13
Mar2017

The first of three distinguished speakers at PRIM&R's 2017 IACUC Conference is Craig L. Franklin, DVM, PhD, DACLAM, professor of veterinary pathobiology at the University of Missouri.

In addition to his professorship, Dr. Franklin directs the Mutant Mouse Resource and Research Center, a National Institutes of Health-funded repository of genetically engineered mutant mice; the Comparative Medicine Program, a post-DVM laboratory animal medicine residency and advanced degree program; and the Veterinary Research Scholars Program, a summer research program for veterinary students. He is also an associate director of the University of Missouri Metagenomics Laboratory and is a co-investigator for the Rat Resource and Research Center.

We spoke with Dr. Franklin about his background and field of study and how they relate to research ethics. The interview has been lightly edited for clarity.

PRIM&R: How did you develop an interest in your current research area of microbiota?
Craig Franklin (CF)
: We’re interested in how the complex communities of bacteria that live in and on our body impact health and disease, and as a lab animal vet who spent 25 years in diagnostics, I’ve always been interested in how those might modulate some of our phenotypes of the models we used. I also developed an interest in intestinal diseases along the way, and as the tools became more and more available to characterize these complex communities, we really had always been interested in how the gut microbiota might be influencing models; so once the tools became available we started to run with it. So it’s really been a combination of my lab animal background, my interest in intestinal diseases, my interest in microbes, my interest in the immune system, all came together to large overarching questions, namely: how are these communities, especially the ones that live in our intestinal tract, potentially modulating our animal models? And how is that impacting the reproducibility of those models? Because we know that there are issues with reproducibility of animal models; we try to control everything we can, but one of the variables we’ve been unable to really control and characterize has been the microbiota. We’re now able to do so, so we’re now trying to think about new paradigms that can really help animal modeling in general.

PRIM&R: Can you talk about the tools and the evolution of the tools making your work easier?
CF: Historically, if we wanted to identify specific bacteria, we had to try and culture them and we knew that there were a lot of microbes, especially living in our intestinal tract (where there is an anaerobic environment) and we knew we couldn’t grow a lot of them. In fact, a vast majority of them we still can’t grow. But along came sequencing tools. They’ve been around for a while but now they are more affordable. At the same time, databases began to grow; they are still very deficient in many ways but they’re to the point where we can use sequencing tools as an affordable means to characterize the intestinal microbiota. There are a number of ways we can do that–very expensive ways still, but we can at least have starting points with some of the sequencing tools.

There’s still a lot to do, because we’re not necessarily considering viruses, protozoa, parasites; those aren’t present in most of our lab mice, but whether or not they should be is another question–that’s also kind of an interesting ongoing paradigm that is emerging. Should we be looking at things like wild mice and pet store mice and things of that sort that really are more similar to people in that they do get viral diseases? We’ve simplified our mouse models over the years and that’s been a good thing and it’s been intentional, but it also may be detrimental to the translatability and reproducibility of our models.

PRIM&R: How would you explain your area of study to someone unfamiliar with it?
CF: I always ask people what they know about bacteria. Most people think about bacteria in a detrimental way—the diseases we can get from bacteria, such as salmonella or the plague. But I remind them that there are a lot of bacteria that live in and on us and they’re actually good for us. They help us in digesting our food; they help us in combatting some of those bad bacteria; they help our immune systems develop. We’re also beginning to understand that even those populations that we consider part of a healthy human or animal may also have subtle influences on diseases that we never thought they did. Those aren’t just intestinal diseases—we’re now beginning to understand and identify the fact that different populations of these bacteria can influence our behavior, and that’s kind of a far-out concept! So the way we try and couch this sometimes is that we have thousands of genes—and people are familiar with how those genetic changes can alter our health—but we have ten times as many bacterial genes. We really are a superorganism, and that includes our genes as well as the genes of the microorganisms that we live with. They are also influencing our health and our disease and were really only scratching the surface of understanding how that happens.

PRIM&R: What do you hope the audience will take away from your talk at the 2017 IACUC Conference?
CF: There are several things that might be takeaway points. We’re basically trying to remind people to consider these complex communities as variables and as components of the [animal] model, and also encourage people to not be afraid to characterize these things. We can start to ask questions about them and we can embrace the complexity that they have. It’s a very daunting thing to think about the complexity of this world we’re jumping into, but if we embrace it there are probably little diamonds in the rough in doing so. We have, for example, models that aren’t reproducing very well and we’ve identified that that’s associated with different microbial communities: that’s a good thing. We have to figure out why and how that’s happening, and I think it’s going to improve the reproducibility and translatability of our models.

Generalist scientific approaches are very reductionist and that’s great, but this is a more holistic view, and those two really complement each other. They don’t have to be opposing factors, because through holistic approaches we can identify bacteria and then we can go in and ask with a more classical reductionist approach: what role are they playing?

There’s also been a resurgence of gnotobiology to create mice that have a very simplified microbiota. We produce them in a germ-free state and then we might inoculate them with a very simple microbiota. And it tells us a lot, but it’s not what people have. And I don’t want to say not to do gnotobiology, but we need to recognize the caveats of that and couple it with trying to do more complex microbiota studies.

The title of the talk includes reproducibility and translatability, and again we like to encourage people to embrace their complexity. And then from a regulatory standpoint for an animal welfare standpoint, we can better define what the role is of these complex communities, and we can make our models more reproducible, and we could actually probably reduce our animal numbers. Because we now have this as a variable, we are controlling and modifying some study designs if we identify some factors that modulate the microbiota. We can even potentially develop new biomarkers for endpoints of disease, so there are lots of things that we can exploit by better understanding these microbial communities.

PRIM&R thanks Dr. Franklin for sharing these thoughts with our community and for his contribution to the conversation at IACUC17.

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