Defeating Superbugs 🦠 An Evolutionary Battle (Part 3)

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Hey everyone. Welcome back to the TechLink Health Podcast. I'm Dr. Sarah Samaan, and I'm excited to welcome Jessica Satcher, a postdoctoral research scientist and Phage Australia manufacturing lead from the Westmead Institute for Medical Research. As many reflect on the past few years of the pandemic and continue thinking about emerging threats of the future, it's important to bring awareness to that very topic, the future, and what's on the horizon in public health. Today's episode is part 3 of a series that focuses on the emerging threat of antimicrobial resistance, which has been deemed by the World Health Organization as one of the top 10 global public health threats facing humanity. This episode digs deeper into innovations happening globally to help defeat superbugs and evolve the applications of phage therapy. This episode's guest is Dr. Jessica Satcher, a Canadian phage microbiologist and co-founder of the Phage Directory, as well as Phage Australia. The Phage Directory is founded in helping doctors find phage scientists willing to share their phages to rescue patients dying from antibiotic-resistant infection. Phage Directory is now the global phage community's central source of news and connection. They support hundreds and thousands of phage professionals from 80 or more countries, and they assist clinicians to source phages for their patients, as well as help organizations manage, grow, and learn from their phage collections. Jessica also serves as a postdoctoral research scientist and phage manufacturing lead at the Westmead Institute for Medical Research. She's also the founder of Capsid and Tail, the phage community newsletter. Now, it goes without saying that Jessica has a passion for phage therapy and innovating in the space, and we look forward to getting her perspectives. So, without further delay, we're excited to welcome Jessica to the podcast. Jessica, thank you for joining us today.

Thank you so much for having me.

So to start and to give our listeners some background, can you take a moment to introduce yourself in a bit more detail and tell us about your journey into the phage applications and therapeutics space?

Sure. Yeah. So I started my phage journey by accident, as many do. I was studying biology at the University of Alberta. I wanted to be a veterinarian at first, and so that's why I was doing that, and I was taking my courses and stumbled across microbiology. Hadn't really even heard of that as a subject, but I just got enamored by it and started taking more microbiology classes and then ended up taking a research lab course that was the 4th-year project course. And the lab that I was in had a phage project, one of its many projects related to phage. And so that's where I learned what phage were, and I thought they were just so cute, these little sort of moon landing type spider structures with a little head and tail. And I remember my supervisor in the lab saying, you could pick this or you can pick all of these other things, carbohydrate science and all the things that she was really excited about. But I picked phage and she was like, okay, you could do phage. And so I just kept following them and trying to understand how they interact with their host bacteria. kept working on phage, and that is where I met my Phage Directory co-founder, Jan. And so I didn't know Jan very well at the time. We knew each other from swing dancing. And so I told him about phages and what I was studying in the lab. And then when I was sitting with him one day, we saw on Twitter people were starting to ask for phages for patients. And this was the first time I thought about phages as a realistic kind of option in the health space. I really hadn't been thinking of them as anywhere close to ready for that, but it was because of Jan seeing them from the outside and being like, he's a software developer and user experience designer and he's a computer guy and he does startups and he knew you could just start something from scratch if you wanted to. And I, so I followed his lead and he said we should make a system so people don't have to use Twitter to find pages. And if if labs like mine have phages and doctors were using Twitter to find people like me. He wanted to build a better system. So that's how we started Phage Directory.

What a fantastic story and such an emblematic story of our times. So tell us more about the Phage Directory and some of the global initiatives and innovations that are happening. And also, as these innovations continue to evolve in the space, how will these developments continue to engage with doctors who are looking to help patients?

Yeah. So Phage Directory, from that point, 2017, started just as a side project, a small, simple website where if you had phages in your lab as a research scientist, no matter where you were in the world, you could list your name on the website and say what kind of phages you have. And then you would also receive an alert. We call it a phage alert, and it's essentially a newsletter, an email newsletter that we send out Whenever we have a physician who's got a patient in need. So you can subscribe to get it, to get the phage alert if you're a research scientist with phages. We set that up and it exists in that form today. We've done more with it in various ways, but the core kind of mechanic is still preserved. And so just that very basic list yourself if you wanna be found and sign up if you wanna know when somebody needs a phage. And we've, right away, we got some traction for this idea, and that was really surprising. We were trying to help this specific person get phage therapy, the one that we saw on Twitter, Mallory Smith. And she was a cystic fibrosis patient and she was about 25 and she was dying of a superbug infection. And so that's originally, it wasn't, we're creating the system for everyone. It was like, let's help Mallory. And so we, we got all these researchers starting to hear about us and sign up. And then unfortunately Mallory passed away that same week that we started it.

