Building Artificial Antibiotics
Infections caused by antibiotic-resistant bacteria represent a growing public health crisis. Globally, by 2050 as many as ten million people are predicted to die each year as a result of these infections unless new treatment modalities are discovered and implemented. To address this looming crisis, we draw inspiration from biomolecules produced in the biological world, focusing on proteins. Proteins perform the amazing cellular tasks required for life, such as protecting all existing organisms on earth from potentially harmful invaders. Proteins are thus the workhorses of life and a source of biologically active molecules with therapeutic potential that we are just beginning to explore.
The versatility of proteins is due, in part, to their vast unparalleled combinatorial space: 20n (n is the number of amino acids present in any given protein chain and 20 is the number of natural amino acid monomer building blocks). Yet, we do not have the tools to properly engineer these diverse molecules. Proteins are also promising drugs, as their primary amino acid sequences can be easily tuned to achieve specific biological functions inside living cells. Despite the potential of protein-based therapeutics, exploration has stagnated because naturally occurring peptide scaffolds have only limited diversity and are expensive to produce. Moreover, methods of rational design do not yet exist for proteins. We aim to provide solutions to these grand challenges in protein engineering by bridging synthetic biology and computational biology.
Our approach is to start small: we build foundational computational synthetic biology frameworks to rationally develop peptides, tiny proteins that display great sequence diversity but are more amenable than larger molecules to redesign and engineering. We aim to expand nature’s repertoire by basing the design of synthetic peptides on useful properties discerned in natural peptides. Our overarching vision is to generate a universal encyclopedia encompassing peptides that target every medically relevant microbe and to devise antimicrobial therapies that nature has not previously discovered. The synthetic peptides that we are developing offer solutions to some of the most pressing unmet clinical challenges we face, including the treatment of currently untreatable antibiotic-resistant infections.
Discovering New Antibiotic Properties in Biological Information
To achieve our goal of discovering novel therapies to treat some of the most devastating diseases in our society, including drug-resistant infectious diseases:
1) We perform bio-prospection expeditions to discover new antibiotics in nature. We have already described numerous peptide antibiotics derived from natural sources such as animals, plants, marine invertebrates, and insects. Several of these peptides are efficacious not only in vitro but also in animal models;
2) We decrypt biological systems for the discovery of novel useful tools and therapies. For instance, small amino acid patterns are often encoded in larger proteins. Because their biological function is unknown, however, the therapeutic potential of these protein fragments has not yet been exploited. To interrogate biological systems, we develop synthetic computational biology approaches (e.g., pattern recognition algorithms) to browse through large biological datasets (e.g., protein databases or experimental datasets). We can then extract amino acid sequences associated with a predicted function.
Generating Technologies for Microbiome Engineering
The gut microbiome plays roles in nutrition, immunity, metabolism, and the development and function of the nervous system. Suitable tools, however, do not yet exist for engineering the microbial communities that constitute the human microbiome. We are developing such tools to precisely understand the functions of microbiome communities and to provide potential therapies for diseases mediated by the gut microbiota.
Developing Tools for Synthetic Neuromicrobiology
The gut microbiome communicates with our brain to regulate important aspects of physiology and behavior. Multiple diseases have been linked to defects in this communication. Targeting the gut-brain axis via precise manipulation of our microbes thus offers an unprecedented opportunity to access and influence brain centers involved in fundamental physiological processes and conditions that imperil health. Positioning ourselves at the interface of microbiology and neuroscience, we seek ways to modulate gut-brain interactions.