FOLIUM Science CEO Interviewed by FeedInfo

Could FOLIUM Science's CRISPR Technology Mean the End of Pre- and Probiotics?

UK-based FOLIUM Science has developed a unique way to fight unwanted bacteria in animal production; remove the organisms from an animal’s gut by causing them to self-destruct.

The patented technology, being developed at the company’s research and development laboratory in Bristol, could potentially reduce the need for antibiotics in farmed animals and, therefore, help stem the growing problem of anti-microbial resistance. Its targeted action against unwanted bacteria could also be employed to maintain a healthy microbiome, which, the company believes, could mean that current antibiotic alternatives, like pre- and probiotics, will no longer be needed in the future.

This selective removal of the bacteria responsible for production issues in animal agriculture and how the process could be used to fight anti-microbial resistance was the idea behind FOLIUM Science’s creation in 2015. Founded by CEO Ed Fuchs, a former food industry executive, along with systems biology professor Morten Sommer, veterinary and human medicine expert, Dr Christian Grondahl, and patent attorney, Jasper Clube, the company has turned this concept into its own patented system called ‘Guided Biotics™’, which it plans to develop into zootechnical additives that can be added to feed or drinking water.

Through the use of CRISPR, the biological sequences that make up the bacterial immune system, FOLIUM’s system directs the organism into believing it is being attacked thereby causing it to self-destruct. FOLIUM can tailor the technology to target a specific bacterium or a defined range of bacteria, which means that, unlike the kill-all approach of many antibiotics, it can be used to remove only the unwanted bacteria in the animal’s digestive tract and leave beneficial gut flora unchanged.

Feedinfo News Service recently caught up with the company’s CEO to find out how the company sees its technology affecting the animal agriculture industry when it hits the market in late 2020 and what its role in the fight against anti-microbial resistance will be.

[Feedinfo News Service] You credit antibiotic/antimicrobial resistance in animal agriculture as a reason for establishing FOLIUM Science. In your view, has the industry made sufficient changes to slow its growth?

[Ed Fuchs] The link between the use of antibiotics in animal rearing and the rise in anti-microbial resistance is now widely recognised, hence the move away from sub-therapeutic use in feeds in many parts of the world. Recent studies have shown that many salmonella and E.coli found in chickens are resistant to a range of commonly used antibiotics. Importantly, these bacteria enter the human food chain and are potential zoonotics, meaning they can cause health problems in humans. Antibiotic resistance is estimated to contribute to the death of approximately 700,000 people at a cost of USD 40 billion annually across the globe, and is predicted to increase if current practises do not change.

Since restrictions came into force in Europe and the United States on the use of sub-therapeutic antibiotics, the industry has focused on trying to find viable and effective alternatives that will prevent the proliferation of undesirable gut bacteria and promote animal health. However, the range of options currently available to producers, whilst supportive of gut health, are less than fully effective in removing unwanted bacteria.

[Feedinfo News Service] Your approach to helping them fight these unwanted bacteria involves CRISPR. Most people will probably know it as a gene editing tool, but in bacteriology it is something different. Can you take us through what it is and how FOLIUM Science is applying it to livestock production? How reliable is this technology?

[Ed Fuchs] Guided Biotics™ are based on patented CRISPR-Cas technology. CRISPR is an acronym that describes repeating sequences of DNA that form part of the bacterial natural immune system that has developed to recognise and destroy the DNA of invading elements, such as bacterial viruses. Guided Biotics™ use CRISPR to identify and target specific sequences of DNA only in the targeted undesirable bacteria.

This natural bacterial immune system involves a nuclease enzyme (Cas) that cuts the DNA of an attacking virus. Guided Biotics™ redirect this enzymic mechanism so that undesirable bacteria cut their own DNA. This causes bacteria to self-digest, meaning that the specific unwanted bacterium is removed from the animal gut.

