Michael Terns of the University of Georgia is the recipient of a $3 million Maximizing Investigator Research Award, or MIRA, from the National Institutes of Health to further research on CRISPR—bacterial immune systems harnessed as powerful human gene-editing tools—and to begin studying Anti-CRISPR, or ACR, proteins used by viruses to evade the CRISPR immune systems.
“We’re studying a global viral pandemic. Rather than a virus against humans, it’s other viruses against bacteria. This happens everywhere in every environment across the planet,” said Terns, Distinguished Research Professor of Biochemistry and Molecular Biology in UGA’s Franklin College of Arts and Sciences and principal investigator for the project. “We have been studying how the bacteria defend themselves against potentially lethal viral infections. Now we are also investigating how the viruses respond and protect themselves against the CRISPR immunity.”
Fundamentally, CRISPR functions as the immune system inside single-celled organisms to ward off viruses. When a virus attacks a bacterium, small segments of the viral DNA are captured and incorporated into the bacteria’s genome. With this new information, the bacteria make RNAs that bind with proteins to form immune complexes that seek out and destroy the viral DNA and prevent infection.
As the bacterium encounters new viral threats, it accumulates a memory bank of past infections in its genetic code that help it fight off any repeat offenders, but some of these viruses have found a way to circumvent the immune system using ACRs.
There are over 30 distinct CRISPR systems, and researchers are only beginning to understand the complex molecular processes that make some of these systems work and the diverse ways that ACRs selectively disarm specific CRISPR systems.
“This is an evolutionary arms race between bacteria and viruses,” Terns said. “Bacterial CRISPR systems provide powerful immunity against viruses. In turn, viruses have evolved ACRs to intercept and block the CRISPR immune systems of the bacteria. This grant will enable us to expand our understanding for how specific CRISPR systems provide viral immunity as well as to elucidate how viruses thwart CRISPR immunity via encoded anti-CRISPR proteins.”
Like a pair of skillfully guided molecular scissors, CRISPR allows scientists to precisely edit sequences of DNA in everything from plants to humans, and it could one day be used to alter the genes that predispose humans to myriad diseases, including cancer, diabetes, cardiovascular disorders and mental illnesses. A key goal of Terns’ research is to exploit knowledge of the CRISPR systems and components to establish innovative research tools with associated transformative biotechnological and biomedical applications.
Terns is quick to point out that this project is focused primarily on basic science and the examination of fundamental biological processes.
“We didn’t know where this research would lead when we first started, and now researchers across the globe are using several innovative CRISPR-based technologies that each stemmed from fundamental research into the biology of bacterial/virus interactions. These systems are having revolutionary impacts in biotechnology, medicine and agriculture,” Terns said. “There are many more systems to be characterized and added to the CRISPR toolbox to help or supplement existing CRISPR research tools. That’s why we were awarded this grant, to explore the diversity of these fundamental immune systems, as well as the biology of how viruses combat them.”
“Dr. Terns has been a true scientific adventurer over the years, and now he is at the forefront of exploring new CRISPR systems with even greater potential to revolutionize gene editing,” said Christopher West, professor and head of the department of biochemistry and molecular biology. “The renewal of his NIH-MIRA grant will enable his group to study the biochemical foundations of these new systems, which will be essential for their potential exploitation for the next generation of gene-editing tools. The beauty of the MIRA grant mechanism is that it entrusts and supports the scientist to find and pursue the best new leads that might not even have been imagined at the time of writing the grant proposal.”