEA and now shares the ELSA lab with Colin Murrell, Jenny Pratscher and Andrew Crombie working on a number of aspects of the biogeochemical cycling of carbon, nitrogen and sulfur compounds in the environment.

Laura says: My research group studies the ecology and physiology of microorganisms involved in the terrestrial nitrogen cycle. We focus particularly on ammonia oxidising archaea, which are the key players in the global nitrogen cycle and among the most numerous living organisms on the Earth. We use enrichment and isolation, physiology and molecular approaches to understand how ammonia oxidising microorganisms adapt to their environment and the consequences these adaptations have for soil nitrogen cycling and climate change.

For more details on Laura’s research please see:

Multi-disciplined science approach improves diet and health

The cutting edge study of epigenetics to unravel how nutrition can regulate the genome and impact on health and wellbeing throughout life; the important insights from epidemiological research about diet-disease relationships; the discovery of new food components such as phytochemicals and their potential role in disease prevention, are just a few of the areas discussed in the Special Issue. It charts progress in knowledge about diet and health, through the work of eminent experts, and the role of BNF over the last 50 years in helping to disseminate evidenced based findings and making nutrition science accessible to all.

Paul Finglas, Mark Roe and Hannah Pinchen from Food Databanks, along with Siân Astley from EuroFIR AISBL authored a review, titled ‘The contribution of food composition resources to nutrition science methodology.’ It describes how, over the last century, the development of tools and methods for studying the nutrient and energy composition of foods has underpinned many advances in our understanding of links between diet and health.

The twelve articles published in the Special Issue, highlighting work in the areas of epidemiology, biochemistry, behavioural science, food science and technology, biomedical science, and epigenetics, show that nutrition is “one of the most exciting areas of science with so much potential for positive impact on human health”, according to Professor Christine Williams, Professor of Human Nutrition at University of Reading, Chair of the Board of Trustees at BNF, and author of the Special Issue’s Editorial. Professor Williams is also a member of the Quadram Institute Bioscience Board of Trustees.

The Special Issue illustrates how a multi-disciplined scientific approach, and collaboration between the scientific community and industry, can have a positive impact on health outcomes, reducing risk of cardiovascular disease, obesity, type 2 diabetes and cancer. Professor Williams believes that reformulation of foods through processing and innovations in agriculture have played an important role in reducing potentially harmful and enhancing potentially beneficial dietary components in people’s diets. She says: “We need a clear code of practice for research collaborations between academia and industry, both to protect the independence of the researcher and to ensure the role which industry could play in improving the diets of populations is optimised.”

Professor Williams’ comments echo the findings of a recent report by the Office for Strategic Coordination of Health Research on the state of nutrition and health research, which highlight that funders and researchers need to work with all stakeholders, including those across all sectors of the food industry, as well as emphasising the global nature of the challenges in tackling nutritional health. In order to ensure that the track record of successes described in this Special Issue over the past 50 years can continue in the decades to come, it’s vital that funding across the scientific disciplines is maintained and multidisciplinary work continues to be centre stage.

‘Nutrition science past and future: Celebrating a multi-disciplined approach’ is available to download from

Reference: Finglas, P., Roe, M., Pinchen, H. and Astley, S. (2017), The contribution of food composition resources to nutrition science methodology. Nutrition Bulletin, 42: 198–206. doi:10.1111/nbu.12274

Press release from Quadram Institute website.

New study highlights how processing affects fat absorption from plant-based foods

Preserving the natural structure of plant-based food during processing can limit the amount of fat and energy absorbed by the body, a new study in the Journal of Functional Foods reports. During this innovative multi-centred study researchers from the Quadram Institute, King’s College London, the University of Surrey and the University of Messina showed that preserving the natural structure of plant based foods can limit how quickly fats are exposed to digestive enzymes in the stomach helping to regulate the amount of fat absorbed by the body.

Focusing on almonds, which contain 50 per cent fat, researchers investigated the effects different processing methods had on how almonds are ingested by the body. Despite being a high fat food, it has been shown previously that eating whole almonds doesn’t result in weight gain. Investigating why this might be, the researchers provided a study participant with two almond muffins, one made with almond chunks (2 mm) and one made with almond flour, which has much smaller particles (at less than half a millimetre).

