Interview with Ry Young: Phages and Phage Therapy – Pros/Cons and History

February 17th, 2018 by Amy Proal

Ry Young is a Professor in the Department of Biochemistry and Biophysics at Texas A&M University. He is also director of the Center for Phage Technology. Since the early 1970s Ry has studied bacteriophages: viruses that infect bacteria. He is now one of the world’s leading bacteriophage experts. His lab investigates bacteriophages as models for a new class of antibacterials. He has also participated in several “phage therapy” cases – in which bacteriophages are used as therapeutics to treat pathogenic bacterial infections.

Background information:

Tom Patterson phage therapy case: A recent medical case in which phage therapy was successfully used to treat an antibiotic resistant infection. Please watch this TED Talk for more context.

The interview:

Amy: Hi Ry. Thanks for taking the time to speak with me. You’ve researched phages for decades. How did you get interested in the topic? 

Ry: That’s a tough question. I don’t remember a time when I wasn’t interested in phages. I was a graduate student at MIT in 1968. At the time, one of the founders of the Phage Church was named Salvador Luria. He won the Nobel Prize in 1969, along with Max Delbrück and Alfred Hershey, for work on phage genetics. Luria was my microbiology instructor at MIT and turned me on to phages. So I learned about phages from what they call the horse’s mouth – Sal was a very charismatic person.

Phages attach to the outer membrane of bacteria with a thin “tail,” and inject their DNA into the bacterial cell.

Soon after however, I got my Vietnam War draft notice. I left graduate school to spend three years in the Navy. When I got out I went back to graduate school and started working on molecular biology. But as a postdoc, I got an NIH fellowship and chose to work in the lab of a brand new Harvard faculty member, Mike Syvanen, who was a phage guy. In 1978 I started my own phage lab here at Texas A & M. What I like about phage biology is the rigor of the field. Phages are easy to work with and have powerful genetics. You can posit hypotheses, do experiments, and get quick results.

Amy: So when you started researching phages I assume there wasn’t much of a concept of the human microbiome? 

Ry: No no. We had no concept of that. In fact, when I started working here in 1978, I had little idea that I would be one of the last people to start a phage lab for about 15 years. The entire phage movement, or Phage Church, was disassembling itself during the late 1970s and 1980s. This was based on an attitude in which phages were valued strictly as model systems for genetic experiments; as organisms that could help us work out the fundamental rules of molecular biology. But even then, many phage researchers decided it was time to move away from phage genetics to study other model systems. So the people who went on to found important fields of genetics research – like C. elegans for neurobiology and zebrafish for developmental biology – were mostly all phage people who moved away from the field.

This shift was largely started by a researcher named Max Delbruck, who founded modern phage biology. He was a physicist and reductionist: and if you’re a physicist you study the hydrogen atom and then, when you’ve got a predictive understanding of that…you move up to helium and so on. In fact Delbruck himself moved away from phages in the 1950s. So when I started my lab, I was one of a new wave of researchers who were interested in phages per se, rather than using them as a tool to study something else.

Max Delbruck in the early 1940s.

Amy: I see. I didn’t know that.

Ry: If you’re gonna keep up with phage you should get a copy of a textbook called “The Bacteriophages.” It’s edited by Richard Calendar (he’s retired now in San Francisco). I wrote the book’s one-page foreword in 2006. As part of writing it, I did an analysis of  NIH grants for phage research over the past ~ 30 years. I compared 1972, the height of the phage era, with 2002 (30 years later). I discovered that the number of NIH grants on phages had dropped down enormously. The number of RO1s for real phage research had gone from over 200 in 1972 to less than 10 in 2002. Basically the field had died.

Amy: Yes. But now it seems that the field has recently been reborn. 

Ry: Yes. Which is a real problem because suddenly there’s all these people who want to research phages, but few labs set up for phage research.

Amy: Interesting. Does this situation have anything to do with phage therapy?

