Instant Genius - How a scientist used viruses to save her husband’s life from a superbug

Episode Date: January 4, 2021

In this week's episode of the Science Focus Podcast, we're joined by AIDS researcher Professor Steffanie Strathdee. In 2015, Strathdee's husband was infected by superbug that was resistant to every antibiotic that the doctors could throw at it, but she was able to save his life with an experimental treatment made of viruses found in sewage. In the New Year issue of BBC Science Focus Magazine, we cover the biggest ideas that you need to understand in 2021. This episode is one of a series in which we talk to the experts who will explain these ideas in their own words. Let us know what you think of the episode with a review or a comment wherever you listen to your podcasts. Subscribe to the Science Focus Podcast on these services: Acast, iTunes, Stitcher, RSS, Overcast Listen to more episodes of the Science Focus Podcast: Marcus Chown: Does the Big Bang really explain our Universe? Sonia Contera: How will nanotechnology revolutionise medicine? Professor Catharina Svanborg: Is the cure for cancer hiding in human breast milk? Brian Switek: How did bones evolve? Bill Bryson: What should we know about how our bodies work? Dr Monty Lyman: What does our skin tell us about ourselves? Hosted on Acast. See acast.com/privacy for more information. Learn more about your ad choices. Visit podcastchoices.com/adchoices

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to learn more. You're listening to the Science Focus podcast from the BBC Science Focus magazine team. With the UK's best-selling science and technology monthly, available in print and in several digital formats throughout the world. Find out more at ScienceFocus.com or look out for us in your app store. Hello and welcome back to the Science Focus podcast. I'm Dan Bennett, the editor of BBC Science Focus magazine. Today I'm joined by a very special guest,

Professor Stephanie Strathde. In 2015, Professor Strathdie's husband was infected by a superbug that was resistant to every antibiotic that doctors could throw at it. but she was able to save his life with an experimental treatment made of viruses found in sewage. It's a fantastic story and I'll let her tell it. I think let's start at the very beginning then.

So I think it was over five years ago you were working in HIV research, is that right? And then you went and had what appeared to be a very normal holiday in Egypt perhaps at a weird time, but it all started there. Egypt. Is that right? Yeah, that's right. My husband and I are both AIDS researchers at the University of California, San Diego. And we went on holiday to Egypt. My husband had always wanted to see the Valley of the Kings and King Tut's tomb. And over what was Thanksgiving in the United States in 2015,

we took this wonderful trip. There had just been a terrorist attack in Sharmal Shake. So everybody else canceled except us. My husband said, oh, it's the perfect time to go. There'll be nobody on the ship and he was right. We were the only one there. And so that was where this all started. So it was at some point during the trip that Tom picked

up this infection. That's right. In fact it was our last night there. We had this wonderful meal on top of the top tier of this cruise ship and we thought we were going to see King Todd's Tomb the very next day and my husband all of a sudden, you know, a couple

hours after this meal, he got very ill and he was vomiting and just feeling miserable and I just thought well you know there was seafood in the meal I figured he got food poisoning and I really didn't think anything of it until the next day when he wasn't getting any better. And so what happened next? Well he couldn't keep anything down and not even water I realized he was getting dehydrated now I'm not a medical doctor but I do have a rusty old degree in microbiology. And I was literally calculating incubation periods in my head for different organisms that he could have acquired him. And when he started complaining of back pain, I realized, you know what, this isn't food poisoning if he's got back pain. So I called a friend of

ours who happened to be the head of infectious diseases in the department we work in back home. And his name is Dr. Chip Schooley. He played an essential role in Tom's recovery. many months later. But at that time, he said, you know, get him to the nearest hospital. He's, you know, he's really at risk of something serious here. And, but there was no hospital in Luxor where we were based. Really?

