Phages – “bacteria eaters” against dangerous infections

00:00:00: Imagine looking at something tiny that resembles a small robot or an alien.

00:00:10: But this isn't science fiction.

00:00:13: It's a virus measuring just a few nanometers.

00:00:16: These are phages, viruses that are not dangerous to us.

00:00:20: In fact, they are like specially trained hunters of bacteria.

00:00:24: These natural viruses could bring under control bacterial infections that classic medications, such as antibiotics, can no longer combat.

00:00:33: How does it work?

00:00:35: Phages attached to the surface of bacteria smuggle their genetic material into the cell and take control.

00:00:41: They reprogram the bacterium so that it only produces phage genetic material.

00:00:46: Eventually, the bacterial cell bursts, releasing many new phages that continue fighting the infection and ideally eliminating it.

00:00:55: That's the theory.

00:00:57: In practice, however, it's anything but easy.

00:01:00: One reason is that bacteria develop defense strategies against phages.

00:01:04: just as they do against antibiotics.

00:01:07: And this is precisely where Professor Jens Hör´s research comes in.

00:01:12: He heads the molecular basis of RNA-Phages research group at the Helmholtz Institute for RNA-Based Infection Research, HERI, a site of the HZI in cooperation with Julius Maximilian University of Würzburg.

00:01:26: Why Jens Herr is researching RNA-Phages, what distinguishes them from DNA-Phages, and what still needs to happen before phages can be used therapeutically on a large scale in Germany.

00:01:38: We discuss all this here in our new episode of In Fact.

00:01:44: Welcome Jens, nice that we can talk to each other about phages.

00:01:50: For the transparency, I'm sitting in Cologne and you're sitting in Würzburg and we're talking remote with each other.

00:01:57: Jens, you had the research group Molecular Principles of RNA Phages.

00:02:02: at the Helmholtz Institute for RNA-based Infection Research in Trott-Hiery.

00:02:07: Please explain to us what pages actually are.

00:02:10: Yeah, so phages are basically just viruses that specifically infect bacteria.

00:02:16: And you can imagine them similar to viruses that you know that infect humans, such as, you know, corona or influenza viruses.

00:02:25: But as I've mentioned, they exclusively infect bacteria, and they also need to infect these bacteria in order to reproduce.

00:02:33: So they are obligate intracellular parasites.

00:02:36: And if there are... Are there phages?

00:02:39: There must also be DNA phages.

00:02:42: Can you explain the differences?

00:02:44: DNA phages, they have, as the name suggests, they have DNA as a genetic material.

00:02:49: And if we just stay with the DNA phages for a little bit, they are actually the majority of phages that are known today.

00:02:56: So around ninety-five percent of phages, maybe even more, have DNA as a genetic material.

00:03:02: And they are also the most common biological entity on earth.

00:03:08: In contrast to the DNA phages, RNA phages as the name also suggests they have RNA as the genetic material and they are much rarer in the environment than DNA phages and that's why especially in the past they have been overlooked quite a lot and they are much understudied in comparison to DNA phages.

00:03:31: But over the last couple of years, maybe five to ten years, new methods have allowed us to identify RNA phages in the environment via new sequencing methods.

00:03:44: And here we discovered that RNA phages are actually much more abundant than we previously thought and they are basically in every biome that you can think of.

00:03:55: We also know now that there are many more families of RNA phages than we previously knew and much of their biology is currently unknown.

00:04:04: Apart from their genomic material, RNA phages also have fundamental differences when it comes to the morphology of the actual virions which are the virus particles.

00:04:15: So DNA phages usually have a head tail structure looks a little bit like a dye that has like a little foot attached to it.

00:04:24: But these RNA phase, they don't have this little foot, this tail structure, for example, so that makes them much more similar to eukaryotic viruses, for example.

00:04:32: And similarly, they don't need any DNA during their replication cycle, meaning that bacteria can also not use any DNA detecting systems in order to detect the infection.

00:04:44: The theory generally deals with RNA and its role in infection biology, making it the first institution to combine these two areas of research.

00:04:55: Why is this so important?

00:04:56: to have a unique institute to research these two topics?

00:05:02: RNA is much more versatile than previous people usually give it credit for.

00:05:08: is often just seen as a messenger between DNA and proteins, but RNA can actually do much more than that.

00:05:14: So it can be a catalytic molecule in ribosomes that produce proteins, for example, but it's also heavily involved in the regulation of gene expression.

00:05:25: And here at the HEERY, we are really interested in the involvement of RNA in infection processes.

00:05:32: For example, how do bacteria pathogens use RNA to regulate virulence?

00:05:37: factors and how can we also use RNA as a target to treat, for example, bacterial pathogen infections.

00:05:48: And this is exactly what we study here, the interplay between RNA and infection biology.

00:05:54: Do bacteria defend themselves?

00:05:57: So against an infection with phages, they don't have a proper immune system, do they?

