Using Viruses to Fight Disease

Summary

Podcast Summary: "Using Viruses to Fight Disease"

Podcast: What’s Your Problem?
Host: Jacob Goldstein
Guest: Paul Garofolo, Co-founder & CEO of Locus Biosciences
Release Date: July 16, 2026

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Episode Overview

In this episode, Jacob Goldstein interviews Paul Garofolo, CEO of Locus Biosciences, about the renewed and high-tech push to use bacteriophages—viruses that attack bacteria—for treating infections, especially as antibiotic resistance rises. The discussion dives deep into the promise and challenge of phage therapy, the use of genetic engineering to make phages more powerful, the role of AI and robotics in designing new therapies, and the potential for phages to tackle diseases beyond infectious ones. The tone is curious, engaged, and optimistic about innovative solutions in biotechnology.

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1. Introduction to Phages and Locus Biosciences

Key Timestamps: 01:44–03:55

• Phages Abound: The episode starts with Jacob and Paul marveling at the sheer abundance of phages on Earth.

  • Jacob Goldstein: “Phages are unimaginably abundant.” (01:44)
  • “There are a trillion phages for every grain of sand on earth.” (01:49)

• Essential but Untapped:

  • Paul Garofolo explains: “We actually have been trying to figure out how to selectively remove bacteria from the human body without touching any of the good bacteria…” (03:15)
  • The company’s "big dream" is to selectively target bad bacteria, contributing to longevity and health.

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2. The Problem with Antibiotics

Key Timestamps: 03:55–05:47

• Limitations:

  • Growing antibiotic resistance: “We’re beginning to see exponential increases in drug resistance from almost all mainstream antibiotics… at some point, none of them work.” (04:11, Paul Garofolo)
  • Toxicity of stronger antibiotics and the side effects on the body and microbiome.

• Unwanted Side Effects:

  • Recurrent infections, long courses of antibiotics, and damaged microbiomes leading patients with chronic infections to highly restrictive diets or other complications.

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3. Why Phages and What’s Different Now?

Key Timestamps: 05:47–09:51

• Precision medicine for bacteria:

  • Paul Garofolo: “Phages are one of the most unique and creative ways… to selectively attack a very specific bacterial pathogen…” (05:47)

• Downside of ‘Wild Type’ Phages:

  • Historical efforts used unmodified phages, which typically showed only 50–70% efficacy, compared to traditional antibiotics’ 95%+ cure rates.
  • Resistance can build up even with phages.
  • “It sounds perfect. Why hasn’t it worked that well so far?” — Jacob Goldstein (07:29)

• Notable quote:

  • Paul Garofolo: “...an individual phage to go after... a large population of bacteria in the human body will begin to see resistance.” (09:31)

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4. The New Approach – Genetically Modified Phages & CRISPR

Key Timestamps: 09:51–12:04

• Genetic Engineering Advances:

  • Locus uses CRISPR Cas3 ("the gene shredder") rather than just regular CRISPR (“the gene scissors”).
  • “It works like essentially a Pac-Man... It chews that strand back by hundreds, if not thousands of base pairs to the point where it renders that cell dead.” (10:22, Paul Garofolo)

• Phage Cocktails:

  • Locus’s main clinical candidate is a cocktail of six engineered phages, most carrying CRISPR Cas3, optimized to kill E. coli (11:09–11:48).

• Differentiation:

  • Multiple engineered phages in one treatment + CRISPR = higher efficacy, possibly clearing infections entirely.

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5. The Clinical Trials: Focus on UTIs

Key Timestamps: 12:04–14:21

• Current Study:

  • Ongoing clinical trial for women with recurrent urinary tract infections (UTIs).
  • “We just dosed patient 229 yesterday. … the idea is that it would … deal with the acute infection … but actually either eliminates or dramatically reduces the number of recurrent infections …” (12:20, Paul Garofolo)
  • Over 10 million people in the U.S. have recurrent UTIs; 2 million suffer multiple recurrences each year.

• Treatment Protocol:

  • Delivered intraurethrally and intravenously over three days, targeting both bladder and kidneys (13:32–14:13).

