You could say that the Human Genome Project missed 99 percent of the genes in the adult body. That’s because it didn’t sequence genes belonging to the vast communities of bacteria that normally live on and in us. Now a $1.45 million grant from the W.M. Keck Foundation to researchers at the Washington University in St. Louis School of Medicine will help fill this gap by funding a study to develop new approaches for isolating, sequencing and analyzing the genomes of “friendly” bacteria that inhabit the intestine and identifying the natural metabolic products that they synthesize in their native gut habitats.
The W.M. Keck Foundation, established in 1954 by the late W.M. Keck, founder of the Superior Oil Company, focuses its grants on pioneering efforts in the areas of medical research, science and engineering.
The grant supports a project led by Jeffrey Gordon, M.D., director of the Center for Genome Sciences (CGS) at Washington University in St. Louis, and reflects a partnership between his lab, the lab of Sean Eddy, Ph.D., associate professor of genetics, and members of the Washington University Genome Sequencing Center.
The CGS is an innovative, interdepartmental, interdisciplinary enterprise strategically placed next to the Genome Sequencing Center. It is a major facet of the University’s BioMed 21 initiative, which aims to translate genomic science into patient care. The CGS plays a catalytic role in helping to devise new ways to translate the genetic data obtained from genome sequencing projects to allow researchers to better understand the evolution and diversity of life on Earth, as well as help create new methods to diagnose and treat patients with common and uncommon diseases.
“The CGS represents a community of faculty and students with expertise in the biological, computational and physical sciences,” Gordon says. “We are dedicated to integrating concepts and technologies from a variety of disciplines so that we can analyze the massive amounts of information encoded in genomes and experimentally test predictions about gene functions that come from our computer-assisted analyses.”
Gordon views the human gut as “a bioreactor programmed with at least 800 different species of bacteria.” “Fortunately, these microbes endow us with key metabolic functions that we have not had to evolve on our own,” Gordon says.
He and his colleagues have used mouse models of the human gut ecosystem to show that intestinal bacteria allow calories to be harvested from otherwise indigestible components of the diet, such as polysaccharides. These microbes also regulate the amount of extracted energy that is stored in fat cells. The implication of these findings is that variations in the composition of gut microbial communities among different people may be an important factor that influences predisposition to obesity and obesity-related disorders such as diabetes and heart disease.
Unfortunately, comprehensive analysis of the composition and functions of these microbial communities, in health and in disease, has been hampered because the majority of gut bacteria are difficult or impossible to grow and study outside of the intestine. With the support provided by the Keck Foundation, the researchers will create new techniques for harvesting microbial communities along the length of the intestine and sequencing the genomes of new species, without having to culture them in test tubes.
They are also developing new computational methods for mining genome sequence data so that bacterial species can be more rapidly and accurately classified. A large publicly accessible database will be established that provides detailed molecular information about the gut ecosystem for researchers.
A second aspect of the project aims to directly identify the products of bacterial metabolism in the intestine. The goal is to characterize previously unknown chemical compounds that play important roles in regulating the properties of the microbial community and human physiology. To do so, the researchers will use a new type of mass spectrometer with an unprecedented capacity to accurately and rapidly identify these metabolites.
“We very grateful to the Keck foundation, which has committed itself to funding high-risk projects designed to overcome key obstacles in emerging fields in science so that rapid progress can subsequently be made,” Gordon says. “Their support of our studies of the genomic and metabolic foundations of mutually beneficial (symbiotic) relationships between microbes and humans will allow light to be shed on this previously mysterious interior world. Our objective is to understand how the human body functions as a carefully woven fabric of interacting species. Ultimately, such understanding promises to provide new ways of fortifying health and preventing or treating a variety of diseases both inside and outside of the gastrointestinal tract.”