“We now know that bacteria can lead complex social lives, communicating and cooperating within multicellular groups,” says Sam Brown, professor in the School of Biological Sciences and a member/past director of Georgia Tech’s Center for Microbial Dynamics and Infection (CMDI).

Getting out and about in the microbial world leaves bacteria facing challenges such as competition from other bacteria, threats from bacteria-eating viruses, drugs that target them, and starvation when they can’t find a host organism. Brown and his fellow CMDI scientists now want to know how bacteria modify their behaviors in response to their social and physical environments. 

Two new grants totaling nearly $1.5 million will give them that chance.

One of the grants, a National Science Foundation award, focuses on how bacteria use clustered regularly interspaced short palindromic repeats — better known as CRISPR, a cellular immune system that helps bacteria ward off threats. CRISPR is perhaps best known as a gene editing tool.

The NSF grant also includes Rachel Kuske, professor in the School of Mathematics and a CMDI member, and Edze Westra, Professor of Microbiology at the University of Exeter in the United Kingdom. The NSF is partnering with the UK’s Biotechnology and Biological Sciences Research Council (BBSRC) for this grant.

The other grant from the Army Research Office (ARO) will study quorum sensing, a form of cell-to-cell communication, to determine how bacteria use it to “count” cells so that collective behavior can be turned on.

Both grants can help CMDI understand microbial behavior in ways that could eventually lead to manipulating or controlling bacteria, says Steve Diggle, CMDI director and a professor in the School of Biological Sciences.

“We are delighted by these new grants as they align closely with the core mission of CDMI because they will advance our understanding of microbial interactions, behaviors, and community dynamics,” Diggle says. “The knowledge generated could have transformative impacts on both academic research and practical applications.”

CRISPR protections, but only in a crowd 

Brown wants to make it clear that he and his colleagues won’t be doing any CRISPR gene editing themselves. “Our questions are more basic, focused on how the ‘inventors’ of CRISPR, bacteria, use this system to protect themselves from infection by phages (viruses that attack bacteria) and other molecular parasites of cells,” Brown says. 

CRISPR’s role is to recognize and cut out specific sequences of foreign DNA within bacteria. Yet what Brown calls the “dirty secret” of microbiology is that lab bacteria rarely use CRISPR to deal with novel viruses.

“Instead, they use the simple trick of deleting the surface receptors that the virus uses to gain entry to the cell,” he explains. Previous work by CMDI Early Career Award Fellow Ellinor Alseth found an answer to this puzzle: bacteria are more likely to use CRISPR as an immune mechanism when they are living in a multi-species community.  What Brown hopes to decipher are the molecular and ecological mechanisms that determine how life in a community can activate CRISPR functions.

“We further aim to build mathematical models of community dynamics, capturing both species interactions and evolutionary changes in a focal species undergoing viral attack,” Brown says. “This will have applied significance by helping the design of more robust microbial communities.”

Quorum sensing = a bacterial census 

Regarding the ARO grant, Brown says the standard view for quorum sensing is that bacteria use those signals as a way of counting cells. When the extracellular signal is above a certain threshold, the population is “quorate” (that is, reaches a certain number of cells), and collective behaviors can be turned on. 

Yet an increasing body of theory, along with experiments in Brown’s lab and others, has challenged this view “by highlighting that quorum sensing behaviors can also be shaped by the physical environment, such as diffusion, flow rate, and containment,” he says. 

Also, behaviors are not “turned on” in a threshold manner with increasing density. “In a high density ‘quorate’ environment, not all cells are expressing canonical quorum sensing-controlled behaviors. These challenges leave us with limited understanding of the functional roles of QS.”

“By examining the balance between intracellular mechanisms and multicellular behaviors, we will obtain a more comprehensive understanding of how bacteria collaborate and respond collectively to their environment,” Diggle adds.