• Patient Profile & Unmet Need:

  • Treatment intended for severe cases with frequent, debilitating recurrences.
  • “There’s nothing that they can really do about them except … treat them with antibiotics as the occurrences happen and just keep giving them antibiotics...” (14:21, Paul Garofolo)

• Safety:

  • Mostly mild side effects (low-grade fever, nausea). “You’re giving a lot of virus.” (15:35, Paul Garofolo)

• Trial Timeline:

  • “We believe we’ll be finished dosing sometime in the late fall to early winter and then within 90 days from that last dose we’ll have the data.” (15:48, Paul Garofolo)

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6. Other Applications and Expansion

Key Timestamps: 16:06–17:10

• Crohn's Disease:
  • Oral phage treatment targeting adherent invasive E. coli, implicated in Crohn’s.
• Hospital-Acquired Pneumonia:
  • Another phage treatment approaching clinical trials.
• Multiple "Assets":
  • “In theory, by the end of this year and the beginning of next year we would have three to four assets that were moving through the clinic.” (16:14–17:05)

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7. AI and Robots for Phage Discovery

Key Timestamps: 19:55–23:48

• Automated Discovery:

  • “We use what we call AI driven robotics… we discover phage at a volume I don’t think anybody in the past has used.” (19:58, Paul Garofolo)
  • Automated sample processing 24/7 from wastewater near international airports for global diversity.

• From Robot to AI:

  • Robots screen phages, AI predicts the optimal phage "cocktails" (like Netflix recommendations for phages).
  • Over 8,500 uniquely identified phages catalogued (21:57).
  • “The three that we have that are coming this year were all built using that approach.” (23:26)

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8. The Bigger Idea: Beyond Infectious Disease

Key Timestamps: 24:08–30:16

• From Bugs to Inflammation:

  • Hypothesis: Many chronic diseases (like rheumatoid arthritis, neurodegenerative disease) are triggered by chronic low-level bacterial infections.
  • “Our hope for this platform is that it can reach into the human body via precision medicine and pull those pathogens or pathobions out.” (27:38, Paul Garofolo)

• Potential for Cures:

  • Most of medicine is suppression, not cure; phages could address root causes if specific disease-triggering bacteria can be identified and targeted.
  • “If we’re able to show direct causal relationships between certain pathogens that are in the body and improvement and disease symptomology, I think we’re onto something really, really big.” (29:37, Paul Garofolo)

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9. Lightning Round & Reflections

Key Timestamps: 32:51–37:47

• Favorite Phage:

  • Paul: Macrophages (giant phages) due to potential for large payload delivery (“like taming a really big bull,” 33:28).
  • “If you could replicate it, that’s pretty exciting…” (33:04, Paul Garofolo)

• Being a Non-PhD CEO:

  • “You can ask dumber questions of your team and get away with it. Like, why do you think that I don’t understand? Explain that to me.” (34:44)
  • Company culture is “biased towards more execution” (34:59).

• Biotech’s Surprising Evolution:

  • Positive: There is real progress toward cures that once seemed out of reach.
  • Negative: Post-Covid, the flood of money led to too many low-quality companies, which diluted talent and industry focus. “The curse of too much money.” (37:05, Jacob Goldstein)

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Notable Quotes

• On the Phage-Antibiotic Race:

  • “The efficacy difference between those two wild type phages and antibiotics is just so stark.” (08:40, Paul Garofolo)

• On the Promise of Engineered Phages:

  • “Using phages as a delivery vector is essentially centering around the fact that they're exquisitely unique to the bacteria that they've evolved to infect.” (06:09, Paul Garofolo)

• On the Long-term Vision:

  • “If you have a platform that can remove those bad actors, you likely also get the benefits of being able to improve the health of the human body … and that we believe will do things like increase the lives of most people in society.” (28:16, Paul Garofolo)

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Episode Structure (Timestamps)

| Segment | Timestamp | |----------------------------------------------------|--------------| | Phage abundance & basics | 01:44–03:55 | | Antibiotics' problems | 03:55–05:47 | | Limitations of wild phage therapy | 05:47–09:51 | | Engineered phages & CRISPR Cas3 | 09:51–12:04 | | Clinical trials: UTIs | 12:04–16:06 | | Pipeline: Crohn’s, pneumonia, other assets | 16:06–17:10 | | Robotics & AI for phage discovery | 19:55–23:48 | | Vision beyond infections (chronic disease, cures) | 24:08–30:16 | | Lightning round, biotech reflections | 32:51–37:47 |

