Using 'Phage' Viruses to Help Fight Infection In the days before modern antibiotics, some researchers saw viruses that can seek out and destroy bacteria — called bacteriophages — as promising candidates for fighting infections. Now, as more organisms develop resistance to existing antibiotics, phage research is finding new favor.

Using 'Phage' Viruses to Help Fight Infection

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IRA FLATOW, host:

Continuing with our bacteria. Look at the wide world of bacteria as more and more bacteria become resistant to treatment with antibiotics. Researchers are looking for new ways to fight the deadly bugs, and some are turning to an old method, back to pre-antibiotic times, back before these wonder drugs of World War II to a treatment that was first discovered around the turn of the last century. It's called bacteriophage therapy, and it recruits viruses to attack and kill bacteria the way they normally do it in nature.

Joining me now to talk more about it are my guests. Thomas Hausler. He's author of "Viruses vs. Superbugs: A Solution to the Antibiotics Crisis?" He's a trained biochemist and a science reporter for a Swiss public radio. He joins us from Switzerland.

Thanks for your - being with us this evening.

Dr. THOMAS HAUSLER (Author, "Viruses vs. Superbugs: A Solution to the Antibiotics Crisis?"): Yeah, hi. It's my pleasure to be with you tonight.

FLATOW: Thank you.

Alexander Sulakvelidze is vice president of research and development, and chief scientist at Intralytix Incorporated. He joins us from Baltimore, Maryland.

Welcome back to the program.

Dr. ALEXANDER SULAKVELIDZE (Vice President, Research and Development, Chief Scientist Intralytix Incorporated): Thank you for having me, Ira.

FLATOW: Let's talk about - I guess, maybe for people who've never heard of phages, they're also called phages by some people, right, Dr. Hausler?

Dr. HAUSLER: Yeah. That's right. I think especially the Brits call them like this.

(Soundbite of laughter)

FLATOW: Let's begin at the beginning. You start your book with a story of a man with a bone infection and then it gets very, very interesting and complicated. Tell us about that story?

Dr. HAUSLER: Yeah, right. It was a Canadian musician who worked on a cruise ship, and he broke his leg when he went in the mountain in Costa Rica, when he had just some time to - for himself. And so he had this open wound where the bones actually stuck out, and he got an infection there, which they only realized when he was back in Canada.

And so for like four years, he had this infection there and was under heavy antibiotics. And then, in the end, the doctors actually told him he had to have his foot amputated because they couldn't get rid of the bacteria. And then, he kind of freaked out and looked — I guess understandably, and he looked for another method and came to this bacteriophages.

And then, it really turned interesting because he went to Tbilisi in Georgia, which is a republic which belonged to the former Soviet Union. And there, they practiced this bacteriophage therapy for the last 60, 70 years, and he got treatment there.

FLATOW: Hmm. Alexander, let's talk about these. What are these — and the Soviet connection, which is very strong, as Thomas says. I imagine many of our listeners may never have heard of bacteriophages. Tell us what they are first and how they work?

Dr. SULAKVELIDZE: Bacteriophages are basically viruses that infect bacteria and bacteria only. They are the most ubiquitous organism on this planet. We literally live in the sea of bacteriophage. I mean, to give you some examples, the number of bacteriophages on Earth is estimated to be somewhere in the range of 10 to the 30, 10 to the 32. So, imagine 10 with 32 zeros, so that's how many there are. And they are basically everywhere — our skin, our mouth, our gastrointestinal tract is loaded with bacteriophages. Foods that we eat contain bacteriophages.

So, we really live with them. We eat them and drink them every day. They were — they existed on this planet for — somewhere around two to five billion years. They were formally discovered, as you mentioned earlier, in the early 20th century. 1915, 1917 is the formal discovery date. And those were the times when antibiotics did not exist, and so infectious diseases were basically untreatable. And so, the minute phages were discovered and they were found to have this remarkable anti-microbial activity, they were used therapeutically in humans almost immediately.

And since that time, I - it's hard to exactly estimate how many people were treated, but I think millions is probably not an overestimation have taken phage therapeutically at one time or another.

Now, you mentioned the former Soviet Union country of Georgia. That's the country where I was born and grew up and I was exposed to phage therapy since I was a kid. And in fact, I have been treated with bacteriophages myself for various mild infections and almost anybody that I knew in that country has been treated with it.

