Bacteria (illustrative). (photo credit: REUTERS)
Until a decade ago, scientists were not aware that bacteria had complex immune systems that could keep up with the pace of evolution in viruses called phages that infect bacteria. That changed with the discovery of what is now the most famous bacterial immune mechanism: CRISPR. This is a natural gene editor that has revolutionized the world of biological research in thousands of labs around the world. Researchers now understand that most microorganisms have sophisticated immune systems of which CRISPR is just one element; but there has been no good way to identify these systems.
In a massive, systematic study, Prof. Rotem Sorek and his team at the Weizmann Institute of Science in Rehovot have now revealed the existence of 10 previously unknown immune defense mechanisms in bacteria.
“The systems we discovered are unlike anything we had seen before,” said Sorek. “But among them, we think there are one or two that might have the potential to increase the gene-editing toolbox and others that point to the origins of the human immune system.” The results of their study were recently published in the journal Science.
Bacteria cannot rely on CRISPR alone in the war against phages, explained Sorek, a member of the institute’s molecular genetics department. Indeed many phages have “anti-CRISPR” proteins that cancel CRISPR activity, suggesting that other systems take up the slack.
Sorek and his team began their search for these systems by creating a computer program to scan all the bacterial genomes that have ever been sequenced – around 50,000 genomes in all.
Rather than look for sequences with predefined characteristics, the algorithms they created searched for the “statistical signatures” of genes involved in defense – for example, their location in “defense islands” where several defense-related genes are found near one another. Then, because immune system genes rarely work alone – even in bacteria – the researchers developed complex computer analytic methods so as to understand which genes join forces and work together to form a defense system.
Once they had narrowed down the possible defense genes from millions to several hundred, the researchers needed to test the candidate mechanisms they had identified. Rather than attempting to isolate the genetic sequences from hundreds of different bacteria, the team turned to synthetic biology: getting the genes made to order. They sent the strings of gene code – totaling something like 400,000 bases, or “letters” of genetic code – to a commercial lab where dozens of different multi-gene systems were synthesized for testing.
These synthetic systems were inserted into lab bacteria whose natural immune systems were inactivated. The bacteria were then exposed to phages and other infective elements to see if the transplanted defense system was a viable one. Out of the various systems the researchers examined, 10 strongly protected the lab bacteria from infection, thus identifying them as new immune defense systems. The researchers still don’t know how the new bacterial immune systems function.
“The fact that we managed to find 10 new bacterial defense systems implies there are even more out there,” concluded Sorek.
“The new discoveries are exciting because of the new windows they provide on the evolution of immune systems and the eternal battle between viruses and the organisms they infect. Any one of the new systems we found might be the next gene-editing tool – or perhaps even the foundation of even more exciting molecular tools.”