Ry: No. The first stirrings of renewed interest in phages (and phage therapy) occurred in the early 2000s. That’s because the terrible antibiotic resistance problem we face was becoming more well-known. Even then, we still didn’t know anything about the human microbiome. So there are two separate current justifications for the renewed interest in phage therapy – One: we’re not getting any good new antibiotics. Two: even if we did we shouldn’t be using them. It’s kind of a double whammy in that regard.

Also, since the time when phage biology mostly died out in the 1980s, all sorts of new technologies have emerged – like next generation sequencing, laser technologies and high resolution fluorescence microscopy. The development of cryo-electron microscopy was especially important, because resolution power became so great that we could finally see the details of the phages. Suddenly, phage-related questions that had previously been beyond anybody’s ability to think about could be studied. Not only that, there’s a huge tide of new genomic information that’s bringing home to everybody what an important role phages play in the biosphere.

Because, back in the 1930s, phage biology was classically so powerful that the phage research community would get ahead of itself. That’s what happened with the original phage therapy. In the 1930s phage therapy was pioneered by a guy named Felix d’Herelle. He was a force of nature and went all over the world promoting phage therapy. So thanks to him, phages became the first widely used biological therapeutic.

But in the 1930s science in general was premature –  we didn’t even know about DNA. And because there were no standards, and no FDA or anything like it, most of these early attempts at phage therapy were kind of hopeless. We’d have been a lot better off if d’Herelle had not discovered phages until the 1940s or 1950s, when the scientific community knew more about molecular biology.

But there are other arguments about why this early phage therapy eventually fell out of favor. Part of what caused the decline was personality driven. And a lot was economics driven, because cheap antibiotics like penicillin were also discovered in the 1930s. No biological treatment like phage therapy is cheap. You can’t mass produce phages like you can penicillin. Also, to treat a patient you need thousands of phages versus one penicillin.

Amy: But in parts of Europe and Russia phage therapy did continue, right?

Ry: The very best person in terms of the history of phage biology and phage therapy is Bill Summers at Yale. He’s a great guy to talk to. He’s gives the world’s greatest seminars. They’re funny but illuminating. He was a phage and virus person way back when he was a junior faculty member, but now he’s become a very prominent scientific historian. He’s written any number of articles and books about phages. He’s the only person who knows the whole story. And unlike some people who mercilessly promote phage biology, he can tell you the underside too. And there are some undersides.

Amy: I want to go into those undersides. But before that let me ask you: Now that the microbiome has been better characterized, how would you describe the role that phages play in the human body?

Ry: Oh I don’t think anybody knows right now. Most of the information we have about phages in the actual body is derived from huge metagenomic experiments. For example, they might sequence your gut microbiome and discover there’s an awful lot of phage sequences in there. But by far the most common phages found by such studies are lysogenic phages – the ones present as prophages inside bacterial DNA. That’s a little misleading because all you can tell from that data is that those prophage sequences are being carried by bacteria. You don’t necessarily know if  the phage in question is even functional, or if it’s actually floating around doing anything.

Bacteriophages seen under an electron microscope.

But I think it’s clear that any microbiome community can’t be understood without understanding the phages too. We know phages are going to play a prominent role in the microbiome – there’s no way it can be avoided. Phages clearly interact, both positively and negatively, with the other species. We also know that the human microbiome changes as people develop. But nobody knows how many of these changes are mediated by phages. One of the things about phages in the gut is that there’s a lot of bacteria in the gut microbiome. This crowded environment allows phages to have a massive and rapid effect. Because phages have to absorb bacteria to kill them, and this rate of absorption is proportional. It’s a two body collision. The more phages and the more bacteria you have, the faster those collisions happen. For example, 200 phages can get made out of one bacterial cell.

So it’s a population density issue: when you have lots of any particular bacteria they become suddenly vulnerable to a single phage particle in the population. Whereas if the bacteria are very dilute, you could have 10^5 bacteria X and 10^5 phage Y (that would be able to grow on X) in the same microbiome community, but they might never encounter each other.

Amy: Right. But phages have been detected outside the gut right?

