Microbes: the great interconnectors of all life on Earth

Penn State undergraduate Tom Sontag interviews professor Seth Bordenstein  about his pioneering research in the burgeoning field of microbiomes

Thomas Sontag
Undergraduate student at Penn State double majoring in Microbiology and German

Seth Bordenstein
Professor of Biology and Entomology, Huck Chair in Microbiome Sciences, and director of the One Health Microbiome Center at Penn State

Transcript

 [THEME MUSIC]

Mark Shriver: 

From Penn State’s Center for Human Evolution and Diversity, this is Tracking Traits

 [MUSIC FADES]

Cole Hons:

Greetings fellow homo sapiens, this is Cole Hons from The Huck Institutes of the Life Sciences. Welcome to season three of the podcast. 

This time around, we bring you seven more conversations featuring Penn State undergrads interviewing researchers here at the university who do truly innovative work centered on questions about our own species. How have we evolved over time? How are we continuing to evolve? And what are some of the mechanisms behind the incredible diversity that we collectively express as human beings here on Earth?

For this first episode of the new season, Brazilian-born Biology student Thomas Sontag interviews Seth Bordenstein, professor of Biology and Entomology, Huck Chair in Microbiome Sciences, and director of the One Health Microbiome Center at Penn State.

Bordenstein’s long-term devotion to the topic of microbiomes has earned him a stellar reputation in the field, on an international level. As he expresses in this interview, science has only begun to scratch the surface of what remains to be discovered about why and how microbial life forms living in humans, animals, and the surrounding environment interact and relate to one another. The potential implications for our health and quality of life are vast, and Bordenstein’s pioneering research and infectious passion for the material really come through in his conversation with Tom. 

Here's Tom Sontag interviewing Seth Bordenstein about “Microbes: the great interconnectors of all life on Earth.”

[MUSICAL INTERLUDE]

Tom Sontag:

Thank you so much for joining me today. To get us started, do you think we could hear an overview of your research?

Seth:

Yeah, it's wonderful to be here. Thanks for hosting this chat series. I am very interested in animal microbe interactions because microbes form the base of the biosphere, and there's no animal that is sterile on this planet that doesn't have microorganisms in it.

This is a realization that we've really appreciated only in the last couple of decades, and I think it does two things. It reminds us that there are threats from the microbial world that can cause harm and pathogenesis, but it also reminds us that there are many types of harmless or helpful microbes, even more so than bad microbes, that sometimes we require or animals require. And so we're very interested in understanding the major rules, principles, and applications of animal microbe symbiosis.

Now, our lab can be divided into, I'd say, three buckets, three thematic buckets of interest. The first is, what is the most widespread animal microbe symbiosis, and how can we leverage it for doing good in humans? And that turns out to be about a story about a single bacteria called Wolbachia that occurs in half of the world's arthropod species. So it's estimated it occurs in millions of animal species. And I think we'll talk a lot more about that today, Tom.

The second and third questions are interrelated, and they have to do more with, what are the general rules and trends about microbiome variation, the microbial communities that live in and on host? What are the rules of microbiome variation within a host species? And there, we focus on humans because there's publicly available data and, of course, medical relevance to those studies.

And the third related question to the set of buckets, thematic buckets of our research is, what are the rules of microbiome variation between host species that are related? So let's say humans and our primary relatives or close relatives of plants or close relatives of mosquitoes, will we expect to find any textbook-like patterns that could also be used to understand the evolution of those animal species?

Tom Sontag:

As a microbiologist student, this all fascinates me. How exactly is the human microbiome connected to our evolution?

Seth:

Yeah, that's actually a very big active question right now. It's clear that the microbiome of humans has changed from our closest relatives. And so if you look at the diversity of microbes that occur inside our gut microbiome, where most of the microbes tend to colonize, versus the guts of our closest relatives, especially in Westernized countries, our microbiome diversity, that is the number of species that exist there, has declined markedly and significantly. 

