Genomic ‘tweezer’ ushers in a new era of precision in microbiome research

In a landmark study recently published in the journal Nature Methods, researchers at the Icahn School of Medicine at Mount Sinai have unveiled mEnrich-seq—an innovative method designed to substantially enhance the specificity and efficiency of research into microbiomes, the complex communities of microorganisms that inhabit the human body. 

Unlocking the Microbial World with mEnrich-seq

Microbiomes play a crucial role in human health. An imbalance or a decrease in the variety of microbes in our bodies can lead to an increased risk of several diseases. However, in many microbiome applications, the focus is on studying specific types of bacteria in a sample, rather than looking at each type present. For example, when studying infectious diseases, researchers might only be interested in a few harmful gut bacteria, but they are mixed in with many other bacteria. 

"Imagine you're a scientist who needs to study one particular type of bacteria in a complex environment. It's like trying to find a needle in a large haystack," said Gang Fang, PhD, Professor of Genetics and Genomic Sciences and the study's senior author. "mEnrich-seq essentially gives researchers a 'smart tweezer’ to pick up the needle they're interested in."

Once pulled out by the “smart tweezer,” researchers can assemble the genome(s) of the targeted bacteria, facilitating the study of diverse biomedical questions about them. This new strategy addresses a critical technology gap, as previously researchers would need to isolate specific bacterial strains from a given sample using culture media that selectively grow the specific bacterium—a time-consuming process that works for some bacteria, but not others. mEnrich-seq, in contrast, can directly recover the genome(s) of bacteria of interest from the microbiome sample without culturing.

mEnrich-seq effectively distinguishes bacteria of interest from the vast background by exploiting the “secret codes” written on bacterial DNA that bacteria use naturally to differentiate among each other as part of their native immune systems. 

Transforming Research and Health Care

The advent of mEnrich-seq opens new horizons in various fields:

• Cost-Effectiveness: It offers a more economical approach to microbiome research, particularly beneficial in large-scale studies where resources may be limited.
• Broad Applicability: The method can focus on a wide range of bacteria, making it a versatile tool for both research and clinical applications.
• Medical Breakthroughs: By enabling more targeted research, mEnrich-seq could accelerate the development of new diagnostic tools and treatments.

"One of the most exciting aspects of mEnrich-seq is its potential to uncover previously missed details, like antibiotic resistance genes that traditional sequencing methods couldn't detect due to a lack of sensitivity," Dr. Fang added. "This could be a significant step forward in combating the global issue of antibiotic resistance." 

Indeed, as demonstrated as one of three applications in this study, the authors used mEnrich-seq to directly reconstruct pathogenic E. coli genomes from urine samples from patients with urinary tract infections, which allowed the comprehensive analysis of the antibiotic resistance genes in each genome.

In another application, the authors used mEnrich-seq to selectively construct the genomes of Akkermansia muciniphila, a bacterium that has been shown to have benefits in obesity and diabetes, among several other diseases, as well as a response to cancer immunotherapy. This bacterium is hard to culture, so mEnrich-seq can be a useful tool to reconstruct its genome in a culture-independent, sensitive, and cost-effective way, which may facilitate larger-scale association studies with different human diseases.

The Future of mEnrich-seq

Looking ahead, the team has ambitious plans for mEnrich-seq. They aim to refine the method to improve its efficiency further and to expand its range of applications. Collaborations with clinicians and health care professionals are also in the pipeline to validate the method's utility in real-world settings.

"We envision mEnrich-seq as a sensitive and versatile tool in the future of microbiome studies and clinical applications," said Dr. Fang. 

The paper is titled “mEnrich-seq: methylation-guided enrichment sequencing of bacterial taxa of interest from microbiome.”

This work was supported by a grant number R35 GM139655 from the National Institutes of Health.

Competing interests

Lei Cao and Dr. Fang are the co-inventors of a pending patent application based on the method described in this work.

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About the Icahn School of Medicine at Mount Sinai

The Icahn School of Medicine at Mount Sinai is internationally renowned for its outstanding research, educational, and clinical care programs. It is the sole academic partner for the eight- member hospitals* of the Mount Sinai Health System, one of the largest academic health systems in the United States, providing care to a large and diverse patient population.  
 
Ranked 14th nationwide in National Institutes of Health (NIH) funding and among the 99th percentile in research dollars per investigator according to the Association of American Medical Colleges, Icahn Mount Sinai has a talented, productive, and successful faculty. More than 3,000 full-time scientists, educators, and clinicians work within and across 44 academic departments and 36 multidisciplinary institutes, a structure that facilitates tremendous collaboration and synergy. Our emphasis on translational research and therapeutics is evident in such diverse areas as genomics/big data, virology, neuroscience, cardiology, geriatrics, as well as gastrointestinal and liver diseases. 
 
Icahn Mount Sinai offers highly competitive MD, PhD, and Master’s degree programs, with current enrollment of approximately 1,300 students. It has the largest graduate medical education program in the country, with more than 2,000 clinical residents and fellows training throughout the Health System. In addition, more than 550 postdoctoral research fellows are in training within the Health System. 
 
A culture of innovation and discovery permeates every Icahn Mount Sinai program. Mount Sinai’s technology transfer office, one of the largest in the country, partners with faculty and trainees to pursue optimal commercialization of intellectual property to ensure that Mount Sinai discoveries and innovations translate into healthcare products and services that benefit the public. 
 
Icahn Mount Sinai’s commitment to breakthrough science and clinical care is enhanced by academic affiliations that supplement and complement the School’s programs. 

Through the Mount Sinai Innovation Partners (MSIP), the Health System facilitates the real-world application and commercialization of medical breakthroughs made at Mount Sinai. Additionally, MSIP develops research partnerships with industry leaders such as Merck & Co., AstraZeneca, Novo Nordisk, and others. 
 
The Icahn School of Medicine at Mount Sinai is located in New York City on the border between the Upper East Side and East Harlem, and classroom teaching takes place on a campus facing Central Park. Icahn Mount Sinai’s location offers many opportunities to interact with and care for diverse communities. Learning extends well beyond the borders of our physical campus, to the eight hospitals of the Mount Sinai Health System, our academic affiliates, and globally. 
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* Mount Sinai Health System member hospitals: The Mount Sinai Hospital; Mount Sinai Beth Israel; Mount Sinai Brooklyn; Mount Sinai Morningside; Mount Sinai Queens; Mount Sinai South Nassau; Mount Sinai West; and New York Eye and Ear Infirmary of Mount Sinai. 
 
 

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