Ry: Oh yeah. Anywhere where you find bacteria in the human body you’re going to find phages. And for every type of bacteria there’s a different phage profile. Phage biology was really started with the study of laboratory strains of E.coli and closely related bacteria like Salmonella. Probably 99% of phage biology research was done on those microbes in the pre-therapy days (including my own research). And with E. coli, we found that you can go into any sewer or pond and find all kinds of different E.coli phages, in their every possible lifestyle. You’ll find lysogenic phages, and then all kinds of what people call lytic phages. Still, much of the variety of phages for E. coli has still not been tapped – we keep finding new ones.

On the other hand take Staph aureus – a high profile bacterial target (MRSA is surging in hospitals etc). There’s actually very little phage biology for Staph aureus. There’s basically two lytic Staph aureus phages. One is called Phage K (a big myophage). The other is a little podophage (a phage with a short stumpy tail). That’s all there is. No matter where you go in the world, if you look for lytic phages for Staph aureus, you’ll only find Phage K, its cousins, or the little podos.

That makes one ask: Why does Staph have such little phage variety? It’s seems like there was a bottleneck way, way back in evolution and those two phages won. It’s unfortunate in some ways, because we would like to have a lot more different kinds of Staph phages. On the other hand, phage K may have “won” because it evolved in a unique fashion. For a phage to affect a bacterial cell, the bacterial cell wall has to have a receptor that the phage can bind to. The bacterial cell wall receptor phage K and its friends use is a molecule called teichoic acid. And this teichoic acid receptor is essential for Staph: it can’t survive without it. So Staph cannot mutate to lose the receptor.  That’s probably why phage K “won”: it learned to recognize that essential receptor and then all the other phages were out of luck.

Amy: So Phage K outcompeted all the other phages? 

Ry: Yes and because the little podo phage has a very narrow host range, phage K is the only phage that’s useful. So there are a bunch of companies that have made phage cocktails against Staph, and they all turn out to be Phage K (plus friends and family). If fact, phage K has probably been patented 30 times.

Ry:  Do you know about the Bayne-Jones-Eaton report of 1934 that supposedly was the death knell of phage therapy?

Amy: No I don’t.

Ry: In 1934, the American Medical Association commissioned two scientists (Stanhope Bayne-Jones and Monroe Eaton) to survey phage therapy, to see if there was any anything “real” to it. They report they produced was very long – it was published in three separate issues of JAMA. They did a thorough study of all the different reported uses of phage therapy. Their general conclusion was that there was no demonstrated therapeutic benefit. And that’s not saying that phage therapy doesn’t work, just that the science hadn’t been done to show it could. However, the report did have an asterisk which stated something like “maybe we’re being too harsh, it does look like phage therapy works for Staph aureus, but nothing else.”

They came to that conclusion because they didn’t know about molecular biology. And if you don’t know what you’re doing, phage K will still work, because no matter how badly you use it it’ll still work. So there’s plenty of good evidence from thousands of cases showing that phage therapy works for Staph infections – evidence that goes way back to the 1910s – 1920s. But the Bayne-Jones-Eaton report still states that phage therapy has no demonstrated benefit (especially if you just read the top line). Also, that was right about the time when antibiotics started becoming available. So that was it: game over for phage therapy.

Félix d’Hérelle

I recently read the Bayne-Jones-Eaton report in depth while preparing for a two-day FDA workshop on phage therapy in July. I did a historical overview to see what the regulatory landscape was back when it was originally written. My interpretation is that “the fix was in for phage therapy,” because Bayne-Jones had a conflict of interest.

In the report, Bayne-Jones actually refers to the “failure” of phage therapy as the “d’Herelle Phenomenon”. And when you start calling something by somebody’s name, you instantly recognize that Bayne-Jones had something in mind about d’Herelle. At the time of the report, d’Herelle had been in the United States as a professor at Yale. There, he did what he did everywhere: frustrate many of his colleagues – he had a real talent for making enemies. He was self-educated with no college degree, much less a Ph.D. I think he was always very defensive about that. So eventually d’Herelle left Yale and Bayne-Jones took over his position. In modern times that would have instantly disqualified Bayne-Jones as an author of the 1934 report: You take somebody’s job and then write a report on the previous guy’s work!? I don’t think that’s a recipe for fairness. Although the report mattered less because antibiotics were going to wipe out phage therapy anyway.

