NEB Podcast #83 -
Transcript
Interviewers: Lydia Morrison, Marketing Communications Manager & Podcast Host, New England Biolabs, Inc.
Interviewee: Dr. Paul Turner, Ph.D., Rachel Carson Professor of Ecology and Evolutionary Biology, Yale School of Medicine
Lydia Morrison:
Welcome to the Lessons from Lab & Life podcast brought to you by New England Biolabs. I'm your host, Lydia Morrison, and I hope this episode brings you some new perspective. Today, I'm joined by microbiologist and virologist Paul Turner from Yale School of Medicine. He studies bacteriophage and he joins us to explain how these viruses can be used to treat and kill bacterial infections and what the future of this technology looks like. I'm so excited that you could join us today. Could you tell our audience what your lab at Yale studies?
Paul Turner:
Happy to be here today. My lab at Yale studies many different questions concerning viruses and how they evolve. On the one hand, we are interested in virus pathogens of humans and how they evolve and may emerge in the future, but we're equally interested in how viruses could be used to solve human problems such as drugs that don't work well and seeing whether virus technology can step into that space.
Lydia Morrison:
So you've had a really interesting career path. It spans academic research and now into translational applications of that research. How did that unique path evolve?
Paul Turner:
Yes, I do plenty of basic and now more recently applied research. I first entered into biological research wanting to know the fundamentals. How does biodiversity evolve on earth? And especially in microbiology, how can we better understand this? So back in the day when I was an undergraduate, I considered going to medical school and focusing a lot on biomedical problems, and then I drifted away from that into the basic research space. About 10, 15 years ago in my academic career after I'd become a professor, I got more and more interested in biomedical problems and applied uses of viruses to solve problems in biomedicine.
In between all of that, I think there was a very big turning point for me that was when I was still back in graduate school doing plenty of basic research, the AIDS epidemic was really taking off unfortunately, and I happened to be in Southern California doing my studies then. It impacted our graduate program because a student unfortunately contracted HIV and progressed to AIDS not long after and passed away. So I didn't immediately go into applied research, but I've always thought, could I use time and talent in my group to focus on more biomedical problems of urgency where we could do translational work?
Lydia Morrison:
That's really interesting. You mentioned using viruses to solve medical problems or to treat medical conditions. Could you talk a little bit more about that?
Paul Turner:
Sure. There are lots of ways that we try and solve medical problems. And although most listeners and most people you stop on the street hear about viruses and immediately consider how dangerous they are and how they can threaten humans for disease and even mortality, but there's a very longstanding tradition of trying to use viruses to kill bacteria. And that's called phage therapy because the viruses that kill bacteria have a special name bacteria phage or eater of bacteria. That's what that translates to, and it's often shortened to phage.
So the long story short is, as I was doing my basic research on bacteria and their interactions with these phages, everybody who works on phage biology has heard of phage therapy, even if the general public hasn't heard of it much. And that's because it's been around for a hundred years and it's been surprisingly effective. In the current day, I focus on that because antibiotics that we use in the clinic don't work as well. And we're going back to this old idea about whether viruses could be harnessed to do that work when antibiotics cannot. And can we use phages especially to treat bacterial infections when drugs fail?
Lydia Morrison:
So as you mentioned, many listeners might not know what phage therapy is. Could you describe phage therapy in simple terms?
Paul Turner:
Sure. The basic idea of phage therapy is that we're trying to leverage natural enemies of bacteria to do the work in addressing infections. So what do I mean by this? It's a big biodiverse world out there. Plenty of microbes exist on planet earth, but the thing that is most abundant are viruses that happen to interact with bacteria and kill them essentially in order to make more baby viruses. So these phage infections happen a lot in nature. And historically, phage therapy is the practice of literally going out into natural environments, finding examples of these viruses called phages, and trying to leverage them to cure infections in animals and people, a little bit more recently in plants. So it's a very old idea dating back to about 1910. And phage therapy in essence is using a biological enemy of bacteria to kill bacteria. And all this was developed and studied long before antibiotics were accidentally discovered by Alexander Fleming. So it's a very old tradition that is regaining popularity.