So where did you, what did you have to do to get him to treatment? Well, there was a clinic and it was staffed with, you know, wonderful Egyptian doctors. And they did their best with what limited. resources they had. They did diagnose pancreatitis, which is an inflammation of the pancreas. But they said, look, there's likely to be some serious complications here that are going to be above what we can handle. So they helped us get a medevac first to Germany and then finally back to San Diego. So when did you know that this was an infection you were dealing with? And when did you,

can you just tell me that story of how you found out that this was? was a sort of super bug that he'd caught? Well, at first we thought, okay, pancreatitis, inflammation of the pancreas. The doctors in Germany found that there was a gallstone that had stuck in his bile duct, and it caused an obstruction and led to this giant abscess the size of a small football in his abdomen. And, you know, I was pretty shocked. The doctor showed me this flask of putrid fluid, and he said, you know, there's something growing inside this abscess and it's been there for a little while.

If this abscess had just formed, this fluid would be clear. So I still wasn't that worried. I was thinking, okay, so, you know, they're going to culture whatever it was growing in this abscess and they're going to give him some antibiotics, right? He'll be right as rain in a couple of, you know, days. Yeah, I mean, modern medicine's pretty good, isn't it? Well, that's what I thought. But he came back, the doctor, in a couple of days.

and by this time he was fully gowned and gloved and had a mask on that covered more of his face than the Egyptians in Luxor. And he stood away from the bed and he said, I've got some very bad news. This is the worst bacteria on the planet. Jeez. So what was it? Well, the official name is Acinetobacter Bomaniae. Now, he said this in a thick German accent. I had to get him to write it down. And I thought, oh my goodness, this rang a slight bell back from, you know, my 1980s

microbiology degree at the University of Toronto. And I realized that we used to plate this organism on our petri dishes back then. And all we needed was, you know, a lab coat and gloves. And he said this is the worst bacteria on the planet. Like, how can this be? And me, I'm an infectious disease epidemiologist. This was catching me really off guard. So it did a little bit of sleuthing, and I realized that this organism has become a superbug of immense international importance.

It's something of a bacterial kleptomaniac. It's really good at stealing antibiotic resistance genes from other bacteria. And so when we were treating Tom with some very heavy-duty antibiotics that I call Gorillacillins, they were only used intravenously. that was killing off all the friendly bacteria in his microbiome and creating space for this superbug to move in. Its nickname is actually a Raca Bacter because so many veterans were coming back from the Middle East with this organism in the early 2000s. It used the military evacuation system

to populate itself in all these regional hospitals in Western Europe and the United States. So unfortunately, a hospital or a clinic is the most common place you acquire this organism these days. Right, so active soldiers and active duties or veterans were leaving where they were on a tour of duty and then going to a nearby hospital or a hospital slightly further afield in Europe. And it was providing the perfect kind of storm for this bacteria to sort of spread through Europe and those areas. Absolutely.

It was really very sad to read of the cases of veterans that had come back with shrapnel wounds or had their leg amputated and lived through that, but ended up dying of acinetobacter, Bomania, aka a rackabacter. Of course, and it's not alone, is it? It's part of a growing number of these once, fairly innocuous bacteria that are now becoming resistant. That's right. You know, in 1961 was the first superbug was identified, and that was metacillin-resistant staph aureus, which sounds like a big clunky word, but everybody has heard of Mercer. And it was actually identified in the UK. And very quickly, that superbug,

Mercer spread all over the world. But since then, more and more different bacteria have become resistant to multiple antibiotics. And that's when we call them a superbug, when they've acquired resistance to several different antibiotics. In fact, the word escape, if you spell it ESK-A-P-E, each one of those letters stands for a different superbug that is of global importance to human health. And Tom's was the A in the escape acronym. I see. So how resistant to antibiotics was this acolytobacterstrain?