And what that means is there are a whole suite of factors that make us human that are probably driving some of these reductions in diversity relative to our closest ancestors. You might first think about dietary changes, shifting microbes that colonize our gut, but it also could be related to our overuse of medications, our overuse of hygiene practices that are reducing our exposure to microbes.

The consequences of that are equally interesting. “Should we have more microbes in us?” is an enduring question. Do we have missing microbes that need to be there that might explain some of the rise of chronic illnesses in Westernized countries? 

So yes, there have been evolutionary link changes, and yes, these may be related to some very important and widespread medical issues.

Tom Sontag:

Would you say that only looking at what we traditionally consider human cells paints an incomplete picture of what makes up a human?

Seth:

Excellent question. And absolutely, yes. As I mentioned as we started, there is a microbiome revolution happening in the life sciences that some biologists argue this is one of the greatest shakeups in biology since Charles Darwin.

And that has to do with the realization that microbes are everywhere. There's no environment they don't exist in, whether it's biotic or abiotic, meaning whether it's a host or whether it's the environment. We used to think that microbes were relatively uncommon or rare in species. There might be a few microbes that colonize, and their importance wasn't really well established.

Only in the last two decades have we realized, including in our own bodies, half of our cells are microbial. So we are a walking ecosystem of animal life and microbial life. The consequences of that are just being realized. We're in the first decade or two of a century's worth of a paradigm shift in thinking about ourselves differently, that we're not just human, but we are human and microbial. And as a recent term that we like to use and others is called the holobiont, which reflects the whole set of organisms that comprise our bodies and other animals and plants.

Tom Sontag:

And going back to Wolbachia, do Wolbachia only infect insects, or do they also infect other arthropods?

Seth:

Okay, so let's tell the story of Wolbachia. So in 1924, this bacteria was identified by microscopy in the reproductive tissues of a few insect species, including mosquitoes. The individuals who discovered Wolbachia predicted it would be more common. They had sampled a few other insect species and also found it .

With DNA technology, over the last two decades, we've realized that Wolbachia are in half of the world's arthropod species, so that includes insects, but it also includes other types of arthropods, like spiders, mites, rollie pollies or pill bugs. Essentially, all the major orders of insects and many arthropods are colonized by this reproductive bacterial symbiont.

There's also another big part of the story, which is Wolbachia occur not just in arthropods but in the evolutionary relative to arthropods, the nematodes, and in particular, the filarial nematodes. And filarial nematodes are infectious. So they occur in canines, like our dogs and cats, and are famous for causing heartworm. They also occur in humans, where they can cause diseases like an eye blindness or a swelling of the inflammation system called elephantiasis. And Wolbachia is in those filarial nematodes as well. 

Tom Sontag:

Interesting. And from what I understand, Wolbachia can manipulate the sex of different animals. Can you go over that a little bit?

Seth:

Yes. And in particular, Wolbachia are very cunning bacteria that are master manipulators of arthropod sexual reproduction. They play all these wonderful shenanigans, and they do so first because Wolbachia are not transmitted from fathers and mothers. They're only transmitted from mothers to offspring. So they have no interest in helping out males and fathers. They have a very big interest in helping out the mothers who transmit the bacteria.

Now, if we think about this akin to what humans pass on maternally, we can recall that mitochondria and organelles are passed only from mother to offspring inside the eggs. Wolbachia are much like mitochondria in their transmission route. They are passed from the ovaries and the developing eggs to the developing offspring.

But Wolbachia are different than mitochondria. Mitochondria we consider helpful. Wolbachia we tend to consider harmful or parasitic. So they change the sex ratios, the sex determination systems, and the viability of embryos to make sure that Wolbachia-bearing or harboring mothers reproduce far more offspring than the mothers who lack Wolbachia.

And this, in turn, will give Wolbachia a major fitness propulsion and benefit to help spread it in the population against the uninfected individuals. And we can talk about the details of that if you'd like. They're very complex, but they're also very fascinating biological stories.

