The future of cancer prevention (part 2)

April 18, 2019 — In 2018, colorectal cancer was the third-most common diagnosed cancer among both men and women in the U.S., and data indicate that younger adults are increasingly being diagnosed with it. A new research initiative will examine how the microbiome—a collection of trillions of microorganisms throughout the body—affects the development of colorectal cancer. Scientists on the team will also seek out ways to manipulate the microbiome to better prevent and treat colorectal cancer.

In this week’s episode, part two of our miniseries on cancer prevention, we’re speaking with one of the co-principal investigators of the team, Wendy Garrett, professor of immunology and infectious diseases at Harvard T.H. Chan School of Public Health. Garrett is also on the steering committee of the Zhu Family Center for Global Cancer Prevention. In part one of our miniseries, we spoke to Timothy Rebbeck, the center’s director.

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Full Transcript:

NOAH LEAVITT: Coming up on Harvard Chan: This Week in Health…Cancer and the microbiome.

WENDY GARRETT: Let’s say, we could monitor you from a saliva sample or a stool sample, and also from knowing your genetics, that you are at an increased risk for colon cancer. That would be good to know.

NOAH LEAVITT: In this week’s episode, you’ll hear from the scientist who is examining how our microbiome—the collection of trillions of microbes in and on our bodies—can affect the development of colon cancer.

Hello and welcome to Harvard Chan: This Week in Health…I’m Noah Leavitt.

AMIE MONTEMURRO: And I’m Amie Montemurro.

This is the second part of our two-part miniseries on cancer prevention.

NOAH LEAVITT: In our last episode you heard from Timothy Rebbeck, who leads the new Zhu Family Center for Global Cancer Prevention at the Harvard Chan School. Rebbeck explained how many cancers can be prevented using already proven strategies—but he also outlined the importance of developing new strategies both for prevention and screening.

AMIE MONTEMURRO: And this week, we’re looking at an exciting frontier in cancer prevention and detection.

WENDY GARRETT: My name is Wendy Garrett and I’m a professor of immunology and infectious diseases at the Harvard Chan School of Public Health

AMIE MONTEMURRO: That’s Wendy Garrett. She’s on the steering committee of the Zhu Center and her fascinating research focuses on connections between our microbiome and colon cancer.

The microbiome is a collection of trillions of microbes in and on our bodies.

And Garrett and colleagues recently received a 20 million pound grant from Cancer Research UK to seek out ways to manipulate the microbiome to better prevent and treat colon cancer.

NOAH LEAVITT: I spoke with Garrett about the connections between our microbiome and cancer—and the exciting ways in which her research could change how we prevent, diagnose, and treat cancer in the decades ahead. Take a listen.

NOAH LEAVITT: I wanted to start broadly here, because I think people listening to this have probably seen the term microbiome a lot in health stories they’re reading. So for people– I mean they might see that term but they might be unfamiliar with it. Can you explain what is our microbiome? What are we talking about when we use that term?

WENDY GARRETT: So the term has become more broad. So classically, that ome part, microbiome, meant that you were really talking about the genomes, the DNAs, the transcriptomes, the RNAs of the microbiota. And the microbiota are the collection of organisms so that if we talk about the human microbiota live with on and in our body’s surfaces.

And within this vast collection of organisms include bacteria, archaea, viruses, different kinds of parasites, fungi, a whole host of neat things. So by cellular count, now it’s almost cliche, you are outnumbered by your non-human membership. So that’s basically in a nutshell what the microbiota or microbiome is.

NOAH LEAVITT: And I know you’ve spoken before about this idea that microbes aren’t our enemy, that– I mean, people think like microbes, bacteria bad. But I mean really it’s an interesting relationship that we have with them. So how are– what is the relation between our bodies and the microbes within our bodies?

WENDY GARRETT: Sure. So the vast majority of the microbes that live within and on us are harmless. So some people use the word mutualism to describe a very– it’s a broad descriptor for the kinds of relationships that organisms have between each other. So they’re net neutral relationships. They’re relationships where one benefits more than the other and vice versa.

And then there are relationships that are sometimes problematic. Some of those relationships exist within the microbiome. You can think of them as frenemies. Maybe in some settings it works really well. And in some settings it causes problems. The medical term, if you will, or microbiological term would be opportunistic pathogens.

But by and large the microbes that live within and on us coexist with us peacefully. Many of them contribute to our digestive processes and different aspects of our physiology, helping us generate vitamins that we need to live, like vitamin K type vitamins that are useful for clotting so we don’t bleed to death, vitamin B type style vitamins that are important as cofactors in a lot of basic metabolic processes that our body carries out all the time. That’s just one way.

A lot of our microbes help us digest things that we don’t have the enzymes to digest, like a lot of fibers or complex polysaccharides. So digestion is a big way in which our gut microbiota contributes to our well-being. They’re getting food and we’re getting food broken down. So in some cases it’s win-win depending on your perspective.

Microbes in some ways also contribute to this idea of something called colonization resistance. It’s a fancy term for an idea where maybe the microbes that live within and on us prevent or help us from pathogens, invaders, or incursions from foreign microbes that maybe we don’t want because they can make us sick, it’s generally, I would say, a beneficial relationship for most healthy people but not always.

NOAH LEAVITT: What sparked your interest in studying the microbiome? Where did that come from? How did that evolve over time for you?