Well, the Acinetobacterpomania was diagnosed in Germany, and it was only partially sensitive to three antibiotics right off the top. It was resistant to 15. And these remaining antibiotics were only available intravenously, and they have very serious side effects. One of them is Calliston, which is the last resort antibiotic. And yet, after he was metabact back to San Diego, where we live, it was, it was, it, became resistant to those last three antibiotics despite infection control procedures. So you can imagine how nasty this organism really is. Wow. Yeah, in such a short space of time. And so you had this diagnosis and then you, I suppose, did what was, probably would have come natural to you. You started to do some

research. Yes. Well, at first, the doctors who were caring for time in San Diego, there are colleagues and they said, you know, he's too weak for surgery. If we try to take this abscess out of his abdomen, unfortunately, because it's resistant to every antibiotic that we have now, he could become septic and die of septic shock. And so they elected to put these drains or catheters in his abdomen to try to siphon off all that infected fluid. And so unfortunately, it kept spreading. And by the time, you know, February rolled around. He had five different drains, you know, like he looked like a pin cushion, as well as a feeding tube. And unfortunately, one of those internal drains slipped and it poured all that infected fluid into his abdomen, into his bloodstream.

And right in front of me, a doctor and a nurse, he went into septic shock. And I don't know if any of your listeners have ever seen this, but it's horrifying. What happens is your body is kind of overreacting to an invader. that hits the bloodstream. And right away, the heart rate increases, the blood pressure drops, the person flushes, develops a fever, and starts panting. And usually they are starting to shake. And the shaking is called rigors, and it's so intense that in Tom's case, the bed frame

hit the wall. And this is all within, like, the span of two minutes. And so I was pretty stunned. The doctor and nurse knew what was going on, and they rushed him back to the ICU, and they had to put him on a ventilator and a medically induced coma. And, you know, I was just stunned because we were actually supposed to get out of the hospital the very next day, and he wasn't going anywhere. In fact, now, because this organism was, you know, fully colonized him,

he was dying a little bit each day after that. That's something. I mean, I've heard about it. shock, but I've never really considered what the physical, you know, instant reality of it, of the rigors. And yeah, because it's essentially what they were trying to avoid the whole time, wasn't it? The bacteria making its way into his bloodstream. Exactly. So it was terrifying to see this because there was nothing else the doctors could do. There was no antibiotics left. And little by little, he was wasting away. And when I finally realized

that he was dying. I asked him when he was in a coma, and this time he was not in a medically induced coma, he was in a coma that he wasn't really waking up from. But some days, his eyebrows would kind of wiggle, or his fingers would try to reach out. And I thought, you know, the doctors are asking me if I want to start kidney dialysis,

and that's their way of asking if we want to keep him, alive because he was already on what's considered life support. His lungs were failing. So he was on a ventilator. And we see that with COVID these days. And he was on three different medications to keep his heart pumping. And so that the last organ system, the kidneys are part of this trifecta once they start to fail. It's the end. So I wanted to ask Tom what he wanted. And I wasn't sure if he could hear me. But I said, honey, you know, I know that you're fighting really hard and you're tired. And if you want to let go, I'll understand. But I want to grow old with you. And if you want to live, please squeeze my hand. And I'll try to figure out something to do to stop this thing. And I waited.

And he squeezed my hand. I mean, I was elated. But then I realized, oh, crap, you know, I'm not a medical doctor, what am I going to do? But I am a scientist and I know how to do research. So I went home and I hit the internet and the National Library of Medicine has a research engine that's like Google Scholar on steroids. It's really open to the public. So even your grandmother can plunk in keywords like the name of a superbug and alternative treatments and up pops scientific literature that's been vetted and is based on real evidence. And up popped a paper that had something buried. read in it called phage therapy. Wow. So you were confronted with this almost untreatable disease.

And so from there you hit the books, I guess. I think my background and training as a scientist was both a blessing and a curse. Certainly I had the knowledge of what was going on with this bacteria. And what I didn't know, I was able to read about and catch up because really I'd been focused on the HIV epidemic and the superpowers. bug crisis had really crept up on me. And that's one of the reasons that my husband and I decided to tell our story, because if it crept up on me, it's crept up on the average person. But also, I was kind of fragmented, to be honest. There was the wife me and there was the scientist me. And so,

