ADVANCED PROBIOTIC LIVE THERAPEUTICS
AgThera discovers a new class of live therapeutics for gut health and infectious diseases that sicken animals.
AgThera designs, builds and tests advanced probiotics in an agile R&D process. With synthetic biology techniques we engineer hundreds of variant antimicrobial probiotics. With artificial intelligence and computational biology we can guide engineering of these live biotherapeutics, analyze the results of experiments and design new systems for high, consistent performance.
AgThera’s advanced probiotics are used to grow healthy animals.
AgThera and its sister company, General Probiotics, have been awarded Phase I/II/IIb Small Business Innovative Research grants by the US National Science Foundation and the USDA to pursue an AI-enabled, agile R&D program and create value for livestock producers globally.
SUSTAINABLE PROTEIN
INCREASING ANIMAL PROTEIN DEMAND
Global food production must double in the next few decades to meet the demand by earth’s population, which is projected to surpass 9 billion by 2050.
Due to the growing human population and historically high standards of living, there is a substantial increase in demand for animal protein. Global demand for animal protein has nearly tripled in the past three decades and is projected to nearly double again in the following four.
Plant-based protein can be made tasty, but animal protein is more nutritious because it contains all necessary amino acids for a complete diet. According to UNISEF, there are 130 million children worldwide whose growth is stunned because they have access only to plant-based proteins. The world needs more affordable, sustainable and healthy animal protein.
Animal agriculture has elevated human standards of living for thousands of years. It is part of the DNA of Homo sapiens sapiens. Arguably, we became sapiens sapiens thanks to agriculture. But the increasing demand along with a confluence of environmental factors, including water scarcity, climate instabilities and risks of life-threatening pandemics, are exerting pressure on global food security and the production of animal protein.
The U.S., while the leading agricultural producer globally, is not immune to these challenges. The National Academy of Sciences concludes in its recent report “Science Breakthroughs to Advance Food and Agricultural Research by 2030” that “[t]oday, the U.S. food and agricultural enterprise faces formidable challenges that will test its long-term sustainability, competitiveness, and resilience”.
OVERUSE OF ANTIBIOTICS
Science-based improvements have historically sustained the leading position of U.S. agriculture. One important example is the use of antibiotics. For decades, antibiotics have helped producers raise healthy livestock. Over-the-counter antibiotics have also often been used to promote growth and improve feed efficiency, even in the absence of infection. Arguably, antibiotics have facilitated and sustained, along with major advances in animal breeding and in production, major livestock productivity increases. For example, today 1.7 pounds of soy and corn in the feed of chicken will result in 1 pound of chicken meat, whereas forty years ago, farmers needed over 10 pounds of feed for each pound of grown chicken.
However, of growing concern is the continuing emergence of microbial resistance to first line antibiotics. Over 2.8 million people are sickened in the U.S. by multidrug-resistant infections and over 35,000 die every year.
One likely significant source of drug-resistance emergence is the widespread use of antibiotics in farm animal production. An estimated 14,000 tons of antibiotics, or approximately 70% of all antibiotics produced in the U.S., were administered to cattle, pigs and poultry in 2015. In complex systems such as food production, it is difficult to establish causal relationships between the use of antibiotics in animal feed and gastrointestinal infections where antibiotic-resistant microbes affect human populations. Nevertheless, there is ample evidence that transmission of resistant strains to humans does occur through food.
Because of these concerns, the FDA moved to curtail the use of medically important antibiotics for livestock production purposes. Drug companies have voluntarily adopted FDA Guidance #209 and Guidance #213, revising the FDA-approved labeled use conditions to remove the use of antimicrobial drugs for production purposes. The intent is to change the marketing status from over-the-counter to Veterinary Feed Directive (VFD) for antibiotics administered to animals.
With the VFD, beginning in 2017, over-the-counter antibiotics are being phased out in animal production. Antibiotics are now only prescribed for sick animals by licensed veterinarians. This is arguably a step in the right direction, ensuring judicious use of antibiotics and curbing the pace of resistance emergence. On the other hand, farmers now face the great challenge of raising healthy animals without preventive, growth-promoting antibiotics.
ENVIRONMENTAL IMPACT
From an environmental perspective, livestock production has become less sustainable as a result of phasing out antibiotics. Numerous pathogens impact the health of animals and result in staggering losses in animal production. Limiting the use of antibiotics may result in substantial losses of animals because of illness, substantial amounts of food lost, and a significantly negative impact on the environment.
On a global scale, food worth $750 billion is lost or wasted each year throughout the entire supply chain, with approximately 25% of food being lost during production. According to a study by the UN Food and Agriculture Organization (FAO), food loss and waste accounts for about 3.3 gigatones of greenhouse gas emissions (more than 7% of all emissions).
For example, it has been estimated that without antibiotics, 700 million additional chickens will need to be raised to meet poultry demand in the U.S. annually, requiring approximately 2 billion additional gallons of water and 5.4 million additional tons of feed per year.
ANIMAL WELL-BEING
Another important dimension relates to the well-being of animals. Animals raised without antibiotics are more likely to suffer from painful medical conditions. For example, poultry raised without antibiotics are three times as likely to experience ammonia burns in their eyes.
ONE HEALTH
The inter-dependences between a healthy planet, healthy animals, and healthy people were clearly and painfully exposed in early 2020, when mankind was ambushed and brought to a standstill by severe acute respiratory syndrome coronavirus 2. SARS CoV-2 abruptly ushered an unprecedented era of fear and uncertainty. The human toll is immense, with many millions of people sick and dead. Furthermore, the pandemic brought about a catastrophic economic slowdown. This new ‘economic ice age’ disrupted food production and supply chains globally. The urgent need for continued investment in technologies for healthy food, healthy animals and healthy people has been accentuated in unprecedented ways.
