Scientists Engineer Viruses To Battle Bacteria Viruses called bacteriophages make a living picking on certain bacteria. But these viruses have had limited use as antibiotics. Biomedical engineer Jim Collins explains how his team was able create a better bacteriophage, capable of attacking even antibiotic-resistant bugs.
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Scientists Engineer Viruses To Battle Bacteria

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Scientists Engineer Viruses To Battle Bacteria

Scientists Engineer Viruses To Battle Bacteria

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This is SCIENCE FRIDAY from NPR News. I'm Ira Flatow.

Next time you're in the hospital, you'd better hope that you don't have any nasty roommates. And I'm not talking about the guy falling asleep who keeps listening to "American Idol." No, no, no. I'm talking about something much worse: superbugs.

You can launch a battalion of antibiotics at these bacteria and they just keep going and killing, too. But you may be surprised to learn that Mother Nature, in her wisdom, has provided natural antibiotics of her own like viruses called bacteriophages.

These viruses make a living beating up bacteria, and they have been used before, in the pre-wonder-drug era, to attack bacteria. But they've never gone mainstream, really. The Russians did a lot of work with these.

Well, it may be time to welcome them back because now scientists have engineered a better bacteria-battling virus. One that's capable of attacking even antibiotic-resistant superbugs.

This research appears this week in the journal, Proceedings of the National Academy of Sciences. Might these engineered viruses join the antibiotic arsenal, for example, in hospitals?

Our number 1-800-989-8255, if you'd like to talk about it, 1-800-989-TALK. Also on Twitter, you can tweet your question to us @scifri, and at Second Life you can you can find us there and pick up a T-shirt.

Jim Collins is an investigator for the Howard Hughes Medical Institute and a professor of biomedical engineering at Boston University. He joins us on the phone today. Welcome to Science Friday, Dr. Collins.

Dr. JIM COLLINS (Professor of Biomedical Engineering, Boston University): Thanks, Ira. Thanks for having me here.

FLATOW: So this is an old technology then that you have sort of updated?

Dr. COLLINS: That's right. So what we did - so this was work done with Tim Liu, who's a post-doc with our lab, was engineer these bacteriophage, which as you describe are viruses that will infect bacteria. These are viruses that are found in nature.

They've been used in Eastern Europe for decades as part of antibacterial treatment with some success, anecdotally. And what we did as part of our project was to re-engineer them or redesign them so that once they infected the bacteria, they would produce proteins that would work in conjunction with the antibiotics to make the antibiotics more effective at killing the bacteria.

FLATOW: So you create a tag-team…

Dr. COLLINS: That's right.

FLATOW: …of the bacteriophages and the antibiotics.

Dr. COLLINS: That's right.

FLATOW: And you tested them in the laboratory.

Dr. COLLINS: We initially tested them on bacteria in our lab in a dish. And we then went further and actually tested them in mice. And in each case found that they performed remarkably well in conjunction with the antibiotics, making the antibiotics in the dish anywhere from 100 to 100,000 times more effective at killing the bacteria.

And in the mice studies, we found that the mice treated with the phage and antibiotics, we had about 80 percent of those survive whereas only 20 percent of those just receiving the antibiotics alone survived.

FLATOW: Wow. Do you know what happened to that other 20 percent?

(Soundbite of laughter)

Dr. COLLINS: Well, they died.

(Soundbite of laughter)

FLATOW: Do you know why?

Dr. COLLINS: In this study - well, we did not work at this level to try to optimize either the antibiotic dosage or the amount of phage that we gave. We simply wanted to show that we could get a boost over the antibiotics.

FLATOW: Right.

Dr. COLLINS: And we're confident that if we actually did dosage studies - as one normally would as part of a clinical trial - that we could eliminate those 20 percent that died.

FLATOW: Now how do they work as a team? What does one do and the other one follow up with?

Dr. COLLINS: Sure. So the initial one that we focused on in terms of the engineered bacteriophage was we had them express proteins that shut off the bacteria's system for repairing DNA.

What our lab found, going back about a year ago, is that all antibiotics that kill bacteria do so in part by stimulating the production of reactive oxygen species, specifically hydroxyl radicals that will damage DNA.

The bacteria will respond to that and attempt to repair their DNA. And this will lead to some of them surviving the antibiotic treatment. What we did with the phage was to have them express a protein that would keep that DNA repair system off. And so, now you allow the antibiotics to do their real damage on damaging DNA so that, as a result, they were much more effective at killing off the bacteria.

FLATOW: Mm-hmm. Now is there not a danger of creating an even bigger superbug here that it could be resistant to this tag-team?

Dr. COLLINS: You know, I suspect that in really any sort of treatment, eventually resistance will arise. What we found was that we actually were able to suppress the emergence of resistance in this case by keeping the DNA repair mechanism off.

And that was for two reasons. One is the DNA repair mechanism itself is mutagenic. And that is, it will lead to mutations, which in many cases will allow resistance to arise.

Second is that we actually used phage that, on their own, don't kill bacteria. So there's not a strong evolutionary pressure for the culture to develop resistance to the phage themselves. And, as a result, we found that we had much lower levels of resistance emerging with our combination therapy.

FLATOW: So let's say that you take the next step and, down the road, what is the ultimate usage for this combination? Is it in people? Is it in cleaning up hospital laboratory areas or equipment, things like that?

Dr. COLLINS: I suspect - we envision a broad set of usages. First would be in humans. And I think the initial target would probably be on topical so looking at skin infections, where people are less concerned in that case because you don't have to necessarily treat by ingestion, and you can treat by applying cream. And so, you don't have to worry about the concerns about ingesting viruses, albeit ones that don't infect us but infect the bacteria.

Two is that we envision these could be used in agricultural applications. So there's a wide use of antibiotics in livestock to keep them healthy.

