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Welcome back everybody to another episode of You Make Me Sick.

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Today we're joined by a very special guest, this is Dr. Shawn Owen.

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Dr. Owen is a microbiologist.

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She is a or was a research fellow in the Department of Biomedical Informatics and

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Laboratory of Systems Pharmacology at the BAME Laboratory at Harvard Medical School.

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She's also completed research at the Jay Hinton Laboratory in Liverpool, England.

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She's an expert in the field of bacteriophages.

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Will be soon starting her own lab in Albany, New York at the Wadsworth Center, correct?

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In conjunction with New York Department of Health.

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She's actually been using experimental evolution and computational approaches to study the

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phenomenon of antibiotic resistant bacteria, among other things and just really innovating

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the way phages are looked at.

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So I'm very happy to have her here today.

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Thank you for joining us Shawn.

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Thanks a lot Andrew, very excited to be here.

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Shawn has also been published in a variety of journals including Nature, Nature Microbiology,

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Science and the International Journal of Molecular Sciences, just to name a few.

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She just completed her post doctorate here at the Harvard Medical School in the BAME

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Laboratory.

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As I said she's going to be heading up her own lab very soon and I'm actually really

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excited to talk to her today about a, it's a subject that a lot of people have no idea

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exists, bacteriophages.

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So I guess question is Shawn to start with, what can you tell us about bacteriophages?

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If I was someone off the street who had no background in biology, had no idea, could

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you explain to me what a bacteriophage is?

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Yeah, so a bacteriophage is a, or a phage.

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I like to go for phage but it's a potato potato, right?

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It's actually, it's your call.

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It's a virus and so I usually like to explain it to people as it's like the coronavirus

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for bacteria.

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So these are exactly the same way as you and I get viral infections, bacteria are susceptible

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to the exact same problem and frequently encounter these viruses in their everyday lives which

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will infect them and often kill them.

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And so more specifically in terms of the biology, a bacteriophage is debatably alive when it's

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outside of a living cell.

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A phage is just a protein shell surrounding some nucleic acids and that's either DNA or

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RNA.

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But that, those nucleic acids code for the instructions that the virus uses once it gets

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inside a cell to repurpose that cell into a factory to make more of itself.

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Exactly the same as when you and I get viruses ourselves.

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How long have you had this great appreciation for phages?

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Is this something, is this something that, I know you were telling me you grew up in

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the south of England, a really big forested area, lots of nature around you.

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Have you always been a biology fanatic?

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Yeah, I think I've always been really interested in the natural world.

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I've also always had a morbid fascination with infectious disease.

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I think it's that my mum was also a nurse and so I think she instilled in me a kind

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of interested disease and gross things.

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And so yeah, I always remember being interested in microbiology.

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I remember the first time I learned about bacteria was in high school science class

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and we would go around the school swabbing surfaces and culturing them on bacterial plates.

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And I just remember being amazed that there was this whole world that we couldn't see

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going on.

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And yeah, I think microbiology is so fascinating in that respect.

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It's just a window into, we are titans, you know, in this like world that we cannot even

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see.

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Yeah, I have a, I had a microbiology professor that said it's their world.

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We're just living in it because they're everywhere.

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They're ubiquitous.

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Exactly.

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With regard to phages, so do you know anything about their history as far as when they were

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first discovered, their first uses, especially in the field of medicine?

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Yeah, so phage has a very, the field of phage has a really interesting starting point.

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So phage were first kind of discovered in the late 1800s when scientists, I think the

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first accepted kind of people who identified these were scientists in India actually who'd

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noticed that the cholera bacteria they were growing would sometimes just kind of die when

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they added water from the Ganges River.

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And it was kind of known to be this sort of principle, this kind of lytic principle that

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would occur sometimes in bacteria.

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But that was kind of as far as that got.

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And then it wasn't until the early 1900s and the First World War, a British microbiologist,

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very proud of this, Fred Twart published a paper describing what he found when he was

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growing some micro-cockas, I think it was, bacterial colonies.

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And he noticed that on top of these colonies occasionally, he'd see these little glassy

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spots of kind of like transparent circles in the bacterial colonies.

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And crucially, he found that he could transpose those little areas of lysis from one colony

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to the next.

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So if you like, he could infect one of these glassy colonies into a healthy colony and

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cause infection.

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And so he, and secondly, so at that point we weren't really sure what this like agent

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causing this lytic morphology was, but he showed that if he filtered this diseased part

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of the colony through what was known as a chamberland filter, so basically a filter

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that had such small holes that bacteria cannot pass through, you could still infect healthy

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colonies, suggesting that whatever this thing was was smaller than bacterial cells.

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And at that point, it would come known as like an ultramicrobe, they were calling it.

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And I kind of, yeah, it's a really fascinating story involving many characters.

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There's another, there's a lot of actually debate about who it was who first identified

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the bacteriophage.

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And another kind of famous name that often comes up is Felix Durell.

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That's the name I'm familiar with.

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Yeah.

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So he's like often, I think, often was like first credited with studying the bacteriophage

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for a long time, certainly because he was much more flamboyant personality.

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But technically his paper came out a little bit later, but he was working on bacteria

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causing dysentery in France, a chagella bacteria, and discovered like very much the same thing.

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But I think Felix Durell is also often celebrated because he was the first person to really

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think about therapy and what we could do with these ultramicrobes that could kill bacteria.

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And he was very confident and kind of a bit of a maverick.

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And he very early started pioneering the use of actually using these bacteriophages to

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treat soldiers and patients who are suffering from enteric disease.

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And it was successful, right?

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They actually they had success using phages to treat disease early on.

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This is pre-antibiotics.

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So this is the turn of the century.

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1900, 1920s, 1930s, correct?

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Correct.

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And obviously like a caveat here is nobody's reporting when it doesn't work.

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That's like a you're going to realize that's a long standing issue with the phage therapy

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literature.

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But yes, it had early success.

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Studies won't let you do that anymore, will they?

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And so phages were actually acceptable in science.

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And even here in the United States, I'm pretty sure Eli Lilly was the first manufacturer of

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laboratory produced phages to treat just different forms of diseases.

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Ankinteric diseases, you said, were one that were used quite commonly for.

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I know that they were also used topically.

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I'm not sure how early that was.

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But I don't know if it was staff or what they were treating with that.

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So there was over 100 years ago, I guess.

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So then antibiotics came into play.

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And this is kind of this will play into a lot of what I'd like to talk about today, just

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with regarding phages and phage therapy.

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So antibiotics, when they were first created, they've been used now for about 100 years.

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And we're really starting to see just kind of the repercussions of their misuse and their

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overuse and just a misunderstanding of how bacteria mutate to survive.

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So from your perspective, what advantages do you think phages can provide over antibiotics

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or in conjunction with antibiotics?

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And can you kind of explain the difference of how phages destroy bacteria as opposed to

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how antibiotics might kill bacteria?

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Yeah.

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And first, let's go back a little bit and talk a bit about what happened when antibiotics

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were discovered, because that's kind of an important part of the history of phage research.

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So you're right.

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There was a lot of interest, I think, after Dorell was showing that phages could help

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patients.

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But shortly after that, phage therapy was particularly taken up in Eastern Europe.

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And so there were some Georgian scientists who happened to be studying at the Pasteur

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Institute in France with Dorell and kind of took this technology back to Georgia and Eastern

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Europe with them and did some really good work and a lot of pioneering work into bacteriophages.

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And then the 1930s comes, or late 1920s, and penicillin is discovered.

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And so I think at this point, in the West, bacteriophages in comparison were seen as

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very complicated things.

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So a feature of bacteriophages is they tend to be very strain specific.

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They are not great at curing every kind of E. coli infection you might have.

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Like one phage might just hit one single strain of E. coli.

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And so to actually formulate a therapy with these things is quite challenging and can

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be very inconsistent.

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Versus antibiotics, which were easy to mass produce.

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You just grow fungus, you extract the antibiotics.

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They tended to kill super broad spectrum kinds of bacteria, so you didn't need to have loads

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of individual kinds of phages.

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You could just have one antibiotic and hit everything.

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And so pretty much the Western world stopped working on phages and really focused their

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efforts towards antibiotics and very successfully, right?

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Like antibiotics really hugely improved our human lives in the 21st century.

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So yeah, it's kind of an interesting story.

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But then obviously now we're kind of reaching a point where antibiotics have been so successful.

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We are using them in really every part of life.

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And so I think 66%, for example, of all antimicrobials are used in agriculture now.

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They're not even used directly to treat human disease.

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And the result of that is that we are just really putting a high degree of selection

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on bacteria to evolve resistance to antibiotics in areas that aren't even the human body.

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And hence we're having this huge problem with antibiotic resistance.

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But back in Georgia and Eastern Europe, they've actually been using still phages this whole

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time.

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So you could go to Georgia and I have colleagues who were there for conferences and you can

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go into a pharmacy and buy vials of phages for ear infections and gastric upset.

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So we're now finally going back to our colleagues in Eastern Europe in Georgia to try and really

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understand what these therapies are that they've been using and see if we can learn from them

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as we become re-interested in phage therapy.

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So there was an online article that was published from the pharmaceutical processing world.

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That was the name of the public online publications in 2023.

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From that article, they said that quote, the global antibiotics market size was valued

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at approximately $42.33 billion in 2023 and is expected to grow because of due to increase

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to antibiotic resistant infection and rising demand for novel antibiotics.

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Do you feel that with phage therapy, you know, it's kind of an afterthought due to the monster

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of some amount of revenue that these pharmaceutical companies bring in?

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Do you think that, you know, I know that, and I saw again, this was Eli Lilly just pledged

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another just large amount of money towards more antibiotic research and I don't even

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know if they've dipped their finger in phage research or not.

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But do you think that's something that's being overlooked that should be more closely

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paid attention to?

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Yes.

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Well, I think the issue is very complicated.

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The problem is we are way behind in terms of phage research compared to what we know

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about antibiotics.

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So because we abandoned the field for so long, we are really in the very early days of understanding

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phages and using them to treat patients.

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So you can kind of imagine we are back in terms of, in using phage, we are back in the

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1930s still as far as our understanding goes.

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And so I would say more than maybe pharmaceutical companies needing to invest in phage, I think

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we do need more basic science research to be done.

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And then I think later, once we're at the point where it does seem like we have technology

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to really push these things into therapeutics, it would be great.

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But I would say in general, we just need more government level support and reward for antimicrobial

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development.

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To that point, so last year the pharmaceutical health and beauty industry spent about $378

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million in lobbying in the US.

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Knowing how much profit these pharmaceutical companies can make from antibiotics, do you

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feel that lobbyists are kind of, they're slowing things down governmentally with regulations

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because they know that phage technology, even though it might be more successful, they're

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making more money with antibiotics.

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And at least in the United States, the dollar rules everything, even our political system,

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which is how it goes, I guess.

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But do you think that if there were more lobbying groups or proponents of phages and phage therapy,

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that this would be more research and more funding would actually be, I don't know, they'd

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be compelled to do more research and more funding?

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Yeah, perhaps.

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I mean, I think we also, as researchers need, there is some onus on us to really demonstrate

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the therapeutic potential of these things.

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And certainly that is not something that I'm 100% convinced of.