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Memorable Moments

• “It works like essentially a Pac-Man … chews that strand back … renders that cell dead.” (10:22, Paul Garofolo)
• Locus’s sample collection method: “We pull wastewater from all 50 states outside of international airports.” (20:59–21:15)
• “If you had a urinary tract infection … and then within a month to two months, you got another one … there’s nothing that they can really do about them except … keep giving antibiotics every time they happen.” (14:21, Paul Garofolo)
• “It gives our culture inside of our company a bias towards more execution… once you pass a certain point where you’re moving into the clinic it’s time to execute.” (34:59, Paul Garofolo)

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Takeaways

• Phage therapy is making a comeback as engineered viruses promise more precise, potentially curative treatments for antibiotic-resistant infections.
• Locus Biosciences leverages CRISPR technology, AI, and robotics to discover and optimize phage cocktails rapidly.
• Possibility to expand to chronic and autoimmune diseases if bacterial triggers can be targeted.
• The field is evolving from “suppression” to possible “cure” in infectious and potentially non-infectious diseases.

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This episode offers an accessible but deep dive into the state and future of phage therapy, focusing on both the science and the real-world challenges of bringing these innovations to patients.

Transcript

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[Jacob Goldstein]

Phages are unimaginably abundant.

[Podcast Producer/Host]

A trillion phages for every grain of

[Jacob Goldstein]

sand on earth according to one estimate.

[Podcast Producer/Host]

Which, what does that even mean?

[Jacob Goldstein]

Qualitatively?

[Podcast Producer/Host]

It means phages are all around us.

[Jacob Goldstein]

They are inside of us. They are essential to life on Earth

[Podcast Producer/Host]

and they may help to improve human health in a profound way.

[Jacob Goldstein]

Jacob I'm Jacob Goldstein. This is what's yous Problem.

[Podcast Producer/Host]

And my guest today is Paul Garofolo.

[Jacob Goldstein]

He is the co founder and CEO of a company called Locus Biosciences.

[Podcast Producer/Host]

Paul's problem is can you use genetically engineered phages to cure disease? People have been trying to use phages to cure infections for over 100 years now. But in most cases, naturally occurring phages just don't work as well as antibiotics as drugs.

[Jacob Goldstein]

Phages reduce infections, but they often don't

[Podcast Producer/Host]

wipe them out entirely.

[Jacob Goldstein]

So Paul and his colleagues are taking a different approach.

[Podcast Producer/Host]

They're genetically engineering phages to make them better at killing bacteria.

[Jacob Goldstein]

For now, the company is testing its

[Podcast Producer/Host]

first phage based drug in patients in combination with antibiotics.

[Jacob Goldstein]

But Paul says the long term dream

[Podcast Producer/Host]

is bigger than that.

[Paul Garofolo]

So we actually have been trying to figure out how to selectively remove bacteria from the human body without touching any of the good bacteria that's in there. And we believe that that is a key to longevity of human life. We're starting with trying to replace antibiotics, but we believe that any number of diseases in the human body are actually the body's reaction to inflammation from bad bacteria getting in there and not leaving. And so that's what Locus is trying to do.

[Jacob Goldstein]

That's the big dream. There's a narrower dream that I'm also interested in. Yes, and maybe a question that gets at the narrower dream is what are the limitations of antibiotics that you're trying to address?

[Paul Garofolo]

I think there are two things that are wrong with antibiotics. So one that most people are very, very familiar with is resistance is now everywhere. And so effectively, we're beginning to see exponential increases in drug resistance from almost all mainstream antibiotics, if not all. So there, it's sort of a math problem. From here, at some point, none of them work. And the further up in strength you move in antibiotics, the more toxic they are to your body. And so if you're really sick and you have to go on a really strong antibiotic, the antibiotic itself can be your demise. So that's one thing. Another example might be people with recurrent ear infections or recurrent bladder infections end up going on to frequent batteries of antibiotics, say, you know, starting at 15 days, but eventually getting to things like 30 days or 45 days of, of low volumes. And that can wreak havoc on your body. You know, it could basically destroy the balance in your microbiome. And you can have things that are long ranging side effects, like having to go on substantially simplistic diets for a long period of time because your intestinal tract can't handle the variety of food that it likely needs for longevity. So those are just a couple of

[Jacob Goldstein]

examples why my phages help to solve this problem.