you know, when I tell people about our story, some people say, well, like, didn't you realize that once they put him on a ventilator, he wouldn't be able to talk? It's like, well, rationally, you can realized that, but it hadn't really sunk in that I might never be able to hear my husband speak again. We may never be able to communicate. And that's what people with COVID are going through right now when it comes to their families. It's really hitting people close to home these days. But for me, a lot of this was a shock because I knew just enough to get me into trouble about medicine. Yeah. You're right. It's not, you know, when you're making me, decisions, especially on behalf of someone, you know, the kind of reality of it kind of has a habit of

slamming into you before you can see it. Well, that's right. And there's a human element to this, too, because my husband and I are second time around couple. You know, he has two older daughters that are my stepdaughters and I have always had a good relationship with them. But it's a different dynamic when, you know, I was the one who had the power of attorney who had to make the medical decisions and yet I wanted to consult with them. I wanted their approval and here I was stumbling upon an experimental treatment which was going to be crazy that was derived from sewage that I was going to, you know, try to save his life and I had to convince him that this was the right thing to do. So, so yeah, that's a good, good place to come in. So you hit the books and

you discovered phage therapy. So did you discover it in relation to particularly a senior bacta? Or, you know, how far back did you start discovering phase, you know, the story of phage therapy? Well, the first paper that I found was alternate treatments for multi-drug resistant acetatobacter bomania, which was the name of his superbug. And a couple of these treatments were not developed yet or they weren't, you know, possible. like a vaccine. We don't have a vaccine for this. Or, you know, some kind of treatment that would be used on the skin. Well, he was fully colonized, so this was not going to work.

But phage therapy, I knew what phages were. It's short for the word bacteriophage, which is derived from the Greek word, which means to eat or to devour. And so it essentially means bacteria eater. And bacteriophage had been discovered by, a French-Canadian microbiologist named Felix de Jarrell in 1917. In fact, a British scientist named Twart observed phage activity a couple of years prior and had reported on it in The Lancet, but didn't know that this was a virus.

In fact, Felix de Jarrell didn't know it was a virus either, but he deduced it. And it wasn't until the electron microscope was developed in the 1940s that, Felix was vindicated because up until that point, people weren't really sure what they were looking at. They knew that something, some kind of filterable agent that was smaller than a bacteria could pass through a pasture filter and still kill bacteria. And so that's how phage therapy came about.

Phage were actually used to treat bacterial infections first in 1919, in Paris where there was an outbreak of dysentery among children. It was used in animals and had something of a heyday in the 1920s and 30s. In fact, Felix de Jarrell was the inspiration for the award-winning book Aerosmith. But then, of course, penicillin came on the scene and the wonderful history of Fleming and his colleagues identifying penicillin, but it really didn't come on the scene until World War II in 1942, it really became scaled up. And phage therapy was relegated to the back burner in the West because, of course, now we had this wonderful wonder drug, penicillin, and it can be used broad spectrum. So that means basically you don't even have to diagnose what kind of bacteria it is.

You can just give somebody penicillin and it'll kill whatever is there a lot of the time. And of course, nowadays we know that broad spectrum antibiotics, you know, aren't necessarily a good thing if they kill all the friendly bacteria in our microbiome as well. But at the time, the West was very excited about penicillin. And in the former Soviet Union and parts of Eastern Europe, it was – penicillin was not widely available. And it was actually treated as a war secret by the allies. And so the folks in the former Soviet Union in Eastern Europe continue to use phage therapy. And still, to this day, they've amassed the most clinical experience with it.

And yet it became seen as like pink-ocami science because the Russians were using this treatment. And so it was a Russian science. And so that geopolitical bias really put a cloud over phage therapy for decades. So how did you go from there? And how did you end up at an actual treatment? Yes. Well, in fact, it's had several false starts.

There's been interest in phage therapy, but there was different barriers that were encountered. And so my husband's case, because ultimately we were able to source phages with the help of a global village of phage researchers and the US Navy, it was really a spectacular effort of total strangers that came together to save the life of one man.

My husband's case really has been described as the case that brought phage therapy back to the West. So just to rewind a little bit there. So you'd found that there was this potential phage therapy literature out there, and that chances were out there, there were some kind of viral, viruses that could, you know, you could give your husband and if there was any luck, it could treat him. How did you go about finding these and sourcing them and, you know, ending up with an actual treatment?