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Cards on the table, I think like it's still not, I would still not bet that in 50 years

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we'll be using phages widely to treat bacteria.

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The jury's still out a little bit.

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So I think we, yeah, a lot more basic science research needs to be done and time will tell

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whether phages are really going to save us.

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So it's something that we encounter a lot in the healthcare system, our multi-drug resistant

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organisms.

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Phages and especially some of the ones you've been studying have shown potential to actually

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treat a lot of these that antibiotics can't kill.

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And these are different strains of bacteria that just have gained resistance to some of

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them multiple antibiotics and become really, really hard to kill.

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There was a recent study in nature microbiology, it was the BT100 study, it was pretty small,

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but it found that phage therapy used in combination with antibiotic treatment proved to be highly

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effective in treating MDROs both in vivo and in vitro, so in the lab and in humans.

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It was small, the sample size, but it did provide data just to show that phages are still effective

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and can be very effective in conjunction with antibiotics.

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Do you think that there may be a day when phages themselves could be as potent or even

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more effective at treating and killing these multi-drug resistant organisms?

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Yeah, so that study was hugely celebrated in the phage field.

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It was a real labor of love primarily pushed by these researchers in Belgium and really

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answers a lot of very important questions with regard to the success of phage therapy,

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which has been something that's been very hard to answer for a long time because in

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general the way phages have been used for therapy is very unsystematic.

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So typically as there is no official regulation of phages as therapeutics, the only way in

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which clinicians are able to use them is in these compassionate use cases.

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And therefore every trial is a little different, the formulations are slightly different,

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patients don't really have comparable illnesses.

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And so it's been up until now extremely difficult to really know where the phage therapy is

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working and of course there's quite a few case studies in the literature about successful

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cases, but as we mentioned before how many failed cases were there for every successful

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case.

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And so this particular study, the VTE 100 study is really exciting because they didn't

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cherry pick the data at all.

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They really just systematically took the first 100 cases that they had done and were super

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transparent about the data and it's actually a kind of optimistic picture.

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So what it shows is that interestingly phages when they were delivered on their own weren't

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particularly good at clearing infections.

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The clinical prognosis didn't tend to improve too much.

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But more happily when you combined phages with antibiotics there was a pretty convincing

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increase in patient infection prognosis.

252
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So it was pretty promising data that combined with antibiotics phages might be a pretty useful

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clinical strategy.

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So kind of staying on the subject of these MDROs.

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So this year, this past year, or this spring or the end of last year, the CDC they released

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data from a 2019 antibiotic threats report and in the United States here they stated

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that more than 2.8 million antimicrobial resistant infections occur every year and 35,000 people

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die as a result.

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That's just here in the United States.

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And then even beyond that the WHO, actually this is actually an article from the Lancet,

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I'm sorry, from 2022 that again kind of confirmed and this is using, it might be even the same

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data from 2019.

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It's estimated that worldwide there were about 4.5 million deaths associated with antimicrobial

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resistance.

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A lot of death from this, you know, a lot of these, obviously they can't be treated

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with antibiotics, they lead to a lot of bloodstream infections, sepsis and subsequent death.

267
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The numbers are pretty staggering and with such an urgency that we have right now and

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especially in the last few years there's something called the antimicrobial stewardship

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and this is seen in hospitals where you're not prescribing antibiotics unless you are

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100% certain someone has a bloodstream infection or if you're suspicious you stop them as soon

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as if they don't have one you stop the antibiotics as soon as they're shown not to have one and

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then you get a specificity as soon as possible and you narrow down the antibiotic and this

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is to try and control some of that resistance in these microbes.

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But with such an urgency do you think that like phage therapy there could be more attention

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paid to this because it is a problem that's going to continue to grow and increase especially

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over the next 25 years or so?

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Absolutely.

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Absolutely.

279
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And so actually the reason why phage therapy has been kind of neglected, interestingly

280
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all goes back to that history we were talking about.

281
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So because phages were kind of abandoned in favour of antibiotics they were kind of seen

282
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as too complicated I think.

283
00:21:08,320 --> 00:21:13,080
But the cool thing is that even though they were completely abandoned by people interested

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in therapy they were taken up by molecular biologists and physicists who decided that

285
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bacteriophages were a really fascinating way to study.

286
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They considered them to be the simplest organisms so if we were going to understand life we

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could start with a bacteriophage.

288
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And so there was a huge effort to understand phages at the molecular level and that led

289
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to all kinds of really important scientific breakthroughs in the 20th century including

290
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the discovery of DNA as heritable material and tons of other interesting things.

291
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The enzymes we use in molecular biology most of them come from bacteriophages.

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And so it's kind of a double-edged sword here because even though we did kind of abandon

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00:21:58,000 --> 00:22:03,960
phages in terms of therapy we got a huge, we learned a huge amount from them in terms

294
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of molecular biology.

295
00:22:05,240 --> 00:22:12,080
And so hopefully we're now at a point where we need phages again perhaps therapeutically

296
00:22:12,080 --> 00:22:17,160
but we have all of these tools in our pocket from almost kind of 80 years of studying them

297
00:22:17,160 --> 00:22:23,760
at the molecular level and we can maybe now kind of combine our knowledge and take a kind

298
00:22:23,760 --> 00:22:28,520
of synthetic biology approach to improve phages.

299
00:22:28,520 --> 00:22:31,480
And it's very analogous really to what happened with antibiotics.

300
00:22:31,480 --> 00:22:36,800
So when antibiotics were first discovered they are a natural product of fungi, right?

301
00:22:36,800 --> 00:22:42,560
And originally people were just using the raw, the real natural product of fungi to treat

302
00:22:42,560 --> 00:22:44,120
patients and it wasn't that great.

303
00:22:44,120 --> 00:22:48,360
It had a lot of problems so occasionally these antibiotics were toxic to humans, they were

304
00:22:48,360 --> 00:22:49,920
hard to produce.

305
00:22:49,920 --> 00:22:54,520
And very quickly with research people moved from using these natural product antibiotics

306
00:22:54,520 --> 00:22:58,760
to modifying them and making synthetic versions of those original antibiotics.

307
00:22:58,760 --> 00:23:03,440
And now most of the antibiotics we're using don't look quite like the original natural

308
00:23:03,440 --> 00:23:05,840
products that fungi are producing.

309
00:23:05,840 --> 00:23:10,840
They're things that we have expanded upon and elaborated.

310
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And I really think the phage field is going down the very much very similar trajectory.

311
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So at the moment we're still in the early days where we have these like natural bacteria

312
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phages and what we need to do is start expanding them and editing them and turning them more

313
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towards our purposes.

314
00:23:32,160 --> 00:23:38,520
So my personal feeling and it's controversial perhaps and not everyone in the field might

315
00:23:38,520 --> 00:23:44,840
agree with me but my personal feeling is phage therapy as we know it today is never going

316
00:23:44,840 --> 00:23:47,360
to be widely uptaken.

317
00:23:47,360 --> 00:23:55,520
But as we move towards kind of custom therapies or edited or even machine designed bacteria

318
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phages these things I think have the power to really influence the way we treat infectious

319
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disease.

320
00:24:02,840 --> 00:24:06,040
I'll touch on that a little bit later especially using artificial intelligence to help kind

321
00:24:06,040 --> 00:24:10,080
of create or guide the production of these.

322
00:24:10,080 --> 00:24:15,200
So the WHO recently released their list of priority pathogens.

323
00:24:15,200 --> 00:24:21,760
This includes 24 pathogens 15 different families of antibiotic resistant bacteria included in

324
00:24:21,760 --> 00:24:29,160
the list are Salmonella, Shijella, Nasiria gonorrhea, Pseudomonas, Pseudomonas aeruginosa

325
00:24:29,160 --> 00:24:31,160
and Staph aureus.

326
00:24:31,160 --> 00:24:34,640
I kind of wanted to talk a little bit you've done quite a bit of research actually with

327
00:24:34,640 --> 00:24:41,000
Salmonella correct and phages and how phages can be used to treat MDI Rho Salmonella.

328
00:24:41,000 --> 00:24:45,880
And I also wanted to talk a little bit about Pseudomonas and then MRSA the Methacillin

329
00:24:45,880 --> 00:24:51,080
resistant Staph aureus which are two of the most common hospital acquired multi drug resistant

330
00:24:51,080 --> 00:24:52,440
organisms.

331
00:24:52,440 --> 00:24:56,880
So with your research with Salmonella exactly like how were you able to use phages to actually

332
00:24:56,880 --> 00:25:01,200
treat that MDI Rho Salmonella strain that you guys were working on?

333
00:25:01,200 --> 00:25:04,920
Yeah so it's an interesting story.

334
00:25:04,920 --> 00:25:10,600
So I was originally working on Salmonella during my PhD and that's how I first got

335
00:25:10,600 --> 00:25:14,400
interested in bacteriophages.

336
00:25:14,400 --> 00:25:19,520
The way I stumbled upon them is I was working on two strains of Salmonella.

337
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One was kind of a European classic gastrointestinal strain, Salmonella typhimurium and the other

338
00:25:26,200 --> 00:25:31,640
was a derivative of Salmonella typhimurium from sub-Saharan Africa which had emerged

339
00:25:31,640 --> 00:25:39,920
to cause bloodstream infection in the kind of immune compromised HIV positive population.

340
00:25:39,920 --> 00:25:43,960
And but at the genomic level so when you looked at the DNA sequences of these two strains

341
00:25:43,960 --> 00:25:47,240
of Salmonella they're actually very related like very similar.

342
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So in Salmonella genome there's around 5 million base pairs of DNA and you could align end

343
00:25:53,720 --> 00:25:59,880
to end these two genomes from the European and the African Salmonella.

344
00:25:59,880 --> 00:26:04,480
So my task was kind of like look at these two genomes and figure out what is it in this

345
00:26:04,480 --> 00:26:10,640
African Salmonella that made it more virulent, made it able to invade and cause these bloodstream

346
00:26:10,640 --> 00:26:11,640
infections.

347
00:26:11,640 --> 00:26:17,800
And the most obvious thing that struck me as soon as I looked at these genome sequences

348
00:26:17,800 --> 00:26:23,920
was in the African strain there was these large insertions of new genetic material that

349
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weren't present in the European strain.

350
00:26:27,360 --> 00:26:30,520
And those it transpired were phages.

351
00:26:30,520 --> 00:26:37,200
So one thing we haven't talked about yet is that phages can have this kind of dual lifestyle.

352
00:26:37,200 --> 00:26:42,120
So they can behave very much like your classic virus where they'll infect a cell, make it

353
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a virus factory and then explode the cell and go on and infect more.

354
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Or they can do this more kind of covert lifestyle that's kind of analogous to what HIV does

355
00:26:52,080 --> 00:26:53,840
right in humans.

356
00:26:53,840 --> 00:27:00,480
They can infect the cell but instead of making it into a virus factory they will integrate

357
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themselves into the genome, into the DNA of the bacteria and they'll just like hang

358
00:27:05,360 --> 00:27:11,840
out there until you can imagine like some conditions get particularly good and then

359
00:27:11,840 --> 00:27:14,640
the phage might emerge.