Wow.

And so everybody was ready to help. And then all of a sudden we had to say, actually, no, we didn't help in time. And that was just gutting and made us all realize that, like me, my co-founder, and also just the phage researchers that were wanting to help, they're like, wait, what? Oh, it really is emergency. This was not how we were thinking about it as researchers. So we, and we got featured in STAT News at the time because they were writing about Mallory's story and they pointed, at least there's a phage directory now, so we won't have this happen again. What? It's all just on this little tool? That can't be. But anyway, so we used Twitter to get the word out, tried to get the word out to other researchers I knew, and eventually there was another phage alert that somebody listed with us, and that was in France. And we tried to help that patient, but every time we would coordinate one of these phage hunts, we call them, something would cause it not to go to the very end, and either the patient passed away before they could get phages. Often the only patients whose doctors are willing to pursue this are, it's the last option. Or sometimes the patient would get better, and so we wouldn't need to use the phages. And so they would tell the researchers, okay, hold on, just in case we need you, we know where you are, but no need right now. And then sometimes institutions wouldn't get their correct paperwork arranged in time. You gotta go through your regulator and talk to the FDA if you're in the US, for example, and It takes a lot of work also getting your hospital on board, and they need to know what they're doing. And so all these things can mean that there's like a reason that it doesn't go to the very end. But one of our phage alerts in 2019, so this is 2 years after we started, we've, we had done around 40 alerts at this point and tried to get phages for patients, and 2 of them had led to treatment, but we hadn't heard back. And then we finally had one that everything worked. And this was a girl in Sydney. And so a 7-year-old girl who was in a car accident and her leg was in danger of having to be amputated because of an infection and they couldn't treat it. And 12 labs actually responded to our Australian, our first Australian phage alert, and they all shipped phages and they were able to get it to happen. And so They saved her leg, and this was like our first major success from our Phage Directory side. And so that's to give you more background on that, which almost takes us to the present, which is we actually are now working with that center in Sydney, and we have moved out there to join them in helping them start Phage Australia, which is an Australia-wide phage therapy ecosystem they're trying to set up.

Wow.

And it was all because of the success of this little girl, led to a grant. And then they were able to bring in some people and it snowballed from there. And we've been super excited to partner with them on helping them make sure they have sages for the patients, make sure they can scale up to more and have the right partners on board and things like that. That's, yeah, I'll stop there. I know I probably, there's aspects of your question that you might need to remind me about.

No, that's great information and so interesting. And just this idea of connecting bench research to physicians who are fighting to save patients' lives. And honestly, I don't think you can overstate the importance of what you were able to do for that young girl who, you know, for the rest of her life, she'll have her leg. And the importance of that is just mind-blowing. And that you were able to do that through this project that you started and just through this, almost homemade website to then becoming this really important and global initiative. So, from a global perspective, there's several initiatives focused on phage applications. And from your perspective, what are some of the most promising applications, particularly as it relates to consumer health? How will phage therapies enter our day-to-day lives? What do you anticipate for the future? And also, along these lines, one of the hot topics across all industries right now is ChatGPT, OpenAI, and the powers of AI technology. So tell us more about how these technologies can potentially work alongside the phage applications, or even more broadly, other technologies or devices that might coexist along phage therapy. Yeah.

So, to think about phage therapy around the world, because I've been able to sit in this bird's-eye view position for a while doing the phage community building that I've been doing, just as a something to help us get more researchers on board, it has been a side effect of, almost. And we've seen all kinds of strategies of doing phage therapy, and this has been true for way before we got into it, but there's always been these 2 camps. You can classify them as personalized phage therapy and off-the-shelf or cocktail phage therapy, where you're trying to make one-size-fits-all.

Yeah.