The muffins were chewed as normal but instead of swallowing were put into an instrument known as the Dynamic Gastric Model, which accurately mimics the physical and chemical conditions of the human stomach and small bowel, enabling the researchers to calculate how much fat had been released.  After 60 minutes in the model stomach, which is the time calculated for this meal to pass through in humans, over 40 per cent of the total fat content had been released from the muffins made with almond flour, but just under 6 per cent had been released from the muffins made with larger almond chunks. Samples taken from the simulated small bowel showed that after 9 hours of digestion, almost all (97 per cent) of the fat from the muffin made with flour was released, and only 60 per cent of fat in the muffin made with almond chunks was released.

These findings were supported by results from a human study with a volunteer who had an ileostomy operation, allowing a direct comparison with the model. The researchers concluded that maintaining the structural integrity of the tough cell walls, which form dietary fibre, surrounding the fat-rich cells in almonds was the main factor in determining the digestibility of fats.

Dr Cathrina Edwards from the Quadram Institute said: “What we have found is that if the natural plant structure is maintained the level of fat the body absorbs is greatly reduced, helping in weight management and potentially helping to reduce incidences of cardiovascular disease”.

The study was funded by the Biotechnology and Biological Sciences Research Council and the University of Messina. The Almond Board of California supplied the almonds.

Reference: In vitro and in vivo modeling of lipid bioaccessibility and digestion from almond muffins: The importance of the cell-wall barrier mechanism Terri Grassby, Giuseppina Mandalari, Myriam M.-L. Grundy, Cathrina H. Edwards, Carlo Bisignano, Domenico Trombetta, Antonella Smeriglio, Simona Chessa, Shuvra Ray, Jeremy Sanderson, Sarah E. Berry, Peter R. Ellis, Keith W. Waldron Journal of Functional Foods Volume 37, October 2017, Pages 263–271 doi: 10.1016/j.jff.2017.07.046

Press release from Quadram Institute news pages.

Q and A with Sarah Worsley

Sarah is a PhD student working with Matt Hutchings (School of Biological Sciences, UEA and co-supervised by Colin Murrell, School of Environmental Sciences, UEA). Visit Matt’s website to find out more about this exciting work.

What is the background of your work?

Almost all eukaryotic organisms interact closely with a large number of microorganisms that make up what is known as the organism’s “microbiome”. Many of the microbial members of this microbiome are known to be of benefit to their host. I’m interested in a group of bacteria in the genus Streptomyces that are thought to offer protection to their host by producing a large number of different antibacterial and antifungal compounds. I’m particularly interested in the interaction between Streptomyces and plant roots and aim to increase our understanding of the mechanisms that allow their recruitment to roots. I also study leafcutter ants which use their leaves to farm a fungus for food- they use the antibiotics produced by Streptomyces bacteria (which accumulate and grow on the cuticle of the ant) as weedkillers to prevent the spread of pathogenic infection in their fungal gardens. I am interested in understanding the mechanisms underlying the recruitment of Streptomyces to these two microbiomes because this may help us to enhance their representation in the microbiomes of other species, such as crops or the human microbiome, and thus increase protection against pathogens.

What is the aim of your work? 

I aim to understand how large organisms such as plants and ants recruit beneficial species of microorganism to their microbiome, particularly Streptomyces bacteria which are thought to offer them protection against pathogens. We think that the host organism may provide them with nutrients which are either specifically metabolised by this group of bacteria, or are provided in such large quantities that the bacteria can produce lots of antibiotics and out-compete other organisms during the colonisation of the larger organism. I aim to detect the flow of nutrients from the host to their bacteria by tracking a stable isotope (13C) label from the host to the DNA of the bacteria that metabolise the nutrients.

What have you learnt so far?