Well, when I realized that these bacteriophage, which I had learned about in my microbiology class back in like 1986, but they'd actually been used to treat people and could cure people of bacterial infections. I got very excited, but then I first realized that my hopes were somewhat limited because this was considered experimental. The FDA, the Food and Drug Administration in the United States, has not licensed phage therapy because clinical trials haven't been done to show that it's efficacious compared to antibiotics. So, you know, it was looking like an insurmountable task, but I didn't want to give up. I read. I read. wrote Chip Schooley, who was then the head of infectious diseases at the University of California, San Diego, where Tom was being treated. He was a friend of ours and had been involved in the case from the beginning. And I said, Chip, I know we're going to lose Tom unless something drastic is done to turn him around. What do you think about phage therapy? And he wrote me right back. And he said, what an interesting and intriguing idea. If you can find phage that can match his bacterial isolate, I'll call the

FDA and get permission to use it on a compassionate basis. And that's an emergency investigational new drug status, which is used when there's an experimental treatment that they don't have data for. And so then, of course, I was very excited again, but I was daunted by this seemingly impossible task because the more I learned about phage, the stranger the whole idea got. essentially phage are the oldest and most populous organism on the planet. There's 10 million trillion trillion. That's 10 to the power of 31 phases that are estimated to be out there.

And they have to match to the bacteria that you want to kill. So it isn't like any phage can kill any bacteria. It has to be a specific kind. Because they have these receptors that they attach to. And in the case of acetatobacterbolomania, the superbug that Tom had, it has to match not just the genus and the species of the bacteria, but the exact isolate. So Tom's Accinetobacter bomania is like, oh my God, how are we ever going to find these phages?

But I didn't want to give up. I went to the internet again, and I made a list of all of the researchers I could find in the United States anyway that were studying this superbug and phage. And it was a mighty short list. wrote them cold. They were total strangers. This isn't my field. I sent them a picture of Tom lying in a coma with a t-shirt draped over him that said, I survived a rackabacter that our student had given us. And our story, and within 24 hours, I heard back from Dr. Ryland Young at Texas A&M University, who offered to help. And so you were on the hunt for these phages, and then if I'm

if I'm right here, you found them in a place that might probably made explaining what you're doing to friends and relatives a little bit tricky. Well, you know, it almost seemed like a headline that you'd see on the daily mail or something because phages are found in places where you find a lot of bacteria. So if you can just think for a minute, where would you find a lot of bacteria? Well, a great place to find them is sewage because that's where the perfect predator is to kill these bacteria, the phage. So when I talked to Dr. Young, he said, you know, do you have any boots that have soil on them from where you were in Egypt? And he was asking because he would warrant samples of the soil from the boots. And I said, no. He goes, well, he says, I guess we'll have to rely on our environmental samples here at Texas.

And he says, you know what I'm talking about, don't you? So essentially he was talking about sewage and barnyard waste and, you know, people have found phages on your kitchen sponges. But it isn't just these gnarly places. I mean, our bodies are just like, you know, swimming in phage. Literally there's 30 billion phages that are thought to move in and out of our bodies every day. So they're not something foreign. It's just that we haven't had, you know, the science and the tools to be able to study them until, you know, at least therapeutically until fairly recently.

So when you had acquired these samples, how certain were you that you had isolated phages that were going to be able to treat the acedio factor? Well, the group at Texas A&M University basically turned their lob into a command center, And so they were looking for phages from, you know, these crazy sources. But they also reached out to the phage community internationally and to see if people had already isolated phage

that were active against Acinidobacterbolamanii. And we had offers from, you know, Belgium and Switzerland and India. I mean, it was really amazing. And yet we didn't need to rely on a lot of these international sources because the Texas lab found four fages within about a week. that really did kill Tom's bacterial isolate. We sent them a sample. They cultured it,

and then they were able to, you know, essentially put drops of the sewage and other suspension on the petri dishes and incubate it. And if it comes back 24 to 48 hours with holes, essentially looking like Swiss cheese in the plates, then even though you can't see phage with your naked eye, they're 100 times smaller than bacteria,

you can see that they've been at work. They've gobbled up the bacterial colony and left a hole there. So you get excited because you know that you've got a phage that matches that bacterial isolate. And you pluck it out and you add more bacteria in a suspension and then you grow it up. And then you have to purify it. And that can be a bit of the tricky part. That certainly was in Tom's case. That took more time than anything else.

