University researchers are smarter than the average bacteria.

Recent developments in life science have uncovered the Achilles heel of bacteria is that which keeps it safe — its immune system.

“We’re studying an immune system that exists in prokaryotes,” said Rebecca Terns who co-authored the research with her husband Michael Terns, both on the faculty in biochemistry and genetics at the University. “It’s an immune system that, for as long as we’ve been studying bacteria, people didn’t realize existed until just five or so years ago. It’s a very recently discovered immune system.”

And for these researchers, leading the way is an exciting endeavor.

“We are really lucky to be in the position of delineating this new bacterial immune system that nobody knew anything about five years ago and you’ll be reading about in your textbooks someday,” M. Terns said. “It’s really cool to be in the position of being the first ones to understand how bacteria defend themselves against viruses and plasmids.”

The discovery

The bacterial immune system works differently than the human immune system, which R. Terns cited as a possible reason it was undiscovered for so long.

“In our immune system we have antibodies, protein-based molecules that recognize invaders and bring in the rest of the immune system to target the invader for destruction,” she said. “This immune system is RNA-based, so the recognizing molecules are small RNAs — which is probably part of the reason the immune system went undetected for as long as it did.”

When bacteria are infected, they take on part of the invader’s DNA or RNA, effectively learning about the invader.

“When a bacteria, for example, is infected with a virus, this system somehow acquires a little fragment of the virus’ DNA and takes that little fragment and incorporates it into a special locus in its own genome,” R. Terns said. “That locus, where that little fragment of identifying viral DNA is integrated is called the CRISPR. Within the CRISPR locus, that bacteria can have 200 little fragments of viruses that it can now recognize — just like your body has lots of different antibodies that recognize different invaders.”

Once the bacteria knows its invader, its immune system kicks in. The bacteria employs specific proteins to fight and eventually rid itself of the invader using the CRISPR-Cas system — composed of the CRISPR locus and Cas proteins encoded in the bacterial genome adjacent to the locus.

“The bacteria makes an RNA — a copy — of its CRISPR locus and that’s processed down to these little RNAs,” R. Terns said. “So what happens is that the CRISPR RNA recognizes that virus when it’s present in the cell and brings the Cas proteins with it and the Cas proteins cleave or somehow destroy the viral DNA or RNA.”

 Behind the scenes

To produce such groundbreaking discoveries requires a certain degree of teamwork.

And M. and R. Terns have the bio-chemistry it takes to work well together.

The two, who have been co-authoring work for 16 years, have been authors of many research endeavors at the University.

“It’s always a true joint effort,” M. Terns said.

But this research has been particularly special for the two.

Despite the various projects they work on — including the handful they have now — this discovery has “trumped everything.”

“We’re really excited about this particular project,” M. Terns said. “We have a lot of different projects going on but this particular project has captivated us and we’re really happy to be pioneering the research in this area.”

The research

As researchers are wont to do after discoveries, the Terns began to seek implications and dig farther into what the discovery meant for science.

“So our thoughts were: Can we get this same system to cleave any RNA that we wanted to cleave to utilize it as a research tool or for other purposes?”

And the questions pushed the Terns to the Beta-lactamase gene, which provides bacteria with resistance to Beta-lactam antibiotics — the most broadly prescribed class of antibiotics including amoxicillin.

“We decided to see if we could get the complex to cleave that RNA and we were successful,” R. Terns said. “We can engineer one of these little CRISPR RNAs to recognize a specific site in the Beta-lactamase messenger RNA and cleave that mRNA at a predictable site.”

But that predictable site does not necessarily have to be the Beta-lactamase gene.

“We can engineer those RNAs and program the system to cleave not only its natural targets, but the RNAs of the cell itself,” M. Terns said.

By using this technology, researchers could map unknown parts of a bacterial genome.

“If we wanted to know, for example, what a particular gene does, we could knock out the function of that gene by introducing one of these engineered RNAs to cleave that particular gene product and look to see what the phenotype of the bacteria is when you knock that gene out,” R. Terns said.

But the implications of the research theoretically reach farther than the lab. M. Terns cited the agricultural and industrial sectors as spheres this research could influence.

“If you had a strain of bacteria that you used for some particular purpose, like producing biofuels, and there was a particular gene in those strains and it would be beneficial to reduce the production of that gene product — maybe to make the bacteria grow more robustly or faster or under different conditions — you could tinker with the gene expression within that commercial strain to improve production,” R. Terns said.

However, despite the many ways this research could affect industries in the future, M. Terns said this is only the beginning of what is to come.

“There are a lot of applications to this work but they’re down the road,” M. Terns said. “We think of this as sort of developing a research tool that will open up a lot of avenues for industrial and biomedical applications.”

Moving forward, the two plan to expand their research in this area.

“We’re branching off to study different immune systems in other organisms,” M. Terns said. “There’s just a huge scope to this research and we’re exploring that.”