Lydia Morrison:
As you mentioned, it's been around for a very long time. Where do you see phages fitting into the future of treatment?
Paul Turner:
Great question about how phages will or will not be generally used for this purpose. First thing I'll say is that for generalized treatment in some countries, shortly after people started doing phage therapy in the early 1900s, they adopted it as basically a therapy that was approved. The Russians were quite famous for this. Also, researchers in Poland and the eastern block nations adopted this and did it in earnest a long time ago when antibiotics were being popularized in Western countries. So the expectation is that unfortunately everybody's going to get on board with this for a very good reason. Antibiotics have saved countless lives of humans through time. And in using them in earnest, we've selected for bacteria to become resistant to antibiotics, so they don't work that well anymore. And the basic idea of can you harness something else as an alternative or in replacement? That's where phage therapy comes in.
And then to really answer your question in places like the United States, it's done on an emergency basis because it's not approved as a general drug. So in the next 5 to 10 years, the thing that I'm expecting to happen is that all around the world, greater and greater interest in this will keep growing. And we're on a path so that this kind of therapy will be approved perhaps everywhere. And nations like the US will catch up to other ones where it's already available as hospital treatment. So that was a bit of a long-winded answer, but I would say that the near future of phage therapy is mixed. It'll continue to be legal and available in places where it's already approved. Meanwhile, in places where the ambitions are to get it approved and get it as a generalized treatment, that will also occur. And largely what we're talking about is personalized medicine in between so the patients can access it before it becomes generally available.
Lydia Morrison:
So I imagine that traditionally isolated phages were used for this sort of treatment, but have we moved on to engineered phages at this point? And are there roles for each in terms of these treatments?
Paul Turner:
So the expectation of whether you would continue to see people around the world use naturally isolated phages versus those that are engineered is a super interesting direction for where is this field going? And look, historically back in the early 1900s when phage therapy was first being developed, I'll remind the audience, there weren't that many good tools in microbiology, full stop. So people were using this with ambition and it was working, but it wasn't really as if their experiments were allowing them to fully understand what they were doing. And a biological drug is what we're talking about here, so it's got an inherent sloppiness to it compared to something that's a purified chemical, solely. It's different than penicillin. Penicillin doesn't change. But if you're growing phages to use them in therapy, you're creating a stock of them and you may get some mutations that cause those particles to differ from one another.
The main point is that if you want to continue to use something that you can find in nature, that's probably fine. There's an elegance to engineering that we need to increasingly rely on, and especially because the tools are coming about, that if you engineer phages to do something as good or better for what they're doing, if you just naturally take them from environmental samples, there's also a better way to understand your biological drug because you're taking part in designing it. And I'll give you a concrete example. Some phages we take straight from nature and they work fine and we fully genome sequence them now because we have the availability to do that. And we might discover that, oh, wait a minute, there's a toxin gene that this phage has picked up from somehow interacting with bacteria. And it may look good for me to use it in therapy, but I'd better beware because that toxin gene may have some bad effects if it's expressed as the virus is growing in the patient and you're trying to use it in therapy.
I think that that's kind of obvious. So the question is, do we have enough genetic data to always recognize a toxin gene? And I don't know that we do. So there are these little hidden... More than little, I mean, there's a lot that we rely on in phage biology without understanding explicitly what every single gene does. It would be a lot more elegant to design phages, maybe remove genes that are unnecessary, especially if they're of unknown function, and streamline things down as best we can. That's often a goal of synthetic biology is that you strip away the things you don't need and you better understand what's left over. And that gives you more confidence to use something that's been engineered for a purpose.
Lydia Morrison:
Yeah, I really can understand that. It seems like there is inherently a lot of variability in a living system. And so if you can control exactly what that system is and what it expresses, you can have a lot more confidence in the outcome and maybe the potential harmful side effects of something like a toxic protein. Are we approaching a turning point in how we think about viruses? Are they going from threats to tools in your mind?