Tom Sontag:

And do you think this field of research, Wolbachia research specifically, can help the everyday man in any way?

Seth:

Yes. And that's a great connector to talking about what Wolbachia does and what are its applications. So Wolbachia does two very important things that scientists have discovered in the last decade or two.

One is that they can block the replication of pathogenic RNA viruses like Zika virus and dengue virus, and chikungunya virus inside mosquito vectors that, when they bite us, they can transmit these diseases to humans. They're widespread in tropical areas. They are major human health concerns. And there are many organizations, including the World Health Organization, that have control methods on their radar to reduce these kinds of mosquito-borne diseases.

Wolbachia naturally blocks their replication. So when a mosquito with Wolbachia bites us, they don't transmit the virus, or they don't do it as well. So that's a good thing. I have colleagues who are trying to figure out the mechanism of that, and they're making good progress.

The second major benefit is that Wolbachia can spread themselves essentially selfishly through host populations, including mosquitoes. And one of the ways they do that is through a sperm-egg incompatibility called, and this is a mouthful, cytoplasmic incompatibility.

Essentially, what happens is eggs with Wolbachia can develop fine if they're fertilized by sperm from males that had Wolbachia or from sperm from males that did not have Wolbachia. Those eggs are compatible with both types of sperm, but the uninfected eggs are only compatible and viable if they receive sperm from an uninfected male. An infected male cannot reproduce successfully with the eggs of an uninfected female.

So, in short, this mechanism provides a big fitness advantage to the infected females and their infected eggs that spreads Wolbachia rapidly through host populations. When that is coupled with this RNA virus-blocking capacity, it also results, then, in the spread of this RNA pathogen-blocking ability. And therefore, mosquito populations can be essentially transferred from ones that lack Wolbachia and transmit the viruses to ones that have Wolbachia and now can no longer transmit the viruses and diseases.

This is not science fiction. This has actually happened in over 10 countries across the world, and resultingly, they've seen declines in Zika and dengue virus incidences, up to 95% declines in those populations after the releases of the Wolbachia-infected mosquitoes. Just an extraordinary application of entomology, bacterial symbiosis having great good on human diseases.

Tom Sontag:

Amazing. And I heard you and your wife are involved in a very cool initiative that engages students starting at middle school in genetics research. Can you tell us about The Wolbachia Project?

Seth:

Indeed. So about 15 years ago, a group of us got together and decided that technology and concepts that are universal at the college level needed to move down a level in the education system to high schools and maybe intro-level college courses. This includes things like biotechnology, such as DNA extractions, amplification reactions that amplify DNA, visualizing DNA, and then sequencing DNA.

This is a technology that most, if not all, biological labs have the capacities to do, and we thought we should get it down to a next level, all while leveraging the Wolbachia system because, to students, a bacteria that does all these sexual shenanigans and modifies sperm and egg and reproduction is just brain candy for them. So we could couple the science teaching with the fascinating concepts and adaptations of Wolbachia.

My partner in life and science, Sarah Bordenstein, is now directing this project we call Discover the Microbes Within! The Wolbachia Project. And for anybody that has students or know schools that would like to get into the biotechnology and discovery-based areas, not just cookie-cutter labs, they can go to wolbachiaproject.org and find a whole set of free resources, where we offer five labs that take students in classrooms from discovery of arthropods to discovery of the DNA of Wolbachia to sequencing DNA, and ultimately, to publishing that with a DOI link for resumes to show the students' work.

We emphasize that this work is beautiful, that it's discovery-based, that they're doing the work and they have ownership of it, and that we might someday make more biological scientists or at least increase scientific literacy around biotechnology.

Tom Sontag:

And to our listeners who want to engage with this project, can you tell us how to write down Wolbachia?

Seth:

Great question. Yeah. So it's a mouthful. Wolbachia is spelled W-O-L-B-A-C-H-I-A. The bacteria was named after Dr. Wolbach, who discovered the bacteria in 1924. And I like to liken that name to Chewbacca, but it's the bacteria Chewbacca, which is now we call Wolbachia.

