This episode of Meet the Microbiologist is featured in the Spring 2026 issue of Microcosm.

Episode Summary

Glen McGugan, Ph.D., Director of ASM’s Mechanism Discovery Unit, discusses how curiosity‑driven research—from parasite virulence to CRISPR and complex microbial systems—drives tomorrow’s breakthroughs.

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Highlights:

  

Ashley's Biggest Takeaways:

• Mechanism discovery encompasses foundational research that explains how microbes grow, adapt, communicate, cause disease and even promote health—spanning physiology, genetics, biochemistry and cell biology.
• Basic research is the real R&D pipeline.
• Today’s “impractical” curiosity‑driven questions often become tomorrow’s transformative tools and therapies, even when no application is visible at the start.
• Developing therapeutics for parasitic diseases is particularly challenging due to complex life cycles and limited financial incentives for pharmaceutical companies; much of the progress relies on government and philanthropic funding.
• From Entamoeba histolytica’s odd organelles to Leishmania thriving in lysosomes and toxoplasma’s cat‑restricted sexual cycle, parasitic microbes challenge textbook paradigms and expose unexpected targets for intervention.
• Drawing on nearly 2 decades as an NIH Program Officer, McGugan describes how review and priority setting favor well‑developed, lower‑risk projects—often squeezing out bold, early‑stage mechanisms work that could be game‑changing.
• ASM's Mechanism Discovery Unit serves as a neutral hub to convene interdisciplinary stakeholders to identify gaps, seed new research areas and advocate for the next generation of curiosity‑driven microbial science.
• Safeguarding future scientific breakthroughs depends on the involvement of and connections between researchers, policymakers, funders and industry partners to close gaps between discovery, implementation and impact.

Featured Quotes

What is Mechanism Discovery and How Does it Underpin Everything?

Mechanism discovery really encompasses all foundational, basic research across the microbial sciences. It's really aimed at understanding the how and the why of microbial life. So, another way to put it would be the basic science that reveals processes that allow microbes to do everything—to allow them to grow, to survive, to adapt, to communicate, to form communities and, under certain conditions, allow them to cause disease or even promote health.

Understanding those things is really what we mean by mechanism discovery. If you had to try to pin it to a few subdiscipline areas, these would include microbial physiology or genetics, biochemistry, microbial interaction, cell biology. That's what I mean by underpins everything. 

I would have [listeners] think about a major advance that they use in their own lab or that they appreciate now, and I would remind them that all of those major advances started from someone asking a really fundamental question that, at the time, probably seemed completely impractical. What I mean by that is they didn't have some practical application they were thinking of. A good example that a lot of people point to is scientists looking at these really interesting repeating patterns in the DNA of bacteria that we now call CRISPR. At the time, they weren't setting out to be able to cure genetic disorders or to create something that we could use to edit genomes, right? They were just really curious and interested as to why the patterns were there.

I think a really uncomfortable truth is that we are astonishingly terrible at predicting the most transformative technologies in modern biology. And for that reason, mechanism discovery is not, or at least it should not be, a luxury. It's the R&D pipeline for everything that we will call practical 20 years from now, 50 years from now, and a fundamental thing that we should invest in now.

How Did You Become Interested in Microbiology?

I trained in a very typical cell biology lab, so it wasn't really a classical microbiology lab. And in that particular lab we just happened to be working on a human pathogen that happened to be a eukaryotic microbe. And we were asking some really fundamental questions about this eukaryotic pathogen. If you remember going back to your very first microbiology course—or your general biology course—you kind of learn these are the organelles. Everybody learns, this is the mitochondria, this is the powerhouse of the cell, and here's the ER and the Golgi—and you learn how these cells are supposed to do things. And then I went to graduate school, and I started working on this really early, branching eukaryote; everything I learned about how things are supposed to work, I found out that they work differently, in this particular organism.

I remember one of the first things that we did early on was some sequencing work, as many people do. And I remember seeing—I don't remember exactly the number—but it was like, why are there 7 copies of this gene, for example? And then when I would do microscopy, it was like, where's the mitochondria? Where are the ER, where's the Golgi? It's really strange, when you look under the microscope, it was just chock full of these vesicles. And so, the question is, how does this organism survive? How does it do what it does? How does it cause disease in humans? And I think that's what the hook for me was—just curiosity as to how these organisms are able to do what they do in their environment.

The beauty of parasitism is that these things have evolved alongside us, and I think that's why they've evolved these mechanisms of doing some really strange things.

If you want to go back even farther than that, my parents often tell me that when I was a kid, I would ask these really crazy questions, wanting to know how things worked. And when I was given a toy, I would try to pull it apart and see how it works. And that's really what mechanism discovery is—just in a laboratory. You want to pull things apart, and you want to see how they work and understand them, and then once you understand them, you can apply that to other things.

Studying Intracellular Parasites at the NIAID Laboratory of Parasitic Diseases

When I was a postdoc at the NIH I was in the lab of parasitic diseases, and we studied parasites, again—all sorts of parasites. I did a little bit of entamoeba work there, and I also did some leishmania work—these are more the intracellular type of parasites. And what's interesting about them is, our immune system usually gobbles up these bad things and destroys them in lysosomes and things like that. But there are organisms, like some of these parasites, that are perfectly happy in these lysosomes, like, ‘Oh, this is great hanging out—spa time for me.’ [We were] trying to understand how they're able to survive under these conditions, and we were a typical biochemistry lab. We were looking at the release of enzymes from this organism and how that contributed to its ability to cause disease in humans. And so, there's still tons of unanswered questions about how that contributes to the pathogenicity, and also about how you can exploit it for novel treatments for these particular pathogens.

