Research sheds new light on how the CRISPR immune system has evolved

Reviewed by Emily Henderson, B.Sc.November 25, 2020

With new insights into how the CRISPR genetic tool – which allows direct editing of our genes – has evolved and adapted, we are now one step closer to understanding the basics of the constant struggle for survival that takes place in nature. The results can be used in future biotechnology.

In 2020, the Nobel Prize in Chemistry goes to Emmanuelle Charpentier and Jennifer A. Doudna for their discoveries on the molecular mechanism behind CRISPR-Cas and for the use of technology as a genetic tool. Although CRISPR-Cas has found many uses in biotechnology and medicine, it originates in nature, where it functions as a microbial immune system.

Just as our immune system remembers the pathogens we were exposed to earlier in life, CRISPR-Cas provides microorganisms with the ability to quickly respond to viruses they encountered previously by storing a small amount of viral DNA in their own genome.

CRISPR-Cas occurs naturally in most bacteria as well as so-called archaea. When examining the origin of life on Earth, the archaea are particularly interesting, as they form a kind of “missing link” between bacteria and higher eukaryotic cells like ours. Studies on these organisms can therefore provide us with important insights into how the CRISPR-Cas immune system has evolved over hundreds of millions of years.

New findings reveal why toxins are present among CRISPR-Cas genes

New research results from researchers from the Department of Molecular Biology and Genetics at Aarhus University – obtained in close collaboration with leading researchers from the University of Copenhagen and Old Dominion University in Virginia, USA, and published in two articles in leading journals international – has now shed new light on how CRISPR-Cas emerged early in the development of life on Earth and how this immune system is constantly adapting to new challenges.

Aarhus’s research team – led by Associate Professor Ditlev E. Brodersen – discovered how part of CRISPR-Cas that is responsible for incorporating foreign viral DNA into the microorganism’s genome originated from another very common type of genes. in bacteria and archaea which surprisingly encode toxins.

The new knowledge then provides insights into an evolutionary process in which toxin genes were present early in the development of life and over time were integrated and adapted as part of the CRISPR-Cas modules that many microorganisms possess to date. For the first time, we have an answer to a question that has puzzled researchers for a long time, which is why toxin genes exist among CRISPR-Cas genes.

This understanding of how certain proteins are “recycled” in different situations is extremely useful for researchers. because when one understands the entire repertoire of functions that certain proteins possess, it opens up the possibility of using them as specific tools in genetic engineering. For example, it might be possible to get pathogenic bacteria to direct their CRISPR-Cas systems towards themselves and thus avoid infection. “

Dr. Ditlev E. Brodersen, Associate Professor, University of Aarhus

An ongoing battle between microorganisms and viruses

In another article, published in the renowned magazine, Nature Communications, the researchers describe new findings that provide insight into the constant battle between microorganisms and viruses that represent their worst enemies.

In a puddle of boiling mud in Iceland lives a very special organism, an archaea called Sulfolobus islandicus, which for millions of years has adapted to life in this place, which with a constant temperature of 80-100 ° C and a corresponding acidity acidity of the stomach is one of the most inhospitable places on earth.

But even though Sulfolobus has chosen a very unattractive place to live, it still encounters resistance, not least from small rod-shaped DNA viruses that constantly puncture cells and shoot their foreign DNA into them, causing Sulfolobus to explode in a wealth of new viral particles. To avoid this fate, Sulfolobus developed a CRISPR-Cas defense, thanks to which it stored small parts of the viral DNA in its genome in order to resist these attacks.

Anti-CRISPR – Tilt the cart

But in the ever-escalating battle between life and death, the virus has developed a countermeasure: it has managed to pull it off by producing a small weapon, an anti-CRISPR protein that, like upsetting the cart, blocks the CRISPR-Cas response to Sulfolobus.

New results from Aarhus University’s Ditlev E. Brodersen group – generated in close collaboration with Associate Professor Xu Peng of the Department of Biology at the University of Copenhagen – now show for the first time how this fight plays out in boiling pools. .

The researchers were able to visualize how the anti-CRISPR protein binds strongly to the larger protein in the CRISPR-Cas system, thus directly preventing it from destroying viral DNA. In this way, the virus bypasses – at least for some time – being rejected by CRISPR-Cas. The new findings provide scientists with insight into the arms race that is constantly taking place in nature and how the evolution of life is actually a constant struggle for survival.

– “We now know the details of how the anti-CRISPR protein can block the CRISPR-Cas immune system, so the question is what will be the next move in this arms race,” says Ditlev Brodersen. “Maybe the microbes will start forming anti-CRISPR proteins, a third type of protein that can prevent the anti-CRISPR protein from working, but we have yet to find them in Sulfolobus archaea. So now the ball is back. Sulfolobus’ la half the field, “says Ditlev Brodersen,” and the cold war is always hot in the boiling pool. “