00:06:01: Well, you know, it's something that is only becoming more evident in the last maybe six or seven years, is that bacteria actually do have an immune system.

00:06:14: So for decades, we have known restriction modification systems, for example, that recognize invading DNA for example from a phage and then they cleave this DNA to stop the infection.

00:06:26: This has been known for decades and a bit later on we discovered CRISPR-Cas systems that are mostly nowadays known as genetic tools.

00:06:36: but in their natural environment, so their actual biology is also in phage defense, where they, similar to what I've just mentioned about restriction modification systems, they can recognize foreign DNA from a phage, for example, that's entering a bacterium, and then it gets recognized and cleaved to stop the infection.

00:06:56: But over the last six, seven years, we found an additional more than two hundred such immune systems that bacteria use in order to defend themselves against phage infection.

00:07:07: And now we see that bacteria have this very complex immune system where many of the human innate immune systems for example actually have their evolutionary origin in.

00:07:20: So this means that these systems are so powerful in the antiviral function that they have been kept during evolution all the way from bacteria to higher eukaryotes, such as humans, but also plants and others.

00:07:34: So what can we learn from this coexistence or maybe better call it conflict between phages and bacteria?

00:07:41: What can be done with the phages?

00:07:44: Yes, I've just mentioned they are, for example, important to understand the evolutionary origin of the human immune system in greater detail.

00:07:55: We can also use these systems in order to search for new immune systems in humans, which also has been done successfully actually.

00:08:05: use our knowledge in order to find new biology even in us humans.

00:08:10: Furthermore, phages are an extremely important source for molecular biology tools, such as the aforementioned CRISPR-Cas systems that we now use to do genetic modifications, for example, but also they are a very important source for all kinds of different enzymes.

00:08:27: If we look at one example, RNA polymerases that are able to produce RNA in the lab, they are extremely important, for example, for the production of mRNA vaccines, such as the Corona vaccine and others.

00:08:42: And these enzymes that make this possible, they come from phages.

00:08:47: And there's a ton of more examples that are more specific where we use phage enzymes in the lab.

00:08:54: Additionally, phages are also the natural predator of bacteria as we've already discussed.

00:08:59: And this means that they can actually infect and kill bacteria, including pathogens.

00:09:05: And this is why we can use phages also as therapeutics in order to treat infections.

00:09:10: Yeah.

00:09:10: And I think most of us probably heard or read about phage therapies in films or books, like science thrillers or something like this.

00:09:20: So where are the therapeutic phages already being used as medicine?

00:09:25: So phages were discovered more than a hundred years ago and they were pretty much used almost immediately in order to treat bacteria infections in humans.

00:09:34: So, phage therapy is actually something that's rather old and actually not that new.

00:09:39: But after antibiotics, especially penicillin, were discovered, phage therapy or the science of phage therapy actually went down quite a lot and people, especially in the Western countries, focused much more on the research of antibiotics.

00:09:57: In contrast to that in the Soviet Union and especially in Georgia, phage therapy was actually widely researched and is still being used nowadays.

00:10:07: In Germany, for example, there's currently no therapeutic that's on the market that uses phages as the drug basically, but generally they are allowed to be used on patients.

00:10:20: So for example, if you have an infection with bacteria that is not treatable anymore by any common drugs.

00:10:26: It is possible also in Germany to use phages to treat these patients.

00:10:31: For example at the MHH in Hannover this is being done and here it's called the National Center for Phage Therapy where people try to treat difficult to treat infections using phages.

00:10:44: But since for the last years antibiotics resistances have been on the rise Globally, phages also are being researched more and more again, especially when it comes to their potential use to treat infections.

00:10:58: And there's also several clinical trials that are running currently where companies are developing phages into therapeutics to be potentially used as a drug for regular human treatment.

00:11:10: And one question about Georgia, why can we just translate it to Germany?

00:11:18: I think there currently are just some regulatory hurdles that have to be overcome because we currently don't have a clear plan when and how to use phages as therapeutics and also as I've mentioned there's no drug on the market that we can actually prescribe.

00:11:35: So here we have to do more research and we also have to make sure that we start processes in order to enable the standard use of phages in the case of difficult to treat infections.

00:11:50: Your group is also researching for new phages.

00:11:54: Where do you find them and how do you study them?

00:11:57: What do you do with them?

00:11:59: We mostly look for phages where we think that they would be in nature considering the bacteria that we are interested in finding new phages for.

00:12:10: So for example, if we look at a bacterium like E. coli, it lives in the gut of, for example, of us humans.

00:12:17: So here we would look in wastewater, for example, for phages that infect E. coli.

00:12:23: If we look at a bacterium like Bacillus subtilis, which lives in soil, we would rather go into our garden for example and then dig for some phages in the soil.

00:12:33: So this would be the most common way of looking for... new phages.

00:12:38: What we do with them is that we want to characterize them to better understand them.

00:12:43: This means that we want to look at them on a macroscopic level, for example via electron microscopy to understand how their structure looks like.

