Discovering new strategies used in arms race between bacteria and the viruses that infect them

We usually think of bacteria as the enemy. Historically we’ve focused on the bad actors that infect and even kill us. However, bacteria have enemies of their own, which they must constantly ward off to survive. Dr. Kevin Forsberg, a postdoctoral fellow in Dr. Harmit Malik’s lab at Fred Hutchinson Cancer Research Center, considers bacteria’s struggle every day. His obsession with these bacterial skirmishes has now been rewarded with a significant accolade.

Forsberg is one of 10 people approved for a New Innovators Award from the National Institute of Allergy and Infectious Disease. He proposes to uncover novel ways that bacteria have evolved to defend against their viral assailants and how those viruses have evolved to overcome bacterial defenses. The $1.5 million grant, given to exceptionally creative scientists with potentially high-impact but early-stage ideas, will support Forsberg for five years as he establishes his own laboratory.

The New Innovator Awards, usually given to faculty members early in their careers, were only opened to postdocs like Forsberg this year. 

It presents a rare opportunity, said Forsberg, who earned a perfect 10-point score on his application.

“There is a great deal of uncertainty in the success of my proposal. I don't think other funding mechanisms would have considered me because of its inherently high risk. Apart from the money, getting approved for this grant is a pretty cool stamp of approval.”

Malik, his postdoctoral mentor, agreed.

“Kevin has always been comfortable operating in a space that might be seen as high-risk by many, but also has the potential for highest reward in opening up new avenues of research in this exciting area. I am delighted that his creativity and insights have resulted in this award, which will give him the perfect springboard to his independent lab,” he said.

Revealing the arms race between bacteria and their viruses

Like us, bacteria must protect themselves against viral infection. Bacteria-infecting viruses are called bacteriophages, or phages for short. Bacteria have evolved numerous defense systems to protect themselves against phages. For example, CRISPR, the precise gene-editing tool that’s swept the scientific community, is derived from a defense system that bacteria like Streptococcus pyogenes use to chew up phage DNA. Forsberg has developed methods that have allowed him to discover novel counter-defenses, dubbed anti-CRISPRs, that viruses use to overcome CRISPR’s protection.

But he believes that CRISPRs and anti-CRISPRs are just the tip of the iceberg in a billions-of-years-old battle between bacteria and phages.

“Many, if not most, defense and counter-defense systems are not described,” Forsberg said.

He proposes to find new ones by sifting through DNA extracted from microbiomes found in different areas of the body, which are not only chock full of bacteria but also the viruses trying to infect them. He plans to set up “combat chambers” in which bacteria will win against phages if they can defend themselves, and phages will win if they can counteract these defenses. Forsberg’s discovery system, unlike those designed by others, can find defense and counter-defense systems without knowing anything about them beforehand. This makes it perfect for finding systems that are unknown to science.

Ultimately, Forsberg is interested in understanding how these systems work.

“We might see that some defense systems are very specific in their ability to block certain phages, whereas others are more general,” he said. “I will also find many systems that have already been described, but some will be new — and that's where the juiciest stuff will be.”

Potential applications: microbial manipulations

Studying the unseen battle between bacteria and phages isn’t as esoteric as it sounds. As our understanding of the interplay between our microbiome and our physical and mental health grows, so too will our need for precise tools to manipulate our microbiome. And the growing threat of antibiotic resistance means we need to come up with different strategies to treat deadly bacterial infections.

Phages are already part of our arsenal against bacterial infection, though phage therapy has yet to be optimized. Right now, finding the right phage for the job takes trial and error. Forsberg’s approach could help scientists refine phage therapy giving them a better ability to predict which phages will or won’t work against bacterial infections.

His findings may also help investigators hoping to manipulate the microbiome in a more nuanced way, Forsberg said. Understanding the defense systems of specific bacteria could help us target specific strains to improve our health.

And there’s the potential to discover molecules that could become the basis of new biological tools. CRISPR may be the most famous, but modern molecular biology was built using tools adapted from this virus-bacteria arms race. But these potential applications depend on foundational discovery studies like those Forsberg plans to perform.

“My main goal is discovery: finding and characterizing and describing these new defense and counter-defense systems,” he said.

His next challenge? Finding a job. The New Innovator funding is contingent on securing a faculty position within the next year.

“I see plenty of reasons for Kevin to be optimistic,” Malik said.