[Paul Garofolo]

So we think that phages are one of the most unique and creative ways of getting into the human body to selectively attack a very specific bacterial pathogen or pathobion of interest and only that particular target. So I'm sure you've heard about precision medicine on the, on the gene editing side for human cells that might be able to fix some of the world's roughest diseases. But on the bacterial side, precision medicine is, is quite new. And the idea of using phages as a delivery vector is essentially centering around the fact that they're exquisitely unique to the bacteria that they've evolved to infect. And so I think the largest, most abundant and oldest biological organism on the planet, besides, bacteria is fish.

[Jacob Goldstein]

Yeah. It's amazing, right? Like the earth is full of phages in the sea. What? Every day half of the bacteria in the sea get killed by phages or something. Like it's wild, Right. It's like, it's incredible.

[Paul Garofolo]

Yeah. They say that half the bacteria on the planet, soil, sea, in you and

[Jacob Goldstein]

you every day, like it's happening all around us. It's happening inside our bodies.

[Boost Mobile Announcer]

Right.

[Jacob Goldstein]

There are phages that naturally occur inside our bodies. Yes.

[Paul Garofolo]

And bacteria actually double at a very similar pace. Right. So this is one of nature's oldest and most established ecosystems.

[Jacob Goldstein]

And this, this is an old idea. It's super exciting when you hear it. And they're like, oh wait, people have been trying to attack bacterial infection with phages for literally like a hundred years. Correct. Right. And they haven't got that far with it. It sounds perfect. Why hasn't it worked that well so far?

[Paul Garofolo]

I think there are probably two or three reasons of note. One is that people essentially, since I'd say a century ago when they were discovered, they use wild type phages, meaning they don't do any type of enhancement to that virus. They don't change the genome in any way. They simply search for one that is a effectively a good killer in an academic lab, and then they take that killer and they put that into the human body expecting similar results. And you can see efficacy levels of those types of what we call wild type phase treatments in anywhere from 50 to maybe even 65, maybe even in best cases, 70% range, which you would say, well, that sounds decent, pretty good. But antibiotics have traditionally, up until when resistance has started to come into fray, those typically work around or above 95%. So the efficacy difference between those two wild type phages and antibiotics is just so stark. In the days of the Cold War, antibiotics were not really available to people that were behind the iron curtain. And so phage therapy actually continued in many places inside Georgia, Russia, et cetera, and advanced into treatment centers that really were geared around a single phage for a single bacteria. And what that leads me to the sort of the second, I think, not shortcoming, but just natural component of phage, which is an individual phage to go after, let's say a large population of bacteria in the human body will begin to see resistance.

[Jacob Goldstein]

So that's the story of, as you said, wild type phages, naturally occurring phages. You are doing something much more 21st century. Right. In a few ways. So we should introduce another sort of idea. Slash piece of jargon now. Right. Which is CRISPR CAS3. People are used to thinking of CRISPR as like the gene scissors. Right. I think people are relatively familiar with that. But this is a variant that is like the gene shredder, Right? As opposed to a scissors.

[Paul Garofolo]

Yes. It works like essentially a Pac man, if you remember the old arcade game. So it essentially makes a small nick in one strand of the DNA of the double helix and then it chews that strand back by hundreds, if not thousands of base pairs to the point where it renders that cell dead. And by no means, and I think this is an evolution of our company and perhaps many others, CRISPR systems are not the only thing that you can engineer into a phage. Peptides, other enzymes, all kinds of things.

[Jacob Goldstein]

Oh, interesting. But that's, I mean, just to be clear, like the. Can I call them drugs? They're drugs, right? They're drugs. The drugs that you have in clinical trials are combining CRISPR Cas3 with a phage, right?

[Paul Garofolo]

Yes. Our lead asset is an E. Coli based product. It has six phages inside of that product. So it's a cocktail of phages and the majority of those phages are engineered to carry the entire CRISPR Cas3 construct inside.

[Jacob Goldstein]

So it's basically six different phages, each of which you've engineered to put on this gene shredder gene Pac Man. So the idea is the phages go into the infecting cells, the E. Coli, the bacteria, and then the CRISPR eats up the DNA of those bacteria, thus killing the bacteria. That's the basic idea.

[Paul Garofolo]

That's the basic idea.

[Jacob Goldstein]

So basically the idea is if you do A, a bunch of different phages and B, add to them something like CRISPR Cas3 that makes it extra deadly, then you can clear the infection rather than just reducing.

[Paul Garofolo]

Correct.

[Jacob Goldstein]

And so now you are running a clinical trial on is it women with recurrent urinary tract infections, is that right?

