In this interview, we talk with Dr. Jacob Bobonis on his new discovery about retrons and how they could be used to tackle antimicrobial resistance.
Could you please introduce yourself and tell us what inspired your latest research on retrons?
My name is Jacob Bobonis and the goal of my PhD in the laboratory of Dr. Nassos Typas at the European Molecular Biology Laboratory (EMBL) in Heidelberg was to find the biological function of a mysterious group of bacterial genetic elements called retrons.
What are “retros” and what characteristics make them difficult to study?
Retrons were discovered in the 1980s in bacteria because of their ability to produce massive amounts of small single-stranded DNA in vivo. Early work showed how this small DNA, called multicopy single-stranded DNA (msDNA), is generated by dedicated reverse transcriptases and retron-encoded small RNAs, but the function of msDNA and retrons remained a mystery for nearly four decades.
The main challenge in finding their function was that the retrons appeared to be non-essential for bacteria, but as is so often the case, people were not looking in the right place.
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In your latest research, you discovered a new feature of retrons. Can you please tell us more about how you did your study and what you discovered?
Our study details the discovery of how a retron affects the fitness of a pathogen (Salmonella) and how we used this phenotype to discover that retrons are growth-inhibitory switches that use their mRNA to sense the presence of viruses (beech trees).
We showed that retrons contain toxins, which are normally kept inactive by both reverse transcriptase and mRNA, but specific phage proteins can directly activate these retron toxins, which then inhibit Salmonella growth. This self-targeting toxicity makes the phage-infected bacterium unable to produce more phages, thereby protecting the bacterial population from viral catastrophe.
Image credit: Creative Team/EMBL
What implications could your research have for the field of immunology? How could using these switches help treat bacterial infections?
In contrast to common knowledge, our research points to the existence of a highly specialized and elegant prokaryotic antiviral immune system. Bacteria have hundreds of growth-inhibitory switches that work like retrons, collectively called toxin-antitoxin systems, but for decades researchers couldn’t figure out what turns them on.
We discovered the first of these triggering mechanisms for retrons and found that they sense epigenetic signals from phages via their msDNA. This suggests that toxin-antitoxin systems detect highly specific cues from viruses, which, if understood, can be exploited in multiple creative ways as a novel way to inhibit pathogen growth by turning on these internal growth-inhibitory switches . By designing an approach to find how retrons are activated, we provide a tool that can be used to find what activates any of the thousands of other toxin-antitoxin systems.
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Since antimicrobial resistance is one of the top 10 global public health threats facing humanity, do you hope your discovery will help us understand antimicrobial resistance better? What would this mean for global health?
Our research will be invaluable in leading to alternative treatment options to antibiotics. Finding how toxin-antitoxin systems are activated may lead to the development of artificially designed trigger molecules that enter a pathogen and inhibit its growth in vivo. On the other hand, phages themselves can (and already are) beginning to be used in clinics to counter bacterial infections.
We discovered that phages carried their own weapons against retrons and built a roadmap for how other researchers can find phage weapons against other toxin-antitoxin systems. This knowledge may lead to designing decorated phages equipped with sufficient counter-mechanisms to defeat the immune systems of bacterial pathogens and eliminate potential infections.
When you researched these “switches,” you combined the disciplines of genetics, bioinformatics, and proteomics. What are the advantages of having a multidisciplinary approach when making new scientific discoveries?
Scientific endeavors are inherently challenging, and often one approach quickly leads to a dead end. The privilege of using multiple approaches allowed us to avoid these dead ends and thus solve the next step of the puzzle.
Bioinformatics is a relatively new scientific discipline, combining biology and computer science. What advantages does this have for research? Do you think that as the life sciences sector continues to evolve, we will see more researchers using bioinformatics tools in their studies?
Today, not using bioinformatics tools is a major setback for any scientific project in biology, and this distinction will no doubt deepen over time. The main advantage is that, just like having a multidisciplinary approach to exploring problems, computational biology offers clues that can lead us directly to crucial experiments.
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Your research team was a collaborative effort made up of different researchers from different institutions. How important was the collaboration to your research and the scientific sector as a whole?
Collaboration between (at least) seven different laboratories on two continents was key to the success of our research efforts. Perhaps just as importantly, working with motivated collaborators makes the scientific process more enjoyable, more creative, and more human.
What’s next for you and your research?
I will soon start working as a postdoctoral fellow at the University of Vienna in the laboratory of Dr. Martin Polz to explore the molecular complexities of phage-bacteria interactions in the oceans.
Where can readers find more information?
About Dr. Jacob Bobonis
Postdoctoral researcher at the University of Vienna studying phage-bacteria interactions.
Ph.D. Graduated from the European Molecular Biology Laboratory (EMBL) in Heidelberg.
Received the 2021 Nat L. Sternberg Dissertation Award for Outstanding Ph.D. Work in bacterial molecular biology.