But the Texas team were fantastic. And as well, the U.S. Navy had phages active against assassinated bacteromanii. and they made a cocktail for Tom. So now we had two cocktails. And from my first email to the day we were ready to treat him with phage therapy, it was three weeks. I mean, compare that to an antibiotic that takes 10 to 15 years to develop and a billion dollar price tag or more.

There's no comparison. And so you then get to the point where you've got a treatment. And although you were confident in the science, It was by no means a sort of a certain thing, was it? Well, you're right, because Tom was fully colonized with this superbug. So Dr. Scully, who had been, you know, appointed as the protocol chair because he's the doctor and, you know, somebody had to take responsibility for this experimental treatment. And he really put his reputation on the line.

It was very scary. He really deduced after talking to experts, in the field that we would need to treat Tom intravenously. And that was seen as somewhat of an innovation. It has been done before, but even the folks in the former Soviet Union and Eastern Europe that have been using phage therapy for decades, typically don't inject billions of phages into somebody to cure them from their superbug. They might use it topically or a nebulizer where they're breathed in or even as a suppository,

but to inject a billion phages per dose into somebody to try to kill them of their superbug, I mean, if we didn't purify the suspension enough, he could die of septic shock. And we all know what that looks like. Yeah. Well, fortunately, that didn't happen. So quite the opposite. In fact, Tom recovered. What was that like?

Well, it was really a dramatic moment. I mean, when we injected the phages into Tom's bloodstream, Nobody really knew if this was going to cure him or kill him. But we did know that if we didn't do something, that he was going to die anyway. And I was told that they expected him to die within a couple of hours. I mean, I literally signed the consent form for kidney dialysis the day that we started phage therapy. And yet, you know, three days after we started injecting the phage into his bloodstream, he lifted his head off the pillow, opened his eyes, and kissed his daughter's hand.

It was just fantastic. exceptionally rapid. Yes, I mean, he did have some bumps in the road after that. I mean, he had lost 100 pounds and all of his muscle mass. And because he'd been on a ventilator for a while and in a coma for two months, he had to learn how to, you know, swallow again, to talk, to sit, to stand, everything. I mean, the rehab was intensive. But nevertheless, he was on phage therapy for about a month.

He cleared the bacterial infection within three months. He got out of the hospital. He, you know, nowadays, he goes for a walk three and a half miles every day. He takes that garbage every time I ask him. Yeah, I was going to ask, do you, does that drop into your arguments now? And you need something to tilt your way. He's like, well, I did save your life. Well, you know, we have to have a sense of humor about this.

I mean, I can literally tell my husband that he's full of, er, you know. This is clearly, you know, an incredible story that I'm sure many could late to and understand. But it was more than just that, wasn't it? This was a scientific moment. This process and what you went through advanced the field by some way. I mean, just for a start, just the delivery method that was used for this treatment was new. Yes.

I mean, the interviewer's delivery of the phages was certainly an innovation. in this case, especially for the United States, which really had no experience doing anything like this. There certainly wasn't anything documented in the literature about how to do this. I mean, the dose, we just basically guessed based on his weight. But the other aspect is that the phages were personalized for him. So it was really taking personalized medicine to a new level. And the idea that you could inject phage, like a billion phages per dose, and for the scientists out there, that's 10 to the 9 pfU per mill.

And we did this every two hours. It really, we have not seen any negative side effects of this at all. And we subsequently went on to treat other people with phage therapy. In fact, when Tom was still in the hospital, a two-year-old child was treated with phage therapy. therapy intravenously based on the protocol that was used in Tom's case. And that's when we both broke down in tears and realized, you know what, this is bigger than us. You know, maybe this is the reason we're on the planet, you know. And you just realized that total strangers stepped up to save the life of one man.

