Episode 52: Number One Worldwide

Karie Dozer [00:00:02] I'm Karie Dozer and this is TGen Talks. When it comes to infectious diseases and deadly viruses, COVID-19 has dominated the headlines for much of the past two and a half years. Now that the number of COVID infections worldwide has slowed and vaccines and treatments have vastly reduced the number of COVID deaths, an old and familiar bacteria is once again the number one infectious cause of death. On this episode of TGen Talks, we talk tuberculosis and we find out why this disease has been so prevalent and so deadly for so long. We're here at TGen North again for this episode of TGen Talks and our guest today is Megan Folkerts. Megan, nice to meet you. Can you tell me a little bit about yourself and how you came to at TGen?

Megan Folkerts [00:00:48] Yeah. So my name is Megan Folkerts. I'm a microbial geneticist, and my research has primarily focused on trying to understand the mechanisms by which bacteria do the things they do to try to understand how that influences health and disease states when a bacteria infects a human being. And so I came to TGen because I was very interested in some of the infectious disease work that we have going on here. I originally started in the microbiome core and then transitioned to TB research where I've been very interested in learning more about antibiotic resistance and TB. 

Karie Dozer [00:01:21] TB is tuberculosis, and I think most of our listeners probably are shrugging a little bit and saying, What's the big deal about TB? What is the big deal about TB? 

Megan Folkerts [00:01:30] So living here in the United States, you have probably not encountered TB, so you probably are wondering what the big deal is. Well, here's what the big deal is. So in the developing world, TB affects approximately a third to a quarter of the total world's population. So we're talking 2 billion people are currently infected with latent tuberculosis, and annually we have about 10 million new infections with this disease and it causes approximately 1.5 million deaths. So while you don't hear about it in the United States, in other parts of the world, this is actually the number one killer by a pathogen, except in the past few years, COVID has taken that title. But prior to COVID and now in 2022 and going into 2023, this is the leading cause of death by a pathogen. And so it’s a huge deal that we're studying this particular organism.

Karie Dozer [00:02:18] Why don't we see it as much in the United States?

Megan Folkerts [00:02:21] So tuberculosis is endemic in regions of the world where there are high rates of poverty and people are living, you know, in substandard living conditions, a lot of crowding. We're very fortunate in the United States that we generally don't experience this. And so we have a much lower prevalence of this disease.

Karie Dozer [00:02:39] But we obviously still see. TB Where in the United States do we see it?

Megan Folkerts [00:02:43] So oftentimes when we see TB, it's people that have traveled. So people that have gone to these regions where TB is endemic, we also will occasionally have outbreaks in institutions and jails and things like that where people are being housed close together.

Karie Dozer [00:02:59] And is that why it's so important? Is that your why so that we can help to treat TB where we see it? Or is this more about a global solution?

Megan Folkerts [00:03:08] I view it as a global solution. You know, the number of people in the world that this impacts, you know, this is a huge deal.

Karie Dozer [00:03:15] What's the focus of your research? What is it that you are looking into at TGen? And if there's a question that you are seeking to answer, what would it be?

Megan Folkerts [00:03:24] So the focus of our research is looking at trying to better diagnose and treat antibiotic-resistant infections in tuberculosis. So antibiotic-resistant infections in Turkey is like most bacteria is on the rise and it presents a huge problem for treatment. First of all, you know, talking about these areas where TB is endemic, even just getting access to a correct diagnosis that says these people do in fact have a resistant infection is sometimes difficult. And so some of our work is focused on trying to design better diagnostics that will allow patients or allow clinicians to apply these diagnostics to patients and know right in that moment what antibiotics to give to a patient. We're also interested in learning more about how antibiotic resistance actually progresses, because for some of our newer line TB treatments, you know, the full spectrum of what causes antibiotic resistance still isn't known. And so if we can model that here at T gen, it can give us better insight into how not only to prevent or to reduce the likelihood of antibiotic resistance but to how better to treat antibiotic-resistant infections when they arise.

Karie Dozer [00:04:31] I guess my next question is how do you research TB if there isn't any TB around to research? Not that many people in the United States suffer from it. So how do you conduct that research?

Megan Folkerts [00:04:42] So we have collaborations with universities in areas where TB is endemic. So South Africa, Moldova, Malawi, places in the Philippines. We collaborate with both medical doctors and researchers there that are actually seeing high volume TB patients. And so those samples actually come. From those regions straight here to see, Jan.