360
00:27:14,640 --> 00:27:18,640
But the kind of really interesting thing about this in Salmonella and in some other very

361
00:27:18,640 --> 00:27:23,880
notorious bacterial pathogens is that because they're spending a lot of time inside the

362
00:27:23,880 --> 00:27:29,920
bacterial genome it's kind of in their interest to increase the fitness of the bacterium

363
00:27:29,920 --> 00:27:31,160
itself.

364
00:27:31,160 --> 00:27:37,080
And a lot of virulence factors in Salmonella and in many other bacteria, so cholera, staph

365
00:27:37,080 --> 00:27:44,440
aureus, dip, the pathogen that causes diphtheria, many of these like famous infectious diseases,

366
00:27:44,440 --> 00:27:50,360
the actual virulence genes that are making you sick are encoded on one of these viruses

367
00:27:50,360 --> 00:27:52,760
that's integrated into the bacterial cell.

368
00:27:52,760 --> 00:27:53,760
Crazy.

369
00:27:53,760 --> 00:27:55,560
Yeah, it's really cool.

370
00:27:55,560 --> 00:28:01,720
So it's worth thinking about in terms of therapy because phages aren't always bad to bacteria,

371
00:28:01,720 --> 00:28:04,840
sometimes they're very good for bacteria.

372
00:28:04,840 --> 00:28:11,280
So in this particular case in Salmonella I had an immediate hypothesis that these new

373
00:28:11,280 --> 00:28:15,760
phage sequences that had integrated into the chromosome must be bringing some new virulence

374
00:28:15,760 --> 00:28:18,640
factors that we hadn't found yet.

375
00:28:18,640 --> 00:28:24,400
So I spent most of my PhD studying these phages, I got sent to an amazing phage conference

376
00:28:24,400 --> 00:28:29,120
called Viruses of Micropes which happens every two years and just focusing on the viruses

377
00:28:29,120 --> 00:28:33,600
and not just bacteria but also fungi and archaea.

378
00:28:33,600 --> 00:28:38,360
And I just became very quickly completely fascinated by bacterium phages.

379
00:28:38,360 --> 00:28:44,520
And in the end though we didn't find any virulence factors encoded on these new prophages.

380
00:28:44,520 --> 00:28:49,040
Instead we found something else that the prophages were doing to help the Salmonella and that

381
00:28:49,040 --> 00:28:51,360
was phage resistance.

382
00:28:51,360 --> 00:28:58,040
So another thing that is good for bacteria is to be able to defend against viruses, right?

383
00:28:58,040 --> 00:29:04,160
So it turns out that often these phages will integrate into a bacterial genome and then

384
00:29:04,160 --> 00:29:08,320
make that cell resistant to other phages.

385
00:29:08,320 --> 00:29:11,440
So it's kind of like get off my lawn kind of thing.

386
00:29:11,440 --> 00:29:15,440
I'm here and no one else can come in and take my host.

387
00:29:15,440 --> 00:29:22,120
And so actually now in the last five or so years this whole field of phage defense and

388
00:29:22,120 --> 00:29:27,200
understanding how bacteria defend themselves against phages is huge.

389
00:29:27,200 --> 00:29:31,760
And it turns out all of these genes that bacteria had that for a long time we didn't understand

390
00:29:31,760 --> 00:29:32,920
what they did.

391
00:29:32,920 --> 00:29:38,640
We now know a lot of them are actually involved in defending bacteria against phages.

392
00:29:38,640 --> 00:29:42,280
And sometimes those are just on the bacterial chromosome and sometimes they're brought in

393
00:29:42,280 --> 00:29:47,240
by other mobile genetic elements like phages and plasmids.

394
00:29:47,240 --> 00:29:51,000
And that's kind of one of the fears regarding the use of phages when I was doing a little

395
00:29:51,000 --> 00:29:54,360
research on them was just like similar to antibiotics.

396
00:29:54,360 --> 00:29:58,560
Bacteria, they've been here forever and they know how to mutate.

397
00:29:58,560 --> 00:30:02,000
There are no free lunches in nature like there's no silver bullet.

398
00:30:02,000 --> 00:30:07,560
And bacterial infections, phage resistance is something that is one of the, I don't

399
00:30:07,560 --> 00:30:11,360
know if it's a stumbling block, but it's something that has to be definitely brought

400
00:30:11,360 --> 00:30:16,400
to light when trying to research phage therapy and create phages that will actually treat

401
00:30:16,400 --> 00:30:17,400
these bacteria.

402
00:30:17,400 --> 00:30:22,920
Because bacteria for even just being very small organisms are very, very crafty.

403
00:30:22,920 --> 00:30:23,920
Very crafty.

404
00:30:23,920 --> 00:30:30,720
And don't forget that bacteria have been defending themselves against phages for a few billion

405
00:30:30,720 --> 00:30:32,600
years now.

406
00:30:32,600 --> 00:30:37,200
The phages have probably existed for as long as bacteria have.

407
00:30:37,200 --> 00:30:44,240
And so bacteria are exquisitely good at finding ways to evolve resistance to bacteria phages.

408
00:30:44,240 --> 00:30:48,520
And certainly the first thing you see in the lab when you start working with phages is

409
00:30:48,520 --> 00:30:52,320
how quickly bacteria can mutate to become resistant.

410
00:30:52,320 --> 00:30:56,640
And I would argue probably it's even easier to become phage resistant than it is to become

411
00:30:56,640 --> 00:30:59,840
resistant to antibiotics.

412
00:30:59,840 --> 00:31:02,360
With gene editing, you mentioned gene editing prior to this.

413
00:31:02,360 --> 00:31:07,280
Is there a way that you might be able to prevent phage resistance in the bacteria just kind

414
00:31:07,280 --> 00:31:08,640
of manipulating gene editing?

415
00:31:08,640 --> 00:31:13,640
And is that something that every so often would have to be recalculated for every batch

416
00:31:13,640 --> 00:31:17,320
of new phages you brought out to make sure the resistance didn't last?

417
00:31:17,320 --> 00:31:22,480
Yeah, that's a really interesting area that's starting to be explored.

418
00:31:22,480 --> 00:31:28,720
So there's a lot of interest in kind of delivering some of these gene editing technologies within

419
00:31:28,720 --> 00:31:30,360
bacteria phage particles.

420
00:31:30,360 --> 00:31:35,640
And that's a really exciting idea because the phage, we're really like repurposing the

421
00:31:35,640 --> 00:31:36,640
phage here.

422
00:31:36,640 --> 00:31:40,600
The phage would no longer contain its own native genome, so it wouldn't be able to escape

423
00:31:40,600 --> 00:31:43,560
and just like start replicating as a phage.

424
00:31:43,560 --> 00:31:45,920
Instead it would be just used as a delivery vector.

425
00:31:45,920 --> 00:31:50,320
So we are just tracking down the bacteria that we want to be, for example, a sensitive

426
00:31:50,320 --> 00:31:52,240
to antibiotics again.

427
00:31:52,240 --> 00:31:58,520
And we would deliver our gene editing technology and just get rid of those resistance genes

428
00:31:58,520 --> 00:32:00,600
from a bacterial pathogen.

429
00:32:00,600 --> 00:32:05,880
And there's quite a lot of interesting synthetic biology companies now developing those kinds

430
00:32:05,880 --> 00:32:06,880
of products.

431
00:32:06,880 --> 00:32:10,160
But it's still the early days, but I'm pretty excited about that direction.

432
00:32:10,160 --> 00:32:11,160
It's so crazy.

433
00:32:11,160 --> 00:32:12,640
It's like something out of a sci-fi novel.

434
00:32:12,640 --> 00:32:13,640
Right.

435
00:32:13,640 --> 00:32:15,480
It's really neat.

436
00:32:15,480 --> 00:32:18,640
So you were recently published in Nature Communications.

437
00:32:18,640 --> 00:32:22,200
In your article there were significant findings that actually might be relevant to treating

438
00:32:22,200 --> 00:32:24,800
and stopping antimicrobial resistance.

439
00:32:24,800 --> 00:32:28,640
I don't know if you can kind of go into that a little bit and then kind of explain how

440
00:32:28,640 --> 00:32:31,960
these findings could help aiding against the antimicrobial resistance.

441
00:32:31,960 --> 00:32:37,000
And maybe help explain there was one in particular, FT Midnight, which is a great name.

442
00:32:37,000 --> 00:32:38,720
How did you guys come up with that name?

443
00:32:38,720 --> 00:32:40,600
Who got to name it?

444
00:32:40,600 --> 00:32:46,080
That's actually a cool story because we had one postdoc in the lab who was characterizing

445
00:32:46,080 --> 00:32:48,840
those particular groups of phages.

446
00:32:48,840 --> 00:32:53,000
She was goth, really into gothic stuff.

447
00:32:53,000 --> 00:32:58,560
So she named all of her phages like dark colors because we have a general color theme for

448
00:32:58,560 --> 00:33:00,520
our phage names.

449
00:33:00,520 --> 00:33:05,280
And so all of Lucy's high-Lucy phages are dark goth colors.

450
00:33:05,280 --> 00:33:06,280
It's awesome.

451
00:33:06,280 --> 00:33:10,360
But yeah, so I can talk a little bit more about that project.

452
00:33:10,360 --> 00:33:17,800
So essentially, so we've already talked about phages and how they enter bacterial cells.

453
00:33:17,800 --> 00:33:22,240
And they typically, I told you, have a very narrow host range.

454
00:33:22,240 --> 00:33:26,280
And that's usually dependent on some proteins on the surface of bacterial cells.

455
00:33:26,280 --> 00:33:31,680
So phages just like human viruses, they use these receptors, molecules on the surface

456
00:33:31,680 --> 00:33:35,040
of cells to know which cell they want to enter.

457
00:33:35,040 --> 00:33:38,000
Similar to influenza, you'll have the H in the end.

458
00:33:38,000 --> 00:33:39,840
So hemoglobin in, nernimides.

459
00:33:39,840 --> 00:33:43,080
So it's like the H1N1, H5N1.

460
00:33:43,080 --> 00:33:48,200
These are binding receptors essentially for viruses or just protein binding receptors

461
00:33:48,200 --> 00:33:49,200
in general.

462
00:33:49,200 --> 00:33:50,680
Exactly, exactly.

463
00:33:50,680 --> 00:33:56,480
And so bacteria have an array of proteins and other structures on their surface that

464
00:33:56,480 --> 00:34:00,680
phages can recognize and enter with.

465
00:34:00,680 --> 00:34:05,120
And the one interesting thing about antibiotic resistance plasmids, so these are like these

466
00:34:05,120 --> 00:34:12,320
mobile pieces of DNA that are frequently transmitting resistance genes, is they themselves produce

467
00:34:12,320 --> 00:34:15,400
a structure on the bacterial cell surface.

468
00:34:15,400 --> 00:34:17,600
And that's this like tube-like apparatus.

469
00:34:17,600 --> 00:34:25,400
We call it conjugative pilus that's essentially there to mobilize the plasmid from cells to

470
00:34:25,400 --> 00:34:26,400
cells.

471
00:34:26,400 --> 00:34:29,800
And that's part of why antibiotic resistance is such a problem right now is these genes

472
00:34:29,800 --> 00:34:32,440
can move themselves between bacteria.

473
00:34:32,440 --> 00:34:39,840
They encode their own vehicles to transmit across bacterial populations.