One consequence of this was that d’Herelle had very sad life. He got nominated for the Nobel Prize about 28 times, but always had enemies high up in the scientific hierarchy that would blackball him. Because by any standard he should have gotten the Nobel Prize. He completely invented the whole area of phage therapy.

Amy: It would be interesting if d’Herelle could see new molecular data on phages.

Ry: Oh gosh yeah. He did a lot of fundamental research with no molecular tools, the lessons of which have turned out to be true a hundred years later. But because he was on the outs with the hierarchy, he ended up gravitating to to the left. The book he wrote about phages was dedicated to Joseph Stalin! Not exactly the way to endure yourself to the academic community. He had a real talent for painting himself into a corner.

That’s how he ended up starting the Phage Institute in the Soviet Union. As a result of that he ended up under house arrest all during World War II, because the fascists took over France. It was almost like a bad airplane novel. So now, in 2018, there’s a new phage therapy era. But to me this era is a rebirth of d’Herelle’s original idea.

Amy: I see. So this current rebirth of phage therapy: What’s the climate here in the U.S.? I know the FDA doesn’t allow it. What are the reasons for that?

Ry: Actually the FDA has been nothing but positive about phage therapy. It’s just that no phage therapy cocktail has been put through FDA tests yet. But the FDA has been very proactive: they’re trying to figure out what to do next. In fact, starting with the Tom Patterson case, they’ve set up a system where if a physician reports an appropriate phage therapy case, the physician can get “expanded access” (what we used to called compassionate use) to use phage therapy. This expanded access can be authorized within a day.

So while the FDA is not going to open the floodgates and say, “OK you can start injecting phage into people, don’t even bother calling us,” they’ve agreed to this expanded access (especially in life and death situations). Most of the time expanded access is used for cancer patients – at the end of life, one might as well give experimental treatments a try. So many potential cancer treatments that aren’t ready yet for clinical trials are also used in the same way.

Amy: But in the USA do you have to exhaust all antibiotic options before being allowed to use phage therapy? 

Ry: I think in general that’s correct. Right now if you want to use something that is not approved by the FDA you have to at least say there’s no other treatment option. That’s not a phage-specific guideline but true for all experimental drugs.

Amy: Might that change in the future because of the current antibiotic resistance problem?

Ry: Yeah I don’t know. I doubt that phage therapy will take the place of antibiotics. In the foreseeable future phages are going to be last resort items, mainly because of FDA approval issues. But there are several other problems with phage therapy. One is that we’re not going to find a broad-acting phage like penicillin. And since you know about the microbiota you could say, “we shouldn’t try to find a phage like penicillin!”

Amy: Yes, that’s a benefit in my mind. Because penicillin acts like an “atomic bomb” to the microbiome. It depletes entire microbiome communities in an effort to target one bacterial species. 

Ry: Right exactly. It would be better if we had antibiotics that targeted the disease bug and not the rest of your microbiota. But one reason we don’t have any small molecule-specific antibiotics is that there was no demand for them in the past. Up until recently Medicine wanted broad spectrum antibiotics.

But now there’s going to be a market for specific antibiotic molecules. I’m confident that pharmaceutical science and the industry are going to try very hard to find mass producible molecules that can target Staph, Psuedomonas etc. Those antibiotic molecules would be “round pegs” that fit fairly well into our established FDA drug testing system. For example, if you can find molecule X that kills Staph aureus, and doesn’t kill your microbiome, that molecule will be of great value. Then, somebody will be able to afford to pay the $100 million to $300 million necessary to put that molecule through the FDA drug approval process. I also think that the lysin technology that’s derivative of phage biology will become relevant, because it’s also a cheaper treatment option than phage therapy itself.

Amy: What is lysin technology?

