Are Phages A New Page In Medicine?

IRA FLATOW: I want to end the hour focusing on a very intriguing possible solution to the global antibiotic resistance crisis. And it’s an old solution that’s, well, new again. It involves using bacteriophages to treat infections.

Now, a phage is a virus that exists solely to kill bacteria– bacteriophages– and they are abundant in nature, a gazillion of them everywhere. And while scientists first discovered phages’ ability to treat bacterial infections, oh, about a century ago, the advent of antibiotics around World War II put a damper on phage research. There’s been little investment to turn phage medicine into treatments for patients with antibiotic-resistant infections until recently.

Joining me now to talk more about phage science is my guest, Dr. Graham Hatfull, professor of biotechnology at the University of Pittsburgh, of course, based in Pittsburgh, Pennsylvania.

Welcome to Science Friday.

GRAHAM HATFULL: Hi, Ira. Great to be here.

IRA FLATOW: You’ve been researching phages since what, 1988, some 35 years. What prompted you to get into this?

GRAHAM HATFULL: Well, it sounds like a long time, doesn’t it? For serendipity, really. I was interested in another topic entirely, really. I was interested in some ways in which systems do DNA recombination, and heard about a phage system that we might like to investigate. I started digging deeper, getting DNA sequences and doing genomics, and realized that there was a whole new world out there that we hadn’t really even imagined unearthing. And we’ve been delving into that ever since.

IRA FLATOW: It’s funny, that first pun of this segment– unearthing– because that’s where you find the phages, don’t you?

GRAHAM HATFULL: Absolutely. Well, phages are everywhere. And certainly, earth and soil and compost is a place that we and our students– many of our students– have gone and searched for phages, successfully finding them– in fact, some of the bacteria that we’re interested in. But they are everywhere. And so wherever you go, you can usually find some phages.

IRA FLATOW: Let’s talk about the word you use, “success.” Because you have been successful in treating patients with phages– treating their antibiotic-resistant illnesses– successfully. Tell us about that.

GRAHAM HATFULL: Well, we were first contacted by a colleague that I know from London about five years ago, when they had a couple of patients that had infections that they just couldn’t resolve with antibiotics. The patients were very poorly. And after some conversations, they sent us a couple of bacterial strains.

We have a large collection of bacteriophages that were isolated on similar strains. And so we set about a search to see if any of the phages in our collection might be useful potentially for a therapeutic intervention for those patients. And although it took a lot of effort, a lot of screening and some engineering, we were able to come up with a cocktail of three phages that we thought might be a good candidate therapy.

They were administered after all of the appropriate regulatory approvals, et cetera. And they were administered on a compassionate use basis. And I think the patients clearly did very well in terms of being able to resolve much of the infection, at least, and to get back to the semblance of a normal life.

IRA FLATOW: I’m Ira Flatow, and this is Science Friday, from WNYC Studios.

And how many people have you treated in total successfully?

GRAHAM HATFULL: Well, we’ve treated a total of about 35 now or so. Some of those are ongoing. But we’ve written up and reported some details about a consecutive series of 20 cases. And there are definitely successes there, but not universally so.

And of those 20 cases, five we couldn’t really easily adjudicate for various complex clinical circumstances. Of the other 15, four we didn’t obviously see any improvements in the infections. Of the other 11, we saw favorable outcomes, either clinical outcomes or microbiological outcomes.

We take that as a very encouraging sign, especially as these are patients who are very sick, have many difficult and complicated clinical manifestations. And so it’s not universal success. But I think it’s an indication that maybe this is worthwhile looking into in greater detail.

IRA FLATOW: And how would you look into it in greater detail?

GRAHAM HATFULL: All of these cases that we’ve been involved in are on a compassionate use basis– so individual cases. They’re essentially anecdotes. And if you have a series of them, you can certainly see some patterns that emerge. But, nonetheless, they’re anecdotes. And that’s really not good enough for us.

What we’d like to see a clinical trials, where you can do it in a controlled and a blinded way, and try to get real data, real insights, on the variables that influence whether they work or not. The safety, the efficacy, routes of administration, dosage, all of that are basically just guesses at the moment. So we’d like to do the science, the clinical trials, and get some answers.

IRA FLATOW: And what is stopping you from doing that?

GRAHAM HATFULL: There’s still a lot that we don’t know. And one of the underlying complications, especially for the types of bacteria that we’re interested in, is that if you look at the clinical isolates of those strains from different patients, they all behave very differently when we try to kill them with phages. Some of the phages kill some strains, but not others. And there’s a great deal of specificity of the phages for individual patient isolates.

So we don’t have a cocktail, a vial of medicines, that we could use in a clinical trial for all the patients that would enroll because we don’t have phages that are going to address all of the clinical isolates. So this question of specificity, what determines it, is really a core question that we’ve got to get some answers to.

IRA FLATOW: Yeah. So it’s a matter of finding the right phage for the right infection?

GRAHAM HATFULL: Much of it is really like doing personalized medicine, finding phages that might work for a particular individual patient. And we’ve been really interested and delighted to do that from a compassionate use basis to see if we can provide some help for patients with those infections. It just is a real complication when you want to do a clinical trial.

IRA FLATOW: You actually run a program called SEA-PHAGES, where undergraduate students actually hunt for phages, which then get sequenced and entered into your giant database. Where do the students find these phages?

GRAHAM HATFULL: Anywhere that students want to look. As you can imagine, there’s a lot of opportunities there.

Yeah, we started developing phage discovery programs that students could actively be involved in bacteriophage discovery and genomic analysis back in 2002 really. And we developed those programs in Pittsburgh and then at schools, institutions– community colleges can participate– essentially, run a course, where we train faculty to teach that course and to provide the resources and the databases, all the common entities that they need to do that.

And then students, over a course of usually two terms, usually as first-year students, go and discover new phages. They isolate them. They characterize them. They name them, look at the genomes, and add them to the database. And some of those are ones that we’re using for therapies in patients.

IRA FLATOW: Right. Well, you say that one of the problems with the phages is that they’re so specific for an infection. Is it possible to genetically engineer them a bit so that they might be a little more broadly used?

GRAHAM HATFULL: Yeah, we think that’s part of the solution. One of the things that makes the therapeutic use of phages a bit more exciting than it might have been a few years ago is the ability to be able to engineer the phages a lot more readily, to maybe add genes that will make them act better or more efficiently or to change them in ways in which we can overcome that problem of specificity, to expand the numbers of types of strains that they infect. And so that’s something that we’re actively engaged in.

And it’s a step-by-step and relatively slow process. But I think that engineering and just doing the underlying genetics on some of these phages is going to provide some solutions to using these for broader therapeutics.

IRA FLATOW: Well, Dr. Hatfull, don’t be a stranger. Come back and tell us about your advances.

GRAHAM HATFULL: Well, thank you. Always happy to talk about phages, every day, every day.

IRA FLATOW: Dr. Graham Hatfull, professor of biotechnology at the University of Pittsburgh, of course, in Pittsburgh, Pennsylvania.

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