CONOR: On today's episode of Discovery Matters Dodi, we will continue our journey exploring therapies that are making comebacks. Like AC/DC, therapies that had their moment in the limelight and then drifted and were eclipsed, misunderstood, or just disappeared, and now they're hitting the headlines again.
DODI: The one hit wonders of biotechnology.
CONOR: Exactly, but they're coming back like AC/DC with Back in Black and storming the stage.
DODI: So last time, we met and spoke to Professor Eric Vermetten about psychedelics and their uses in treating psycho trauma and PTSD. What do you have for us today, Conor?
CONOR: Okay, so this one is super cool. You may have heard that medicine as a whole is facing being thrown back into the nineteenth century because of antibiotic-resistant bacteria, hospital-acquired infections, MRSA, and so on. Well, today we are talking phage, specifically bacteriophages, which might have the answer to this health crisis that would make COVID look like a bit of a head cold.
DODI: I look forward to that on today's episode of Discovery Matters.
CONOR: Meet Anton Peleg, Professor of Infectious Diseases and Microbiology and the Director of the Department of Infectious Diseases at the Alfred Hospital and Monash University in Melbourne Australia. Anton is literally all about phages.
ANTON : It's a simple virus that infects bacterial cells specifically. So, it's not like other viruses like COVID, which everyone knows infects human cells. Phages are highly specific in terms of what they will infect. They're highly specific for a certain type of bacterial species, and even as a strain within that species. So, the benefits of this are that if you find a phage - and it's active against the bacteria - that phage won't have untoward consequences or hurt other healthy bacteria, such as your gut microbiome or your skin. It doesn't have the same broad effects that you might see with an antibiotic. That's a real benefit.
CONOR: And phage therapy goes way, way back.
ANTON : I think some of the descriptions of active phage dates back to the late 1800s. The fascinating thing was that it was river water from the Ganges. Some people noticed that it had activity against Vibrio cholerae. There was a lot of cholera at the time, but they made a link that people who drank or had something from the Ganges River had less cholera which is a bit counterintuitive because you think the water might have been dirty and contaminated. But that was one of the first sort of early descriptions. Then it wasn't until early in the 1900s, that Professor d'Herelle identified that these bacteria were susceptible to infection from a small organism that they called bacteriophage, and then they characterized them as small viruses that attack bacteria.
CONOR: Phage therapy took hold in the early 1900s through to the 1940s for treating gastrointestinal infections such as cholera, dysentery, and skin infections, and phages were being used to kill bacteria that caused these infections but then came along our favorite poster child of modern medicine, penicillin.
DODI: Well, penicillin plus sanitation, but penicillin was a world-changing discovery.
CONOR: That's right. And then all of a sudden it ruined everything for everyone in the phage community. So, suddenly, you had this really simple way of treating all sorts of infections.
ANTON : It was more easily produced, it was a single product, it had good stability, and it was in tablet form. All of these benefits later led to a reduction in interest and work on phage.
DODI: Does that mean phage therapy really got put on the back burner during this time?
CONOR: Well, it didn't completely disappear. There were pockets of fans. There were some diehards, such as clinics with links to the early 1900s researchers who continued to work on phages.
ANTON : At the Alavi Institute in the Republic of Georgia and the Ludwig Institute in Poland, there were people who had links, and were students with a real interest in continuing to pursue phages.
DODI: Okay, let me check if I understand this right. Each phage corresponds with a particular bacteria strain. So, what is it that happens when you've got a bacterial infection? Do you have to go looking for the exact corresponding phage?
CONOR: Yeah, that's exactly right, you go on a phage hunt.
ANTON : Obviously, you need the bacteria that's causing the infection and then we obtain it from a lot of different natural sources. Whether it be river water, streams, sewerage, water, or soil. Phages are one of the most common kinds of organism in our environment. But we have met examples where we have not been able to find a natural phage from our sources that attack some of the bacteria we want to target. Certain bacteria can be much more problematic than others. There is a whole idea of engineering of phage, actually designing and developing a phage. That takes a lot of time and more work, but that probably is something for the future.
CONOR: Part of Anton’s research has been driven by his experience at the Alfred Hospital.
ANTON : We've been working on a few different bacteria and phages acting on them. One is called Acinetobacter, and that's a type of bacteria that is more commonly found in hospitals and causes hospital outbreaks. But it was also the most common bacteria found in army personnel, who were in the Iraq-Afghanistan war, it caused wound infections. It can be resistant to all available antibiotics. But we did some interesting studies that showed the importance of combining phage with traditional antibiotics. So, this synergy and the combination appears to be important because the phage changed some of the surface characteristics of the bacteria. And that can make it more susceptible to a traditional antibiotic.