474
00:34:39,840 --> 00:34:44,520
So but the interesting thing when looking at this from a phage perspective is that kind

475
00:34:44,520 --> 00:34:50,200
of that conjugative pilus, so that tube that the plasmid has made on the bacterial cell

476
00:34:50,200 --> 00:34:55,880
surface becomes visible to phages because anything on the cell surface can be targeted

477
00:34:55,880 --> 00:34:58,360
as a phage receptor.

478
00:34:58,360 --> 00:35:03,240
So kind of interesting thing that was discovered in the kind of 70s and 80s is that there's

479
00:35:03,240 --> 00:35:11,520
a whole populations of phages that have adapted to use these plasmid-encoded proteins as receptors

480
00:35:11,520 --> 00:35:12,520
to infect cells.

481
00:35:12,520 --> 00:35:14,760
So we call these plasmid-dependent phages.

482
00:35:14,760 --> 00:35:20,560
And it's really cool because essentially now you have a way to specifically infect cells

483
00:35:20,560 --> 00:35:22,480
that have resistance plasmids in them.

484
00:35:22,480 --> 00:35:28,880
So we could, these phages won't do anything to a salmonella that isn't resistant to antibiotics,

485
00:35:28,880 --> 00:35:33,520
but once that salmonella like gains a antibiotic resistance plasmid, it becomes sensitive to

486
00:35:33,520 --> 00:35:34,520
these phages.

487
00:35:34,520 --> 00:35:39,760
So I think they have like immense therapeutic potential because of that.

488
00:35:39,760 --> 00:35:45,680
So back in the 70s and 80s, these plasmid-dependent phages were pretty widely reported, so people

489
00:35:45,680 --> 00:35:50,040
were finding them all across the world for many different kinds of plasmids.

490
00:35:50,040 --> 00:35:54,960
But then for some reason that I still don't quite understand, the field kind of shut down.

491
00:35:54,960 --> 00:35:58,920
I think the labs who were working on it just happened to close and nobody took up that

492
00:35:58,920 --> 00:36:00,160
research.

493
00:36:00,160 --> 00:36:04,320
And phage research for a while kind of went out of fashion.

494
00:36:04,320 --> 00:36:09,360
And then so recently, and yes, the other sad thing about that kind of research stopping

495
00:36:09,360 --> 00:36:12,960
is it was pre-the genome sequencing era.

496
00:36:12,960 --> 00:36:18,160
So we don't have any genome sequencing memory of what these phages were.

497
00:36:18,160 --> 00:36:23,440
We don't, phages don't last all that long in the lab, so they've subsequently kind of

498
00:36:23,440 --> 00:36:24,440
like died off.

499
00:36:24,440 --> 00:36:26,840
We don't have any record of them physically.

500
00:36:26,840 --> 00:36:32,160
We just have these reports that plasmid-dependent phages exist and they are widespread and

501
00:36:32,160 --> 00:36:36,040
can target many different kinds of resistance plasmids.

502
00:36:36,040 --> 00:36:41,680
So in our work, we kind of set out to rediscover these lost plasmid-dependent phages to see

503
00:36:41,680 --> 00:36:49,880
whether actually we could start to go towards translation of these phages to healthcare.

504
00:36:49,880 --> 00:36:55,440
So we designed an assay to systematically detect them from the environment, which was

505
00:36:55,440 --> 00:36:58,120
previously kind of challenging.

506
00:36:58,120 --> 00:37:02,840
But now with our assay, it's very easy and we were super surprised to find that these

507
00:37:02,840 --> 00:37:05,520
things are extremely abundant.

508
00:37:05,520 --> 00:37:10,720
So in the early days of this project, it was happening really during the COVID times and

509
00:37:10,720 --> 00:37:13,000
we weren't allowed too much time inside.

510
00:37:13,000 --> 00:37:19,480
So my co-first author and me on the project, we were biking around Boston and Cambridge

511
00:37:19,480 --> 00:37:26,200
going to community gardens and sampling the compost and the soil and any kind of like

512
00:37:26,200 --> 00:37:29,320
gross samples we could find and testing for these phages.

513
00:37:29,320 --> 00:37:34,920
And we were amazed to find like every single sample we tested contained these plasmid-dependent

514
00:37:34,920 --> 00:37:36,720
phages.

515
00:37:36,720 --> 00:37:39,720
They were really just absolutely everywhere.

516
00:37:39,720 --> 00:37:45,000
And so we went on to characterize the phages, we sequenced them, we showed that there's

517
00:37:45,000 --> 00:37:50,800
a lot of genetic diversity in the collection that we've found.

518
00:37:50,800 --> 00:37:56,120
And so FT Midnight, you mentioned, is one of these plasmid-dependent phages that is dependent

519
00:37:56,120 --> 00:38:01,280
on a plasmid that's very commonly found in E. coli bacteria, the F. plasmid.

520
00:38:01,280 --> 00:38:06,720
And the reason why FT Midnight kind of features more prominently in the paper and has maybe

521
00:38:06,720 --> 00:38:11,800
a special name is because it's a unique amongst our collection.

522
00:38:11,800 --> 00:38:16,600
And the FT Midnight looks like the classic bacteria phage that you might have in your

523
00:38:16,600 --> 00:38:17,600
mind.

524
00:38:17,600 --> 00:38:25,480
So this kind of spaceship, moonland-like structure I'm wearing earrings of this structure.

525
00:38:25,480 --> 00:38:29,960
And that's maybe might not sound that interesting, but a weird thing about plasmid-dependent phages

526
00:38:29,960 --> 00:38:31,720
is they never have that structure.

527
00:38:31,720 --> 00:38:35,840
They actually tend to be very unusual in their morphology.

528
00:38:35,840 --> 00:38:39,000
They have like very non-canonical structures.

529
00:38:39,000 --> 00:38:43,920
And so we were very excited to find FT Midnight because it's a suggestion that there is much

530
00:38:43,920 --> 00:38:48,920
more diversity in these plasmid-dependent phages than we currently know.

531
00:38:48,920 --> 00:38:55,240
And also that many types of phages might be able to evolve to target these antibiotic

532
00:38:55,240 --> 00:38:58,880
resistance plasmid-encoded receptors.

533
00:38:58,880 --> 00:39:02,840
So I'm really excited going forward to just find more of these things and really see like

534
00:39:02,840 --> 00:39:07,800
how broadly can we target antibiotic resistance plasmids with phages.

535
00:39:07,800 --> 00:39:12,560
And would that kind of present a solution to some of the resistance that the bacteria

536
00:39:12,560 --> 00:39:18,360
would gain over time if you could have these phages that are specific that do not affect

537
00:39:18,360 --> 00:39:20,800
essentially resistance genes for being created?

538
00:39:20,800 --> 00:39:21,800
Yeah.

539
00:39:21,800 --> 00:39:27,440
So you can really cure bacteria of antibiotic resistance with these phages.

540
00:39:27,440 --> 00:39:33,680
The only way bacteria can become resistant is by completely losing these plasmids that

541
00:39:33,680 --> 00:39:35,440
encode the resistance.

542
00:39:35,440 --> 00:39:41,480
Or the second way is they can mutate the genes that encode that protein tube.

543
00:39:41,480 --> 00:39:45,920
But if they do that, the resistance plasmid can no longer move through bacterial populations.

544
00:39:45,920 --> 00:39:51,400
So we're targeting dissemination of these genes and we're targeting the resistance

545
00:39:51,400 --> 00:39:52,400
itself.

546
00:39:52,400 --> 00:39:57,760
So it's kind of an exciting, like win-win evolutionary outcome that has given me a lot

547
00:39:57,760 --> 00:39:58,760
of optimism in terms of therapy.

548
00:39:58,760 --> 00:40:01,320
It's pretty amazing pride when you think about it.

549
00:40:01,320 --> 00:40:03,000
So that's so cool.

550
00:40:03,000 --> 00:40:06,120
And this is the disco technique that you guys used?

551
00:40:06,120 --> 00:40:07,120
Disco, yeah.

552
00:40:07,120 --> 00:40:10,000
And can you tell me how you guys came up with that name?

553
00:40:10,000 --> 00:40:14,040
Yeah, well there's so much pressure inside us to come up with catchy names and show your

554
00:40:14,040 --> 00:40:15,040
stuff.

555
00:40:15,040 --> 00:40:16,240
So it took us a long time actually.

556
00:40:16,240 --> 00:40:23,200
We went through many iterations of Bacronyms until we landed on disco.

557
00:40:23,200 --> 00:40:24,440
But it's very simple.

558
00:40:24,440 --> 00:40:26,720
The disco means discovery by co-culture.

559
00:40:26,720 --> 00:40:33,200
And essentially our assay relies on there being two different types of bacteria co-cultured

560
00:40:33,200 --> 00:40:36,200
together so we can find these plasmid-dependent phages.

561
00:40:36,200 --> 00:40:37,200
Catchy name.

562
00:40:37,200 --> 00:40:38,200
It's memorable.

563
00:40:38,200 --> 00:40:39,200
It's memorable.

564
00:40:39,200 --> 00:40:40,200
People seem to like it.

565
00:40:40,200 --> 00:40:42,280
It's going well.

566
00:40:42,280 --> 00:40:46,720
I know that I think I read the samples from your research, a lot of them for this project

567
00:40:46,720 --> 00:40:50,000
actually came from a wastewater treatment plant.

568
00:40:50,000 --> 00:40:52,080
So who gets to actually procure that wastewater?

569
00:40:52,080 --> 00:40:53,400
You guys get to travel there.

570
00:40:53,400 --> 00:40:54,400
We get to go.

571
00:40:54,400 --> 00:40:55,400
How much fun was it?

572
00:40:55,400 --> 00:40:56,400
Us ourselves.

573
00:40:56,400 --> 00:40:58,440
It's the highlight of our week going down.

574
00:40:58,440 --> 00:41:00,840
No, and I'm not even joking here.

575
00:41:00,840 --> 00:41:04,560
I'm a big fan of Deer Island wastewater treatment plant.

576
00:41:04,560 --> 00:41:06,840
It's down in East Boston.

577
00:41:06,840 --> 00:41:10,280
It's the second largest wastewater treatment plant in the mainland US.

578
00:41:10,280 --> 00:41:13,160
I think the largest is in Illinois.

579
00:41:13,160 --> 00:41:17,440
But Deer Island is incredibly futuristic.

580
00:41:17,440 --> 00:41:22,400
You wouldn't believe this, but people from all over the world come on infrastructure

581
00:41:22,400 --> 00:41:28,600
tourism to visit Deer Island because it's so famous amongst wastewater treatment plants

582
00:41:28,600 --> 00:41:33,240
in terms of the technology it uses.

583
00:41:33,240 --> 00:41:39,920
It's a fantastic place to find phages because it's just a mix of all of these effluents

584
00:41:39,920 --> 00:41:43,600
from so many different local constituencies.

585
00:41:43,600 --> 00:41:47,520
And actually I would really encourage the listeners of this podcast if you're local

586
00:41:47,520 --> 00:41:54,480
to Boston, a little known fact is that actually the MWRA offers free tours to the public of

587
00:41:54,480 --> 00:41:58,320
Deer Island Waste Waste Treatment Plant and they let you go all the way up the top of

588
00:41:58,320 --> 00:41:59,320
the eggs.