I mean, it really puts the word kind in humankind. And at a time when there's so much negativity in the world and it just, I can't even tell you how grateful we are because we realized that we were privileged if most of the people who are dying of superbug infections live in developing countries. And yet because of this, you know, the training that I'd had and the fact that we were based at a world-class university and we were able to use connections to have people help us. Most people don't have that. And that's why we decided to tell our story and to write our book, The Perfect Predator, because we were really caught off guard by the Superbug crisis, me even as a scientist.

And yet a 100-year-old forgotten cure has been there all along and has been buried, at least in the West. So we decided that it needs its fair shake. It needs to be evaluated in clinical trials. And when... Because there was there, it didn't just sort of, you know, it didn't end there. There was also a British case recently. and Isabel Howaway, who was a teenager, who I believe she even, she had obviously not a similar story, but she had an infection by a superbug, and she got in touch, didn't she, or her family did for treatment?

Is that right? Yes, Isabel's case is even more spectacular than Tom's in many ways. At the time, Isabel, who has cystic fibrosis, had had a double lung transplant, and her new lungs were being attacked by a terrible pathogen called mycobacterium obsesses. Listeners might be familiar with mycobacterium tuberculosis, a cousin to this superbug, which causes tuberculosis. That's the biggest bacterial killer in the world, kills almost 2 million people every single year. And mycopacterium obsesses is very difficult to treat. She was not responding to antibiotics. In fact, she was in hospice. And her mom heard about talking about

Tom's case, contacted Isabelle's doctor. Isabelle's doctor reached out, and Dr. Schooley, who treated Tom, also got involved. And we had been in touch with a researcher at the University of Pittsburgh who essentially has developed a course where university freshmen learn how to isolate phage, just like fage were used in Tom's case from sewage, et cetera. And if they find new fage, they get to name it. It goes into a database. there's a big phage library, all like 10,000 pages that are active against mycobacterium.

But nobody had ever thought about their therapeutic potential until Isabel's case. Well, when Dr. Hatful, who's at the University of Pittsburgh, in fact, he's a Brit as well, when he was approached to see if he had any phages in this giant phage library that were active against Isabelle's case, he said, sure, I'll look. And he found one that was perfect. I mean, it would kill her organism. It was actually sourced from a rotting obergine in South Africa by a student there. If you can believe that.

That's true. But the other two phages he found, and you want to have a phage cocktail when you treat people with phage therapy, because the bacteria can become resistant to the phage very quickly if you only have one. So he knew he needed more. But they were what we call in our book the lazy kind of phages that enter the bacterial. cell and instead of killing it after multiplying, they hit the snooze button and they don't really do anything. And they can carry antibiotic resistance genes or toxin genes. So you really don't want to use these for phage therapy if you don't have to. So what Dr. Hatful did is he clipped out a gene

that made it the sleepy kind and he forced it to become the lytic or phage rage kind as I like to think of it. And so now we all of a sudden had the first genetically modified fage cocktail. And of course, it was going to be proposed to be used for Isabelle in the UK. And this is the first time ever that a genetically modified fage cocktail would be used to treat a human. And so we had to convince the UK government that this was a good thing, that it wasn't a GMO. And they debated about this and realized, okay, well, I guess you took away a gene. You didn't add. a gene, so it's not a GMO, so yes, we'll let you go ahead. Well, oh my God, it was a big, debate. And also, we had to find the right courier to take it across because people thought, oh, are we going to, you know, contaminate the postal service and things like that. And anyway, it was the same kind of issues came up in Tom's case, too. But no, that doesn't happen. Fages are everywhere in our environment. You don't have to worry about that, unless you're a

giant bacterium, of course. Then you're a big trouble. But anyway, Isabel received phage therapy intravenously based on Tom's case. And even though she literally was at death's door, the doctor had given her a 1% chance of living. She left the hospital within a week. Wow. That was just, and now this is ushered in a new era where it's possible to use genetically modified or even synthetic phage to treat superbug infections. And so biotech and pharma are getting very excited about this because they're easier to patent this way.

