UW Researcher's Papers Ranked Among 'Most Influential'

Telling bacteria “Stay!” or “Go!” really is like giving commands to man’s best friend to sit or fetch -- you just need to know the key words in micro-speak to unlock the language.

One such key is cyclic dimeric guanosine monophosphate, mercifully shortened to c-di-GMP and, in bacterial-speak, is responsible for their deciding to stay put or swim away.

University of Wyoming molecular biologists were among the first to determine how the molecule is made and broken down.

Two papers by Professor Mark Gomelsky’s laboratory were nominated by the editorial board members of Journal of Bacteriology to represent the 100 most influential papers published in this journal since 1916. Journal of Bacteriology, the flagship journal of the American Society for Microbiology, is celebrating its centennial.

The Gomelsky papers published in 2005 helped open a new field in bacterial signaling. Each paper has acquired about 400 citations, according to Google Scholar.

“We stumbled upon this new field quite unintentionally,” Gomelsky says. “But, in some ways, intentionally.”

Gomelsky wasn’t aware of c-di-GMP and had no intention of studying it. The late professor, Moshe Benziman of Hebrew University, Israel, discovered c-di-GMP and described enzymes involved in its syntheses and hydrolysis (Gomelsky dedicated both papers in Benziman’s honor).

Gomelsky’s lab was studying light-activated proteins at the time (it still does), and one of their proteins was strange, containing “domain of unknown function 1” and “domain of unknown function 2.”

Domains are large modules from which proteins are made. Gomelsky wanted to understand how their strange, light-activated protein worked.

“I was stunned,” he recalls. “Unknown domains 1 and 2 were not just in ‘our’ protein; they popped up everywhere in the bacterial genomes. It was difficult to believe people would not know about this apparently undiscovered universe.”

He decided to address the issue head on, driven by scientific curiosity, by deciphering what these domains actually do.

And did.

“Our studies were not overly sophisticated,” Gomelsky says. “We explained that c-di-GMP was made by the domain of unknown function 1 and that it is broken down by domain of unknown function 2. We also offered hard evidence that c-di-GMP is a widespread and probably important molecule.”

Once these papers were published, along with a few others about the same time, a surge began.

“Suddenly, there was the gold rush,” Gomelsky says. “At the beginning, there were just a few papers exclusively from the Benziman group, then a handful of influential papers appeared in 2004-05, and now the annual number of papers about c-di-GMP is in the hundreds.”

Why is understanding whether bacteria attach to a surface and stay put or swim by without attaching important?

Gomelsky explains that when grown on surfaces -- whether human organs, medical implants or water pipes underneath kitchen sinks -- bacteria form biofilms. Biofilms are like bacterial cities in which cells are very diversified.

Gomelsky compares bacterial diversity to human diversity.

“Like in a city, people differ by occupation, incomes, origins, mentality. The same type of diversification happens in bacterial cities, biofilms,” he says. “Growth on surfaces within self-made protective matrices produces bacteria with different physiologies. Diversification provides strength to bacterial communities, just like it does to human communities. It’s difficult to eradicate a diverse population.”

Antibiotics dropped into a test tube culture, where bacteria are similar, will kill practically all the bacteria.

“If you do the same thing with biofilm, the antibiotic will kill the top layer but won’t necessarily even reach the inner areas due to physical and chemical constraints,” Gomelsky says. “Some of the cells in the bacterial city are dormant and not even susceptible to antibiotics.”

Treated chronic bacterial infections go away, but usually come back because some of the bacteria survive the antibiotics onslaught. After multiplying in the absence of the antibiotic, they can cause another episode of acute infection, Gomelsky says.

If scientists could command bacteria to go instead of allowing them to build a biofilm or, if they could tell bacteria in an existing biofilm to disperse, antibiotics would destroy bacteria more readily.

“Speaking bacterial language helps us design ‘psychological warfare’ agents against pathogens,” he says. “We want to trick bacteria into making bad decisions during infection.”

By combining antibiotics, which are regular warfare agents, with drugs that meddle with bacterial “minds,” Gomelsky says bacteria could be eradicated more efficiently. Studies on c-di-GMP opened the ways for designing new types of antibacterial drugs.

Former Ph.D. student Dmitri Ryjenkov, postdoctoral researchers Marina Tarutina and Oleg Moskvin, and technician Andy Schmidt worked with Gomelsky on this project. Ryjenkov is employed by a U.S.-Russian biotech company; Tarutina returned to Russia; Moskvin is a research scientist at the University of Wisconsin; and Schmidt went on to study medical technology.