589
00:41:59,320 --> 00:42:02,280
And it's a fantastic experience that everyone should do.

590
00:42:02,280 --> 00:42:04,000
How bad does it smell?

591
00:42:04,000 --> 00:42:09,240
You know, people always ask that wastewater isn't that gross to work with.

592
00:42:09,240 --> 00:42:14,240
It really is just kind of like brown, cloudy liquid with the large particulates have been

593
00:42:14,240 --> 00:42:15,920
filtered out.

594
00:42:15,920 --> 00:42:19,240
It smells bad, but the bacteria smell worse, trust me.

595
00:42:19,240 --> 00:42:20,240
Yeah.

596
00:42:20,240 --> 00:42:24,240
I get to deal with the fresh poop in my job, so at least you get some of the filtration.

597
00:42:24,240 --> 00:42:25,240
This is much better, yeah.

598
00:42:25,240 --> 00:42:28,080
So I can imagine it.

599
00:42:28,080 --> 00:42:32,480
We kind of mentioned earlier some of the barriers to phages and phage therapy.

600
00:42:32,480 --> 00:42:36,400
At the moment, and you had mentioned this earlier as well, at least in the United States,

601
00:42:36,400 --> 00:42:40,320
it's only allowed as expanded access, which is otherwise known as compassionate use.

602
00:42:40,320 --> 00:42:45,520
So compassionate use, we actually saw this during COVID with a number of drugs that were

603
00:42:45,520 --> 00:42:49,440
just trialed just to try and see if they worked, kind of throw the spaghetti at the wall and

604
00:42:49,440 --> 00:42:52,280
see if it sticks.

605
00:42:52,280 --> 00:42:59,120
So it means that quote, and this is from, I think it's a USDA, treatment outside of

606
00:42:59,120 --> 00:43:04,800
clinical trials when no comparable or satisfactory alternative therapy options are available.

607
00:43:04,800 --> 00:43:08,040
And right now, that's the only way phages can be used to actually treat illness here

608
00:43:08,040 --> 00:43:10,880
in the United States.

609
00:43:10,880 --> 00:43:14,680
What do you see as the current barriers to actually being able to provide phage therapy

610
00:43:14,680 --> 00:43:20,280
as an everyday treatment to kind of kill some of these hard to treat bacterial infections?

611
00:43:20,280 --> 00:43:21,280
Yeah.

612
00:43:21,280 --> 00:43:26,480
So I think the biggest issue is there are so many kinds of infections that people want

613
00:43:26,480 --> 00:43:27,480
to treat.

614
00:43:27,480 --> 00:43:33,960
And with developing phage therapies, it really has to be on A, a pathogen by pathogen basis,

615
00:43:33,960 --> 00:43:39,160
and you need a therapy that's specific to each kind of infection.

616
00:43:39,160 --> 00:43:42,800
And the biggest challenge tends to be delivery of these things.

617
00:43:42,800 --> 00:43:47,120
So there are certain sites in the body that seem to be slightly easier to get to.

618
00:43:47,120 --> 00:43:52,920
So there's a lot of promising research that respiratory diseases, a lot of people interested

619
00:43:52,920 --> 00:43:58,080
in cystic fibrosis treatments, are using phage because phage are very easily nebulized.

620
00:43:58,080 --> 00:44:02,540
So it's quite easy to deliver them into areas like the lungs.

621
00:44:02,540 --> 00:44:09,760
On the other hand, areas of the human body that are harder to reach or are challenging,

622
00:44:09,760 --> 00:44:14,040
phages are proteinaceous, so they elicit an immune response sometimes.

623
00:44:14,040 --> 00:44:20,680
So delivery, intravenous delivery is something that's kind of not well explored because there's

624
00:44:20,680 --> 00:44:26,960
a lot of, you have to get an extremely pure product to not elicit a dangerous immune response.

625
00:44:26,960 --> 00:44:31,720
And even then, some phages seem to elicit high responses and will just be cleared by

626
00:44:31,720 --> 00:44:36,440
the immune system as though they're a foreign virus or something.

627
00:44:36,440 --> 00:44:44,520
So yeah, so it really needs to be kind of pathogen specific and infection specific.

628
00:44:44,520 --> 00:44:46,760
But there's certainly some hope.

629
00:44:46,760 --> 00:44:52,640
And in terms of compassionate use, that's like one of the other issues here is because

630
00:44:52,640 --> 00:44:59,120
phage is such a new and unheard of therapy, there have been very few actual clinical trials

631
00:44:59,120 --> 00:45:03,760
using phage therapy and therefore we only have these case studies, these compassionate

632
00:45:03,760 --> 00:45:04,760
use cases.

633
00:45:04,760 --> 00:45:10,280
And in some ways, those are really interesting data because they really allow researchers

634
00:45:10,280 --> 00:45:14,840
and clinicians to do things that you wouldn't be allowed to do in other ways.

635
00:45:14,840 --> 00:45:22,040
So an example of this was there was a quite high profile case of a mycobacteria obsessus

636
00:45:22,040 --> 00:45:23,040
case.

637
00:45:23,040 --> 00:45:33,440
I think it was in the UK actually and it was like a really awful systemic, I think, mycobacteria

638
00:45:33,440 --> 00:45:41,000
obsessus case infection that was like pretty nasty and bad and they were eventually given

639
00:45:41,000 --> 00:45:43,320
compassionate use grounds to use a phage.

640
00:45:43,320 --> 00:45:50,080
And one of the interesting things about mycobacteria obsessus is there's no known phages that don't

641
00:45:50,080 --> 00:45:52,280
enter this integrative lifestyle.

642
00:45:52,280 --> 00:45:58,200
So we only have phages that we know can just integrate into the genome.

643
00:45:58,200 --> 00:46:06,240
But Graham Hapful, who's a fantastic researcher in Pittsburgh, has kind of been working on

644
00:46:06,240 --> 00:46:12,600
mycobacterium phages for a long time and knows how to make mutants so he genetically engineered

645
00:46:12,600 --> 00:46:18,680
a version of these mycobacterium obsessus phages, preventing them from going down this integrative

646
00:46:18,680 --> 00:46:27,280
life cycle, which means you essentially now have a GM phage that's much more idealized

647
00:46:27,280 --> 00:46:29,440
for phage therapy purposes.

648
00:46:29,440 --> 00:46:34,760
And in normal terms, right, you'd never get permission to use a GM bacteriophage.

649
00:46:34,760 --> 00:46:40,160
It's so untested and unheard of, but they were given permission to use this in this case

650
00:46:40,160 --> 00:46:43,000
and it was a successful outcome to the treatment.

651
00:46:43,000 --> 00:46:50,720
So in that way, these kinds of like compassionate use cases can really push the field forward

652
00:46:50,720 --> 00:46:54,760
because you can be given the chance to do something kind of wacky, something that you

653
00:46:54,760 --> 00:46:59,240
might not get permission to do in a much broader clinical trial.

654
00:46:59,240 --> 00:47:02,560
And it could be very successful and we can get amazing data.

655
00:47:02,560 --> 00:47:07,600
So it's not all bad, but I think we definitely need kind of a combination.

656
00:47:07,600 --> 00:47:11,600
So we can only go so far with compassionate use.

657
00:47:11,600 --> 00:47:18,400
There are also difficult cases to get good data from because they tend to be cases where

658
00:47:18,400 --> 00:47:24,920
patients are in pretty bad diastrates and the actual like improvements tend to be fairly

659
00:47:24,920 --> 00:47:27,120
short term anyway.

660
00:47:27,120 --> 00:47:35,160
So yeah, getting better clinical trials in other kinds of patients is something that's

661
00:47:35,160 --> 00:47:36,160
really needed.

662
00:47:36,160 --> 00:47:40,680
Yeah, it's even when looking to try and find cases, a lot of them, I wouldn't say they're

663
00:47:40,680 --> 00:47:46,080
anecdotal, but there's definitely not a lot of concrete data to support like where they've

664
00:47:46,080 --> 00:47:49,360
been used.

665
00:47:49,360 --> 00:47:54,120
As far as funding goes for phage therapy, it's significantly lower than antibiotic research

666
00:47:54,120 --> 00:47:58,760
by many, many, many, many millions of dollars.

667
00:47:58,760 --> 00:48:02,480
What do you feel needs to happen to actually help to grow and expand funding for research?

668
00:48:02,480 --> 00:48:08,800
Do you feel that there needs to be just a louder voice in the biology or even the medical

669
00:48:08,800 --> 00:48:11,600
community to try and gain more funding for this?

670
00:48:11,600 --> 00:48:17,120
Yeah, so change in science tends to be slow and I'm actually optimistic about that.

671
00:48:17,120 --> 00:48:22,680
It does seem like most funding bodies do have an appetite for phage research now and certainly

672
00:48:22,680 --> 00:48:27,360
funding for phage research is increasing.

673
00:48:27,360 --> 00:48:31,960
So I think things are moving in the right direction.

674
00:48:31,960 --> 00:48:36,680
I think funding for science in general needs to increase.

675
00:48:36,680 --> 00:48:44,600
That's something that tends to be fluctuate a little bit depending on the political climate.

676
00:48:44,600 --> 00:48:49,000
Certainly I think I'm optimistic that phage research is going to be funded, but we just

677
00:48:49,000 --> 00:48:53,320
need general funding for basic science research.

678
00:48:53,320 --> 00:48:58,920
So you had mentioned earlier just with the use of antibiotics and how a majority of that

679
00:48:58,920 --> 00:49:02,600
is actually not for treating illness, but it's actually prevention and agriculture and

680
00:49:02,600 --> 00:49:05,000
other areas.

681
00:49:05,000 --> 00:49:09,960
I want to talk about some of the additional uses for phages just beyond right now treating

682
00:49:09,960 --> 00:49:11,920
for MDIROS and such.

683
00:49:11,920 --> 00:49:20,000
I know that there's a fellow phage researcher, Hanyi Nani, and he's a pretty big proponent

684
00:49:20,000 --> 00:49:23,320
of using phages just to improve food safety.

685
00:49:23,320 --> 00:49:26,320
Beyond food safety improvement, what other possibilities do you think phages could be

686
00:49:26,320 --> 00:49:30,440
used for just in everyday life or maybe antibiotics are used right now?

687
00:49:30,440 --> 00:49:31,440
Yeah, it was.

688
00:49:31,440 --> 00:49:34,960
The food safety field for phages is very successful.

689
00:49:34,960 --> 00:49:39,480
If people don't realise, but if you buy sliced meat and cheese in the US, it's probably

690
00:49:39,480 --> 00:49:41,400
being sprayed with phages.

691
00:49:41,400 --> 00:49:45,880
I love your consuming them every day.

692
00:49:45,880 --> 00:49:49,600
Those kinds of products are outside of the human body.

693
00:49:49,600 --> 00:49:52,320
Phages are much easier to make products for.

694
00:49:52,320 --> 00:49:55,040
They're not really regulated in the same way.

695
00:49:55,040 --> 00:50:01,560
So there's a lot of interest in therapy for, not therapy, but treatment for acne, things

696
00:50:01,560 --> 00:50:02,560
like this.

697
00:50:02,560 --> 00:50:07,240
If you go to San Francisco, I think you can buy from a startup there, tubes of phage that

698
00:50:07,240 --> 00:50:11,800
you can put on your face to help reduce your acne.