[Paul Garofolo]

Correct.

[Jacob Goldstein]

So tell me about that trial. Like where is it? What's happening? What's the, you know, what's the outcome?

[Paul Garofolo]

Yeah, so we just dosed patient 229 yesterday. We've got probably 288 to maybe 308 patients that we're going to dose. And the idea is that it would not only deal with the acute infection that you're getting hit with right now, but it actually either eliminates or dramatically reduces the number of recurrent infections that you'll see in the future.

[Jacob Goldstein]

Yeah. So tell me about like recurrent UTI

[Paul Garofolo]

as a problem inside the United States alone. Over 10 million people get recurrent infections, of which 2 million of that patient block get multiple recurrences. Once you get into a pattern of having multiple recurrences, it's very difficult to get rid of those. Many patients evolve through decades into a state of colonization, which just simply means that that bacteria embeds itself somewhere in your body and reinfections occ, you know, maybe for some a few times a year, but for many five, six times a year.

[Jacob Goldstein]

And how are you delivering the face treatment?

[Paul Garofolo]

So we have an intraurethral delivery into the bladder. So we use a catheter, we void the bladder of its content and then we reverse flow the drug product into the bladder and in the process we also expand the bladder to make sure that the bladder wall is coated and we hold the drug product there for, for about 40 to 50 minutes before the patient's void again. We do that on the first day and the second day and then simultaneously we have an intravenous backdrop that really is meant to try to get to the kidneys. And we do that on day one, two and three. So the total time and duration is three days.

[Jacob Goldstein]

So this is an intense treatment. This is like your UTI would have to be extremely bad to want to do this, frankly.

[Paul Garofolo]

You're in that 2 million patient population. And you know, if you had. Just think about it this way. If you had a urinary tract infection that was so bad that you had to stay home from work for three or four days until the antibiotics that you got called in for, you kicked in, and then you were still under the weather for another six or seven days. And then at the end of that period, within a month to two months, you got another one. And those infections, in fact, when we talk to urologists and we talk to urogynecologists, they say that this particular infection is the one that they feel the worst about for their patients over anything that they deal with, because there's nothing that they can really do about them except for treat them with antibiotics as the occurrences happen and just keep giving them antibiotics every time they happen.

[Jacob Goldstein]

What are the risks? What are the risks associated with the phase treatment?

[Paul Garofolo]

So we have not seen any crazy averse events, but the amount of viral particles that we put into the body, some patients can get low grade fever, some patients can get a little nauseous.

[Jacob Goldstein]

You're giving people a virus, right?

[Paul Garofolo]

You're giving a lot of virus.

[Jacob Goldstein]

So when are you going to know if phage plus antibiotic works better than antibiotic alone?

[Paul Garofolo]

So we should be finished dosing. We believe we'll be finished dosing sometime in the late fall to early winter and then within 90 days from that last dose we'll have the data.

[Jacob Goldstein]

So next less than a year you should know.

[Paul Garofolo]

Definitely less than a year.

[Jacob Goldstein]

So this UTI study is the one that's farthest along for you. What else do you have in clinical trials?

[Paul Garofolo]

So we have applied for an IND for a Crohn's asset to try to essentially have an oral product that is similar to the UTI product but works more towards adherent invasive E. Coli, which is in many areas of medicine considered to be at worst associative, at best causal of Crohn's disease. In addition to that one, we're very close to being able to submit an IND for this hospital acquired pneumonia asset and that should be if we're on time, that one should get approved before the end of the year. So in theory, by the end of this year and the beginning of next year we would have three to four assets that were moving through the clinic.

[Jacob Goldstein]

And an asset is a drug.

[Paul Garofolo]

An asset is a drug.

[Jacob Goldstein]

A drug that you own. That's why it's an asset for you.

[Paul Garofolo]

Well, in some cases partnered, but yes, one that we own or co own.

[Jacob Goldstein]

Yeah, somebody owns. We'll be back in just a minute.

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[Jacob Goldstein]

Tell me about how you're using AI at your company.

[Paul Garofolo]

Yeah, so we use what we call AI driven robotics. And so we discover phage at a volume I don't think anybody in the past has used. And then when we get those phage isolated, we sequence them, we run full characterization on them, and then we start running them through prediction engines that help us figure out what payloads to put into their genomes and which ones of those should go together into a fixed drug.