Paul Turner:
I think that's a great question, and I would say unequivocally, yes. The answer is that both are happening at the same time. We have to respect the power of virus disease and emerging viruses and the likelihood we're going to see more and more of these. To better understand viruses and virology along the front of better protecting ourselves or other creatures, plants and animals, and domesticated systems from virus attack is just part and parcel of being on planet earth, frankly. But the better understanding of virology that we attain through what I just said, and if you think about it it gives us more and more understanding about how viruses function and how they grow and replicate and all that in general. So the really exciting thing is that the tools are coming around faster and faster to do design work and engineering on viruses and to have this be tools that are not so super fancy for the equipment and the methods that it puts it out of reach of the average researcher.
Instead, those tools are getting easier and easier to utilize because people are getting more and more creative about general tools that'll help, let's say, in engineering your average phage. And not necessarily a whole bunch of information that you have about the system that that phage is interacting with, the kind of host bacteria that it infects. You can maybe achieve those goals through a surrogate, use E. coli, which is a workhorse of microbiology to help you design a phage that is capable of infecting something else entirely. So if we can get to that point, and now you're really talking because those generalized tools start to be very efficient and available in the hands of lots of people doing the work.
Lydia Morrison:
Yeah, it sounds very promising. Are there potential risks of phage therapy, environmental risks or risks to patients that have been brought up or thought about? And what can we do to mitigate those?
Paul Turner:
Great question about the potential risks. So I'm going to start maybe in a strange way in answering that, is reminding the audience that you have a microbiome and we know more and more about the bacteria, especially that reside, for example, in your gut or on your skin, and they help you be healthy. They help you digest food or they help create a barrier to bacteria that might enter through the skin. And they're out competing those pathogens because the ones that are protecting you just sit on your skin happily in that environment where they belong. But what I'm getting around to is that phages exist in and on your body as well. They're not that well studied. But what I'm saying this for is that there's an intimacy already between humans seeing phages anyway.
Which suggests that if you use them in therapy, as long as you're careful about choosing which phages, there's no inherent risk that you'd expect these phages leveraged as biological drugs because the human body sees them all the time and they would've attacked. Our human body would've attacked them as foreign invaders through our immune system right at the dawn of our own evolution. And it hasn't happened because they are not inherently dangerous. Now getting a little bit more to the meat of your question about the risks for anything that you engineer and you want to use it for a purpose in biotechnology. The interesting thing is you can develop that through research and design and you'll often look at it in isolation. But when you're using phage therapy or any biotechnology harnessing phages, you then launch it and use it in the background of other microbes in a community because you can't control that.
So I think the shorter way for me to have answered your question is, there's no inherent risk, I would say, for phage therapy, but there is an inherent uncertainty about how well would it work if I use it in, let's say, the human gut to try and solve a disease problem. If I haven't in the laboratory looked at the incredible species diversity that exists in the gut alongside the therapy that I'm developing in my lab, then necessarily I've missed something because it may matter. When I use that phage in some setting and suddenly these other microbes are around, does it make the therapy less efficient, for example? I don't think it would make it dangerous. It's more about the efficiency of the therapy you are developing. So I hope that makes sense.
I'm trying to say in short that we need to be careful about anything new that we develop. We need to have controls that convince us that something is not inherently risky to a patient when you're rolling it out for the first time or starting to develop it. But there's also a lot of work that suggests we have to roll up the sleeves and get at the lab bench and see that, all right, it works in our hands and we understand it. Now let's look at it in the backdrop of how all microbes function alongside other microbes. And does it matter if you use a therapy in a human or an animal or whatever you're doing for the other residents of a microbiome that exists alongside?
Lydia Morrison:
Yeah. So lots of research left to do at the bench. I'm curious, what role do organizations like New England Biolabs play in accelerating innovation in this space? I know you've worked closely with some of our scientists around bacteriophage genomes. I'm curious, what impact has that had and how do you hope to work with companies like NEB in the future?