Karie Dozer [00:05:04] Are the samples of TB that you received from these far-flung places. Are they the same? Do they look the same? Do they behave the same as TB you might find in, say, a prison setting or someplace in the United States where you find cases of TB? 

Megan Folkerts [00:05:20] I would say that it's not one of the issues you have in these places where the endemic is. People often have higher levels of co-morbidities, so different diseases on top of tuberculosis that make the tuberculosis even more dangerous. And, you know, tuberculosis has been around for millennia infecting people, you know, for thousands of years. And so there are what we call different lineages of tuberculosis, so that the genome is actually different. And so these samples that are coming from regions where TB's endemic, I would say that they're not going to be quite the same as the sample you would receive in the United States.

Karie Dozer [00:05:54] You mentioned how long tuberculosis has been around. What is the first recorded case of it, if I can call it a case? And what was it called?

Megan Folkerts [00:06:03] I don't know that I know what it's called, but we found it in Egyptian mummies. So we're talking several thousand years that we know of that this has been infecting humans.

Karie Dozer [00:06:12] Does that mean it's a strong bacteria, a stubborn bacteria? It by itself is a tough guy.

Megan Folkerts [00:06:18] Extremely so. So if you I don't know if you know how much about how TB actually infects the human being, but you have an immune system in which your immune system normally does is if a bacteria inhabits you, you have immune cells that actually attack those bacteria. Well, in the case of tuberculosis, it's evolved to live inside those immune cells. And so when your immune cells actually attack tuberculosis, tuberculosis just inhabits those cells and thrives. And it makes it nearly impossible for your body to clear the infection once it's started. And that's why 2 billion people are currently infected with latent tuberculosis.

Karie Dozer [00:06:52] Latent means it's not showing up. You don't have any symptoms, but it's there, and it can recur at any time, at.

Megan Folkerts [00:06:58] Absolutely any time. If that person's immune system weakens in any way, they'll stop you being able to contain it within these immune cells. And it will it will become an active case and that person will actually have symptoms.

Karie Dozer [00:07:09] When we first met, you said to how excited you were to be here. You're super excited to be at ten because of the technology and the team. Tell me about the new technology that is in your lab and how you use it to research TB. 

Megan Folkerts [00:07:20] Yeah, so there's a couple of types of really interesting technology that we use. One type of technology that we have, it's been around for several years now. We call it single molecule overlapping reed technology. Now that's really complicated.

Karie Dozer [00:07:33] It's terribly complex, but I'm here to try to help you help me understand.

Megan Folkerts [00:07:37] So what this means is without getting into too much of the technical details of it is it's a type of sequencing technology that allows us to detect drug-resistant mutations when they occur at very, very, very low levels in a patient. And so why that's important is because if you can detect drug-resistant resistance in a patient, as soon as it arises, you can change that patient's treatment immediately and make sure that they're always getting the correct the correct antibiotic. And so that technology is something that we're trying to develop to go from this setting heritage on to something that it could actually be delivered to the patient's bedside so that a clinician can use it to detect drug resistance right when it arises.

Karie Dozer [00:08:17] What is the BSL three lab? What does that mean?

Megan Folkerts [00:08:20] So BSL three stands for biosafety level three. So there are four biosafety levels of organisms and they increase in complexity as you go up. And so biosafety level one refers to organisms that really aren't capable of causing disease. Biosafety level four refers to organisms that cause disease that for which there's often not a vaccine and for which they're usually highly lethal. So we are just one level down below that with a biosafety level three facility. And what this facility is, is it's an enclosed room that contains multiple barriers in place so that a researcher can safely work with the tuberculosis itself without being at risk of actually being infected by the organism.

Karie Dozer [00:09:00] What does that look like?

Megan Folkerts [00:09:01] So our BSL three is quite small and it's not uncommon for these rooms to be small because of the nature of the work that happens there. So you're talking like a ten by ten-foot room and that room is a room that has a high level of gas exchange and is always under negative pressure. So if something were to happen in that room, air is flowing into the room rather than out, and it keeps the rest of the building safe within that room. To even go into that room, you need a significant amount of safety gear on. So I will have a personal air-powered respirator on that keeps me from being able to inhale anything that might happen in that room. And that's HEPA filter.

Karie Dozer [00:09:39] Wow.