00:12:51: But we also are very much interested in understanding the biology on the molecular level, meaning how do they actually infect the host and then how do they replicate and take over the host cell in order to produce new phages.

00:13:07: What else do you need to find out about these phages so that they can or could be used more widely as a therapeutic?

00:13:15: And what goals or what hopes do you have for the newly isolated phages and what long-term goals do you have?

00:13:24: There's many things that we still have to understand for phages to be used as therapeutics on a regular basis.

00:13:33: We've already discussed, for example, the immune system of bacteria, meaning how bacteria can actually defend themselves against the infection by phages.

00:13:43: And this is obviously something that we have to understand in order to use phages as therapeutics, because otherwise the bacteria would just... defend against the phages and then you know the treatment is not possible.

00:13:55: Similar to that we have to understand how bacteria become resistant after not being resistant against the infection in the beginning of treatment.

00:14:02: for example.

00:14:03: this is the classic problem with antibiotics right you you treat and then the bacteria become resistant against the the treatment.

00:14:10: and this can also happen with phages and for this it's important to understand also all these processes at the molecular level meaning you know the real interplay between single proteins at the level of protein-protein interaction, for example, in order to understand the actual mechanisms behind the infection, host takeover and also the defense from the bacteria against the phages.

00:14:34: And this is exactly what we are interested in studying in my group.

00:14:40: hope to achieve with these new phages that we are isolating is that first of all we are really interested in finding new biology.

00:14:49: As I've mentioned RNA phages are really understudied and we have only isolated very few over the last five decades.

00:14:59: roughly that they have been known to us.

00:15:02: But we know from sequencing of environmental samples that they are much more diverse and abundant than we appreciated before.

00:15:11: and here there's a lot of potential to discover new biology and also new mechanisms of infection and host takeover for example that we then could use in in phage therapy to use a completely new.

00:15:24: family or species of RNA phages for treatment that works differently than the phages that we currently use.

00:15:32: And this would make it, for example, easier to prevent resistance mechanisms from occurring.

00:15:38: Additionally, phages as we've discussed earlier are also very important sources for molecular tools.

00:15:47: And if we discover new phages, these also have the potential to bring new tools such as CRISPR that we already talked about.

00:15:54: So there's also this part that we are really interested in.

00:15:59: And what is a realistic time frame for this?

00:16:03: Do you also wish or would like to see from politicians in this regard?

00:16:09: A realistic timeframe, I think, is that in the next five to ten years, I think we should be at a point where phage therapy, for example, should be available on a broader scale in the country.

00:16:24: Countries like Belgium for example are one of the prime examples in Europe that really drive forward phage therapy.

00:16:30: So here I think our politicians could also look at to get a feeling how this can be done and how we can actually progress phage therapy research into potential therapeutics that we use on a regular basis.

00:16:43: And also obviously we need funding.

00:16:46: so it's important that for example the DFG further funds phage research in order to understand the biology of phage is better, which is then an important foundation for the development of phage therapy.

00:17:00: where and how did you get into phages?

00:17:03: There was more of, it was basically by chance.

00:17:07: So during my PhD, I was working on RNAs and RNA binding proteins in bacteria.

00:17:15: And I basically just stumbled upon a gene that is encoded in a so-called prophage, which is a phage that's integrated into a bacterial genome, similar to how HIV, for example, integrates into the human genome.

00:17:28: And when I found this gene, I got really interested in it and I started reading more and more about phages and how they interact with their hosts and so on.

00:17:36: and then I decided to actually do my postdoc at the Weizmann Institute in Israel in a group that specializes on phage research and after that I then started my own group working also on phages.

00:17:50: but here I really decided to specialize more on these under-researched RNA phages because I think there's a lot of potential and a lot of things that we currently don't know.

00:18:02: that just awaits discovery.

00:18:04: When you're not researching how do you balance your work?

00:18:07: I like to take long walks with my dog, you know, to clear my head and just enjoy walking and nature.

00:18:16: And also I really listen to a lot of music and I go to a lot of concerts and both these things really help me to clear my mind to then regain creativity.

00:18:27: for the day and start thinking about science again.

00:18:30: And finally, maybe as a take-home message, is there anything each and every one of us can do well to come at the one field of antibiotic resistance?

00:18:40: So, I mean, it's not that easy to just have a general advice for each and every one to prevent antibiotic resistances from spreading.

00:18:51: Obviously, the easiest way would be just to stay healthy, but that's not... Always possible of course.

00:18:56: so what we can do to prevent infections and also to prevent the spread are simple things like for example vaccinations against diseases that are caused by bacteria such as grouping cough, diphtheria or tetanus stuff like washing your hands regularly and also safer sex for example to prevent the spread of sexually transmitted diseases.

00:19:18: These are the things that everyone can do on a regular basis on a daily basis to help prevent spreading of antimicrobial resistances.

00:19:28: Really exciting.

00:19:29: Thank you for this exciting conversation.

00:19:32: Thank you for the invitation.