Collections of phages in a vial that you would actually give out just like an antibiotic without, every patient would get the same one kind of thing, versus a personalized approach where every time you have a patient, you're actually culturing their microbe, their specific version of E. coli, for example, and testing it against a whole bunch of phages and picking one from a bunch and formulating that up quickly and giving that to the person. So More similar to something like CAR-T therapy that's very personalized. And so there's challenges with both sides and you still see groups working on each side. And probably I think the consensus and definitely my belief are that both will coexist and will be needed. And, but what I've been focusing on more is the personalized side, especially with Phage Australia now. I'm, have been thrown back in the lab and I thought I was just gonna be helping make all these connections, but Little did I know there was a big need to just someone get in the lab, figure out what phages we actually have, and start responding to patient cases and preparing phages for them. And one of the challenges with the personalized method is you have to have a lot of different phages, and you have to be really quick at knowing which one to use. And this is still, I think, something someone you had on a podcast in this series earlier, Rob McBride from Felix, would've gotten into this, which is picking which phage and rapidly matching them is a big challenge in the phage field. And because if you don't use the right one, it's not gonna work. And that's the consensus. And we can see that in the lab. Phages are, that's their best trait and their most challenging trait is that they are so specific to what bug they're, they're gonna kill.

Yeah.

And so we as a field haven't actually cracked the holy grail of being able to predict just from looking at the bug's genome, which phage will be good for it. You actually have to test it in a Petri dish every time. And so that's insanely inefficient when you think of scaling this up, but we can do it on our current scale. And so we have about 10 patients, I think we just treated our 11th at Phage Australia, that we've prepared phages for. But every single one of those, we had to screen against dozens of phages in the lab. And then it takes a couple weeks of work to do the lab assays to find out which phage to use. And that patient has to be okay for that amount of time waiting. And then that's when the process starts of actually preparing a batch of that phage. That takes another few weeks. So it's, it's to get back to your question about just how things are looking globally and the kinds of initiatives you're seeing. You're seeing phage therapy centers, I call them, which is like an academic medical collaboration, usually somewhere where there's a doctor at a hospital that believes in phage therapy, maybe an infectious disease specialist usually, but it could be other kinds of specialists, and some connection with an academic lab that has microbiology expertise to do the phage work. And so they get together, they get a grant together, and then they start operating as a service to patients that come in, and the patients are getting treated on a named patient basis, like many call it compassionate use, or there's different names for it around the world, but when all other options have been exhausted. And so that patient will come into this unofficial service. It's generally unofficial. There's not really money exchanged for most of these. It's just, it's mostly grant-funded really. And it's all like in the pilot phase still, but you're starting to see these phage therapy centers popping up because luckily everyone's got a bunch of patients that Can't be treated by antibiotics, and there's nowhere to buy sages if you wanted them. So you have to set up your own little setup to deliver them. So that's one of the kinds of initiatives I'm seeing pop up. And there's one in Sydney, of course, where I am. There's one that has been going for a while at Yale University in the US, at UCSD in San Diego. That one started around when we started Sage Directory, and they're all kind of similar variations on the same. Taylor Labs in Texas has a variation on this. There's also lots in Europe. So Belgium is what we look to as new emerging leaders for how to do personalized phage therapy and how to check which phages are safe and have a list of things you go through to check off to make sure that phages are safe. That's the personalized strategy I see popping up. And then there's also lots of biotech companies. Following more of the traditional drug development route that are designing phage cocktails. They take a bug like Pseudomonas aeruginosa and come up with 6 phages against it, put 'em in a cocktail, test that they're gonna be stable together, and try to get that to a shelf point. And so that means full-on clinical trials, just like any other biologic. And there's companies like Adaptive Phage Therapeutics and Armada Pharmaceuticals and Um, lots more. So the 2 different strategies happening. And then you also mentioned OpenAI and ChatGPT. From 2 sides, I think about that. So first of all, everyone's been saying for a long time we should use AI to pick pages and to, to do that matching step. We wanted to do that, but we struggled. And I know Felix had the same idea and they've gotten further on it for sure, cuz that's been their main focus, but. You actually, of course, need the data ahead of time, or at least you used to before everything started shifting with OpenAI and ChatGPT. But you really need a lot of cataloged data that's clean and that has been obtained in a way so that you can start to see patterns. And that data hasn't really been collected very well. And so at Phage Directory, that's one of our other initiatives is helping labs collect their phage data every time they use a phage, test it. And putting in a person, collecting all those outcomes and characteristics and putting them into some database that we can start running machine learning algorithms on it. But with OpenAI and ChatGPT making it a lot more accessible to get going with a lot less clean data, or like even using it to clean the data, we're really excited about that. And so we're starting to play around with that at our Sage Australia lab. And we're even getting ChatGPT to do a lot of stuff in the lab, change our, take our messy lab data that's messy because of the nature of you're running around a lab making notes, take those kind of notes and put them into a format, making the data flow from lab to clinic and to regulator a lot more streamlined. We're starting to build some little AI tools to do that, though I think there's So many ways you could just make everything more efficient with that.