Although CRISPR is more widely known as a gene editing tool, the action of our technology does not involve any gene editing of the target bacteria. Guided Biotics ™ are designed to be extremely specific in targeting the unique sequences of DNA that are found only in the target organism. The data from our in-vitro and in-vivo studies shows that this can be achieved consistently and repeatedly.

Three independent in-vivo studies have conclusively proved that Guided Biotics™ can dramatically reduce salmonella bacteria in poultry. In these three studies, Guided Biotics™, designed to target all 2,400 serotypes of salmonella, were given to test groups of birds as an additive to the drinking water whilst the control groups were not given the Guided Biotic™. All birds were then exposed to a severe salmonella challenge.

Collectively, the data showed statistically significant reductions (p=0.001) in colony forming units (CFUs) of salmonella bacteria in caecal samples when comparing colonisation levels in the test groups with those of the control groups. There was an overall drop in colonisation of at least log 2 across the flock given the Guided Biotic™. Furthermore, salmonella could not be detected in 50% of the birds given the Guided Biotic™ compared to 100% detection in the control animals.

[Feedinfo News Service] Let’s turn to antibiotic/anti-microbial resistance, a subject you’ve obviously considered while developing your Guided Biotics technology. What are some of the developments that you’ve noticed while researching this field?

[Ed Fuchs] Every geography and animal group has unique issues when it comes to antimicrobial resistance and also zoonotic contamination. For example, there are, to a greater or lesser extent, issues with salmonella globally, particularly in poultry products. In regions raising broilers without sub-therapeutic antibiotics, Clostridium perfringens-mediated necrotic enteritis has become a major problem.

Conversely, in piglets Escherichia coli-mediated diarrhoea can cause serious economic losses, while Vibrio species are a particular problem in shrimp production. The list of undesirable bacteria that need control is extensive.

[Feedinfo News Service] And for a long time antibiotics was the way to do this. But, as a result of antibiotic resistance and restrictions on antibiotic use, more and more producers are turning to gut health products, like pre- and probiotics, and phytogenics. How does your technology differ from these alternative solutions in ensuring livestock health?

[Ed Fuchs] What makes our Guided Biotics™ different is that alongside being delivered via a standard probiotic, they also selectively remove undesirable bacteria from the gut, leaving the beneficial and commensal bacteria intact. This supports a positive gut microbiome by allowing these beneficial bacteria to thrive.

No other feed additive is this specific. Whilst some phytogenics, probiotics and prebiotics may have marginal suppressive and competitive exclusion effects on some pathogens this reduction is never more than marginal.

[Feedinfo News Service] In terms of cost, how competitive will your solution be when it is launched? Especially compared to these antibiotic alternatives that are already on the market?

[Ed Fuchs] Guided Biotics™ will be priced competitively with current feed additives such as pre- and probiotics. We are developing our manufacturing capability to ensure our costs of production will support this goal and we have sufficient capacity to meet projected global demand.

[Feedinfo News Service] In your opinion, will your technology replace, to some extent, current nutritional antibiotic alternatives in the future? Or do you see it playing more of a complementary role?

[Ed Fuchs] Because Guided Biotics™ will be effective in removing the undesirable bacteria in the animal gut and thus supporting the growth of positive bacteria, it will mean that some additives such as the probiotics that are currently used to give support to the gut microbiome will no longer be necessary.  For this reason we consider Guided Biotics™ as “next generation” probiotics.

[Feedinfo News Service] We understand that the first version of your technology will focus on eliminating salmonella in chickens. How far away are you from adapting it for other bacteria (like E.coli) and for the beef, pork and aquaculture industries?

[Ed Fuchs] Applications are in development for use in poultry, cattle, swine and aquaculture. Phase one priority targets for poultry applications are salmonella (all serotypes) and then C. perfringens. Salmonella can cause bird production losses and is a major zoonotic human health issue globally. C. perfringens causes necrotic enteritis that has become a significant cause of productivity losses in markets where antibiotic-free poultry is an increasingly important consumer requirement.

Subsequent products are under design for a wide range of pathogens, spoilage and wastage bacteria in all parts of animal production, agriculture and aquaculture.

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