699
00:50:11,800 --> 00:50:17,920
There's a lot of mounting evidence from the microbiome world now that actually bacteria

700
00:50:17,920 --> 00:50:24,320
in your body can affect all kinds of diseases beyond what we traditionally think of as infectious

701
00:50:24,320 --> 00:50:25,320
disease.

702
00:50:25,320 --> 00:50:33,040
So there's pretty good evidence now that your microbiome might be playing a role in your

703
00:50:33,040 --> 00:50:36,680
susceptibility to things like Alzheimer's or type 1 diabetes.

704
00:50:36,680 --> 00:50:40,960
And so as research like that progresses, it's possible that we might even start to be able

705
00:50:40,960 --> 00:50:48,640
to use phages to reduce our risk of other kinds of diseases that we don't think of as

706
00:50:48,640 --> 00:50:50,640
infectious.

707
00:50:50,640 --> 00:50:54,760
Another interesting area is mitochondrial diseases.

708
00:50:54,760 --> 00:51:00,400
So these are very rare diseases in humans, but they often have really terrible symptoms

709
00:51:00,400 --> 00:51:04,080
and can be like really life-altering.

710
00:51:04,080 --> 00:51:10,320
And so far in the gene therapy world, it's very difficult to edit the mitochondria because

711
00:51:10,320 --> 00:51:13,280
it's a part of the human cell that's like enclosed.

712
00:51:13,280 --> 00:51:17,680
And mitochondria themselves were once bacteria.

713
00:51:17,680 --> 00:51:27,600
So mitochondria were engulfed by eukaryotic cells way, way, way, way back when eukaryotic

714
00:51:27,600 --> 00:51:30,800
cells first evolved.

715
00:51:30,800 --> 00:51:33,080
And so there's a potential there.

716
00:51:33,080 --> 00:51:35,880
So mitochondria still look like bacteria.

717
00:51:35,880 --> 00:51:42,360
So there's some interest in potentially using phage proteins or some strategies inspired

718
00:51:42,360 --> 00:51:49,840
by phages to get gene editing technology inside human and animal mitochondria, which is exciting.

719
00:51:49,840 --> 00:51:55,400
It should be pretty crazy, especially there have been links to long COVID and mitochondrial

720
00:51:55,400 --> 00:51:56,400
disorders.

721
00:51:56,400 --> 00:52:01,920
And that's one of the biggest complaints of people with long COVID is just lack of energy

722
00:52:01,920 --> 00:52:06,400
and lethargy, which mitochondrial disorders, they call it the powerhouse of the cell and

723
00:52:06,400 --> 00:52:09,800
it essentially creates, it drives the energy for cells to work.

724
00:52:09,800 --> 00:52:14,400
So if you have a mitochondrial disorder, it's you, a lot of people just have no energy

725
00:52:14,400 --> 00:52:15,400
to do anything.

726
00:52:15,400 --> 00:52:17,320
Your body's just not producing it.

727
00:52:17,320 --> 00:52:18,320
So that'd be pretty crazy.

728
00:52:18,320 --> 00:52:19,320
It's pretty significant.

729
00:52:19,320 --> 00:52:25,320
And it's amazing the avenues that can be discovered that we can go down with phages.

730
00:52:25,320 --> 00:52:28,680
More research.

731
00:52:28,680 --> 00:52:34,160
So in a recent research article that was published, I guess it was in nature May of 2023, you

732
00:52:34,160 --> 00:52:38,280
and some of your fellow researchers, you developed a way to use genetic modification to help

733
00:52:38,280 --> 00:52:40,960
cells avoid viral infection.

734
00:52:40,960 --> 00:52:45,920
Can you actually explain, and this isn't, this is, you know, with viruses, how phages

735
00:52:45,920 --> 00:52:52,560
might be able to help combat viral infections and possible limitations of this and how it

736
00:52:52,560 --> 00:52:55,600
might actually change the way we tend to look at and treat viruses?

737
00:52:55,600 --> 00:52:56,600
Yeah.

738
00:52:56,600 --> 00:53:02,080
So that was a really exciting project I got to be involved with, led by the church lab

739
00:53:02,080 --> 00:53:05,240
here at Harvard Medical School and the VISA Institute.

740
00:53:05,240 --> 00:53:12,040
So essentially the church lab is really interested in reprogramming cells to be virus resistant

741
00:53:12,040 --> 00:53:14,640
because obviously that would be fantastic, right?

742
00:53:14,640 --> 00:53:18,640
But it's a very long-term goal here.

743
00:53:18,640 --> 00:53:24,040
So the first step in this process is start with bacteria.

744
00:53:24,040 --> 00:53:31,600
And the strategy that they're taking is essentially recoding the language that bacteria use to

745
00:53:31,600 --> 00:53:34,840
translate these protein messages.

746
00:53:34,840 --> 00:53:38,840
So what the church lab did, so they took a strain, the original strain had actually been

747
00:53:38,840 --> 00:53:42,160
produced in the lab in Cambridge in the UK.

748
00:53:42,160 --> 00:53:52,520
And in this strain, researchers had removed three of the codons that code for amino acids.

749
00:53:52,520 --> 00:53:59,440
So we have, there are 60 codons, so these are like triplets, three letters, that code

750
00:53:59,440 --> 00:54:01,560
for only 20 amino acids.

751
00:54:01,560 --> 00:54:07,360
So essentially there's a redundancy in the code that we all use to code for our proteins

752
00:54:07,360 --> 00:54:13,640
and that allowed them to take some of these redundant codons and make change what they

753
00:54:13,640 --> 00:54:14,640
code for.

754
00:54:14,640 --> 00:54:19,520
And that means that if a virus, which hasn't been recoded, it's a natural virus, comes

755
00:54:19,520 --> 00:54:25,800
and tries to infect one of these recoded bacteria, it tries to translate its protein messages

756
00:54:25,800 --> 00:54:28,560
and they get, they don't make sense.

757
00:54:28,560 --> 00:54:33,320
They're translated into something that they wouldn't, they're not meant to be.

758
00:54:33,320 --> 00:54:37,840
It's just like in a language, it's like changing a language and now your translation is wrong.

759
00:54:37,840 --> 00:54:43,280
So the virus cannot build its proteins, it cannot replicate.

760
00:54:43,280 --> 00:54:49,720
And so this original strain that was produced in Cambridge in the UK was claimed to be virus

761
00:54:49,720 --> 00:54:54,560
resistant because of this recoding that had been done.

762
00:54:54,560 --> 00:54:58,320
And so the church lab here at Harvard Medical School, though, were a little suspicious that

763
00:54:58,320 --> 00:55:03,400
this is the case and so they set me in my lab about trying to find viruses that would

764
00:55:03,400 --> 00:55:08,520
affect this recoded strain of E. coli and we were actually able to find them pretty easily

765
00:55:08,520 --> 00:55:12,800
in Boston, dear island, wastewater.

766
00:55:12,800 --> 00:55:18,000
And so the way that phages were getting around this was actually pretty simple.

767
00:55:18,000 --> 00:55:24,600
They encoded for their own systems to translate their own protein messages.

768
00:55:24,600 --> 00:55:30,320
And so in the end, so the kind of conclusion of that work was we made further edits to the

769
00:55:30,320 --> 00:55:37,400
E. coli, further recoding that made it much harder for viruses to kind of escape this

770
00:55:37,400 --> 00:55:45,640
process and also added in a kind of containment method.

771
00:55:45,640 --> 00:55:51,960
So we made that E. coli strain dependent on an amino acid that doesn't exist in nature.

772
00:55:51,960 --> 00:56:00,720
So essentially we've locked that E. coli strain into laboratory or special culture so it cannot

773
00:56:00,720 --> 00:56:06,720
escape and there's no fears of a virus resistant E. coli ever escaping the lab.

774
00:56:06,720 --> 00:56:14,000
And so even though this is a long way away from this very far off goal of making humans

775
00:56:14,000 --> 00:56:19,200
virus resistant, it's an exciting development in terms of industry and industrial production

776
00:56:19,200 --> 00:56:23,680
of a lot of compounds and enzymes.

777
00:56:23,680 --> 00:56:30,680
So a lot of the industry produced things are done in bacteria, so enzymes that we use every

778
00:56:30,680 --> 00:56:32,640
day and some medicines.

779
00:56:32,640 --> 00:56:38,000
And actually there's a huge amount of revenue lost and also just wastage from viral phage

780
00:56:38,000 --> 00:56:42,360
contamination into industrial like enzyme preps.

781
00:56:42,360 --> 00:56:47,760
So having this virus is an E. coli strain is actually very exciting, not from a human

782
00:56:47,760 --> 00:56:49,240
health perspective yet.

783
00:56:49,240 --> 00:56:53,360
From a research perspective though, I mean just think about how many lost samples you

784
00:56:53,360 --> 00:56:55,120
won't have if you have something that's...

785
00:56:55,120 --> 00:56:56,240
Exactly, exactly.

786
00:56:56,240 --> 00:56:59,320
And commercially it could be hugely profitable.

787
00:56:59,320 --> 00:57:03,280
So it's a kind of exciting step forward.

788
00:57:03,280 --> 00:57:07,640
And yeah, but who knows, but after one day we'll be able to use the same technology on

789
00:57:07,640 --> 00:57:08,640
animals.

790
00:57:08,640 --> 00:57:09,880
Once again, I don't know.

791
00:57:09,880 --> 00:57:10,880
I'm always fearful.

792
00:57:10,880 --> 00:57:13,760
And once again I said there's no free lunches in nature.

793
00:57:13,760 --> 00:57:19,640
Like eventually a virus will find a way to get you in and it'll probably be really bad.

794
00:57:19,640 --> 00:57:27,920
But when you tinker with science, it's for as much good sometimes you create bad.

795
00:57:27,920 --> 00:57:30,840
But it's really cool.

796
00:57:30,840 --> 00:57:33,160
So this brings me to my next question.

797
00:57:33,160 --> 00:57:39,120
So with the growing use of artificial intelligence and all aspects of science and life in general,

798
00:57:39,120 --> 00:57:43,000
I use it to create silly songs and weird pictures.

799
00:57:43,000 --> 00:57:44,880
But you can use it for...

800
00:57:44,880 --> 00:57:52,280
In science it's being used in so many different ways and it's unbelievable how fast it's growing.

801
00:57:52,280 --> 00:57:54,560
And I can imagine it will be incredibly beneficial.

802
00:57:54,560 --> 00:57:58,800
But how much do you think AI is going to improve phage research in the future?

803
00:57:58,800 --> 00:58:03,120
Yeah, I'm cautious about that.

804
00:58:03,120 --> 00:58:06,360
It's not something I have a ton of experience personally with.

805
00:58:06,360 --> 00:58:11,000
One thing I have used it for though and I'm excited about is the potential for AI to help

806
00:58:11,000 --> 00:58:13,240
us design proteins.

807
00:58:13,240 --> 00:58:19,400
So AI has turned out to be extremely good for understanding the structure of proteins

808
00:58:19,400 --> 00:58:23,960
that we already know about and potentially even designing proteins to have a specific

809
00:58:23,960 --> 00:58:26,720
function that we need.