Yeah, that's really exciting because that could save you and your team a tremendous amount of time, which then opens up your time to work on the Phasias, to do the work that you aren't the only ones that can do. And it's interesting when we think about this, that you do have to have a physician champion at any place that's going to use Phasias, and they have to start thinking about it early because as you say, it takes weeks from the time the email the decision to the time that the phage is ready. So lots of moving parts. So if you think about the next 10 years, and we touched on that, but can you elaborate on what's in store for the future of phage therapies and how the related technologies are going to continue to evolve? And are there any particular technologies that immediately come to mind?

Yeah, I think over the next 10 years, the really exciting, the biggest change that we might see and we hope to see is regulatory frameworks that are developed and get some sort of stamp of approval for phage therapy. So right now they're usually seen as a biologic, just like antibodies or whatever else. They're lumped in with everything. And so they're subject to clinical trials that are basically Very hard to do when it's a personalized population, a personalized technology, of course. And so that's really been hampering progress in the phage field for decades. It's just, it's too hard to get them through clinical trials, or it's too expensive to, and it's hard to own phages. So it's, you know, you can't really make a case that your money, you're gonna get your money back, or you're gonna preserve any kind of ownership at the end of it all. If there was regulatory frameworks that were accommodating of phages specifically and designed around the actual, what do we need to know about a phage to make it safely usable? And what do we need to know about the final batch that makes us trust it? And instead of having the same kind of scale of clinical trials that we expect for antibiotics and things, I think that would just unlock so much innovation and just many more groups will get in. And an analogous thing you can look at is fecal matter transplants, so FMTs, right? And they, at least in Australia, and I know that I believe in other countries, there's starting to be a framework. If this, then you can use fecal matter transplants as long as it's made safely in this way. So it's saying you don't have to put every vial of poo through a clinical trial. You can just say, hey. Here's how we decide on who donates, here's how we check the donated material, and here's how we check the patient is right for this. Something like that for phages, I think, is in the works. Like, we're working with our Australian regulator, the TGA, to talk about what that would look like. They're interested in that, and so is the FDA. And I know in Europe, in Belgium already, they've been able to get phages their own kind of status. And they go through compounding pharmacies, so they're not treated in the same way as a standard drug, and that just unlocks everything without having safety issues come in. That's what I'm really excited about. And the UK has actually just had a parliamentary hearing, so their parliament has been asking for, they've heard enough from the people about phage therapy that they are driving this inquiry and A lot of international voices got asked to give statements, and even ours here in Australia, like, submitted a statement. And they're compiling that at the government level to see what can be done and what are they going to design as a system. So yeah, it's an exciting time on that side. And the other thing on the horizon is, I think, new ways of designing clinical trials that fit phages better, because we don't want to not test phages in the clinic, of course, but how do we test them even though you're not gonna find 100 people with the same type of E. coli that work on that exact same phage? And then what, how do you also test that with another phage? It's kind of impractical, but there should be still ways we can actually test efficacy of phages on either smaller populations or— We are doing it in Australia in a weird kind of unique way. Called the STAMP trial, and it's actually, it's a process trial rather than a trial on the product itself. So it's not everyone getting their same phage, but it's everybody getting their own different phage, but given in the same way. The phage is administered the same time, the same dose, and we do the same monitoring afterward of the patient. So we're taking blood samples multiple times for 2 weeks. It seems simple, but it hasn't really been done. Mostly phages are given and then there's not much monitoring. Or at least it's not coordinated with how someone else is doing it over here. And we just haven't been able to study any of it very well because it's just all these one-offs. So creating creative clinical trial designs that can at least start helping us see what's going on in the clinic and do things that we can systematize, at least systematize those. So that's what I'm really looking at and looking ahead to. And I think another major category would be GMP production of phages. There's a lot of people that say that's the major sticking point for phages to get through to the mainstream is that we don't have GMP facilities to manufacture them. And it's very expensive to set up the good manufacturing practices as they relate to phages, especially when you kind of have to make a different one every time. How do you clean all of that? I think that will require more investment, of course, but I think that's starting to finally come in. And so you're seeing companies setting up GMP facilities for phages around the world, and everyone's setting up their own in-house, and that's becoming the standard. So I guess that's not so much an innovation as like a current system that phages haven't fit into quite yet, but If that does change, then everybody feels a lot better about the products and I think it, it like pushes things forward.