Paul Turner:
Yeah, that's a great question. We've had the pleasure of working with NEB scientists, especially Greg Lohman and his group. And in short, I've long been an advocate for academic industry partnerships because we have a different set of mission goals. And of course academia, we have the education goal, but the kind of research that we do for basic research is to more or less, I have to admit, dabble. We're trying to figure out how things work, trying to fill knowledge gaps. So a lot of it is just open-ended basic research. Whereas a company partner like NEB always has a different kind of a mission, and then that is to create something useful, commercially useful especially. So the question is, how can these entities meet and get things done? And for us, it's been a wonderful example of how the basic knowledge that we've amassed through the years, if we're working with an industry partner who has ambitions to take something like phage engineering and make it more useful and available to the average consumer, then it's best to have the kind of basic research knowledge meet the applied need.
And we work together to see how can we find these common goals and move forward? And as I said before, it was a delight to do this, and I think it's given me even more energy to work with New England Biolabs and scientists like Greg Lohman to just keep doing this. It is the future in my mindset. There's a lot of fantastic research happening at universities and colleges, et cetera, institutes, but the need to work with R&D developers, those who are trying to do things for their companies and meeting their industry goals, I think that we have a common ground that we can easily find and we can work collaboratively in that space on trying to do ever more of that in my own life and research. And I think that that is the near future.
Lydia Morrison:
Yeah, I do think that collaboration really breeds innovation. And we have some incredibly talented scientists in New England Biolabs who are really dedicated to creating tools that help drive science forward. Greg certainly being one of them and he's been on the podcast before, and he's such a great speaker and so interesting. You spoke about the future. Where do you see the field evolving over the next 5 to 10 years? Are there breakthroughs that you're really excited to see?
Paul Turner:
I think the field of phage therapy is hurdling forward in a good way. So we face many regulatory hurdles in places like the United States and other countries where I'm working with researchers, Germany, I'll say for example. So some ambitions for our research in phage therapy, the regulatory space is uneven, and that's up to a country. How many layers and what goals have to be met, what clinical trials have to succeed, and we want to make things that are safe and effective. So the point is, in places where phage therapy is not currently generally approved as a labeled drug option, it has to follow the typical path. As we've seen in the United States, is that we can do a ton of basic research. We can do even compassionate use of phages in the clinic. And what I mean by that is US Food and Drug Administration approved emergency basis treatment to understand how this works better in people who need it now.
But we really need clinical trial data, and that is just the path, and we're not going to step off that path and we should not. So the next 5 to 10 years will be more and more clinical trial attempts to show generality and efficacy for phages and phage therapy against various targets. Could be lung infections in vulnerable patients, it could be urinary tract infections, whatever it is. So that has to happen and it will. The ambitions of using academic industry partnerships like what we've done with NEB, the regulatory hurdles are not as high if you have other targets. Animals, plants, which is vital for food security. When you consider how much antibiotic resistance problems already exist in plant and animal agriculture, in aquaculture, ultimately you have nodes of the network and fewer of them to feed a hungry world. And if you're talking about these places and factories essentially getting outbreaks of antibiotic-resistant bacteria, it shuts the whole thing down.
And they have to clean the space. And that's not trivial because it could be a very giant facility that's suddenly shut down for a period of time. And until they ramp up to general production, then essentially food does not get made. So that's a big deal, and that's why we're also moving into that space. But to get to your question, it's uneven around the world, and I don't expect it to be even. In places it's already fully approved and you'll have clinics that you can go and phage therapy is an option. You have places like the United States where the regulatory path is set and it's moving forward. And I don't want to leave out that phage therapy is not terribly expensive to do, frankly. And the early ambitions of doing it is that phages are not that expensive to grow. Now, if you want to make a lot of them in a bioreactor, that does cost a lot of money and we always need the purity of them.