Ry: Lysin technology is part of the phage story. For 40 years the NIH has been funding me to work on lysis (although I have no stock or conflicts of interest). The last step of the phage infection cycle is called lysis. That’s when the bacterial cell blows up and progeny virons are dispersed. One of the proteins involved is an enzyme called endolysin, or lysin, which means “the enzyme from inside that causes the cell to lyse.” Bacteria are protected by cell walls. But if you degrade the cell wall, which is what the phage does, then the cell blows up and the virus particles come out. So these lysin enzymes have now been developed to work from the outside to target gram positive bacteria like Staph. You take the phage lysin, make a lot of it, and inject it.

Crystal structure of a bacteriophage endolysin.

Lysins are not small molecules, but they’re a lot smaller than a phage. So you can mass produce and patent lysins – two things you can’t do with phages. But I think lysin technology will only be useful for Gram positive bacteria. Gram negative bacteria and mycobacteria have tough outer surfaces that endolysin can’t get at. The mycobacteria have a wax-like coating outside the cell wall that’s very difficult to break open.

Amy: Interesting. Back to phage therapy. Imagine there was a perfect world where we had studied phages in much greater depth. There’s a person with a bacterial infection and you’re trying to find a phage to treat them. You’re allowed to proceed however you choose – how would that work? 

Ry: You have to use multiple phages, otherwise you will probably get resistance very quickly. The word resistance means one thing to you, and a different thing to phage biologists. When phage researchers say “resistance” we are referencing a very specific situation: a phage cannot attach to a bacterium because the receptor it targets on the bacterial cell wall is damaged or missing. To clarify, every phage has a bacterial receptor it targets, and almost all the time those receptors are non-essential for the infected bacterium. So the bacterium can simply delete the receptor by mutation, allowing it to become completely resistant to the phage.

Given that notion, if you want a Pseudomonas phage cocktail to work, you need to have at least three phages that would target every possible Pseudomonas strain they encounter. Each one of those phages would target a different bacterial host receptor. The typical frequency of a knockout mutation for bacteria is one in a million: not a very big number if you’re being treated with one phage (because there are millions of bacteria and phages in the system already, some of which are already resistant). So as soon as you kill off all the bacteria that aren’t, you’re right back where you started within a few hours. But, if you have two different phages attaching to two different receptors, then instead of 10 ^- 6 frequency of a bacterial knockout mutation, it’s 10^-12. If you have three, that’s 10^-18. And nobody has 10^18 bacteria in them, at least no one who’s alive:)

So I’m using your perfect world scenario. In my perfect world there’s a Pseudomonas cocktail that’s ready for strain X of Pseudomonas, and we know its receptor targets. We also know that the bacterial strain we’re trying to target has those three receptors on its surface. Now, we can use that phage cocktail with confidence: we’re probably not going to generate resistant bacteria. That’s my hardliner perspective.

So the use of single phages could create a problem similar to what’s happening with conventional antibiotics? (where treatment can select for mutant bacterial strains) 

Ry: Right. Except resistance to phage happens a lot more frequently and quickly than with conventional antibiotics. If a bacterial cell runs into penicillin, it’s going to die unless it evolves to mutate residues of a particular enzyme in the bacterial cell wall (very difficult). So the mutations that create resistance to antibiotics are actually very rare. The problem is that because we’ve overused antibiotics, and put so much selective pressure in humans, many bacterial disease strains have sucked up genes that were already in the dirt. These are genes that had already evolved to degrade antibiotics.

But bacterial resistance to phages is a major concern. In fact, when I was a graduate student working in the heyday of phage biology, the classical attitude was that the resistance issue rendered phage therapy a joke. My mentor (and other members of the Phage Church) called phage therapy “bizarre” because resistance can occur so quickly. Of course, at the time we were completely unaware of how many more phages existed that we could use for cocktails. This was way before the development of next-generation sequencing.

Amy: To summarize. An upside of phage therapy is the specificity of the bacterial target. But that’s also a downside. And this issue could be addressed by using phage cocktails in lieu of single phages?

Ry: As director of the Center for Phage Technology I get to have official positions which absolutely no one has to listen to. But I always dreamed of being able to make pronouncements:) It’s our considered opinion that no phage should be used in a human unless we know what its receptor is. Period. Full stop. There are plenty of people who disagree with me because they don’t want to go through the trouble of figuring out what the target receptor is. But in the long run I can’t imagine the FDA is going to countenance the use of phages without clear receptor targets. And of course the original history of phage therapy has a bad reputation. There were negative outcomes and bad publicity. So now, when we restart phage therapy 2.0, we need to do it right.