Tom Sontag:

All right. Man, I wish I had been involved in something like that before I rolled my college applications. Can you give us an idea of how large the scope of The Wolbachia Project is? How many people are involved?

Seth:

Yeah, thanks for that. Wolbachia Project has reached probably 60,000 students across the world. We are in over 14 countries. We're in almost all of the United States. And currently, we have seen great success stories. I'll give you one example.

High schools in New Jersey and in Israel have combined forces across international borders and seas to sample the same mosquitoes for Wolbachia infection frequencies. And then, they meet in a collaborative Zoom research experience and talk about which country and which school system found the greatest amount of Wolbachia in their mosquitoes.

We've seen students and teachers publish their work in the scientific literature, peer-reviewed scientific literature, and after 15 years, we're kind of surprised we're still here, but we're delighted to do so. We hope that this technology becomes so normal that we're not needed someday, and we've got a long way to go.

And there are many areas of the world that aren't as developed and need these kinds of resources. We have a free loaner equipment program, we have accessible scientists associated with the project, and we're committed to this kind of transformation in technology and education.

[MUSICAL INTERLUDE] 

Tom Sontag:

And does studying microbiomes have a lot of history, or is this a more or less budding field, something new?

Seth:

Yeah, I think most scholars in the life sciences will find there are dots that connect backwards into a single or a few individuals over the last hundred years. So there is history. There always is a connection because science is truly built on the shoulders of those that came before us.

 I'll give you one example of that. The mitochondria, that is a bacterial derived organelle that mothers pass on to their children, it was thought that that concept arose in the 1970s from a very famous biologist named Lynn Margulis. In fact, early ideas that she credited arose in the 1920s about the bacterial nature of mitochondria. So science is always an evolving landscape of pushes and ideas and then advances and then paradigms. 

The microbiome today, however, is experiencing, arguably, a paradigm shift. We are recognizing that microbes are universal in all environments, in all hosts. We're recognizing that their influences on adaptations on health and disease are so profound that their explanatory power is going to be massively important to explaining how life's diversity and how life's threats, and how life's health ultimately is understood.

I also can think that the industry, pharmaceutical industries that are interested in developing drugs or new treatments for chronic diseases will be looking heavily at the microbiome. It's estimated that it'll be about a 5-billion-dollar industry in the next five to 10 years.

And one quick example of that is there is an antibiotic-resistant gut bacteria named Clostridium difficile. And that difficile is pretty important because it is a difficult bug to cure because it's so antibiotic-resistant and can cause massive bleeding, diarrhea, and pain, and sometimes is life-threatening, especially in the elderly.

Well, what the microbiome revolution has showed us is that if we transplant a healthy microbiome from fecal material into individuals who are afflicted with this infection, we can change the flora of the microbiome, cause that C. difficile infection to go away with almost a 95% success rate. This is better than antibiotic treatment. And this is just scratching the surface of what microbiomes have done and will do for humanity and for our basic knowledge, as we've talked about with Wolbachia and other systems.

Tom Sontag:

And on the personal side of things, how did you end up researching this field?

Seth:

Yeah, good question. So much like many undergraduates who are searching for their love, their passion, their identity in colleges and universities. As a sophomore, I was majoring in the biological sciences. I was pre-medicine because I couldn't find exactly what I wanted to do, so my mom said, "Go be a doctor." And I said, "Okay, I'll go be a doctor, Mom." And I never quite liked the sight of blood and didn't really have the full vision of becoming a doctor.

I had a light bulb moment that I hope everybody has in college, which is I did take a course unexpectedly in evolutionary biology that blew my mind. And from that point on, I said, "What the heck can I do with this?" And found myself in a laboratory to do evolutionary research.

And from that moment on, I realized that I had a complete passion for being in the lab, for taking patients and taking meticulous plans and experiments to fruition to ultimately discover something new about the world.