CONOR: For four and a half years, Anton and his team have been collecting the sort of superbugs that just might terrify you, ones that have been infecting patients in the hospital, and storing all of these nasty bacteria in a freezer. The team has slowly been working through all of them, from the most common down to the least common to find the active phage that corresponds to each infectious bacteria.
DODI: What a huge game of mix and match. And it's so important because like you said earlier, sadly there is that adage about the best place to get sick is in the hospital.
CONOR: That's exactly right. Antibiotic-resistant bacteria are no joke. It's one of the singular most important and listed as challenging risks to global human health. We need to deal with this because antibiotics aren't working. So, what's exciting here is that Anton and the team are developing a phage library. They're cataloging phages by the bacteria that they attack. So, when you identify an infection, you pick the corresponding phage, or a cocktail of phages to unleash on that infection.
ANTON : We have ready almost off-the-shelf phage products or phage cocktails that can be used quickly for very unwell patients.
CONOR: And even the manufacturing pipeline is patient oriented.
ANTON : It starts, firstly, with the patient because we need to isolate the infection. Once we isolate the bacteria, we then bring that into our lab at the hospital, we identify an active phage from those environmental sources I've talked about. And then once you have that active phage, we do a few other susceptibility studies, we look at how well it kills the bacteria. The production part is something that happens with a very close collaborative partner in this initiative of ours at Monash University, and his name's Jeremy Barr, and he's part of our bacteriophage therapy program. That involves growing up our phage to large concentrations.
CONOR: So, to replicate and multiply , phages must infect their own bacterial hosts. I love this idea of fighting an infection with an infection, right? You infect the infected - it's so mad and super cool. The phage just hijacks the bacteria’s cell machinery to reproduce and then all these millions of phage burst out of the cell. So, you grow the bacteria in large volumes in liquid media, you infect them, and then you pass the resultant phage and bacteria soup, through filtration steps and sterilize it until you get a final phage solution put into small vials which can be sent back to the hospital.
DODI: So, I envision a bunch of bacterial cells just living it up in a bacterial bioreactor thinking, 'Oh, this is fantastic. Everything's going dandy' and then suddenly they're blitzed by phages. And then we use that to go out and destroy bacterial infections in the wild.
CONOR: It's absolutely brilliant. There's just this wonderful circularity to it.
DODI: And now revelation time, I'm going to tell you something personal. I'm actually allergic to penicillin.
CONOR: I did not know that. Oh, my goodness.
DODI: Yep. It's been on my medical records forever. So, it is fantastic that there is a more specific alternative to penicillin. So, I love this. But my story alone isn't enough for Anton and his team to see the widespread use of phages. What exactly are the challenges that Anton and the team are going up against?
ANTON : There are a few things. One would be the production process. So having facilities that can produce high-quality phage at scale, as well as the need for quick turnaround times, because, given the specificity you're going to need multiple that’s not one product. I think the other part that we're – globally - up against is having to work together for is the regulation of phage. What are the regulatory bodies classifying phage? Is it medicine? Is it biological? And what does that mean? Regulatory pathways in different countries? So, in Australia, we have actually started a bacteriophage regulatory working group with our Therapeutic Goods Administration, our TGA. So, we’re facing all these challenges around the world.
DODI: We've spoken before about how the biopharma industry needs to work more closely with regulators for the benefit of rapid manufacturing and development. I find it interesting that Anton is doing just that.
CONOR: Exactly. And despite all the challenges, such as the clinical community having to learn about this, regulatory challenges, and manufacturing challenges, everyone is full of hope.
ANTON : When faced with treating patients with superbug infections that are resistant to all antibiotics - or nearly all - you are absolutely driven to find new solutions and ways to treat patients in desperate situations. And we are seeing this more and more day by day, you know, there's not a day that goes by that I don't hear or must be involved in a challenging scenario of bacterial infections that are resistant to almost all our antibiotics. It's a really exciting space to be in because science is intersecting within the clinical world. We're learning both from the patients, the phage, the bacteria, all the way back to what we do in the lab. Then the lab link goes back to its beautiful intersection of bench to bedside and bedside to bench. If we can provide rigorous clinical evidence that this new therapy is groundbreaking for where we are.
CONOR: At the start of this episode, I introduced this topic as being not just fascinating, but one that has real impact on the future treatment of infections, and more widely on human health. We need to be a lot more aware of the imminent threat of antibiotic-resistant bacteria and those avenues that are being explored in treating them.