Yes. I can understand that from the standpoint of, of being a physician. When you have these protocols, it just gives more structure and makes you feel more confident putting a patient into this therapy. It's just a, a more sense of familiarity and confidence that, that I think will help to establish this as a more mainstream way of addressing these really complex infections. And getting this regulatory framework, of course, is going to require more leadership, as you alluded to, in the medical field and in the agencies that are involved. So looking at precision medicine and personalized medicine, because we talked about that in the past on the podcast, we've covered these types of topics. And with that in mind, what are some of the other potential applications for phage therapy? And tell us about the programmable therapies and what the parallels are to perhaps general longevity.

Yeah. Other applications for phage therapy. This is, there's so many, any kind of place that you can see a bacteria causing a problem. And you can actually have some kind of evidence that supports that if you fix that bacterial problem, if you got rid of that bacteria, you would be happier for some reason. You would have, your wastewater treatment plant would be safer, or your fish farm, your fish wouldn't be sick because your pathogen you've gotten out of that water. That's the beauty of phages is they don't care if they're in a human or in a sewage or in a swamp or anything. They just need to find their target microbe and they will do their job. And so it's up to us to identify places where a certain kind of bacteria that's known is causing some kind of problem. And that's hard. It's hard to always pinpoint, of course, which bacteria is causing a problem, especially in these complex communities and environmental places or in agriculture. But it can be done. And, and that's when, yeah, we should be testing phages and plenty are. Like there's some companies doing aquaculture phage work, so fish farming, and they're There's certain pathogens that they're able to target with phages, and phages are pretty well suited for those kind of applications. So these agricultural companies are getting farther ahead than the human health ones, as with probably anything, the regulatory path is easier. And there's examples of them being sprayed on ready-to-eat meats and things to get rid of Listeria and to prevent Salmonella. There's a company called Intralytics in the US that has been doing that for, I think, 20 years or so. And they've been able to get phages as generally regarded as safe, so they can be used on food. So it's great for that. And then there's also companies doing phages as a cosmetic ingredient for acne treatment, but also just for general kind of improving the skin microbiome. I know there's companies that are trying to look at different microbiomes, even the oral cavity. And find out there's some bacteria in here that it would be nice if there was less of them. And, or maybe there's something good that we wanna promote, and if we get rid of this guy, maybe that one will flourish. Phages could be really interesting tools, like precision tools for any microbiome. So I think that's sometimes lost in the whole therapy discussion because that's such a limited place for phages to be useful to us. But there's all kinds of places you could use them. And you mentioned also the programmable side. So I think phages are cool because they come pre-programmed. So if you wanna use them out of the box, they've got their program in their little head and they go and execute it if they have the right conditions. But of course, with synthetic biology and everything ramping up and people are getting much better at deleting genes, adding genes to any organism, and with CRISPR, now there's kits you can just get and make your mutation. And, and so people are starting to use that in phages. And there's like a company called Locus Bioscience in North Carolina that has designer phages almost, you could say. They, they're genetically modified phages to make the phages work better. And I believe they have added CRISPR systems into the phage so that once the phage gets into the bug, it can actually just obliterate all the, the DNA in there. And kill the bacteria even faster and better. So I think we're very much at the beginning too of what we could be doing on that front. I think many people have the view that genetically modifying the phages is like giving a cat bionic claws. It's already a cat. Do you need to give it better weapons? Or let's see if we can get the cat to do its job naturally. There's a lot of people who think that and And then there's others who point to the fact that, yeah, if you actually do genetically modify it and make it your own, you can now own it and now you can actually have a patent portfolio around it. And that is huge, obviously, for investment into it. And so that's why companies like Locus have been able to get investment that really goes way beyond what people have done for natural phages. That's exciting. And I think you could do any strategy and push us forward a little bit depending on what it is, but it's all helping. Wow.