810
00:58:26,720 --> 00:58:31,440
And so as we start to learn more about the proteins that bacteria phage is encode, I

811
00:58:31,440 --> 00:58:37,760
am excited about the potential to maybe take one chassis of one phage and maybe adapt it

812
00:58:37,760 --> 00:58:43,720
a different tail onto it so that it can infect a new host or many hosts.

813
00:58:43,720 --> 00:58:47,680
And that kind of thing I think is going to start to be possible in the next decade with

814
00:58:47,680 --> 00:58:50,480
advances of AI.

815
00:58:50,480 --> 00:58:59,640
And also in terms of phage therapy, more traditionally, we have so much data about what phages infect

816
00:58:59,640 --> 00:59:01,800
what strain of bacteria.

817
00:59:01,800 --> 00:59:06,240
But as yet, that's not possible to do in the reverse.

818
00:59:06,240 --> 00:59:10,720
So it's not possible to look at a strain of bacteria at the genome level and predict

819
00:59:10,720 --> 00:59:15,560
what phages will infect it because it's just so complicated, like understanding what factors

820
00:59:15,560 --> 00:59:21,560
the phage is using to infect that and what genes the bacteria might have that resist

821
00:59:21,560 --> 00:59:23,240
the phage.

822
00:59:23,240 --> 00:59:24,240
We can't yet do that.

823
00:59:24,240 --> 00:59:29,320
But it's possible that as we start accumulating all this data into host range, there is speculation

824
00:59:29,320 --> 00:59:35,840
that we might be able to start to train models, AI models, to just predict from a given bacterial

825
00:59:35,840 --> 00:59:40,120
genome what phages we could use to treat it.

826
00:59:40,120 --> 00:59:44,200
And that would certainly speed up phage therapy because one of the challenges right now is

827
00:59:44,200 --> 00:59:46,920
these phages are so specific to a single strain.

828
00:59:46,920 --> 00:59:51,640
So if you have a patient, you have to first isolate the strain of bacteria that they have

829
00:59:51,640 --> 00:59:56,400
and then screen that bacteria across with all the phages that you have to find maybe

830
00:59:56,400 --> 00:59:58,040
one or two that will work.

831
00:59:58,040 --> 01:00:02,040
So we had a way to just pull from a library immediately.

832
01:00:02,040 --> 01:00:04,320
It might really speed up the process.

833
01:00:04,320 --> 01:00:08,240
And I was going to ask about phage libraries, if you could maybe explain what those are

834
01:00:08,240 --> 01:00:12,400
and how they're used with phage therapy because it's almost like with antibiotics you have

835
01:00:12,400 --> 01:00:14,080
a broad spectrum antibiotic.

836
01:00:14,080 --> 01:00:19,280
It's one antibiotic that can do damage to a lot of different bacteria.

837
01:00:19,280 --> 01:00:24,520
Whereas phage libraries contain numerous phages and can be pulled from to try and treat one

838
01:00:24,520 --> 01:00:29,320
when you don't specifically know the susceptibility of the bacteria to phages, correct?

839
01:00:29,320 --> 01:00:30,320
Exactly.

840
01:00:30,320 --> 01:00:35,080
So it's like, yeah, it goes back to this problem or could be seen as a benefit depending on

841
01:00:35,080 --> 01:00:41,160
how you look at it of phages and that they are very specific, they're narrow spectrum.

842
01:00:41,160 --> 01:00:47,520
And so a phage library is essentially when you collect all the phages against a given

843
01:00:47,520 --> 01:00:49,040
pathogen.

844
01:00:49,040 --> 01:00:53,080
And that can be using one strain or it can be using many strains.

845
01:00:53,080 --> 01:00:57,240
But having that large collection allows you to, when you have a new isolate that comes

846
01:00:57,240 --> 01:01:02,200
in from a patient, you could very rapidly screen hundreds or thousands of phages that

847
01:01:02,200 --> 01:01:08,760
might hit that strain until you have like a few good ones and then you can use them.

848
01:01:08,760 --> 01:01:14,680
Because just putting one phage with one bacteria and hoping it's going to work is the probability

849
01:01:14,680 --> 01:01:15,840
is very low here.

850
01:01:15,840 --> 01:01:20,360
These things are exquisitely sensitive and specific.

851
01:01:20,360 --> 01:01:26,120
And so the other kind of alternative to that, the solution that people have created is what's

852
01:01:26,120 --> 01:01:28,080
called the phage cocktail.

853
01:01:28,080 --> 01:01:33,960
So in this case, you would formulate a mixture of phages from your library that tend to have

854
01:01:33,960 --> 01:01:39,800
a pretty good activity against most of the bacterial strains you're seeing.

855
01:01:39,800 --> 01:01:46,840
So if it's like E. coli, in fact, UTI infections, you might have a cocktail of phages that hit

856
01:01:46,840 --> 01:01:50,320
maybe 90% of the E. coli that people tend to get.

857
01:01:50,320 --> 01:01:55,320
And then you can be fairly certain that your therapy will work and you can administer it

858
01:01:55,320 --> 01:02:01,120
immediately without having to do this retroactive testing of the strain and the sensitivities.

859
01:02:01,120 --> 01:02:04,760
Is that something that AI could help with as far as, because I mean large language models

860
01:02:04,760 --> 01:02:10,000
just at their basic level is just gathering a multitude of information and finding the

861
01:02:10,000 --> 01:02:12,840
best answers or answer for it.

862
01:02:12,840 --> 01:02:16,960
With regard to phage libraries, because some of them are vast, is this something, if those

863
01:02:16,960 --> 01:02:22,400
are all catalogued and you used AI to try and would it speed up possibly or help narrow

864
01:02:22,400 --> 01:02:27,520
down specific phages or phage cocktails that could be used for treating specific bacteria?

865
01:02:27,520 --> 01:02:31,720
Yeah, I know that people are definitely working on that and seeing if they can kind of train

866
01:02:31,720 --> 01:02:38,360
AI models to predict which phages in our library will make the best cocktail for a given strain

867
01:02:38,360 --> 01:02:40,760
or predict the outcomes.

868
01:02:40,760 --> 01:02:47,880
Yeah, so to be continued, I guess, it's like ongoing research in the field.

869
01:02:47,880 --> 01:02:53,120
So let's talk a little bit about the future of phages and then your own future as it pertains

870
01:02:53,120 --> 01:02:56,400
to the lab that you'll be working in.

871
01:02:56,400 --> 01:03:01,320
There seems to be a renewed interest in phage therapy, especially because of the antimicrobial

872
01:03:01,320 --> 01:03:06,360
resistance and antimicrobial stewardship that's happening now.

873
01:03:06,360 --> 01:03:08,360
What do you think the future will actually hold for phages?

874
01:03:08,360 --> 01:03:13,000
You said earlier, you're optimistic, but at the same time with phage therapy, you're not

875
01:03:13,000 --> 01:03:20,040
100% sure that there'll ever be a day where it's used regularly.

876
01:03:20,040 --> 01:03:25,760
What do you hope for anyway with phages in the future?

877
01:03:25,760 --> 01:03:28,520
I hope for more discovery.

878
01:03:28,520 --> 01:03:34,240
So one of the things we haven't really talked about yet is the sheer diversity of phages

879
01:03:34,240 --> 01:03:35,240
on this planet.

880
01:03:35,240 --> 01:03:41,280
So phages are thought to be the most abundant biological entity on the planet, right?

881
01:03:41,280 --> 01:03:52,000
Like it's very hard to understand what these numbers mean, but it's estimated that in your

882
01:03:52,000 --> 01:03:57,280
body right now, there's probably a trillion bacteria phages, right?

883
01:03:57,280 --> 01:04:03,960
For every grain of sand on the planet, there's a trillion bacteria phages, just like inconceivable

884
01:04:03,960 --> 01:04:05,840
numbers.

885
01:04:05,840 --> 01:04:11,560
And so the cool thing there is that there is so much biological diversity, and we only

886
01:04:11,560 --> 01:04:15,000
have a tiny snapshot of it right now.

887
01:04:15,000 --> 01:04:22,840
And so I'm really excited about further discovery and just mining, biological prospecting, if

888
01:04:22,840 --> 01:04:28,040
you like, all of the functions that we might be able to get out of these diverse phages.

889
01:04:28,040 --> 01:04:33,160
And certainly, another thing that I think is going to happen in the future is most of

890
01:04:33,160 --> 01:04:37,560
the phage research has focused on a very small number of bacteria.

891
01:04:37,560 --> 01:04:41,840
We've typically only are interested in human pathogens in microbiology.

892
01:04:41,840 --> 01:04:49,440
There's so many neglected species of bacteria that are just over there infecting, I don't

893
01:04:49,440 --> 01:04:53,840
know, amoeba or something, and we know nothing about their phages.

894
01:04:53,840 --> 01:04:59,720
So yeah, I'm very excited about general discovery.

895
01:04:59,720 --> 01:05:05,480
And yeah, looking into this vast unknown of bacteria phage diversity.

896
01:05:05,480 --> 01:05:06,480
So could they be used?

897
01:05:06,480 --> 01:05:11,600
Do you think I know you're talking about just abundantly different organisms beyond bacteria?

898
01:05:11,600 --> 01:05:13,760
I know that there is malaria.

899
01:05:13,760 --> 01:05:17,800
We're now having malaria resistant strains to antiparasitics.

900
01:05:17,800 --> 01:05:21,040
Is that something that even with parasites that possibly we could find?

901
01:05:21,040 --> 01:05:25,080
I mean, I don't know if they are phages specific just to bacteria.

902
01:05:25,080 --> 01:05:27,840
Is it something that other microorganisms?

903
01:05:27,840 --> 01:05:28,840
Yes.

904
01:05:28,840 --> 01:05:35,000
So phages are the term phage specifically refers to a virus of a bacteria.

905
01:05:35,000 --> 01:05:39,080
But indeed, any other any organism, I think, has a virus.

906
01:05:39,080 --> 01:05:42,080
And yeah, we just don't always know about it.

907
01:05:42,080 --> 01:05:46,840
So there's certain lifestyles that particularly parasites might have.

908
01:05:46,840 --> 01:05:49,880
So malaria tends to live inside human cells.

909
01:05:49,880 --> 01:05:53,760
So you can imagine it would be difficult for a virus to access it.

910
01:05:53,760 --> 01:05:59,200
And therefore, viruses might not be there might not be immediate viruses of malaria.

911
01:05:59,200 --> 01:06:04,640
But perhaps there are viruses of free living relatives of malaria that we could once we

912
01:06:04,640 --> 01:06:07,920
discovered them, we could maybe repurpose them.

913
01:06:07,920 --> 01:06:13,240
And yeah, I'm excited about the general diversity of viruses of microorganisms.

914
01:06:13,240 --> 01:06:16,000
It's such an unexplored topic.

915
01:06:16,000 --> 01:06:20,200
So with your loud that you're going to be heading up soon as you as you get out of Boston and

916
01:06:20,200 --> 01:06:24,600
head to New York, we'll be continuing the same type of research, we'll be doing newer

917
01:06:24,600 --> 01:06:25,600
research.

918
01:06:25,600 --> 01:06:27,160
Do you do you even have an idea yet?

919
01:06:27,160 --> 01:06:28,160
I'm sure you do.