[Jacob Goldstein]

So let me just take a sec to understand that the prediction engines part, that second part that sounds like AI, but what's the robot part and how is it different than what happens in a normal lab?

[Paul Garofolo]

Well, in a normal lab you have a pipette, you know, kind of looks like a.

[Jacob Goldstein]

You're holding up your hand. That's it.

[Paul Garofolo]

Yeah, you have a little thumb thingy that you like depress. So discovering phages using sort of your regular old run of the mill.

[Jacob Goldstein]

So what? So okay, what are you doing?

[Paul Garofolo]

We're using hundreds, if not thousands of 96 well plates with the robot running 24 hours a day, essentially looking at wastewater that we pull from all 50 states outside of international airports.

[Jacob Goldstein]

Oh, you do it outside of international airports because it's a more biodiverse sample. Like sages are flying in from all over the world in people's bodies.

[Paul Garofolo]

And you're sampling them 100%.

[Jacob Goldstein]

I love that.

[Paul Garofolo]

Yeah, it's really cool.

[Jacob Goldstein]

When you say wastewater, like you just go to like the sewer. Like how do you actually do this?

[Paul Garofolo]

You reach out to the municipalities and you set up opportunities to pull them. And I mean, in the early, early days, we would go out there and we'd knock on the door and we'd ask for like, hey, can we get this? And in a lot of cases, you can.

[Jacob Goldstein]

And what's the order of magnitude of, like, how many different phages your system is going through?

[Paul Garofolo]

So we have found probably 8,500 uniquely identified, fully characterized phages against 99 different bacterial targets. So a size and scale that most academic labs, if not any academic lab could ever match.

[Jacob Goldstein]

So then, so that's the robot stage. And then you were saying you move on to the kind of AI stage. What's that?

[Paul Garofolo]

So you maybe the best way to think about it is it can work a little bit like Netflix. So if you're, you know, you watch a particular type of movie and there's a little algorithm behind the scenes that tries to figure out, well, what's the next best movie that's like that, that you might want. And so we essentially apply very similar models to the sequenced information that we have on each of these unique phages. And we start to try to figure out, really, by evaluating quadrillions of different options of pairing hundreds, if not thousands of phages together, which four, five, six or seven of these go best together.

[Jacob Goldstein]

So you want them to be complimentary, you're targeting some particular bacteria, and you're like, okay, give me the best cocktail AI.

[Paul Garofolo]

Yep. And then once it says, try these top three, we go make them. And then we, we grow it up and, you know, manufacture small quantities of it, and then we test them out.

[Jacob Goldstein]

And is that how you got the cocktails that are in trials now?

[Paul Garofolo]

The one that we have that's in trial now probably was a bit more manual because this is our first asset. And it's probably built like seven years ago to. The three that we have that are coming this year were all built using that approach. So we're excited about the second generation assets that are going in.

[Jacob Goldstein]

So let's talk more long term. Let's talk about the sort of phage dream. I've heard you talk about the potential that the kinds of things you're working on might go beyond what we think of as infectious disease someday. Tell me about the sort of big dream for. For phage treatment.

[Paul Garofolo]

I think Crohn's sits in that arena for us. So Crohn's disease is a immune disorder that essentially your body's immune system mistakes something in your intestinal tract for an infection. And it Targets your own intestinal organs and eats away at them to the point where you have small lesions that are actually in your intestinal lining. And what we know how to do in the field of medicine is essentially turn down the intensity of the attacking.

[Jacob Goldstein]

So it's an autoimmune disorder. It's not thought of as an infectious disease.

[Paul Garofolo]

Correct.

[Jacob Goldstein]

So where does phage therapy come in?

[Paul Garofolo]

In many circles of ibd, it's thought that bacteria is what the immune system is attacking.

[Jacob Goldstein]

And IBD is inflammatory bowel disease. Correct. Like that. Crohn's is one of.

[Paul Garofolo]

Yeah, Crohn's, colitis variant forms of those. Anything that essentially diverticulate these types of things that are essentially intestinal organ disorders. There's a big umbrella term for ibd and so many scientists believe that there are bacteria that get stuck in there and are non transient. And it's those bacteria that get stuck in there and somehow adhere to the intestinal walls. That is what the immune system is attacking.

[Jacob Goldstein]

And that makes your immune system freak out and start attacking not just those cells, but the body's own cells.