That's fascinating. Just the vast number of possible applications. And I think most of us wouldn't even understand or realize that some of this therapy is already being used outside of humans. So looking at this from a global health perspective and outside of microbial resistance, what are some of the other threats that we should be thinking about and Perhaps the top 3 from your point of view.

Yeah, I feel like I've been in a phage bubble for very many years and kind of haven't thought about what else is ailing us, but definitely the pandemic really brought to mind that, oh yeah, like viral human viruses. Like I, we need to pay attention to those. And I, when I think about what the other health threats are, it's things like that, like other viruses like COVID coming out of wherever they come out of. And it's wild how everything comes back to human viruses. I see their power, I see their diversity, and that is obviously helpful if you're trying to use them for something. But yeah, the fact that more COVID pandemics haven't happened is more surprising to me. Like, how has this only happened once in my lifetime? It's wild that we've been able to manage all the viruses that are out there. And I think that's scary to think of, but Also, the other one I point to is climate change. And I think that feeds all these other ones too, because as the climates are shifting, more of these viruses are being liberated from habitats they were maybe enclosed in or sequestered. And I think the more that we shift which animals and plants we come into contact with as humans, which is happening as climate change worsens, I think That's just gonna keep giving us more scary viruses coming outta the ground and into the air. And I don't like to think about that because I don't know how to fix those ones. But yeah, that would be my answer. Yeah.

Yeah.

It's very sobering when I think back to when I was in medical school back in the 1980s and how some of these things that we are seeing now, like Ebola, was just this fable. They knew it was out there, but without thinking it could come out into the general population. And things have changed so much over the last few decades. So it's encouraging and heartening to know that there are people like you, scientists that are really on the forefront of addressing these really complex issues in ways that are innovative and that are leading to even more developments and more positive change. So in closing, any final advice for those who want to learn more about the ever-evolving phage applications and therapeutics space? And tell us what the best way would be to stay connected to your work and to updates with the Phage Directory.

Yeah, I think I always point people to our newsletter if they're interested in anything phage or keeping up with the phage field from the phage therapy standpoint, but also from a science standpoint and agriculture too. We cover it all. We have a newsletter that goes out every Friday called Capsid and Tail, you mentioned. So it's just phage.directory/capsid. That's the URL. So you can follow that and that's everything goes in there. And then just staying up to date, it depends. If you're a physician and you have patients that have difficult-to-treat infections, you can always email us. We have even my email, like anything @phage.directory. Um, but I'm jessica@phage.directory. And so you can always email me and see just if it's ever a question of, oh, we would pursue phage therapy, but we don't think we could ever find phages. I, I hope that people can come away with the idea that finding phages is actually not the bottleneck. It shouldn't be the bottleneck. We have pretty much always been able to find Phages, as long as it's from pathogens that people have been studying for some time. Pseudomonas, E. coli, like all the escape pathogens, phages can usually be found. It's usually something else that prevents from being used. If doctors are feeling that they wanna pursue that avenue, but they think phages aren't findable, just come my way and we can put out an alert to the community and we just say, okay, does anybody have Staph aureus phages? And we'll get Responders that are ready to help. And so that can be helpful. And people can sign up for, say, the SAGE Alert System if they're interested. If you're a SAGE Labs interested that are listening, that are interested in responding, it's very low commitment. We try to keep it practical and simple. And if you sign up for, say, the SAGE Alert System, you only hear about urgent vetted alerts. It's not separate from our, our other emails. Yeah, we have kind of ways of, of getting involved that way, and that's probably the best for now.

Fantastic. This has been such an interesting conversation, and thank you so much for sharing your story and your expertise. And it's great to know that physicians and others caring for patients with these really complex illnesses have an option, that there may be options beyond what we might normally consider. And now we have a way to contact and get in touch with you and other people that are working in the phage therapeutics So thank you so much. Thank you.

Yeah, this has been so fun. Thanks for just putting this together and it's really exciting, especially when the medical community starts asking. I think that's the champions that we need.

Yeah.

Happy to help. Thank you.

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