Developing Antiparasitic Therapeutics

I think first and foremost, it's complicated, because these types of diseases often affect the poorest people on the planet. And there is not the financial incentive for pharmaceutical companies to really invest in this space as heavily as some others, and rightly so, because they are responsible for making money for their shareholders. So, the lion's share of the investment in these spaces is really through government agencies or philanthropic organizations. And what you find is that advances sometimes lag behind that of other diseases.

There's been phenomenal advances in some of these diseases over time, but I think the other [challenge] is the complexity of the organisms that I keep driving home. These organisms cycle between various life cycle stages. They've evolved along with humans, and they are extremely crafty at evading the human immune system because of that. All of these things make it really challenging to be able to design therapeutics that are novel, that will target them.

Then if you move on to some neglected tropical diseases—schistosomiasis, for example, is not only a eukaryote, but it is also a multicellular eukaryote. You have organs and organ systems. You have male and female worms. The female can produce eggs. You’re getting more and more complex, and when you try to design drugs or therapeutics for these, you'll often have off target effects because [the parasites are] similar to the host in that way.

What Did You Find Rewarding About Being a Program Officer at the NIH?

It's a big change, because you're no longer directing your own research program. Now you're focused on pushing the science forward in a particular area. I absolutely loved being a program officer at the NIH, and I have so much respect for the people who are still program officers there. I know the valuable things that they do on a daily basis for the research community. It was so rewarding to be able to see a graduate student or a postdoctoral fellow and then encourage them into applying for their first training award, for example, and then their first R01, and then, 10 years later, you're at a meeting, and you're meeting their graduate students and their post-doctoral fellows. You're seeing investigators that discuss their project with you, and then they get this huge publication; they get these awards, and you're able to celebrate with them, and you feel that, at least in some part, you had a hand in that. So, you're not at the bench, but it's extremely rewarding to see the science move forward and to think that you were able to play a role in that.

So, I think, for me, the most rewarding part was just to see the science move forward, published and see this transition, like the grandchildren of the people you know who are in your portfolio.

Major Breakthroughs Start With Basic Research

Some things that I learned throughout my career, both at the NIH and even before that, is that things like drug advances didn't usually, or always, start with a drug development project. They started with people asking basic questions about how does this microbial metabolism work, or what does the strange enzyme do, or why is this strange organelle here, like in the case of the parasites we were talking about. And it's not until much later that the researchers then develop drugs targeting some of those processes in the cell.

One example that I think is really intriguing is toxoplasma. It's also eukaryote, a single celled organism, and in the lab, it can infect most nucleated cells. And it has a form that is actively dividing; it has a form that forms a cyst. Lots of cool work has been done over the years attempting to understand that transition between those different stages in the host. But what's interesting is that it seems to only complete its sexual cycle in the cat. No one knew exactly why. So if you were a researcher, and you wanted to study the sexual stage, like at the NIH, then people would have to be able to pass them through cats at some point. You know, it's a little bit technically challenging. 

So, it turns out that cat intestines provide a unique metabolic environment due to how cats use linoleic acid. The way that they use it is different from the way humans use it in their gut, and that provides a cue to the parasite. 'Oh, I'm in the right place, and now I can go to the sexual cycle.' And so using that information, you could imagine that if you could block it, keep them from forming the oocytes, then you can block the life cycle stage and prevent transmission and things like that. But that, you know, it's just understanding. It's curiosity driven, trying to understand how things work around you. And it's just fascinating, even if there is no practical implication, right? It's just fascinating because you don't know, going back to your question, where those advances might come from. I like knowing everything as much as I can. I'm eternally curious about stuff.

What Brought You to ASM?

I was really wanting to see what I could do outside of the federal government for a while—to kind of push these fields forward in the areas. Because there are constraints whenever you're in the federal government, whenever you would bring people together to identify these gaps and opportunities. But in this role [as ASM Mechanism Discovery Unit Director], it really is purely just about the science, about being an advocate for the science, about serving as a hub for bringing these researchers together with a goal of really advancing this fundamental curiosity-driven discovery. And I appreciated the way that ASM was thinking about that, about forming the scientific units about pushing the science forward in these areas, but in a different way.

ASM Mechanism Discovery Unit

The unit will serve as a hub, bringing together stakeholders from across the microbial sciences, with the goal, as I mentioned, of advancing fundamental curiosity-driven discovery. And the reason for that is the transformative advances that we celebrate now all started with someone asking those kind of questions—how and why these particular things work. Discovery really underpins everything. So understanding how things work at the molecular level to the systems level will hopefully open new research avenues and the transformative advances that we can't even imagine right now. And I know that's very lofty, but it is something that I truly believe. If we can bring these people together in the right way, then we can push the science forward in these areas—at least that's my hope.

I think the biggest challenge is time because with basic science there is no time scale, and I think that's the challenge that we face. So, there is no product that we have in mind that we're going toward. It really is just about this open-ended, curiosity-driven discovery—this vast pipeline that will lead into these discoveries.

The beauty of this is that there is no preconceived agenda. It really is a space where we can bring these people together. And the goal here is purely the science we really want to get at—where these transformative advances may be—and then use the power of ASM to be able to forge the types of connections to make those things a reality—to translate them into something that's actionable. Part of that we are learning as we go along—we'll see what other partners we need to bring in.

The other beauty that I envision for this particular unit is, in my past, I've seen some of the most transformational advances come at the intersection of disciplines, and the microbial sciences now is vast. We've come such a long way from looking at animalcules, as described by van Leeuwenhoek in his microscope, to now the tools that we have available to really ask some of these incredible questions. And that's because of the connections between these other disciplines—mathematics and chemistry and physics and material science and all of that enable us to have the tools to be able to ask some of these questions. So that's my vision, to be able to bring these communities together and ask some of these really big questions. How can we find the tools? How can we find the resources? What is needed to be able to move us forward in those particular areas?

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