Michael Terns

Adjunct Professor
Regents Professor

CRISPR: From basic biology to far-reaching biotechnology and biomedical applications.

CRISPR-Cas systems are recently discovered RNA-based adaptive immune systems that control invasions of viruses and other mobile genetic elements in prokaryotes (bacteria and archaea).

CRISPR-Cas systems function by capturing short invader sequences within the CRISPR locus of the host genome, producing short crRNAs from the CRISPR locus transcripts, and using the crRNAs to guide Cas protein-containing immune effector complexes to recognize and destroy the invading nucleic acids.

CRISPR-Cas based immunity is mediated by numerous and diverse Cas proteins and a given organism may possess one or more of the at least 16 distinct sets of known CRISPR-Cas immune modules. We currently know very little about how the key steps in the fascinating CRISPR-Cas immune response pathways occur for most of the systems. Using a powerful combination of molecular, genetic, structural, and biochemical approaches, we are determining the molecular basis for how various CRISPR-Cas systems acquire foreign DNA sequence in their CRISPR locus memory banks to provide heritable immunity against specific invaders.

We are also delineating the mechanisms by which diverse crRNA-Cas protein immune effector complexes selectively recognize and destroy foreign nucleic acids as a means to combat the viruses and other transgressors. A comprehensive understanding of how the structurally and functional diverse CRISPR-Cas immune systems each function is essential toward understanding the range of mechanisms that have evolved to protect multitudes of prokaryotes from potentially lethal viral attack.

The knowledge gained by our research program will contribute directly to ongoing efforts aimed at exploiting CRISPR-Cas systems as powerful research tools for genome editing and controlled gene expression as well as novel CRISPR-based, sequence-specific antibiotics to selectively combat bacteria and viruses that cause human disease and the spread of antibiotic resistance.

Research Interests:

We study CRISPR-Cas immune systems that protect prokaryotes from viruses and provide powerful research tools for important biotechnology and biomedical applications.

Labs (via personnel):
Labs:

Ottesen

 

Work in the Ottesen lab seeks to understand the structure and function of complex microbial communities, and the ways in which microbes interact with and perceive complex environments.  A major focus is the use of molecular ecological tools to observe microbial behavior in the environment.  This includes not only observing and tracking changes in which microbes are present in an environment, but also using community transcriptomics to observe changes in microbial gene expression over time.  By studying microbial behavior “in the wild”, we hope to gain a better understanding of the roles and significance of diverse members of the uncultured microbial majority. 

 

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Host and microbial contributions to microbiome stability and dynamics

 

We (and most other higher organisms) are hosts to complex gut microbial communities that aid in digestion and help shape our overall health.  We are using the American cockroach (Periplaneta americana) and its gut microbiome as a model system to understand gut microbiome stability and dynamics, particularly responses to dietary perturbation. We use the cockroach as a model host organism because they are robust, low-maintenance insects that reproduce quickly, eat a diverse, omnivorous diet, and their digestive tract hosts a highly diverse gut microbiome dominated by bacterial families found in the guts of many other animals, including mammals and humans. 

 

A key observation underlying our work in the cockroach is that the taxonomic composition of their gut microbiome is exceptionally stable following major dietary shifts.  We have since compiled genomic, metagenomic, and metatranscriptomic data showing that this is not due to an unusual distribution of metabolic roles among cockroach gut microbes, but is rather the result of a robust network of stabilizing interactions in the cockroach gut microbiome.  Analysis of gut metatranscriptomes suggests that fiber-degrading bacteria at the top of the gut 'food chain' are critical to this stability.  They respond to host diet shifts by utilizing whatever polysaccharides present in each diet or by breaking down host glycans under starvation conditions or in response to diets that lack polysaccharides.  This adaptation is sufficient to allow microbes that are 'lower' on the microbial food chain to maintain stable activity across diets.  Follow-up work has shown that synthetic diets containing high concentrations of single purified polysaccharide types can disrupt gut microbiome interaction networks, leading to blooms of specialized microbes and reduced gut microbiome stability.

 

We are now working to better understand microbial functional roles in the gut microbiota and the ways in which diverse microbial taxa contribute to gut microbiota stability.  We are also beginning new work examining how the host immune system and other host activities shape gut microbiome homeostasis.  Finally, we are using germ-free cockroaches to test hypotheses regarding the ways in which individual microbial interactions can shape gut microbiome composition and stability.

 


 

 

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Antibiotic resistance ecology and the movement of AR genes and pathogens across the landscape. 

A second project in the Ottesen laboratory grew out of our work on stream microbial communities.  While we were examining the microbiome of our local streams, we were surprised to find high numbers of antibiotic resistant bacteria and pathogens.  We have since followed up on this work to discover that antibiotic resistance is widespread in the greater Athens area, and is strongly linked to contamination with human fecal bacteria, suggesting that sewer leaks and failing septic systems may be responsible for much of the antibiotic resistance present in our watershed.

 

This work has caused us to become very interested in understanding antibiotic resistance in the human microbiome and how bacteria and antibiotic resistance genes move between humans and the environment.  A follow-up project showed persistent, asymptomatic carriage of antibiotic resistant E. coli in the guts of local residents, as well as horizontal transfer of AR genes between bacteria in the gut.

 

We are now seeking funding to follow up on this work with a population genomic analysis examining the movement of E. coli and antibiotic resistance genes between humans and the environment,  as well as a comparison of commensal and environmental E. coli with pathogenic isolates from human infections.