So this is a story that plays out, as you've highlighted, it plays out all over the world all the time. People can just get bacterial infections, but often it's after some other injury or surgery. So my next question is how viable is this to scale up to the kind of magnitude? that is clearly needed in the future? Well, we've got some work to do before we can scale phage therapy up, you know, to the global level that we need to. First, we need clinical trials to show that it can stand up to antibiotics and is safe. And then we need a giant phage library,

bigger than the one that Dr. Hatful has developed, because his is available only for mycobacterium. And we know that there are multiple bacteria out there that, that are superbugs. So if you imagine having a giant library of superbugs, and it's matched to a giant library of phage, and it's ever expanding because literally these two creatures are dueling it out on an ongoing basis.

So you need to keep up with evolution. But it's possible to do because, remember, there's 10 million trillion trillion phages on the planet. So it's all a matter of finding the perfect predators for each one, isolating them, purifying them, sequencing them and cataloging them and making them available. So we have the first dedicated phage therapy center in North America based at UC San Diego, beginning with Tom's case and all the other cases we've treated in the last several years.

And it's called the Center for Innovative Phage Applications and Therapeutics. And we collaborate with labs and companies all over the world to source phages for patients, but we really need to develop this library because you can't just go to sewage every time somebody's got an infection. I mean, literally, that's what we did for Tom and we were lucky. But if you have a phage library that's all ready to go, you can, honestly, you can get phages ready to match someone's superbug infection within a day or two or even faster if we can have rapid diagnostics to identify the bacterial pathogen right off the bat. And those are coming in along the pipeline too. So those are the things that we need to do next.

And so, and you've just touched something that, I suppose that that is the inherent appeal of phage therapy as well, is that, you know, the, even if the bacteria comes up as resistant, chances are there is, there is going to be something out there in the natural kingdom that has specialized to predate on the bacteria that you're trying to isolate, even if the one that, you know, say you find this works in one case, maybe a year down the line it stops working, chances are there could be a new one out there. Is that accurate? That's right. And even in Tom's case, the bacteria did become resistant to the phages. That was one of the criticisms of phage therapy that people said, oh, it's no better than antibiotics because the bacteria can become resistant to the phage. Well, of course, bacteria are going to become resistant to anything that we throw at them.

But you can generate a second generation phage cocktail within a couple of days if you have a large enough phage library, and we were lucky to do that. Or you can just take a phage and manipulate it, you know, using CRISPR-CAS gene editing techniques to, you know, optimize the phage lifestyle to be a better killer. Right. Brilliant. And so just in case someone is listening who might have had a similar story to you or else,

what would you suggest they do if they, you know, had new, or had somebody who had experienced an infection via a superbug that was antivirate resistant? Well, our center, IPath, is a non-profit, and we have been involved with cases all over the world. We're not the only phage center now. Of course, there's still a phage therapy center in the Republic of Georgia. There's one in Poland that have existed for decades. There's one in Belgium. There's other phage centers popping up.

ours if we can help you you can contact us at iPath at ucsd.edu and more on our story and the book we wrote about it is at the perfect predator.com where there's a lot of different resources and a discussion guide as well that was professor stephanie strath de bear telling the story of how she was able to save her husband's life from a superbug to discover more about her groundbreaking working work in phage therapy, and the journey she and her husband went on, do check out their book, The Perfect Predator. This interview was prompted by the new year issue of BBC Science Focus magazine, which is on So Now. Inside, we take a tour of the scientific ideas that we think will play a part in the national

conversation in 2021. As well as taking a look at bacteriophages, we took a close look at rewilding, swarm spacecraft, virtual reality therapy, and much more. Thank you for listening. See you next week. Thank you for listening to the Science Focus podcast from the BBC Science Focus magazine team. With the UK's best-selling science and technology monthly, available in print and in several digital formats throughout the world. Find out more at sciencefocus.com or look out for us in your app store. This podcast is sponsored by name, audio and focal.

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