Streptomyces that I isolated from plants are capable of inhibiting the growth of many human and plant pathogens. Their genomes also show large biosynthetic potential. They can also be seen to colonise the inside of roots when expressing a green fluorescent protein. My sequencing data also shows Actinobacteria (the phylum to which Streptomyces belong) are abundant in the roots and rhizosphere or Arabidopsis thaliana. Leaf cutter ants recruit a diversity of Streptomyces species that can produce multiple antibiotics to their microbiome.

What do you hope to learn?

By sequencing 13C labelled bacterial DNA associated with the roots of labelled plants I will be able to see if Streptomyces species are capable of eating plant derived resources. I also hope to work out if particular plant defence hormones are specifically being metabolised by this group of bacteria or if their metabolism is more general. I also hope to track 13C from leafcutter ants to their cuticular bacteria to work out if Streptomyces are specifically being fed by the ant. Imaging mass spectrometry may also help us to distinguish the identity of the ant-supplied nutrient and work out if this nutrient regulates antibiotic production.

What does your work prove, why is it important and how is it applicable?

Antibiotic resistance is a problem for human medicine and in agriculture. We need to find new antibiotics. If we can work out how beneficial, protective bacterial species are recruited to microbiomes and how microbiomes are assembled we may be able to develop techniques to enhance the representation of species that we want (such as those that offer protection) over the ones that we don’t want. This could have implications for the health of many organisms including crop plants and humans.

Why did you choose to do a PhD?

I have always had an interest in the problem of antibiotic resistance and the search for alternative treatments to alleviate this problem. I am also fascinated by the complexity of microbiomes. Both the leafcutter ant system and the plant root microbiome are extremely exciting systems to work on and my PhD allows me to combine these two interests. I also love the process of doing science, from formulating the questions to doing the experiments to test them. I can’t think of a more exciting job than being a scientist!

Interview by Emily Kench, ELSA Intern 2017

Plant-produced polio vaccines could help eradicate age old disease

Plants have been used to produce a new vaccine against poliovirus in what is hoped to be a major step towards global eradication of the disease.  A team of scientists, including Dr Johanna Marsian working in Professor George Lomonossoff’s Lab at the John Innes Centre, has produced the novel vaccine with a method that uses virus-like particles (VLPs) – non-pathogenic mimics of poliovirus which are grown in plants.  Genes that carry information to produce VLPs are infiltrated into the plant tissues. The host plant then reproduces large quantities of them using its own protein expression mechanisms.

Professor Lomonossoff, from the John Innes Centre said: “This is an incredible collaboration involving plant science, animal virology and structural biology. The question for us now is how to scale it up – we don’t want to stop at a lab technique.”

VLPs look like viruses but are non-infectious. They have been biologically engineered so they do not contain the nucleic acid that allows viruses to replicate. This means that they mimic the behaviour of the virus, stimulating the immune system to respond without causing an infection of poliomyelitis.  Laboratory tests demonstrated that the poliovirus mimics provided animals with immunity from the disease paving the way for human vaccines to be produced by plants on a major scale with the input of pharmaceutical industry collaborators.  The breakthrough was made by a consortium funded by the World Health Organisation (WHO) which is seeking to eradicate a disease that has been known since antiquity.  The WHO is seeking alternative vaccines that avoid use of the live virus as part of an international drive to completely eradicate the virus worldwide.

A global scourge up to the middle of the last century, poliovirus has been reduced by 99% since 1988 due to the Global Polio Eradication Initiative led by the WHO. Current polio vaccines, however, require the production of huge quantities of the virus. Using the live virus not only represents a risk of the virus escaping, the use of the live attenuated (weakened) virus, effectively maintains polio in the global population.

VLPs were expressed at the John Innes Centre using Hypertrans® transient plant expression system which had previously been developed there. This successful development not only holds promise for the production of vaccines for polio: it could become a frontline diagnostic resource in producing vaccines against other viral outbreaks.

“The beauty of this system of growing non-pathogenic virus mimics in plants, is that it boosts our ability to scale-up the production of vaccine candidates to combat emerging threats to human health,” said Prof Lomonossoff.

