New research tools have let researchers explore the human microbiome, the collection of up to 30 trillion (million million) cells that coexist with the human cells in our bodies, including bacterial cells. Early findings show that most of the bacteria in the human microbiome are beneficial. However, some are linked to diseases. For example, the microbiome in the human gut has been linked to autoimmune diseases including Type I diabetes (T1D), Crohn’s disease, and ulcerative colitis. These are complex diseases which are affected by both host genetics and gut microbial composition. These two factors contribute to disease progression and affect a patient’s response to treatment. The incidence of these diseases is increasing worldwide, suggesting that non-genetic factors, including the microbiome and environment, are at play.
As of 2014, between 19 to 39 million people are estimated to have Type I diabetes (T1D). T1D results from a patient’s own immune system destroying the insulin-producing cells of the pancreas. When these cells are damaged and stop producing insulin, too much glucose (sugar) remains in the bloodstream, where it can damage organs and cause life-threatening complications, including kidney failure and cardiovascular disease. The disease afflicts one in 300 Americans, with incidence rising at 3% annually. T1D typically begins in childhood—although it can begin later—and its onset is preceded by a decrease in gut microbial diversity and an increase in microbial species associated with inflammation. Researchers found that early life exposure to specific bacteria may help or hinder the ability of the immune system to learn to properly recognize and develop antibodies against foreign agents rather than its own body, potentially changing the risk of developing T1D.
Crohn’s disease and ulcerative colitis are chronic conditions that affect millions of people worldwide, with a prevalence between 114 and 500 people in every 100,000 suffering from one of these diseases in various areas of the globe. These diseases are often diagnosed during young adulthood, and are characterized by ongoing inflammation in the digestive tract, frequently leading to debilitating complications. Both diseases are linked to microbial imbalances in the gut, including changes in the bacteria associated with maintaining a proper balance of regulatory immune cells and mucosal barrier function (which helps protect internal cells from a sometimes hostile environment outside of the cells). However, the precise mechanism of how this microbial community interacts with the host cells to mediate disease is still unknown.
Understanding patients’ microbial composition and how these microbes interact with the host immune system is therefore critical for designing novel treatments to eradicate these microbiome-associated diseases.
The microbiome bacteria are difficult to study individually, partly because they are difficult to grow in cultures outside of the body. Instead, gene sequencing has made it possible for scientists to investigate the collective genome of all of these microorganisms, which together contain 3 million genes. (In comparison, the human body has about 20,000 genes.)
The first steps to understanding the microbiome's collective genome and its role is to determine the structure of the protein molecule coded by each gene. The structure of a protein molecule determines its function.
A protein’s functions are a direct result of the structure (shape) that the linear chain of amino acids (protein building blocks) folds into. A protein’s function can sometimes be inferred from its sequence, since many of these sequences will have similar roles in organisms we know more about. However, knowing the structure of a protein can give you mechanistic insight into how proteins function, or give you information about sequences that are unlike other sequences we have seen before, and their role in the organism.
Knowing the structure of the proteins will permit further work in discovering protein function and how the proteins interact with other molecules. (See the Human Proteome Folding project, which ran on World Community Grid from 2004 to 2013, to find out more about genes and protein function prediction.)
But studying millions of genes, proteins, and their interactions is well beyond the capabilities of any traditional laboratory.
The Microbiome Immunity Project will tackle this problem by using computational protein folding, a process through which computers simulate how a protein 1-dimensional sequence folds into its final 3-dimensional structure. (For more information about computational protein folding, see the Human Proteome Folding project.) Knowing the structures of proteins can help researchers predict the functions of the proteins that they are studying.
While effective, protein folding simulations are resource-intensive and often require more computational power than scientists typically have access to. The Microbiome Immunity Project research team is therefore enlisting the help of World Community Grid volunteers, each of whom runs these simulations on their computers.
The protein folding simulations are done using a software tool called Rosetta, which has already been used on World Community Grid for the Human Proteome Folding project and has been used for a variety of other research efforts in antibiotic resistance, parasitology, and cancer genomics. Rosetta is developed in David Baker’s lab at the University of Washington, with collaborators across several academic institutions including New York University. It has been especially effective at predicting the structures of unstudied proteins.
Microbial communities contain vast biodiversity, and thus contain many proteins that have great evolutionary distances (very distantly related) from proteins already understood in well-studied organisms. Any structural similarities to already-known protein structures are impossible to determine by examining the gene sequence alone. But they can be detected once the structure of the protein is predicted using tools such as Rosetta.
The first phase of the project will predict protein structures for the three million proteins coded by the collective genes of all of the bacteria of the human microbiome. Having this structure information will enable the researchers to later do protein-protein docking experiments to better understand the interactions among the proteins. Then, further work will identify which proteins are most involved in enhancing or inhibiting diseases processes. This will lead to docking experiments to find drug candidates which can control those proteins and their interactions. Potentially, this may lead to novel treatments for the many diseases associated with the human microbiome.
The goals for the Microbiome Immunity Project are to:
- Use World Community Grid to generate a set of predicted protein structures of the entire human microbiome, containing 3 million genes.
- Share the results with other scientists around the world to further facilitate research on Type 1 diabetes, Crohn’s disease, ulcerative colitis, and the microbiome.