Redesigning bacterial defense systems

The Nobel Prize-winning CRISPR-Cas9 is one of many biotech breakthroughs in gene surgery that rely on re-engineered enzymes from the bacterial immune system. Yet such new tools may still be hidden in the haystack of unexplored microbial defense mechanisms. In July, Assistant Professor Jacques Bravo, who wants to help shape the future of biotechnology, came to the Institute of Science and Technology Austria (ISTA) in Klosterneuburg. His work could also help make antibiotic-resistant bacteria treatable again. More on this in the interview.

You started your PhD in 2015, shortly after the development of CRISPR-Cas9, a genetic scissors that was unparalleled until then. This technology made it possible to cut and insert specific genes into living cells. Did that encourage you to work in this field?

Although I was aware of the exciting developments around CRISPR-Cas9, I did not start to engage with this topic and improve microbial defense mechanisms until after I received my PhD in 2019. Until then, I had been studying the structure of viruses using structural biology and biophysical techniques.

I then used the COVID-19 lockdowns as an opportunity to delve into the vast literature on CRISPR-Cas9. I also wanted to specialize in cryo-electron microscopy, a rapidly developing molecular imaging technique that can be used to observe biological samples in their natural state and at nearly atomic scales. So I ended up joining David Taylor’s research group at the University of Texas at Austin as a postdoc. This job opportunity allowed me to work on both topics—bacterial immune systems and cryo-electron microscopy.

Having patented three modified and improved CRISPR-Cas9 enzymes, how do you envision the next biotechnological advance in genome engineering?

More than 150 bacterial immune systems have been described in the past six years, and there is still a lot of untapped potential in this field. We are beginning to understand that bacteria have a wealth of mysterious defense mechanisms that require exquisite precision. These defense mechanisms are wonderful tools in molecular biology, and I am very interested in exploring the different systems, analyzing how they work, and figuring out how to optimize them for genome surgery.

If you were a bacteria, what would your ideal immune system look like?

A less understood mechanism is how bacteria protect themselves from plasmids. Plasmids are small, circular DNA molecules that can move between bacteria and different bacterial strains. Plasmids act like parasites in that they reduce the rate at which their host bacteria reproduce. Moreover, their evolutionary fate is not tied to a specific bacterial strain. Although they introduce new genes that can benefit bacteria, such as antibiotic resistance genes, their presence is a burden on the cells, so bacteria typically try to get rid of plasmids while simultaneously trying to get rid of beneficial ones that preserve genes.

Talking about antibiotic resistance: The downside of bacterial immunity is that patients are becoming infected with so-called superbugs. This has been called the “silent epidemic.” Are you looking for the next generation of “super antibiotics”?

There is a new treatment approach against antibiotic-resistant bacteria called phage therapy. This treatment uses special viruses called “phages” which can be translated as “bacteria eaters”. Many powerful antibiotics have a very broad spectrum, meaning they can target different strains of bacteria, but they can also wipe out a patient’s own microbiome, such as the gut flora. Phages, on the other hand, are very selective in terms of which bacterial strains they are effective against. Therefore, phage therapy can be used specifically to combat a specific spectrum of pathogenic bacteria, either alone or in combination with antibiotics. However, pathogenic bacteria can also develop resistance to phages. It’s a balancing act. My work could help find ways to resensitize bacteria to phage therapy.

Are you driven to find new cures for certain diseases?

I am primarily interested in understanding the molecular mechanisms underlying bacterial immune systems and how they can be improved. I am trying to rework the molecular blueprints of bacterial defense systems to make them more efficient and more accurate.

Her career has taken her from the University of Leeds to the University of Texas at Austin to the Institute of Science and Technology Austria (ISTA). How would you describe your journey?

As an aspiring structural biologist, I wanted to grow in a lab with more experience using cryo-EM, a technique that has seen a resurgence in the study of protein complexes in recent years. That’s why I initially moved to the University of Texas at Austin.

I chose ISTA because of its recognized strength in cryo-EM technology, but also because the institute is very diverse and multidisciplinary. Unlike other academic research institutions where departments are separated from each other, at ISTA it is very easy to exchange ideas and collaborate with scientists from different disciplines. I am happy to already have two members of the group, a lab manager and a postdoc, who have been supporting me since my first month at ISTA. I am excited to see how my team will develop and I look forward to working with other researchers from a wide range of scientific disciplines.

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Andreas Rothe
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