So, it is fairly well recognized, fairly widely used in some parts of the world. It was used in the United States in the '30s and '40s. But then, when antibiotics became widely available, people sort of forgot about phage therapy and switched over to antibiotics.

FLATOW: We're talking about phage therapy, biophages at this hour in TALK OF THE NATION: SCIENCE FRIDAY from NPR News. I'm Ira Flatow, talking about it.

Let's talk about — Thomas, if these are so ubiquitous and so wonderful in doing things that some of the antibiotics we have today cannot do, why don't we hear more about these?

Dr. HAUSLER: Well, you see, I think one of the main reasons right now is that antibiotics are very successful and stellar in a way, and that makes it hard for any other method to come up. And it's true that, like, bacteriophage therapy was before antibiotics, as Alexander just told us. But that there were quite a few problems back then in these times in the '30s and '40s. It's actually true that a lot of people were treated, but then also a lot of people were treated in a not-so-good way. I mean, people didn't really know exactly what these phages were. They made a lot of mistakes.

And there were very careful researches, on the one hand, and there were others, which didn't really use the real methods and standards. So already at the time in the '30s and '40s, the method had to — was confronted by a lot of people who were very critical about it. So I think that is probably one of the reasons why it had a hard time to get back.

FLATOW: So, you think now, though, is the right time to rediscover this?

Dr. HAUSLER: Yes. I do think. I mean, when I was doing the research for the book, I met a lot of people who had infections in different parts of their body who were really desperate to find something. I mean, these are people that had infections for six or 10 or 15 years of their lives and nobody really could help them and could get rid of the infection. So, I do really think - I mean, there are a lot of people out there who need something else, and so there is a high demand for such a method, yeah.

FLATOW: Mm-hmm. Alexander, tell us about the product that you're making?

Dr. SULAKVELIDZE: If I can just add a little bit to what Thomas just said.

FLATOW: Sure.

Dr. SULAKVELIDZE: It was absolutely correct. One of the biggest problems with early phage therapy studies were the specificity of phages. They are very specific. They only kill bacteria and they don't kill anything else, including human cells, animal or plants cells and so forth. But even within the bacteria, they only kill their targeted bacteria. In other words, a phage that is killing, let's say, Listeria monocytogenes, a deadly food-borne bacteria, will not kill E. coli and vice versa.

And so, you have - and back in those years, you have, occasionally, you have a patient in a clinic infected with something, and you treated him with antibiotic that had a broad spectrum, and chances were that that antibiotic would be effective. If you treated him with a phage, unless you were lucky to hit on a target what was infecting that particular patient, a phage would not be effective. I think that contributed strongly to the decline of interest in phage therapy.

Now, nowadays, when you have a much more developed and sophisticated diagnostic approaches and you can allow to identify infected agent precisely, I think phage therapy has a very strong chance there to be very, very effective.

The other - speaking about the need is, I think, it's absolutely essential that we develop alternative modalities for treating infectious diseases. Antibiotics are wonderful. They've been wonderful and will continue to save many, many lives, but there is also this increasing and very serious problem for drug resistance. And so the companies are no longer developing antibiotics as they should be and…

FLATOW: But let me tell you to hold that thought because we have to break. And we'll come back and talk about how we're going to get around the resistance and your suggestions and your products.

Alexander Sulakvelidze and Thomas Hausler stay with us. We'll be right back after the short break.

I'm Ira Flatow. This is TALK OF THE NATION: SCIENCE FRIDAY from NPR News.

(Soundbite of music)

FLATOW: You're listening to TALK OF THE NATION: SCIENCE FRIDAY. I'm Ira Flatow.

We're talking this hour about bacteriophage therapy, with my guests Thomas Hausler, who is a science reporter for Swiss Public Radio; Alexander Sulakvelidze, vice president of research and development, and chief scientist at Intralytix Incorporated.

And Thomas has written a book, "Viruses vs. Superbugs: A Solution to the Antibiotics Crisis?"

And we've been talking about these bacteriophages which, if I can sum up in general for listeners who are just tuning in, these are viruses and there's almost an unlimited number of them around found naturally. They're found in nature that can attack bacteria. They've been doing it for their lifetimes, which we - untold numbers of years. And they can attack even some of the superbugs that are resistant to the antibiotics that we have now.

Would that be right, Alexander? Did I get that right?

Dr. SULAKVELIDZE: That is absolutely correct.