This unfortunately leads to large amounts of antibiotics that end up on our tables, into our food. And so, we hope that these phage would enable one to use lower amounts of antibiotics on the livestock and thereby reduce the amount of antibiotics we have in our community.

And then third is industrial settings. Many different situations, water supplies, for examples, will be contaminated with bacteria, specifically those that are in biofilms. So these are bacteria basically encapsulated in a matrix of material and attached to a surface.

We envision that these engineered phage will be quite useful at cleaning up environmental settings that have been contaminated by bacteria and bacterial biofilms.

FLATOW: Well, is this a one-phage-fits-all, or do you have to have engineered different phages for different bacteria?

Dr. COLLINS: So it's definitely not one-phage-fits-all. So phage are species specific, bacterial species specific, and in many cases strain specific. So you need to engineer really a library of phage to go after all these different applications.

And for many applications, including human infections, we would envision that you'd have to have a cocktail of phage, given that in many cases, it's difficult to identify the actual strain the person's infected with and, in many cases, the person may have more than one strain.

FLATOW: Mm-hmm. And so where do you go from here now?

Dr. COLLINS: So we have multiple plans. We are planning to shift towards more clinically-oriented studies where you could look at clearing out catheters, for example, with these phage.

We're also looking to use DNA synthesis technologies in conjunction with our synthetic biology technologies to create a whole library of phage, those that could express many different proteins, as well as engineering phage that could go after a host of different strains and species.

FLATOW: Why haven't we seen this already being used for treatment?

Dr. COLLINS: That's a good question. I think there are multiple reasons. One is cultural. As it was alluded at the beginning of the program (unintelligible) that it was popular in the former Soviet Union for decades, largely used in the military, but most of their successes were anecdotal in nature. There were no solid clinical trials that had been done. And, as a result, there's a general sense of suspicion in the West towards the technology.

Second, there are a range of challenges around the technology. You do have immune responses you have to worry about in the human patients, once they're treated with the phage. There is the phage-specificity problem we talked about. There's the emergency resistance to the phage.

There's the toxicity issue that many of the phage, the ones that kill will kill by blowing up the bacteria and releasing into the host - that could be a human - toxins that are inside the bacteria. And so, there's many, many technical challenges that, in the end, most groups have avoided going after this and instead chose molecule development to get to a drug.

FLATOW: And is it - your partner, your colleague, Tim Liu, has actually set up a company.

Dr. COLLINS: That's right. So Tim currently is, as I said, a post-doc and an MD student at Harvard and MIT, and he along with Mike Koeris and Tanguy Chau and Anne DeWitt(ph) are pulling together a company they're calling Novophage - that they're right now in a very early stage, submitting challenging business plans to different business-plan competitions - but pulling together a pretty good science advisory board, including Bob Langer at MIT and Greg Stephanopoulos.

FLATOW: Will you be able to find a phage for MRSA and think heavy-duty bacteria?

Dr. COLLINS: Potentially yes. And so, you know, going back to the prior question, I think why now you're seeing interest in phage therapy is that because we're faced with this growing incidence of antibiotic resistance and coupling that with the drying-up pipeline of pharmaceutical companies, we need to turn to new and different approaches.

And so I think in the therapeutic side, there will be opportunities coming up. And as we discussed, there are other areas, including industrial applications, where I think a company could actually step up and produce phage that will be of use.

FLATOW: And I guess one of the first things you do is create a library of what phages are good on what bacteria.

Dr. COLLINS: That's right. So you go out, you know, there are many, many natural phage that have been identified. So if we can go in, get those and then redesign them and reengineer them to produce a range of different proteins for a range of different applications, including breaking up the biofilms, which is a very, very big challenge.

FLATOW: Why would nature have viruses that attack bacteria? I mean, we've talked about this for a while that there are all these viruses out that that - you find them in the sewage system, right?

Dr. COLLINS: Yeah.

FLATOW: Now why would - I just think it's amazing that Mother Nature would create viruses to attack bacteria.

Dr. COLLINS: You know, I don't know why we have them. You know, a similar question you could ask, why do we have them that attack humans and other mammals? I suspect opportunistic, the earlier life forms, they latched onto this and were able to kind of do their business by infecting the bacteria, multiply and were able to kind of pass on their genes.

FLATOW: Could you find a natural phage that attacks some of these instead of having to engineer them?

Dr. COLLINS: You can, yeah. In fact interestingly, there are phage that will express, for example, enzymes to break up biofilms. And it's a work that Tim and I then kind of built off earlier and did engineered phage in that case. But, in many cases, it's a challenge to actually find them and then have them of a proper kind of engineered form that can be used as a part of therapy.

FLATOW: And could you - a question from Second Life. As the biology matures, as the bacteria mutate, can you mutate - can you reengineer the viruses to mutate with them, so to speak?

Dr. COLLINS: Absolutely. You know, it's one of these - I think a future strategy to go after the resistance will be to change up what you're actually showing the bacteria. So as they come in, instead of hitting them with, you know, Phage A and Drug B, hit them with Phage C and Drug D.

FLATOW: It's good spy versus bad spy again.

Dr. COLLINS: Yeah.

(Soundbite of laughter)

FLATOW: All right. Thank you, Jim, for taking time to be with us.

Dr. COLLINS: Thanks, Ira.

FLATOW: Jim Collins is an investigator for the Howard Hughes Medical Center and professor of biomedical engineering at Boston University in Boston.

We're going to take a short break, switch gears, talk about how you can be a backyard scientist. Instead of just talking about the climate, you can actually do some valid and useful research on a national scale. We'll tell you how we're going to do that after this break. Stay with us.

(Soundbite of music)

FLATOW: I'm Ira Flatow. This is SCIENCE FRIDAY from NPR News.

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