[Paul Garofolo]

Correct. And so our drugs, and what we think is the holy grail of medicine is to be able to use phage encoded with payloads that can eat through either the biofilms, muco layers or macrophage layers that protect those intracellular pathogens that our drugs would be able to get there. Precisely. And kill just those pathogens, thereby causing the immune system to calm down and to potentially heal that patient with something that's curative.

[Jacob Goldstein]

And just to be clear, is it the case that antibiotics just don't work for the particular. The bacteria in the setting that you're describing?

[Paul Garofolo]

Antibiotics are known to not be able to kill intracellular pathogens. They can't transit into the human cells to kill the human cells.

[Jacob Goldstein]

Which is why they don't kill us, presumably.

[Paul Garofolo]

Why antibiotics don't kill us. Yeah, presumably. I mean, that's one way to look at it. Absolutely.

[Jacob Goldstein]

Yeah, yeah. And this is a trial that you're hoping to sort of start a clinical trial based on this hypothesis, you said in the next year or so.

[Paul Garofolo]

We hope to. We hope to. We still need to raise funds specifically for that one.

[Jacob Goldstein]

I believe it less the way you say we hope to.

[Paul Garofolo]

Yeah. When you're running a company like this, you tend to go where your contracts and partnerships are. And right now we have contracts in three of four areas. And so of course we're busy working on all three of those and we hope to add the fourth.

[Jacob Goldstein]

So what's the bigger idea here, like, we kind of went far into the weeds on Crohn's, but what is the bigger idea for, you know, if you're right, like, what is the big hope for phage therapy in whatever, 10 years or something?

[Paul Garofolo]

So I'll start high level and go down into that.

[Progressive Insurance Announcer]

Yeah.

[Paul Garofolo]

Inflammation in the human body is not good. It causes many diseases without question. Things like rheumatoid arthritis, potentially neuro diseases, things related to dementia, Parkinson's, et cetera. Like when inflammation occurs in certain sections of the body, bad things happen. Our hope for this platform is that it can reach into the human body via precision medicine and pull those pathogens or pathobions out.

[Jacob Goldstein]

Is the underlying hypothesis that this sort of mysterious systemic inflammation is caused by particular kinds of bacterial infections?

[Paul Garofolo]

Yes. Many pathogens that are in the body are bad actors. They're non transient, and the immune system is likely attacking those non transient bad actors. And so if you have a platform that can remove those bad actors, you likely also get the benefits of being able to improve the health of the human body. And that we believe will do things like increase the lives of most people in society. Or if you're genetically predisposed to a disease, you may be able to prevent the onset of that disease for a longer period of time. If you're genetically predisposed to a disease, you might be able to lessen the severity of that disease on your life. A good example might be rheumatoid arthritis. So if you remove pathogens that either aggravate or cause rheumatoid arthritis, can you help that patient with their symptomology? Can you decrease the pain that's associated in your joints with that disease by decreasing the amount of pathogens that you actually have in the body? We believe that that is a theory that is absolutely worth going after trying to figure out. And many people don't really realize this, but a lot of medicine is built on suppression, GLP1s autoimmune drugs. These things are basically shutting something down in the body to help a patient. They're not actually dealing with causes. And so hopefully also then we can start to talk about cures. But certainly if we're able to show direct causal relationships between certain pathogens that are in the body and improvement and disease symptomology, I think we're onto something really, really big.

[Jacob Goldstein]

We'll be back in a minute with the lightning round.

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[Podcast Producer/Host]

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[Jacob Goldstein]

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[Podcast Producer/Host]

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[Jacob Goldstein]

what's your favorite phage?

[Paul Garofolo]

My favorite phage? Yeah, actually I really enjoy thinking about macrophages.

[Jacob Goldstein]

Oh, the giant ones that they didn't even know were viruses because they're so big.

[Paul Garofolo]

Yeah, they tend to evolve really fast and move around on you. So it makes it a little bit interesting to figure out how to actually pin one down and keep it from doing that when you don't want it to. But the possibilities of what you can load into a phage the size of the payload that you could get in there. If you could replicate it, that's pretty exciting.

[Jacob Goldstein]

So as a phage engineer, you're like, if we could tame that guy, we could stick anything in there.

