Connecting Genomes and Microbes to Unlock New Therapies

Before the Human Genome Project, launched in 1990 and completed in 2003, the search for disease genes remained slow, tedious, and imprecise. Without a comprehensive human genome map, researchers relied on sparse genomic landmarks or genetic linkage mapping in affected families. At that point, fewer than 100 disease genes had been identified.

The results of the Human Genome Project, considered one of the most ambitious and important scientific endeavors in human history, greatly accelerated our knowledge of disease genes, ushering in a new era of genomic medicine. Today, scientists have identified more than 4,900 genes associated with single-gene mendelian disorders and traits or susceptibilities to cancer and complex disease.

At the same time, a growing body of evidence shows that the gut microbiome — the trillions of bacteria, fungi, and other microorganisms residing in our gastrointestinal tracts — has an outsized influence on human health and disease. Previous methods of studying the microbiome, similar to the crude genetic techniques used before the Human Genome Project, lacked precision and specificity. Newer research uses high-resolution microbiome analysis that focuses on strains instead of species, opening the door for the development of new biomarkers and therapeutics.

With the launch of a new center in May, the Icahn School of Medicine at Mount Sinai aims to merge discoveries in two critical areas — the human genome and gut microbiome — for the diagnosis and treatment of diseases. The Center for AI-Driven Genomic and Microbiome Medicine will facilitate collaboration among researchers with complementary expertise at Mount Sinai and beyond to help clinicians better predict which therapies will work best for a given patient.

For example, one topic that could greatly benefit from integrative study is cancer immunotherapy, which is only effective for about 30 percent of patients. An ongoing challenge in oncology is identifying patients most likely to respond. Some studies support genomics-guided immunotherapy, while others highlight the emerging role of the gut microbiome in predicting response. Despite sharing the same goal, such findings often remain siloed in their respective fields instead of synergized together.

“A bottleneck in the field of precision medicine is that most people either study the human genome but not the microbiome, or vice versa,”says Gang Fang, PhD, Director of The Center for AI-Driven Genomic and Microbiome Medicine and Professor in the Department of Genetics and Genomic Sciences at Icahn Mount Sinai. “We wanted to build on our momentum of studying both in the past decade, and believe we are uniquely positioned to take this initiative to seamlessly integrate them together.”

In particular, the Fang Lab specializes in long-read sequencing, which enables the sequencing of much longer DNA fragments than traditional methods. It has the ability to resolve more challenging genes or regions of the genome, such as those containing many repetitive elements, and detect previously inaccessible structural variants. Also known as third-generation sequencing, long-read sequencing has shed light on many previously dark regions of the genome from humans and other species.

Fang and his colleagues leverage long-read sequencing for high-resolution microbiome analysis that can pinpoint not just what species of bacteria are present in a sample, but what specific strains. For example, some strains of E. coli are beneficial to humans and naturally found in our intestines, while others can cause severe foodborne illness or even colorectal cancers. The difference between strains often comes down to only a few genes.

“Many current studies only look at the species resolution of the microbiome, like how much E. coli or Salmonella inhabits the gut,” says Fang. “But if we want to do precision medicine based on the gut microbiome, it’s important that we go down to the strain resolution.”

His lab also pioneered the use of DNA methylation — a process that modifies DNA and regulates gene expression — to differentiate strains of bacteria and investigate strain- to-strain variations within a person’s microbiome. Fang believes a more detailed microbiome profile could uncover key drivers and predictors of their individual response to a disease or treatment.

The Center for AI-Driven Genomic and Microbiome Medicine will add core members as well as affiliated members, with an initial research focus on neurodegeneration and cancer, hoping to facilitate productive connections among the attendees.