Microbiomes could hold keys to improving life as we know it

Microbial life forms including viruses, bacteria and fungi are the most diverse and abundant organisms on earth. They have shaped our evolutionary origins for billions of years and continue to have widespread impact on the planet, its environment and the species inhabiting it. Together, they make up microbiomes that influence each other, the environment, and the host organisms that these microbial communities thrive in. The UMIC foresees that the microbiomes populating our planet and its many diverse species and environments could be leveraged through genetic engineering for applications that improve the greater good, and that many milestones could be reached on this front within ten years.

"Microbes are everywhere. Therefore understanding microbiomes, whether they be the ones that live in and on our bodies or the ones in the environment, is essential to understanding life," said Silver, who in addition to being one of the faculty leaders on the Wyss Institute's Synthetic Biology platform, is also the Elliot T. and Onie H. Adams Professor of Biochemistry and Systems Biology at Harvard Medical School (HMS) and a founding member of the Department of Systems Biology at HMS.

The UMIC consists of leading microbiologists, ecologists, physical scientists, engineers, and scientists in the emerging field of synthetic biology. The group coalesced during a series of coordinated but separately convened meetings held by The White House Office of Science and Technology Policy and The Kavli Foundation. The proposal in Science got its roots from the UMIC's efforts to identify challenges and opportunities in microbiome research as well as their strategic recommendations for accelerating discovery that emerged from these meetings.

The power of genome sequencing and genetic engineering has enabled synthetic biologists like Silver and her colleagues on the Wyss Institute Synthetic Biology platform to begin harnessing these microbes for diverse applications that could impact our health, ecosystem, and production of food and energy sources.

"Understanding how [microbiomes] work might hold the key to advances as diverse as fighting antibiotic resistance and autoimmune diseases, reclaiming ravaged farmland, reducing fertilizer and pesticide use, and converting sunlight into useful chemicals," said Jeff F. Miller, Ph.D., Director of the California NanoSystems Institute and corresponding author of the Science paper.

By metabolic processes, microbes synthesize countless different molecules, which through genetic engineering could lead to colonies of microbial "workers" being used for the sustainable synthesis of pharmaceuticals, materials and chemical commodities. Genetically engineered microbes could also produce biofuels through metabolic processes and conversion of solar energy into liquid fuel, according to work already underway by Silver at the Wyss Institute and HMS.

Microbes also play a vital role in balancing biogeochemical processes, such as removing carbon dioxide from the atmosphere. The interactions between soil, plant roots and microbes also play an important role in plant health and crop yield.

Furthermore, the microbiomes in our gastrointestinal tracts regulate wide-ranging physiological, metabolic, immunologic, cognitive, behavioral, and psychiatric traits. Understanding and manipulating human microbiomes could be key to managing physical and mental health. Silver and her team have already begun developing several potential avenues for leveraging gut microbes to improve health. In collaboration with Wyss Core Faculty member James Collins, Ph.D., Silver has engineered genetically programmed bacterial "reporters" that can detect and record conditions in the gastrointestinal tract. And, working with Wyss Institute Founding Director Donald Ingber, M.D., Ph.D., and Wyss Institute Senior Staff Scientist Jeffrey Way, Ph.D., Silver is developing consortia of synthetic microbes that could be used to treat gastrointestinal illness.

Her expertise and experience in these emerging areas of synthetic biology has enabled Silver to contribute her thought leadership as a member of the UMIC to how the proposed Unified Microbiome Initiative could integrate focus areas to accelerate microbiome research.

"I'm interested in engineering microbes as a way to interrogate their behavior," said Silver. "The purpose of this unified initiative is to determine what are the big questions we have about the microbiome and what are the specific technologies we need in order to investigate those questions."

Some of the big questions the group hopes to address through an organized coalition include understanding how microbes assemble into communities and what makes them resilient or resistant to perturbation, how genes in the microbiome interact with one another, which genes in the microbiome are associated with which organisms, as well as how we can beneficially harness the microbiomes of humans, animals, plants and environments.

To find the answers to these questions, scientists must first be supported in the development of breakthrough technologies for investigating microbiomes. Specifically, the group recommends development of improved computational methods for analyzing and predicting the vast number of unknown genes and their functions comprising microbiomes; a transition from gene-specific to whole-genome based analysis through improved genome reference libraries and sequencing methods; developing high-powered imaging methods for visually interrogating communities of microbes down to the individual level; new adaptive modeling systems and data reporting tools; improved genetic engineering techniques for perturbing microbial communities; and novel methods to mimic natural environments for supporting microbiome growth in the laboratory, among others.

"Discovery of the importance of the existence and importance of the microbiome has provided a new frame of reference for our understanding of health and our environment," said Ingber, who in addition to directing the Wyss Institute is the Judah Folkman Professor of Vascular Biology at HMS and Boston Children's Hospital and Professor of Bioengineering at the Harvard John A. Paulson School of Engineering and Applied Sciences. "A nation-wide coordinated effort to invest in understanding and leveraging microbiomes could open entirely new frontiers in biotechnology and medicine, and lead to solutions that would not be possible in any other way."