FLATOW: And you are developing products that make use of these phages that can attack some of these superbugs. Tell us about them.

Dr. SULAKVELIDZE: Yes. One of the most exciting products that we have developed is something called LMP-102. It is a cocktail of six bacteriophages that is specifically targeted against Listeria monocytogenes. Listeria monocytogenes is a very deadly food-borne pathogen. Its fatality rate is up to 25 percent or so. So it kills everyone out of four people that get sickened with it.

FLATOW: From food poisoning, it's because…

Dr. SULAKVELIDZE: Food poisoned.

FLATOW: …is this Listeria the kind of thing that kills a lot of people when they get food poisoning?

Dr. SULAKVELIDZE: That's correct. And so there are a lot of things that people are doing to eliminate or to reduce Listeria monocytogenes in foods, and they are successful to a degree, but still there are lot of people get sick and about 500 people a year die in the United States alone from listeriosis.

And so, what we have developed is a phage cocktail that has six phages that we isolated in - from the environment. Most of them came from Chesapeake Bay and - or other rivers and lakes in United States. And so it's - we have not modified it anyway, so it's fully 100 percent natural. And we just selected the most potent phages that can effectively kill Listeria. And we've done numerous studies on various types of foods, and we've shown that by application of this product you can significantly - in many cases, by several thousand-fold -reduce numbers of this Listeria on those foods. And subsequently, you would hope that this will reduce the burden of human disease due to Listeria monocytogenes.

FLATOW: Now, there are other people developing patches, I understand. Medical patches that you'd put on a cut to kill some of these superbugs that normally would just run infections...

Dr. SULAKVELIDZE: That's right. And as you mentioned earlier, one of the unique properties of bacteriophages is they are - that they are still fully capable of killing bacteria that cannot be killed with any available antibiotics. And so from that perspective this provides a very intriguing alternative approach for treating patients, including patients that have infected wounds.

One, the patch that you mentioned, it's something that is very intriguing in my opinion, a product called PhagoBioDerm. It's a biodegradable polymer that is impregnated with bacteriophages. So it can be applied directly onto the wound. It stays on the site, degrades over time, so you don't have to remove it. You don't have to disturb the wound anymore. And as it degrades - and it's 100 percent natural, so therefore, it's very, very safe. And as it degrades, it releases those natural bacteriophages directly into the site of infection where they can kill bacteria, including bacteria that cannot be killed with any antibiotics. So I think that's a very, very intriguing approach.

FLATOW: Thomas, are we going to be seeing more of these kinds of products coming out?

Dr. HAUSLER: Yeah. I do think probably we will be seeing more because, just in the last of couple of years, quite a few companies have actually now started doing clinical trials. Because in the time before, let's say, five years ago, a lot of companies were claiming that they would start soon, but then, you know, they were running into problems. Also, because the bacteriophages were kind of a hard sell to the regulatory authorities like the FDA…

FLATOW: Right.

Dr. HAUSLER: …because it's not something noble for them. They were not used to, like, using viruses as a drug. And these were mostly small start-up companies, which, you know, they have burned all their money sometimes and they couldn't really then start their clinical trials.

But now, there is one company in the U.K. which says that they completed the phase two, meaning that they have already treated some patients with ear infections and that they have good results. We can't really judge it because it's not yet published, but they claim they have these results and they are now looking for money to go into further trials. And I know some other companies that are doing this. So I think it's a good time now.

FLATOW: Mm-hmm.

Dr. HAUSLER: And I think, if I might add that, you know, there - Intralytix products is also very important in a way that it was one of the first products that actually go to the market, not for human use, but still, it - the visibility of bacteriophages was much better after that. So, I think that was a very interesting and good news…

FLATOW: Mm-hmm.

Dr. HAUSLER: …that Intralytix and other companies went first into veterinary product or in products to treat food stuff and other things.

FLATOW: You know, for those of us who worry about taking these hand - the soap treatments with the antibiotics in it or other antibiotics that are in the kitchen, let say, some of the salmonella or some of the bacteria like salmonella and Listeria. Would it be possible to develop, let say, a little spray that is - has the bacteriophages in that that are just for those kind of bacteria that we worry about in cooking and be able to spray it on your counter or your utensils?