But what I'm getting around to is that plenty of low and middle income country physicians and researchers are interested in this because it could be cost affordable and they could be doing just as elegant and rigorous as the science that happens in my lab and others, but they have an opportunity to solve problems in their backyard that are not necessarily problems that are medical and disease problems elsewhere, and they can't expect others to solve those problems for them. So there is an amazing amount of interest and ambition, let's say in the continent of Africa, in South America, we're working with partners there, but all over the world, there's a disparity between economic access to R&D and phage therapy and phage biotechnology more broadly. I think it's super exciting that low and middle income country partners are very interested in this and we want to work with them. And I encourage others who are interested in this problem to go and do the same.
Lydia Morrison:
Yeah, super exciting. Lots of promise for the future. I agree that I hope folks who hear the podcast and are in a position to work with them, reach out. It would be great to see this come to fruition sooner rather than later. Before we let you leave the podcast, I'm curious if you have a lesson from your lab that applies surprisingly well outside of science.
Paul Turner:
That's great. So I think my message relates to the current day, but what has always been the challenge is that people who want to do science want to focus on doing science. And they often have to be resilient in their own careers about as they are establishing their own independence, ideally they can keep taking steps forward and doing everything that interests them. But there's something about you need to just stay in the system. You need to keep becoming more talented, get more methods, development in your own toolkit, I'll call it, to be better for your career options and hiring options down the line. So as people become mature across levels in science and they build their independence, it's getting harder and harder to get dollars for science in the hands of people who want to do this in the United States in the current day. And I encourage people who want to do science to keep at it, keep trying, be resilient, and ideally more money will flow into the system because right now it's just not enough to really meet the ambitions of those who want to do it.
More generally, I would say what I've learned in evolutionary biology, and I consider myself an evolutionary biologist foremost, a microbiologist second, is that evolution is powerful because biological populations face challenges on earth. And it is a potent force to be able to overcome those challenges by the variation in the system meeting the environmental challenge to solve those problems and that's how new traits evolve and even how new species arise. So there is an adaptability that is inherent when we observe evolution. And scientists always need to adapt to the current times in order to get their work done, in order to train scientists of the future and to mentor properly for those to continue contributing to the scientific enterprise. And it is remaining as exciting as it ever was, but we really need to have the lay public understand what science really is and how we do it. And we don't need to be preachy about it, but it's just like any walk of life. If you're not careful in explaining to people about how do you do this and do it correctly, then skepticism should arise, frankly.
So I think there's a lot of messaging that we need to improve for having career scientists like me work with the lay public, and I try to do this, and I work with educational systems, K through 12 public schools, for example, to just explain how science works and invite them to the table, frankly. Invite them to participate. Citizen science is on the rise, and I think that is fantastic. People can get actually involved in legit scientific questions and hypothesis testing by measuring things in their backyard and reporting them to somebody who's gathering those data together to understand how the world works. So I think science is fun and we should keep having people ambitiously want to do science. We'll need to make sure that the resources are available for them as well. But the main message is that science is fun. You can do it too and don't let anybody tell you otherwise.
Lydia Morrison:
I love it. Keep grinding scientists. We need you.
Paul Turner:
Absolutely.
Lydia Morrison:
And keep communicating about your science and stay curious. Paul, thank you so much for being here with us today. Thank you so much for explaining how powerful phages can be. And I look forward to seeing them come to a point in the US where they're being used for treatment, where they're available for treatment. I look forward to the phase one trials and seeing some movement there. And I know that your collaboration, that working with you has been a really great experience for our scientists as well. So thanks so much for being a part of the broader NEB family.
Paul Turner:
Oh, thank you so much, Lydia. It's been an honor and a privilege, and I really appreciate the ability to do this podcast with you. So thanks for inviting me.
Lydia Morrison:
Yeah, it's been a pleasure having you on. Thank you for joining us for this episode of the Lessons from Lab & Life podcast. We invite you to check out the episode's transcript on neb.com for lots of helpful links from today's discussion. And as always, we invite you to join us next episode.