NECROTIC ENTERITIS
Focusing on the poultry industry, phasing out of antibiotics is resulting in higher frequency of necrotic enteritis (NE). NE is a result of intestinal damage usually occurring from Eimeria species in the presence of a toxicogenic C. perf. strain. It is assumed that Eimeria coccidia weaken the GI tract mucus layer, enabling C. perf. to reach and destroy epithelial cells.
NE causes a significant negative economic impact in broiler production. The acute form of NE leads to increased mortality in the broiler flocks, reaching 1% losses per day for consecutive days. The subclinical form of NE manifests as damage to the intestinal mucosa, decreased nutrient uptake, and reduced weight gain. Estimates of $6 billion annually have been reported as the economic worldwide impact of NE on the global poultry industry.
C. perf. in poultry is also a major risk for foodborne transmission to humans. Type A and type C C. perf. strains cause type A diarrhea and type C necrotic enteritis, respectively, in humans. Approximately 1 million cases of C. perf. infections are reported annually in the U.S.
PROBIOTICS
There are a panoply of alternative technologies to curtail pathogens in livestock in general, and C. perf. in particular, in order to raise healthy birds and produce safe meat. These technologies include vaccination against C. perf. and against coccidia, competitive exclusion products, prebiotics, and bacteriophages.
Probiotics or direct-fed microbials (DFMs) are considered a potential alternative to antibiotics to lower carriage of pathogens in livestock. DFM administration is also purported to induce better nutrient digestion and enhance meat production in animals such as cattle and poultry. In addition, these products are thought to modulate the immune response of animals.
The FAO defines probiotics as “live micro-organisms that, when administered in adequate amounts, confer a health benefit on the host.” A plethora of microbes are considered probiotics, including lactobacilli, bifidobacteria, bacilli and enterococci.
An official list of microbes that can be marketed as generally regarded as safe (GRAS) is compiled by the Association of American Feed Control Officials (AAFCO). These DFMs are considered either as fermentation or yeast products, and are accepted by the FDA as safe.
The responses to the administration of probiotics vary significantly, and are influenced by specific organisms used as probiotics, by livestock species, as well as by varying animal husbandry practices. There is nevertheless a large and rapidly expanding literature on probiotics, including ones active against C. perf.
The modes of action of specific probiotics are generally not well understood. Competitive exclusion has been long believed to be an important mechanism of action, with probiotic organisms colonizing the gut and inhibiting pathogens from taking hold. Inhibition may occur simply as a result of limited resources, or more actively by the expression and secretion of inhibiting substances, such as bacteriocins.
BACTERIOCINS
Bacteriocins are antimicrobial peptides (AMPs) produced by a wide range of bacteria. Numerous bacteriocins are typically very potent, acting at pico- to nanomolar concentrations. Bacteriocins also have a very narrow target spectrum; individual bacteriocins are active against a just few species or genera. Consequently, in terms of potency and specificity, bacteriocins can be very useful in therapeutic treatments where a particular pathogen is to be removed from a complex multi-species environment (such as in the gut) without causing adverse secondary effects as normally occur with common antibiotics.
For all the promise of bacteriocins, in particular, and of antimicrobial peptides, in general, a critical barrier in using these compounds as therapeutics exists. AMPs cannot be administered orally or intravenously for therapeutic purposes. As proteins, they are quickly degraded, and in high initial dosages they may become toxic to host cells. A technology that could safely deliver bacteriocins at the site of infection, inside the GI tract of animals, could unleash the potential of bacteriocins to fight bacterial infections, and offer a viable alternative to traditional antibiotics.
New technologies are urgently needed to replace antibiotics in animal production and to treat gastrointestinal infections in animals and humans caused by C. perf.
ADVANCED PROBIOTICS AND RECOMBINANT LIVE THERAPEUTICS
We develop a technology that eliminates C. perf. in chickens, lowers the risk of NE in birds, and lowers the risk of foodborne C. perf. infections in humans.
Benign bacteria are modified to produce antimicrobial proteins and to deliver these potent antibiotic proteins inside the gastrointestinal (GI) tract of poultry. Animal experiments validated the hypothesis that live biotherapeutic bacteria can safely reduce the carriage of pathogenic clostridia in pre-harvest chickens and lower the incidence of NE-induced mortality.
Commercialization of live therapeutics, as with any drug, requires registration of these organisms with the FDA. We presented experimental results to the FDA’s Center for Veterinary Medicine in December 2019. FDA CVM deemed our technology innovative and granted General Probiotics a waiver of sponsor fees to open an investigational new animal drug file.
The development plan for live therapeutics consists of elements unique to live microbes. These include effectiveness of engineered organisms, safety of use in animals, biocontainment, safe consumption by humans and low risks to the environment.
Upon approval, we will have label claims that have never before been made for other direct-fed microbials or probiotic-based products. Registration with the FDA will provide a major competitive advantage to our products over a vast market of probiotics, sold as alternatives for antibiotics in livestock production.
Ours is a platform technology. For every bactrerial or viral pathogen, we engineer a live therapeutic that kills the pathogen. We have launched efforts against Salmonella and avian flu in chickens, and against diarrheagenic E. coli and African swine Fever in piglets.
Our innovative new technology eliminates pathogens in animals and is becoming a key to human health, food security and a healthy planet.
For more information, contact us at info@agthera.com.