Here’s another problem: right now phage therapy is always used via “expanded access.” When the phone rings in my office it’s always a crisis in which somebody is dying. And I’m not going to tell a dying patient and their family requesting a phage that we need six months to figure out what phage to use. But if we keep operating under these rushed emergency conditions, we’re going to start using phages that all use the same receptor. Then we’re going to get resistance and somebody’s going to die. That could lead to serious legal issues. If someone dies after being given an experimental phage, lawyers could later say, “Doctor yes or no…did you send viruses to this sick man? And were these viruses approved for treatment!?”

Amy: But to use an expanded access treatment the patient has to sign a medical release form right?

Ry: Yeah but that doesn’t help a bit because a patient’s heir’s lawyers are not bound by the patient’s request. So lawyers could still come after you. They wouldn’t come after me because I haven’t got a dime. But they might come after my University. Also, a flipside of the specificity issue is that in order to have any expectation of phage therapy success, we need to know whether the bacteria in a given patient are actually sensitive to the phages we have. That means we need at least one day to screen.

Recently there was a phage therapy case involving a young woman. She had gotten a lung transplant and appeared to be cured from a severe Burkholderia infection. But then the infection came back. So along with 3-4 other labs we tested Burkholderia phages. We tested over 400 phages, but only found three, and all of them were lysogenic. It took us 3 days working 24/7 to do that. Unfortunately she passed away a few days later (for reasons not related to phage therapy, but still).

But if we had already had a refrigerator full of phages, and we had known the receptor for those phages, we could have done some very simple, quick experiments. Or you could use a robot to get the bacterial strain from the patient, and know within 24 hours which of your phages might work against it. And if those phages are already pre-purified they could quickly be in the mail. But right now, no such well-characterized stock of phages for any bacterial pathogen is available. Again, the main reason for that is there’s no market for it. Because as far as I know, with “expanded access” you can’t sell the experimental drug (phage): you have to give it away.

Amy: So again, in a perfect world, it seems like the phage therapy community could use some time to calmly prepare for emergency phage therapy scenarios?

Ry: Yes. We could take highly prioritized pathogens like Baumannii and Pseudomonas and create a well-characterized collection of phages for which we knew the receptor. It wouldn’t even be a multimillion dollar project – more like hundreds of thousands of dollars. Which sounds like a lot of money, but I wonder what Tom Patterson’s bill for eight months in the UCSD ICU was? Maybe something like $10,000 a day? So the money needed to generate phage libraries wouldn’t be that large compared to many related costs. But nevertheless, who’s going to pay for it? And is every reference hospital going to have a walk-in cooler with thousands of phage lysates or purified phages? The other possibility, and the dream of the phage therapy world, is to have phage that works against all targets. For Staph aureus that already mostly exists.

Amy: A superphage?

Electron micrograph images of phage K (American Society for Microbiology)

Ry: Phage K is a “superphage.” You can get a phage K that will eliminate 85% of all the Staph on its own. It would target all Staph, except for the fact that bacteria find ways to fight back against phages that aren’t related to “resistance.” Bacteria also have restriction enzymes and their CRISP-R-associated systems, for example. But I think the dream of a super phage is very close to reality with phage K and its relatives. For other bacteria though, we haven’t found many examples of bacteria with essential cell wall components that phages can be targeted to.

Amy: But we’re discovering new phages every day, right?

Ry: Yes. We’re early in the game. And what’s astounding is that all the technology we’re using to characterize phages (with the exception of molecular sequencing) is really the same that d’Herelle used back in the 1930s. Again, that’s because there’s no current market for phage therapy. But, if people think there could be a market down the road, a lot of progress on how to purify phages could occur. The process could become cheaper than it is now. But currently we make phages for therapy in the same way we do for laboratory experiments. And that’s not something you can do on a large scale.

Amy: It seems to me the FDA will have to “paradigm shift” the way they’re going to evaluate phages and other new biological drugs.