ANTON : What is crucial is this awareness of antimicrobial resistance in bacteria, and the significance of the problem that absolutely needs to get out there. How do we communicate that best? You know, we were part of an important study from the late end of last year, which looked at the burden of antimicrobial-resistant bacterial infections. It showed that there were just under five million deaths in 2019, associated with bacteria resistant to antibiotics.
CONOR: So, if you put that on a scale of all causes of death, that's the third highest cause of death after stroke and heart disease. I mean, it is huge.
DODI: Wow, I didn't realize that. That is a killer.
ANTON : Phage is obviously one path to an alternate therapeutic. But there's others that we need to tackle for this problem.
CONOR: It is really exciting. I love the fact that phage therapy like AC/DC have gone through this process of drifting away, but they've come back with an amazing album. Everybody is rediscovering them and going 'yay phage' and digging out the T-shirts and saying 'yeah, I was there at the beginning'.
DODI: 'I knew them when...'
CONOR: Exactly. So, thanks to Anton for explaining this extraordinary research and really good luck to him for pushing it forward.
DODI: Well, that is a big thing to learn this week. And since every day is the school day, let's get into some more things we learned this week. You go first, Conor.
CONOR: Okay, you know how everyone has been super excited about RNA, right?
DODI: Yeah.
CONOR: You know, it can be used for all manner of things. It's one of the basic building blocks of life. And it's going to create all these marvelous therapies that will allow us to treat difficult diseases. Well, guess what? RNA has been discovered in space.
DODI: I saw this one. It's fantastic.
CONOR: I think it's just absolutely marvelous.
DODI: But tell us more. What's the story?
CONOR: Japan's Hayabusa2 spacecraft – and the paper is in Nature Communications – in samples returned to Earth by the spacecraft, discovered a precursor to DNA called uracil. It's extraordinary that it's present in an extra-terrestrial environment. Previously, it had been found in meteorites but it's potentially the first clearest piece of evidence that some of the foundations of life may be found outside of this wonderful blue globe that we live on called the Earth.
DODI: So, it's not that the aliens are coming, it's that the aliens are us?
CONOR: Well, that's quite a leap. So, all we're saying is that the building blocks that form the structure of RNA and are essential to protein creation in all living cells, are found both on Earth and not on Earth. So, we've got to talk about what the actual evidence really gives us. But there is obviously an origin of life story that suggests that RNA predated DNA and proteins and that ancient organisms that relied on RNA for the chemical reactions associated with life, potentially, those precursors could have come from an asteroid impact or so on. But all we know is that they exist in both places.
DODI: That's so cool.
CONOR: Anyhow, what have you learned?
DODI: Well, mine is a little bit simpler. In the last episode, you talked about what you learned from your daughter and the eye mask. Well, what I learned is also related to family, it is related to bacteria, and it is related to attitudes about bacteria. So, it's really on topic for our episode. We took the dog to the vet. Peter Barker has a clean bill of health, but the vet looked at his mouth and said, 'Hmm, this guy really likes his sticks and tennis balls, doesn't he? But tennis balls are bad for a dog's mouth.'
CONOR: Oh, my God, how bad?
DODI: Well, the fabric on the tennis ball can wear down the teeth. They blunt the canine teeth on the bottom jaw.
CONOR: Right. Okay. So, it's like chewing on sandpaper?
DODI: So, I come home and tell Lars, 'We have got to quit with the tennis balls for Peter, because the vet says they're bad.' I started Googling why are tennis balls bad for the dog. And Lars is like, 'How bad can it be with tennis balls for dogs?'
CONOR: Okay, so he's looking for the worst possible scenario. You're looking for just data?
DODI: Well, I accept the authority of the vet, right? The vet says it's bad, accept that it's bad. Lars is like 'Let’s not exactly accept authority, let's investigate.' And this just really describes me and Lars in a nutshell.
CONOR: The different attitudes to being told information by someone in a position of authority.
DODI: Correct.
CONOR:Absolutely marvelous. That really does point us to the fact that when you hear about a discovery in a newspaper, read about a discovery online, or dare I say it you're watching a TikTok, it's important that you don't leap to assumptions that RNA came from space.
DODI: And we're all aliens.
CONOR: Exactly. Keep that sense of curiosity and distinctly empirical thinking around what science is really. Learning every day because as we know, every day's a school day.
DODI: Thank you for listening to this episode of Discovery Matters. Our producer is Beth Armitt-Brewster. Editing, mixing and supervision by Ulrika Svensson and Tom Henley from Banda Productions, music from Epidemic Sound. My name is still Dodi Axelson.
CONOR: And I am still Conor McKechnie, and make sure you rate us on Spotify on whichever platform you use to discover your podcasts. We'll see you when we come back with another episode of Discovery Matters.
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