A = VLPs in vitreous ice. B = Reconstruction of poliovirus. C = VLP showing empty internal surface. D and E = Views of poliovirus molecular structure

In the past 20 years plants have become serious competitors to bacteria, insect cells, yeast or mammalian cells as production systems for pharmaceutical materials. They are cost-effective requiring simple nutrients, water, carbon-dioxide and sunlight for efficient growth and the transient expression system can be adjusted rapidly with low costs.  The work at the John Innes Centre furthered work of scientists at the University of Leeds, who first discovered a way of producing the virus-like particles (VLP) using the Hypertrans® expression system.  Despite successes of plant-based expression to produce VLPs of papilloma and hepatitis B viruses, poliovirus VLPs had previously proved too unstable to make practical vaccines using this technique. A problem is that the genetic material which causes replication of the virus and which is therefore absent from the VLPs, also has a role in holding the particles together.

However teams from The National Institute for Biological Standards and Control, and the University of Leeds identified mutations within protein coats which enabled the production of VLPs which are sufficiently stable to act as vaccines. Experiments at the University of Oxford showed that these were identical to native poliovirus retaining their shape when warmed, and which are effective in protecting animals against poliovirus.

The team used cryo-electron microscopy at Diamond Light Source’s Electron Bio-Imaging Centre (eBIC) to obtain a clear look at the structure of the VLPs. They confirmed the structure and showed that the external features of the particles were identical to those of poliovirus.  Dave Stuart, Director of Life Sciences at Diamond and Professor of Structural Biology at University of Oxford said, “We were inspired by the successful synthetic vaccine for foot-and-mouth disease, also investigated at Diamond as part of UK research collaboration. By using Diamond’s visualisation capabilities and the expertise of Oxford University in structural analysis and computer simulation, we were able to visualise something a billion times smaller than a pinhead and further enhance the design atom by atom of the empty shells. Through information gained at Diamond, we also verified that these have essentially the same structure as the native virus to ensure an appropriate immune response.”

This collaboration means manufacturing the particles stabilised in plants on a large scale as precursors to vaccines is now much closer to becoming a reality. The results are outlined in the journal Nature communications: Plant-made Polio 3 stabilised VLPs – a candidate synthetic Polio vaccine.

The collaboration includes the John Innes Centre, The National Institute for Biological Standards and Control, Oxford University, University of Leeds, Diamond Light Source, the Henry Wellcome Building for Genomic Medicine.

Background information: Poliovirus: the scourge of summers past

An ancient Egyptian stone engraving provides a clue that the poliovirus has been a disturbing blight on our lives since antiquity. The 3,500-year-old engraving appears show a polio victim, a priest with a withered right leg. From then the virus was widely feared up until the middle of the last century and the arrival of the first effective vaccines. Polio is now down to a few hundred cases a year world-wide, but these numbers remain steady as the virus is maintained in the environment by the use of the live attenuated vaccine.

“The poliovirus is a very nasty disease and certainly until the 1950s was a real scourge.” said Professor George Lomonossoff of the John Innes Centre, based at Norwich Research Park.

“It was known as the summer plague and here in Norwich the main source of it was bathing in the river Yare near Earlham Park.”

“Most people had very mild symptoms but some people got paralytic polio and in worst cases couldn’t breathe properly and had to be put in an iron lung in order to breathe.”

Poliovirus is the causative agent of poliomyelitis which destroys motor neurons in the central nervous system causing paralysis or even death. Transmission is primarily by ingesting infected water. The Global Polio Eradication Initiative led by the World Health Organisation has resulted in 99 per cent fewer cases in the past 30 years by using two highly effective vaccines: the live attenuated (weakened) vaccine developed by Albert Sabin and the formaldehyde-inactivated or killed virus developed by Jonas Salk. Production of both vaccines, developed in the 1950s, requires propagation of large quantities of live poliovirus increasing the risk of accidental re-introductions. Because of this risk, the WHO has intensified its search for cheap and viable alternatives, this breakthrough using the virus-like particles presents an exciting new option. Virus free vaccines will allow polio to be eradicated, they will prevent recurrences without the risks associated with the using the live virus vaccines.

Press release from JIC website news

Earlham institute
Quadram Institute Bioscience
John Innes Centre
The Sainsbury Laboratory
University of East Anglia

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