Megan Folkerts [00:09:39] The room itself contains what's called a biosafety cabinet. So this if you've ever seen a fume hood. Uh huh, familiar? Yeah. Looks like a big fume hood, but it's got a duct that goes to the outside. It's also HEPA filtered and there's air exchanging in that cabinet and rapid rate. And so we work in with the TB actually inside of that cabinet. So when you think about all of this, there's really three barriers in place. There's the room itself. There's this biosafety cabinet and then there's the purifying air helmet that you're wearing. And all of that is just designed to keep you from ever, ever coming into contact with the TB.

Karie Dozer [00:10:12] There's a huge difference between the way you do your research and the way you regard tuberculosis and the way that most Americans probably think of the disease. Yeah, I guess that should be warning enough that it is serious. The way you guys treat it is the way we should.

Megan Folkerts [00:10:28] Absolutely. Absolutely.

Karie Dozer [00:10:30] If your research has an end of the road, a final question, or if there's a final finish line in mind, what is it?

Megan Folkerts [00:10:39] You know, I think there's to finish line one line in mind. So one is diagnostics. Right now, the access to diagnostics in some of these countries is really poor. And it means that patients don't get the correct antibiotics initially because they just don't have access to something that can tell them what the resistant profile is. If we're successful in our research, what that means is that these rapid-fire diagnostics that we're building would be right at a patient's bedside and could be applied multiple times throughout treatment to ensure that as that patient is receiving treatment, that it's always the exact correct antibiotics that are needed. So that's one endpoint. The other endpoint is, you know, I think in order for that to ever happen, we have to completely and totally understand how antibiotic resistance is even happening. And that's really what we're trying to do in our biosafety level three facility with our in vitro modeling is actually working with the organism and understanding, you know, how do these changes in the genome confer antibiotic resistance? Because all of that is different pieces of the same puzzle. And all of those puzzle pieces have to be in place for us to be successful.

Karie Dozer [00:11:46] Compared to these other bacterial infections. How much do we know about tuberculosis? 

Megan Folkerts [00:11:52] I would say that we know quite a lot. So we've been treating tuberculosis for quite a long period of time, and some of our treatment regimens have been in place for, you know, 70 or 80 years, something along that lines. But there's still a lot of questions we don't know, you know, and as antibiotic resistance progresses, then it forces us to find new treatments. And every time we alter a treatment regimen, you know, now we're back to the drawing board. We have to relearn all of these different mechanisms and try to try to understand how these mechanisms contribute to antibiotic resistance every time are presented with this new challenge.

Karie Dozer [00:12:26] Not only tough, but tricky, a tricky, tough bacteria.

Megan Folkerts [00:12:29] Extremely so.

Karie Dozer [00:12:30] In the course of your research, how often do you publish a paper or otherwise release findings that you've made here at TJ in and contribute that knowledge to the general public?

Megan Folkerts [00:12:41] Very regularly. Very regularly. So I've been with the TB core for about two years. And in that time we've published a couple of papers and have a few more manuscripts in preparation. But prior to my joining the TB Court, you know, we were talking several publications a year and that's fairly, fairly good actually for scientific research. And so and a lot of that is fueled by the number of collaborations we have that really allows us to get our research out there as much as possible.

Karie Dozer [00:13:07] When we initially met, you talked about how excited you were to be here at TGen and you've been here a little over two years. Why were you so excited to come here?

Megan Folkerts [00:13:16] You know, I'm just I'm really excited about the work at TGen. and I'm really excited to be doing something that has an impact on so many people. You know, I've studied a lot of different mechanisms and bacteria. This is this is by far the one that has the highest potential implications. And so it's really exciting for me to get to take, you know, all of this knowledge that I've built over the years and then apply it to this this huge global problem.

Karie Dozer [00:13:40] I wish you luck. I hope you find great things. Meghan Folkerts, thanks so much for your time. I appreciate it. 

Megan Folkerts [00:13:44] Thank you so much. It's been great.

Karie Dozer [00:13:46] For more on TGen’s research, go to TGen.org/news. The Translational Genomics Research Institute, part of City of Hope, is an Arizona-based nonprofit medical research institution dedicated to conducting groundbreaking research with life-changing results. You can find more of these podcasts at TGen.org/tgentalks, Apple and Spotify, and most podcast platforms. For TGen Talks, I'm Karie Dozer.