920
01:06:28,160 --> 01:06:33,080
Are you able to help just share with us what you're going to be working on over the coming

921
01:06:33,080 --> 01:06:35,600
months, years and just into the future?

922
01:06:35,600 --> 01:06:40,680
Yeah, so I will be heading to the Wadsworth Center in Albany.

923
01:06:40,680 --> 01:06:45,080
And so the Wadsworth Center is affiliated with the New York State Department of Health.

924
01:06:45,080 --> 01:06:53,160
So they have a remit to do basic science that is kind of adjacent to the public health surveillance

925
01:06:53,160 --> 01:06:56,600
of New York State.

926
01:06:56,600 --> 01:07:00,280
And so I'll be continuing my research into plasma-dependent phages.

927
01:07:00,280 --> 01:07:05,200
I'm still very interested in antibiotic resistance and it's kind of a great grounding point for

928
01:07:05,200 --> 01:07:06,520
me.

929
01:07:06,520 --> 01:07:11,960
So my focus really will be on discovery of more plasma-dependent phages.

930
01:07:11,960 --> 01:07:17,800
One of the exciting things for me about the Wadsworth Center is they are running the wastewater

931
01:07:17,800 --> 01:07:20,440
surveillance for the whole state of New York.

932
01:07:20,440 --> 01:07:27,280
So we're getting wastewater from over 200 wastewater treatment plants on a weekly basis.

933
01:07:27,280 --> 01:07:29,000
It's a phage gold mine.

934
01:07:29,000 --> 01:07:37,160
So yeah, so I'm very excited to do some phage disc going and discover a lot of new phages.

935
01:07:37,160 --> 01:07:41,880
And I'm also interested in how bacteria become resistant to these phages.

936
01:07:41,880 --> 01:07:46,600
So the phage defense field I mentioned earlier has really exploded in the last decade or

937
01:07:46,600 --> 01:07:47,600
so.

938
01:07:47,600 --> 01:07:51,560
But so far these plasma-dependent phages have remained kind of on the sidelines in terms

939
01:07:51,560 --> 01:07:52,560
of defense.

940
01:07:52,560 --> 01:07:58,480
We don't really know how bacteria, what specialized defense systems bacteria have against plasma-dependent

941
01:07:58,480 --> 01:07:59,480
phages.

942
01:07:59,480 --> 01:08:02,680
So that's going to be another focus of my research.

943
01:08:02,680 --> 01:08:04,200
So cool.

944
01:08:04,200 --> 01:08:07,360
With all your hard work, all the time and effort that you put in, the passion that you

945
01:08:07,360 --> 01:08:11,920
have for it, which is obvious, and I love that, the enthusiasm, not only for just the

946
01:08:11,920 --> 01:08:17,400
work you do, but it could help so much, it could change just kind of the way we treat

947
01:08:17,400 --> 01:08:21,760
people and illnesses that are starting to get out of hand right now.

948
01:08:21,760 --> 01:08:25,440
How exciting and do you actually find it really gratifying to now just be heading up your

949
01:08:25,440 --> 01:08:26,440
own lab?

950
01:08:26,440 --> 01:08:27,440
It must be great.

951
01:08:27,440 --> 01:08:28,440
It's a dream.

952
01:08:28,440 --> 01:08:29,440
It's really, really exciting.

953
01:08:29,440 --> 01:08:35,960
I mean, I've been very lucky in my whole career and I've had mentors who've really let me

954
01:08:35,960 --> 01:08:39,840
have a lot of freedom in science and really kind of do my own thing.

955
01:08:39,840 --> 01:08:41,440
So I feel very ready for this.

956
01:08:41,440 --> 01:08:47,120
I feel like I've been always leading a mini lab inside labs for a while now.

957
01:08:47,120 --> 01:08:52,520
But it's very exciting to get to this final stage of total independence and being able

958
01:08:52,520 --> 01:08:56,680
to look for any phages I want without asking for permission.

959
01:08:56,680 --> 01:09:01,200
So it's extremely gratifying, yeah.

960
01:09:01,200 --> 01:09:06,240
For anybody who might be interested in microbiology or phages or just science in general, what

961
01:09:06,240 --> 01:09:12,840
advice would you have with regarding to just pursuing your passion?

962
01:09:12,840 --> 01:09:15,920
I would say be tenacious.

963
01:09:15,920 --> 01:09:17,480
Just keep going.

964
01:09:17,480 --> 01:09:21,880
If it's interesting to you, it doesn't matter if it's interesting to other people.

965
01:09:21,880 --> 01:09:30,920
Sometimes I think we feel pressure to do science that is exciting and is fun and will make

966
01:09:30,920 --> 01:09:33,080
a nature paper.

967
01:09:33,080 --> 01:09:38,000
And I think it's really important to try and let go of that and just follow your nose, follow

968
01:09:38,000 --> 01:09:42,040
the topics that are really interesting to you.

969
01:09:42,040 --> 01:09:49,160
And at the kind of more junior level or the public, I think just talk to everybody.

970
01:09:49,160 --> 01:09:53,880
You'd be surprised at how willing scientists are to just talk to you.

971
01:09:53,880 --> 01:09:57,240
We don't get out the lab that much.

972
01:09:57,240 --> 01:10:02,600
So often scientists, if they're really interested in their research, they will talk your ear

973
01:10:02,600 --> 01:10:04,280
off about it.

974
01:10:04,280 --> 01:10:09,400
So yeah, if you're interested, reach out to your local scientist and talk to them about

975
01:10:09,400 --> 01:10:10,400
it.

976
01:10:10,400 --> 01:10:15,160
And this is proof of that because prior to just a couple of random emails, I had no prior

977
01:10:15,160 --> 01:10:21,000
conversations with anybody at the BAME lab and I was so happy just to actually have you

978
01:10:21,000 --> 01:10:22,000
here.

979
01:10:22,000 --> 01:10:24,360
Thank you so much for coming on.

980
01:10:24,360 --> 01:10:27,640
Any other advice, anything you want to talk about regarding phages or anything we didn't

981
01:10:27,640 --> 01:10:31,920
touch on that you think might be important to discuss when it comes to like phages, phage

982
01:10:31,920 --> 01:10:34,400
therapy, the future of phages?

983
01:10:34,400 --> 01:10:39,840
One piece of advice I have for any undergrads or soon to be undergrads or parents of undergrads

984
01:10:39,840 --> 01:10:44,840
who might be listening and are interested, have any interest in phages is to look for

985
01:10:44,840 --> 01:10:47,400
colleges that run the C-phages program.

986
01:10:47,400 --> 01:10:52,640
So this is an amazing undergraduate program that was spun out of Graham Hattfall's lab

987
01:10:52,640 --> 01:10:54,360
at the Pittsburgh.

988
01:10:54,360 --> 01:11:00,120
And essentially they allow undergrads across the country to find their own phages.

989
01:11:00,120 --> 01:11:03,320
You get to sequence the genome, you get to name the phage.

990
01:11:03,320 --> 01:11:09,240
It's an incredible program and it's a really great way to get into molecular microbiology.

991
01:11:09,240 --> 01:11:13,120
How much lab equipment do you need to have to be able to discover phages?

992
01:11:13,120 --> 01:11:15,880
Honestly, not a lot.

993
01:11:15,880 --> 01:11:20,360
It's really amazing how the techniques we use in the lab today for phage research have

994
01:11:20,360 --> 01:11:23,720
not changed in almost a century now.

995
01:11:23,720 --> 01:11:24,720
Which is crazy.

996
01:11:24,720 --> 01:11:26,720
You would think that with technology.

997
01:11:26,720 --> 01:11:28,120
I mean, we're digital now.

998
01:11:28,120 --> 01:11:29,120
Everything is digital.

999
01:11:29,120 --> 01:11:34,520
Back then it was microscopes and light and that was about it.

1000
01:11:34,520 --> 01:11:42,600
Do you see the future of research being molded to, I don't know, being upgraded I guess.

1001
01:11:42,600 --> 01:11:48,560
With digital technology and artificial intelligence once again and being more computerized.

1002
01:11:48,560 --> 01:11:52,400
I mean, there will always be the lab work that will have to happen, the physical aspects

1003
01:11:52,400 --> 01:11:53,400
of it.

1004
01:11:53,400 --> 01:11:56,880
But just from computing and just from that aspect.

1005
01:11:56,880 --> 01:11:57,880
Absolutely.

1006
01:11:57,880 --> 01:11:59,800
And it's happening in all areas of biology.

1007
01:11:59,800 --> 01:12:05,720
I would say though that phage research has been a little late to kind of develop new

1008
01:12:05,720 --> 01:12:06,720
technologies.

1009
01:12:06,720 --> 01:12:11,520
So that is something I see coming and already is happening as we're starting to develop

1010
01:12:11,520 --> 01:12:15,680
more modern technologies for studying phages.

1011
01:12:15,680 --> 01:12:19,000
And yeah, that's again something I'm integrating into my research.

1012
01:12:19,000 --> 01:12:21,400
Sean, thank you so much for coming on.

1013
01:12:21,400 --> 01:12:22,400
This has been awesome.

1014
01:12:22,400 --> 01:12:23,900
I appreciate it so much.

1015
01:12:23,900 --> 01:12:24,900
Really happy to get you on.

1016
01:12:24,900 --> 01:12:29,360
Especially as you're heading off in just a few days to get out of this place.

1017
01:12:29,360 --> 01:12:30,360
I appreciate it.

1018
01:12:30,360 --> 01:12:34,480
I'll be following you with your new discoveries in your lab.

1019
01:12:34,480 --> 01:12:40,000
And I don't know if you want to share any of your social media, anything like that.

1020
01:12:40,000 --> 01:12:42,640
Or if that's something you want to keep private, it's up to you.

1021
01:12:42,640 --> 01:12:44,040
But if you want to feel free.

1022
01:12:44,040 --> 01:12:45,040
Yeah.

1023
01:12:45,040 --> 01:12:47,760
Thanks, Andrew, so much for having me.

1024
01:12:47,760 --> 01:12:49,160
And thanks everyone for listening.

1025
01:12:49,160 --> 01:12:52,160
You can follow me on Twitter at implosion.

1026
01:12:52,160 --> 01:12:55,160
Which is a great name.

1027
01:12:55,160 --> 01:12:56,160
Awesome.

1028
01:12:56,160 --> 01:12:57,160
Thanks, Sean.

1029
01:12:57,160 --> 01:12:58,640
I appreciate it again.

1030
01:12:58,640 --> 01:13:02,080
And for everybody else listening out there, thank you very much.

1031
01:13:02,080 --> 01:13:12,000
As always, emails at makemesickpod at gmail.com and you can find us on Twitter at makemesickpod.

1032
01:13:12,000 --> 01:13:13,000
Thank you all for listening.

1033
01:13:13,000 --> 01:13:42,800
And remember everybody to please wash your hands.

1034
01:13:43,000 --> 01:14:12,800
And remember everybody to please wash your hands.

1035
01:14:12,800 --> 01:14:42,600
And remember everybody to please wash your hands.

1036
01:14:42,600 --> 01:15:12,400
And remember everybody to please wash your hands.

1037
01:15:12,400 --> 01:15:42,200
And remember everybody to please wash your hands.

1038
01:15:42,200 --> 01:16:12,000
And remember everybody to please wash your hands.