It just so happened that that lab worked on Wolbachia. So my entire research career never left that first encounter behind. And I was lucky to have that experience. But I think the key is that as long as we search for it, as long as we keep an open mind, we can truly be happy in the long run because my father also always told me, "Just do what you love." So I found the thing that I loved, and I hope that college opens the doors for all of us to do that.

To this day, I'm so glad I ended up there. The symbiosis field has exploded. The microbiome field has exploded, and I've been able to watch one of those rare moments where a basic science question about Wolbachia bacteria and their commonality in insects and their effects on arthropods transitioned in front of our eyes, and I've been able to contribute to some of the research to human applications to control these diseases. 

So you never know where your passion might take you and what impacts it might have, but finding the passion is the key to riding the wave of the rest of a career's worth of happiness.

Tom Sontag:

Have you ever looked at your own microbiome?

Seth Bordenstein:

Yes. And it is possible for all of us to look at our own microbiome. There are crowdsource funding campaigns and industry and companies that solicit microbiomes for sampling.

One of the crowdfunding campaigns is called The American Gut Project. And so, for about 99 bucks, you can submit a sample of stool or of saliva, your skin, and send that over so they can profile a microbiome.

What you can find are, how diverse is your microbiome relative to the global population? What are the dominant microbes in your gut versus other people's guts? Are you sort of in the range of normal or maybe outside the range of normal?

I think everybody wants to have a little bit more information at this point about maybe understanding, should they be taking probiotics? Does their microbiome profile reflect an early-disease state? And while these are definitely areas of investigation, I think the general crowdsource funding campaigns companies will not be providing that information. You may have to research that on your own. And I would advise that any kind of medical issue be consulted through a doctor, a dietician, et cetera, or a scientist.

I think that the microbiome revolution is coming, and no matter which direction we look at it from, there will be a period of time when it becomes very normal to do a microbiome sample out of the doctor's office to link that with a human genotype of your genotype and to get the full genetic or genomic or what we'll call the hologenomic profile of your body. And therefore, the elements that make you sick or that keep you healthy will be resolved through a whole system set of DNA sequencing.

Tom Sontag:

Is there any one thing you'd really like the wider public to know about the human microbiome?

Seth Bordenstein:

Yeah, I think there are many things. It's really hard to boil that question down because the topic is entirely universal to our health, our disease status, our biology.

But maybe the thing to think about is our decisions and our lived experiences matter to shaping the microbiome. If you take lots of antibiotics, you might be depleting your microbiome successively, and that depletion might have risk to developing chronic illnesses like allergies and diseases.

If we eat certain types of diets, like a carnivore western diet versus a highly vegetable diet, that has consequences on the diversity of our microbiome and maybe the health of our system. It's generally believed that the more diverse our microbiome, the better. And therefore, some, including myself, were inclined to go on a vegetable or vegan diet. How much we play in the sandboxes and how much we play in the dirt, how much medication we take overall, how much sanitary consideration and hygiene do we use will affect the way we shape ourselves.

And so our microbiomes are windows into our lived world much more so than our genes, and our microbiomes are there as half of our cells. So it's good to be conscious, it's good to be scientifically literate, and it's good to be just thinking about that as we make our decisions about eating, exercising, stress, giving birth, and how our microbes pass on to the next generation. All of this sort of comes into play. So I encourage everyone to think a little bit more about the microbiome, how we live our lives and engage in science to make their best decisions.

 Tom Sontag:

This reminds me of another episode on our podcast where we talked with Dr. Bronwyn Powell about how different people have different food tastes. Do you think this could have any connection to the human microbiome?

Seth Bordenstein:

So this is a very speculative area that's just starting to be scratched by scientists. I think the principle is diet can affect microbiome composition, the types of microbes that are there. What about the reverse question? Can the microbes affect our dietary preferences?

And here's the speculative link that scientists are now considering. If diet enriches for certain microbes, so if you eat more vegetables, you may enrich your body for microbes that have digestive enzymes that can digest down these complex plant materials... They're different from the meat-eating microbes that like to digest down amino acids from proteins and fats.