Dr. SULAKVELIDZE: That's a very attracting idea. The concept of using chemicals that kill everything, I think, it's getting outdated. We - people are increasingly recognizing that we cannot live in a sterile environment. We live in the nature, and bacteria are part of that nature. In fact, we do not want to live in a sterile environment because the life is impossible, and as a result, some bacteria. So there is - there are good bacteria and bad bacteria. And if we are able to separate them somehow and go after bad bacteria only, that could be extremely beneficial. And I think bacteriophages, for the first time ever, allow you to have that type of specificity.

FLATOW: Let's go Shelly(ph) in San Jose. Hi, Shelly.

SHELLY (Caller): Hi, thank you so much for taking my call.

FLATOW: You're welcome.

SHELLY: I actually did my master's degree on looking at naturally occurring phages in Chesapeake Bay. So it was interesting that he mentioned that some of these came from the bay. But my point that I wanted to make is that it seems like a really smart idea to me, a lot smarter than the antibiotics because we're kind of in an arms race with the antibiotics trying to develop new generations of antibiotics as the bacteria developers had since. But in this case, if we use bacteriophages, it seems like we're letting the bacteriophage wage the arms race for us, so they continue to mutate as the bacteria continue to mutate, and you won't have the same kind of problems with, basically, superbugs, it seems to me.

FLATOW: Is that correct, Thomas or Alexander, that the phages will mutate along with the bacteria? So - are there some out there already waiting for mutation?

Dr. SULAKVELIDZE: That is absolutely correct. And that's been happening for the last three-and-a-half billion years. I mean, it's a natural coevolution. You have bacteria that mutate on their own and then you have phages that coevolved with them. So it's a natural process. It will - it was happening, it will continue to happen for as long as they exist.

The beauty there is that with antibiotics, once you have an antibiotic and bacteria develop resistance against that, that is pretty much it. Then you have to develop a new class of antibiotics, and that's very, very difficult. Over the last decade or so, there've been only one or two new classes of antibiotics developed. So it takes a long time, hundreds of millions of dollars, and hasn't been going well - too well recently.

FLATOW: Mm-hmm.

Dr. SULAKVELIDZE: With bacteriophages, you have a natural product that first attacks using a different mechanism. Two, resistance mechanisms against antibiotics and phages are very different. So if you have bacteria develop resistance against antibiotic, the phage can still kill it and the other way around. And so you - and the third is that if you do develop resistant bacteria against phage, you can always go out to the environment and identify a new phage that is effective against this newly emerged phage-resistant bacteria. As I said earlier…

SHELLY: Right.

Dr. SULAKVELIDZE: …this is very different for antibiotics.

Dr. HAUSLER: And it's actually what - I mean, you know this is better than I am, Alexander, that the people, for instance, in Georgia but also in Poland were doing for decades. I mean, they had a system there. Hospitals could send in bacteria that are resistant to the phage treatments and the people at the central institute or checking with their banks or stocks of phages they had, or if they wouldn't find anything there, they would go back to the sewage or back to the rivers and isolate new ones and then develop a new drug.

Dr. SULAKVELIDZE: That's correct. In fact, the LMP-102 - and Thomas mentioned about the FDA approval, LMP-102, the Listeria monocytogenes phage cocktail I mentioned earlier. Our company was the first company ever in the history of mankind to have a phage-based food safety product approved. So LMP-102 was number one ever to be approved,

And one intriguing thing, by the United States Food and Drug Administration. And so, one intriguing thing that is included in that approval is that we have a flexibility to upgrade and update the product if we feel that the development of resistance warrants it. So what that gives you is an unprecedented flexibility to keep up with the changes in nature and have a continuously effective, very safe natural and effective product.

FLATOW: Why - if it is safe and natural, why does it need approval? I mean, it sounds to me like it's like herbal medication?

Dr. SULAKVELIDZE: That's a good point, Ira. And interestingly enough, shortly after we've got Food and Drug Administration approval, another company got a no objection letter from the FDA to classify phages or one of their phages as grass, and what grass means is a generally recognized as safe. So they don't need any approval as long as FDA did not object for its use as a grass, that's fine. They can go ahead and use it. So…

FLATOW: How hard is it to keep these alive so that - I'm talking about a delivery system. If we're talking about, you know, in a spray bottle, do you need a breakthrough to put it in there to keep them alive or…

Dr. SULAKVELIDZE: Well, if you keep them in a liquid form, they need to be refrigerated and kept away from ultraviolet light. You know, the temperature or the sunlight will kill them. If you freeze-dry them, say, put them in a tablet form, then you can keep them for years at room temperature.

