Primer: About the Microbiome and Synthetic Biology

A newly recognized organ essential to the body’s health and function

The human microbiota consists of hundreds of trillions of symbiotic microbial cells that live within and on each of us, and the human microbiome are the quadrillion genes of those cells. To put these numbers into perspective, there are 10 times as many microbial cells than human cells and 100 times as many microbial genes than human genes in each of us. The role of the human microbiome as an agent of health and a potential avenue for therapeutic intervention is rapidly evolving. Recent research has associated the microbiome with a host of diseases including autoimmune, CNS, metabolic and cancer.

Many scientists are beginning to regard the microbiota that resides in our gut as an additional human organ, albeit an organ whose function is still emerging. It weighs as much as many organs (somewhere between two and six pounds1), is highly organized, and carries out functions essential to our health.

In the gut microbiota, about 100 large groups of bacteria, known as phyla, possess a different repertoire of biochemical capabilities for activities, such as synthesizing vitamin B and vitamin K, metabolizing bile acids, sterols and xenobiotics, and fermentation of fiber. The genes of four of these phyla, Actinobacteria, Bacteroidetes, Firmicutes and Proteobacteria2, dominate the human microbiome.

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E. coli : An essential bacteria in the gut microbiome

E. coli is a large and essential family of proteobacteria (the small red slice) naturally present in the gut. E. coli Nissle (EcN) is a particular strain that occurs in the microbiota and has been widely used as a probiotic. EcN has been noted for its safety due to lack of virulence factors and immunogenicity, and these safety advantages make EcN ideally suited to be the starting point for creating new medicines. EcN can be engineered with precision programming to perform a variety of metabolic functions that treat diseases in a potentially safe and effective manner.

When administered regularly, a therapeutically engineered EcN will fulfill an essential metabolic function while blending with the existing flora and will only make up a small portion of the overall microbiome without colonizing in the gut. Just as other groups of bacteria in the microbiota carry out specific and essential activities, a therapeutically engineered EcN will also fulfill an essential metabolic function that is programmed into the organism. Synlogic uses EcN as one of the chassis for building its Synthetic BioticTM medicines.

Synthetic biology opens up product innovation

Synthetic biology is the intersection of biology and engineering. One branch of this burgeoning field is concerned with selecting and organizing enzymes into new synthetic metabolic pathways to solve medical and industrial problems. Examples include engineered bacteria that are used to produce biofuel or to treat oil spills and engineered yeast that produce the precursor of a critical anti-malarial drug. While these pathways do not exist naturally in bacteria or yeast, synthetic biology has been used to engineer these organisms to accomplish the needed metabolic functions.

The power of synthetic biology can be applied to microbiome-based therapeutics to unlock a vast range of new opportunities. Rather than creating new synthetic pathways to convert cellulose into ethanol or long chain hydrocarbons into short chain hydrocarbons, scientists can develop new pathways or shift important functionalities to the human microbiome to treat disease. These new pathways or functionalities are constructed into a genetic circuit composed of selected enzymes and other genetic elements. When these genetic circuits are incorporated into a microbial chassis such as EcN, a potentially safe and well tolerated therapeutic bacteria result. To maximize therapeutic potential, advanced synthetic biology tools and models need to be applied to ensure precise and accurate function of the therapeutic bacteria within the body. Synlogic has a broad set of proprietary synthetic biology tools and models to design therapeutic bacteria.

1 http://www.nih.gov/news-events/news-releases/nih-human-microbiome-project-defines-normal-bacterial-makeup-body

2 Nature Reviews Immunology 14, 827–835 (2014)