So this raises the prospect that if vegetable-loving microbes set up shop from a vegetarian diet, might they encourage your physiology through hormones, through various biochemical pathways for you to have your own preferences change and therefore feed them more vegetable matter to keep those vegetable microbes selectively happy in the gut?

This is a very legitimate question with some preliminary evidence that's very speculative to sort of say if this is a fact worth talking about right now, but the experiments need to be done, and they do might explain why we do have preference changes.

I myself was a vegan for one and a half years in part because I learned that eating lots of leafy green vegetables enriches microbiome diversity, and that was a personal choice that I made. I found myself loving a vegan diet much more than I anticipated and much more than I originally did and wondered along my diet, "Did that diet... Did the microbes have something to do with that?" That's where we'll leave it for future work and more speculation right now.

Tom Sontag:

Is there anything exciting you have just started researching or plan on researching in the future?

Seth Bordenstein:

So many things. So many things, Tom. In terms of human microbiomes, I'm really fascinated by the diversity of microbiomes across the diversity of all of us. I think that there is so much more to learn about variation between people across the world who are diverse, and then that will lead to greater insights on personalized health or population-specific health rather than a microbiome study in which we think one sort of concept or theory applies to all humans the same way. Clearly, that's not the case, and we've got some evidence to suggest that the field needs to move in a more population and personalized way.

Another area would be the roles of microbes in the animal and plant speciation. We tend to think that great life's diversity arises through changes in genes between populations. And when those populations become too genetically different, they can no longer interbreed, have sex, make babies, and therefore, they become different species.

It turns out that microbes are likely as important to genes to the speciation process of animals and plants, and yet, we are truly under-studying this phenomenon. So we have some plans, and we're excited about expanding our experiments and concepts.

And then, finally, as we talked a lot about today, Wolbachia is the world's greatest infection symbiont to cross the animal world. We're digging very hard into the cellular and biochemical mechanisms of how Wolbachia achieves these kinds of sperm-egg problems that have given it such great success in the biological world. So we're looking at the genes, we're looking at the proteins, we're looking at what those proteins do, and dissecting this very interesting organismal symbiosis down to its molecular roots. And that keeps us inspired and fascinated as we dig in further.

Tom Sontag:

All right. To wrap things up, is there any piece of advice you have for aspiring scientists?

Seth Bordenstein:

Yes. First of all, follow your intuition and gut. If you have a preconception about what you are going to become, make sure it's consistent with your passion inside you. 

Second would be, if you doubt what those preconceptions might be, give yourself the confidence and space to explore them.

For me, I transitioned from a pre-medical student to an evolutionary biologist. My mother thought I was crazy, and she couldn't pronounce the name Wolbachia, the organism I'd studied for five years, and questioned me about why I was doing this.

However, one day, they started releasing mosquitoes that have Wolbachia in Florida, where she lives, and suddenly, she became very proud of her son. So again, follow your passion. It might take you into places that you have no idea how fulfilling they can be.

And even when there are doubts about following those passions, even from the people who love you the most, keep an eye towards your happiness in your gut because it really did make the difference for me.

In terms of getting into research, just send these great letters and emails and evidence of your work to laboratory heads that I guarantee you are always keeping an open mind about the next undergraduate student they may take in. Because we're all interested in training the next generation. We are all there at the same point, looking for lab experiences ourselves.

Tom Sontag:

Thank you so much for chatting with me. You gave us insight into a branch of science we don't see very often in popular media. And it's good to see there are options for future scientists who want to start doing research really early. It was great talking with you.

Seth Bordenstein:

Thanks, Tom. I appreciate your questions. I appreciate the podcast you all are running. It's great work. Keep it up, and I look forward to listening in.

[MUSICAL INTERLUDE]

Mark Shriver:

Tracking Traits is a production of Penn State’s Center for Human Evolution and Diversity. Our producer, audio engineer and musical theme composer is Cole Hons, and our logo was designed by Michael Tribone of mtribone design. 

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