FLATOW: I'm thinking of, you know, people wanting to go out and buy spray bottles of certain things to help them, you know, clean things up. Or doctors in hospitals who would like to do that with their patients.

Are there - let me just remind everybody that I'm Ira Flatow. This is TALK OF THE NATION: SCIENCE FRIDAY from NPR News. Talking about bacteriophages or phages, whichever you'd like. There are so many questions, so little time.

For people who have infections that have had chronic infections for years and years and years, like that bone infection we talked about at the beginning, are there places that people can go to get these treatments that are not offered by their family physician or hospital?

Dr. SULAKVELIDZE: Not that many. In the United States, I am only aware of one place, and that's in Lubbock, Texas, that has conducted an FDA-approved-physician-initiated-phase-one clinical trial for using phages to treat chronic wounds. And so the physicians there have enrolled some patients and that is the only place in this country that I know that is using phages to treat patients.

Now overseas, it's a different story. There are hospitals in the country of Georgia and some other Eastern European countries such as Poland, for example, that type of a treatment is still available. But you know, it's slowly making its way into the United States and Western Europe, but it's not quite here yet.

FLATOW: I would imagine that you'll get resistance from the standard, you know, giant pharmaceutical companies or can it come up with reasons why these should not be - you know, they can't make a lot of money on the products if they're not getting any kinds of royalties out of them.

Dr. SULAKVELIDZE: Well, it's a possibility. I haven't come across against any obvious resistance, and I don't know what's happening behind the curtains. But the fact is that the big companies have been very careful before getting into this, and they are sort of in a stand-by mode and watching, you know, how things develop. On the positive side, I know at least of two large companies that have recently engaged into therapeutic phage research, not in humans yet, but something in animal health area, which I think is a one step forward.

FLATOW: Thomas, I got a couple of minutes left, any final comments on where you see this going?

Dr. HAUSLER: Yeah, sure. I mean, what I can say is that there is this Swiss food company, Nestle, the food giant, I guess.

FLATOW: Yeah.

Dr. HAUSLER: They have a guy who is doing clinical trials with phage against dysentery in children in Bangladesh. So I think that that's very interesting, that they have a - that big company could go into this. I mean, it's clearly not their focus of products, but still they think it's worthwhile going into this. So I think it's a good sign as well.

Yeah. And for me, it's really interesting. I started researching for the book about seven or eight years ago. And now, as I look how things are now, I think it really has changed. And what has mostly changed is the attitude of many people towards this therapy. So maybe a nice anecdote is that I spent quite sometime in the archives of the Pasteur Institute in Paris because one of the guys that actually discovered bacteriophages worked there at the time. So, I tried to look at his papers.

And when I discussed what phage therapy was - the researchers there at the time about six, seven years ago, they were asking me why I would be doing this, it was kind of nonsense. And just now in November, I was back at the Pasteur for official bacteriophage therapy and congress at the Pasteur Institute and there was a guy from the institute itself giving a talk because he took up the research again. So I think it's a nice sign.

FLATOW: Now, you know it's been about seven or eight years on SCIENCE FRIDAY since we've talked about it. And we talked about it back then. It was sort of an interesting idea. It wasn't going very far now. Almost a decade later, it looks like it has - beginning to pick up steam.

I want to thank both of you, gentlemen, for taking time to talk with us.

Dr. SULAKVELIDZE: Thank you.

FLATOW: You're welcome.

Dr. HAUSLER: Thank you. It was very nice.

FLATOW: Thomas Hausler is author of "Viruses vs. Superbugs: A Solution to the Antibiotics Crisis?" He is also a science reporter for Swiss Public Radio. Alexander Sulakvelidze is vice president of research and development and chief scientist at Intralytix Incorporated, a company he co-founded that are making these phage products.

If you like to write to us, you can send your letters to the classic way, SCIENCE FRIDAY, 4 West, 43rd Street, Room 306, New York, New York, 10036. Or surf over to our Web site at sciencefriday.com, we're podcasting and blogging. Also videos, we want your videos. Maybe you've got some lab work on phages that you'd like to show us and what stuff that you've been doing on them. Send them to us. You can go to the link there. Also, you can learn about SCIENCE FRIDAY in "Second Life." Also, we're podcasting back issues, podcasting and video podcasting in SCIENCE FRIDAY.

I'm Ira Flatow in New York.

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