Ry: Right, because it’s not just phages. There’s a lot of other biologicals that are like square pegs in the round holes of a regulatory process geared towards developing organic chemicals. I’m hoping the FDA’s “expanded access” phage decision will increase the climate for public and physician awareness of phage therapy. Also, there’s been some progress.

Amy:  What about pressure from Biotech companies? There is a focus in the Biotech community towards the development of personalized treatment approaches.

Ry: Yes. And phages are the ultimate personalized medicine.

Amy: That makes me think the FDA’s current drug approval process is going to become a problem for a lot researchers and drug companies.

Europe is ahead of us in addressing this issue. Partly because the countries involved are much smaller scale countries. If you’re living next door to the Minister of Health, it’s a lot easier for you to get your ideas across. So Belgium, for example, is pretty far ahead of us in terms of making “expanded access” more regularized. They’re going make it easier for physicians to say “I’m going to use phages.” And there will hopefully be suppliers of good phage. Then, the physician will be able to buy/use phages and have protection against being sued.

I don’t think phage therapy will replace antibiotics though. I want to make sure you understand that. I think at least for the foreseeable future phage therapy is going to be a last resort thing. I would like to see a lot more basic phage biology funded. I think in order for phage therapy to best move forward, we also need a rebirth of basic phage biology research. Because almost everything we currently know about phage biology is based on just phages of E.coli (which is of course what I worked on myself.)

Amy: Yes. A recent study estimated that 30 billion phages may traffic the human body on a daily basis. It does seem like we need more research on all these “new” phages!

Ry: Right. DNA sequencing is nice to have, but it doesn’t substitute for doing experiments that help better understand phage activity and function.

Amy: Did you read the recent Georgia Institute of Technology study which showed that the host innate immune response seems to play a role in helping phage therapy work? Because if that’s the case,  then our widespread use of immunosuppressive drugs and steroids seems like a problem. Especially because such drugs are administered frequently in hospital emergency settings.

Phages interact with the human immune system (Roach et al, Cell Press)

Ry: So I suspect that phage therapy will be mostly useful for reducing initial loads of bacteria, under conditions where a patient harbors enormous amounts of a bacterial pathogen. Because once the bacteria get down to a certain level they don’t collide with the phage anymore. Phages are not small molecules, so they can’t penetrate every body niche to find a bacterial target. So I think that phages will be most useful for somebody who’s got a raging infection. You give them a first round of phages and a knock the bacteria down by two or three logs. Now you’ve got a chance for either the body’s own immune system or antibiotics to take over.

Amy: At least in that scenario antibiotics are being used in a careful situation. As opposed to many other ways in which they are over-prescribed today.

Ry: Yes. There’s a lot of speculation out there that many of our current autoimmune diseases, like Crohn’s, may be due to the fact that our generation (my generation) was the first to be massively dosed with antibiotics all throughout childhood. My generation was convinced that if you didn’t get an antibiotic prescription you hadn’t been treated right. It was the golden age of antibiotics.

Amy: Right. When antibiotics were discovered they were perceived as miracles, which they kind of were, especially during World War II. But that has created a situation where the average person has not been well-educated about how antibiotics work. For example, about the fact that antibiotics can’t kill viruses. 

I think that the American Medical Association is at fault for not educating the public better about antibiotics. I mean they really are. For example, you see all these TV commercials for erectile dysfunction or cancer drugs. There ought to be a way that some of that airtime could be used to educate the public about medical topics like antibiotics. Especially because most drugs advertised in these commercials were developed with NIH funding. So I think big drug companies owe at least that to the public. Also, physicians need to have the courage to say “You have a viral infection. I’m sorry but it can’t be treated with antibiotics.”

Amy: Yes. I know you’re considered a “hardliner” when it comes to the future of phage therapy, but I think the caution you advise moving forward in spot on. We don’t want to create a future situation with phage therapy that could repeat problems we’ve encountered with antibiotics. Understanding and correctly managing phage resistance will be critical.

Thanks so much for taking the time to speak with me. I learned so much from this discussion.   

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