[Paul Garofolo]

Yeah, I guess it'd be like taming a really big bull, right? Like what you get from that. I think the idea of being able to put all kinds of different peptides or other enzymatic tools into a phage and getting it very specifically into a certain part of the body and then having it in C2 manufacture that payload right at the site where you want it. It's pretty fascinating. As a someone who's been in the industry for a number of decades, there's tons of good drugs that are on the shelf because of things like half life considerations where it just doesn't stay alive and active long enough. But if you're manufacturing it in the body right where you need it with a phage, what can you do with those peptides that have long since been on the shelf? So I think there's some really cool things you can do with phases that are larger that might be able to carry some cool stuff.

[Jacob Goldstein]

I heard you say that part of the reason you started a company was because you don't have a PhD and you realize that in bigger companies there was just a ceiling on what you could do without a PhD. And I'm curious, have you found any advantages of not having a PhD? Does it give you any kind of insight or edge that you might not have if you did have one?

[Paul Garofolo]

I mean, you can ask dumber questions of your team and get away with it. Like, why do you think that I don't understand? Explain that to me.

[Jacob Goldstein]

That's actually, I will say that's my whole game. That's like my job is saying, I don't understand that. Explain it to me.

[Paul Garofolo]

I also think that it gives us, it gives our culture inside of our company a bias towards more execution. And not that we're any less curious about scientific discovery, but once you pass a certain point where you're moving into the clinic and through the clinic, it's time to execute and so you can stay focused a little bit better.

[Jacob Goldstein]

Right. You're an engineer by training. Right. That's a very engineering mindset. Right. Let's build a thing.

[Paul Garofolo]

Yeah. I'm a project manager by background. I'm a project manager. That's what I was, I guess raised doing is running huge projects.

[Jacob Goldstein]

So you've been in Biotech for what, 30 more than 30 years. Right. Which is a long time. And I'm curious if you sort of look over the arc, if you go back to when you were starting, I'm curious what's surprising to you? Like, what has done better than you expected? What has done worse?

[Paul Garofolo]

Oh, that's a really. No one's ever asked me that one before.

[Jacob Goldstein]

Okay.

[Paul Garofolo]

I mean, I think on the better side, I really have been in awe and excited about cures. When I started, if you said, hey, we're working on a cure, people would look at you and you'd immediately be discredited.

[Jacob Goldstein]

So what can we cure now that we couldn't cure when you started?

[Paul Garofolo]

I don't think you necessarily have all of the cures for things like Duchenne's or Parkinson's or Alzheimer's.

[Jacob Goldstein]

Definitely not for those. But what can we cure?

[Paul Garofolo]

I think they're coming. And that's my answer to your question of what's really cool about biotech. The hard parts, the parts that maybe aren't so fun is I think we had just a huge bolus of garbage ideas that flooded into the industry post Covid. The amount of money that came into the industry post Covid, the craze around SPACs, it basically drained all the talent into a bunch of BS companies, and it took a couple years for that to flood out.

[Jacob Goldstein]

The curse of too much money. It's funny, people mention that more often than I would have thought.

[Paul Garofolo]

In an industry that's used to creating 400 companies per year, you don't want to create 4,000 for two. And that's not. You just don't have the talent enough in the executive and leadership ranks to hold that. And where you get that from is your service partners, your vendors, and then your vendors don't know what they're doing. And so we had to live through that. I think we're through that. I actually think we're on the other side of that, which is, I guess time will tell as we see what actually breaks through.

[Podcast Producer/Host]

Paul Garofolo is the co founder and CEO of Locus Biosciences.

[Jacob Goldstein]

Please let us know what you think of the show, what you want to

[Podcast Producer/Host]

hear more of, what you want to hear less of.

[Jacob Goldstein]

Particular guest ideas, you can email us at problemushkin fm. I read all the emails. You can also find me on x or on LinkedIn.

[Podcast Producer/Host]

Really do appreciate all the messages that we get.

[Jacob Goldstein]

Today's show was produced by Gabriel Hunter

[Podcast Producer/Host]

Chang and Trina Menino. It was engineered by Hans Dale she and edited by Lydia Jean Cott.

[Jacob Goldstein]

I'M Jacob Goldstein and we'll be back

[Podcast Producer/Host]

next week week with another episode of what's yous Profit? When you think about discovering small brands, what store pops into your mind? Well, it should be Walmart. Seriously, Walmart has thousands of small brands and they're all in one place. Just go online or in store, discover and shop. It could not be easier. Every one of these brands has a real story and real people behind it. They're true American success stories and you can find them all at Walmart. Discover thousands of small [e-mail] today.

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