The root of disease is biological, so we should use biology to address it. That’s the sentiment echoed by the leaders in microbial engineering at the year’s biggest synthetic biology conference, SynBioBeta.
Small molecule drugs are static. They cannot respond to a biological environment or microenvironment. The microbial ecosystems in our guts and on our skin are in constant flux. We need drugs that can keep up.
Half of the biomass defining the various microenvironments in and on our bodies is microbial. How can we use those microbes to improve our health?
The concept of using microorganisms to boost health is not new. Probiotics have been popular staples in the supplement aisle for years, but there’s very little evidence that these naturally occurring bacteria actually make a difference in a normal, healthy body.
At the same time, we’ve been using genetically engineered microbes outside of the body to successfully manufacture medicines for decades. Biologics have revolutionized care for diabetics and are occupying a fat corner of the market for treating a variety of additional autoimmune diseases. We also use genetically engineered microbes to make vitamin supplements.
The next frontier for research is almost obvious: can we genetically engineer microbes to produce therapeutic molecules in situ? In principal it makes perfect sense. Bacteria are genetically tractable, we already know we can use them as biofactories, and there is a long list of them that are generally considered harmless or beneficial.
In practice, there are a lot of potential stumbling blocks. To be effective, engineered bacteria have to make it to the target site alive, compete for resources with native bacteria, and do enough of whatever they’re engineered to do to make a real therapeutic difference.
Nonetheless, startups and tech giants alike are making headway, racing to secure a foothold in the market by producing the first clinically proven engineered probiotic. Below, we highlight four companies featured at SynBioBeta 2019 that are using living medicine to treat conditions from eczema to cancer.
Actobiotics is a subsidiary of the somewhat erratic tech giant Intrexon. Intrexon is a biotech company so prolific they managed to secure the domain dna.com. Their interests spread from genetically engineered mosquitos to non-browning apples to CAR-T cell therapy.
Actobiotics was formed in 2006 to focus on developing Lactococcus lactis for various therapeutic applications. Lactococcus lactis is commonly used to make cheese and is generally recognized as safe (GRAS status) by the FDA. Actobiotics has secured more than 250 patents (50 more pending) for the use of L. Lactis to deliver protein-based therapeutics.
The many target applications Actobiotics is currently focusing on include rhinosinitus, irritable bowel disease, oral mucositis, phenylketonuria, metabolic disease, and skin disease. Recently, Actobiotics received approval for clinical trials in type-1 diabetes and celiac disease. Both therapies directly address the autoimmune component of diabetes and celiac by delivering a cytokine.
Azitra is a probiotic company focused specifically on the skin microbiome. Their approach is threefold: applying natural strains that are beneficial, using skin bacteria to deliver therapeutic molecules or antimicrobials in situ, and applying products derived from skin bacteria.
Azitra’s bug of choice is staphylococcus epidermidis, a normal resident of the human skin microbiome. Their target applications include eczema, ichthyosis vulgaris, and orphan skin diseases (including Netherton syndrome).
Phase I clinical trials by Azitra targeting rashes that result from cancer therapy are now underway. In this case, they’re simply using the unmodified S. epidermidis bacterium. Additional products in preclinical development employ genetically engineered S. epidermidis for the delivery of structural proteins or proteinases
Synlogic, a startup that spun out of a collaboration between Tim Lu and Jim Collins at MIT, is taking a more complex approach to engineering living medicines. Instead of simply engineering bacteria to produce a certain protein, they’re engineering entire pathways to produce living medicines that are tunable or respond differently to particular environments.
Synlogic currently has one strain in phase 1 clinical trials that was engineered to produce an enzyme that breaks down Phenylalanine for people with phenylketoneuria. They use a harmless strain of E. coli known as Nissle, and they’ve engineered it to respond differently depending on its location within the body. For the bug currently in clinical trials, that means waiting to produce the target enzyme until the engineered bacteria reaches the small intestine.
Other engineered strains currently in preclinical development by Synlogic include a cancer therapeutic that is designed to specifically activate the immune system at the site of a tumor.
Eligo Biosciences, also a Lu lab spinoff, is taking a slightly different approach to living medicines. Instead of introducing engineered bacteria directly, they’re using phages to target existing microbial populations. Like Synlogic, they’re attempting to deliver not only single genes, but entire genetic circuits.
Eligo’s approach is focused on three target areas:
1) diagnostics: detecting specific strains of bacteria or molecules in the microbiome
2) antimicrobials: expressing nucleases that selectively kill particular bacteria
3) biologics: expressing proteins in situ
Eligo was founded only five years ago, so their technology is still in the early stages of development, but the concept is definitely making headlines.
The next major hurdle for living medicines
Despite challenges, three of the four companies paving the path for engineered probiotics have seen enough evidence for success to invest in clinical trials. But there’s a difference between creating a drug that works and producing it at market scale for a reasonable price and deploying it commercially.
Panel speakers at SynBioBeta agreed that one of the main challenges remaining for living medicines is the time it takes to manufacture engineered microbes in a GMP-compliant environment. Once plausibility is demonstrated it could thus take years to achieve the kind of scalability and stability that is necessary to make living medicines a reality.