WENDY GARRETT: I always thought things like bacteria, and viruses, and fungi were really neat. I was one of those kids in middle school or maybe a little earlier that did science fair. And I had definitely Petri dishes full of bread growing in the basement because I just thought that was super cool.

And I think there are a lot of us that as kids kind of felt that whole tree of life interesting, microbes. That interest grew over time. And I was really lucky to have fantastic mentors during my undergraduate and graduate education that thought the immune system and microbes are absolutely fascinating and brought a lot of energy and enthusiasm to their study.

And I think one thing that I’ve learned is we can better understand how humans work and different parts of the human body work from studying microbes that aren’t friendly to us. Frankly, pathogens, because they know how to manipulate the system. They know how to perturb processes, because they want to live in an office and so I think it’s interesting to study them to understand us better.

Jorge Galán at Yale definitely inspired me in that regard in terms of that thinking. He is a world renowned aficionado from salmonella. So I think definitely Jorge’s mentorship inspired me to think about the microbial world. And that was a long time ago, but that interest grew and evolved over time into me devoting my lab and my postdoctoral studies to studying the microbiota with a twist though. I did clinical training and became very interested in cancer. I’m an oncologist and also inflammatory bowel disease. And I got interested in how the microbiota influence susceptibility to those diseases.

NOAH LEAVITT: And that was actually my next question. At what point did you decide to focus on that relationship with colon cancer, for example? Where did that interest come from? Was there a particular moment as an oncologist when you realized, OK, there might be something going on here between the microbiome and colon cancer?

WENDY GARRETT: I probably didn’t know the word microbiome yet. But in medical school, you see a lot of patients with cancer and infectious complications, so suffering from infectious illnesses and diseases. So that was the start of that, seeing that patient population. In fact, I briefly thought about but was not brave enough to becoming both an oncologist and an infectious disease doctor. And there are a lot of those people around here in Boston, which I think is very heroic and interesting.

I found gastrointestinal malignancies really, really, really fascinating. And I think that definitely pushed me over the edge into the microbiome world in so far as in the colon really there is this one cell layer thick of epithelium that is very complicated, of course, but essentially separates us from this vast microbial world which is the inside of our gut.

And I found colon cancer fascinating. I found mucosal immunity absolutely enthralling. And I thought the microbiome and thinking about triad of relationships was where I wanted to devote my intellectual energies at the bench and leapt into that as a postdoctoral fellow and continue to work on that in my research group.

NOAH LEAVITT: So you used the term there mucosal immunity. So can you explain what that is?

WENDY GARRETT: Sure. Mucosal immunity or barrier immunity has to do with the specializations that our immune system has evolved to live at interfaces with the outside world. So one obvious barrier is our skin. Right. And there are really cool specializations within the skin immunity.

Another barrier surface is actually our gut. We think of it as internal to us, our arrow digestive tract. So that would be our mouth, also our lungs, our respiratory tract, our esophagus, our stomach, our small intestine, and our colon get a lot of environmental exposures through food, through breathing, and so those really outside in or inside out surfaces are a barrier too. And classically, studying those services and the unique specializations of the immune systems that have happened– of the immune system that have happened there are either termed mucosal immunology or, more recently, barrier immunity. The reproductive tract is included in that as well.

NOAH LEAVITT: You and other scientists recently received this 20 million pound grant from Cancer Research UK to study how the microbiome affects the development of colon cancer. So I think you touched a little bit on it there. But what do we know already about the links between our microbiome and colon cancer risk?

WENDY GARRETT: There have been fascinating associations in the literature– excuse me– for decades. And one of those associations medical students learn that if there is a specific blood infection or bacteremia with a specific kind of streptococcus, now called galloliticus, you’re supposed to have this intellectual reflex to look for a malignancy or a premalignant lesion in the colon. And so that’s been known for many, many, many decades.

And over time, scientists began to correlate enrichments in the tissue or the stool between different single organisms and colon cancer. That’s not causation. It’s just seeing a lot of a particular microbe in a tissue. So those sorts of associations have popped up for many decades to just over the last decade.

And many of the individuals that have contributed to not only those associations but understanding those associations from a causal perspective– how does microorganism x potentially contribute in some way to colon cancer– are part of this Cancer Research UK grant challenge, which is a very exciting high risk and high reward proposal and granting entity to study all facets of the microbiome, the collection of organisms that are in some way linked to increased susceptibility or maybe decreased susceptibility to colon cancer that influence response to treatment as well as toxicities associated with treatment.

And so the copia or mycopia– sounds funny– with the cancer grand challenge grant that’s focused on colon cancer and the microbiome is Matthew Meyerson. We’ve collaborated for many, many years. And we’ve focused on a particular bug that emerged from sequencing based studies of the microbiome associated with colon tumors.

And one bug that we’re very interested in, or one microorganism to be more sciencey, is fusobacterium nucleatum. It’s an organism that lives within the mouth of most healthy humans, if not all, but becomes enriched in colon tumors. And we’ve been very fortunate to study that and to delve into the mechanisms over the last nine or so years that underlie that association.

Also, there are other bugs. It’s not just fusobacterium nucleatum that are associated with colon cancer. There are really cool E. colis, E. colis that express toxins that damage DNA. Locally, Emily Balskus in our Department of chemical biology has studied colibactin and how directly that toxin damages DNA. I’ve been really fortunate to collaborate a little bit with her and learn a tremendous amount about how that E. coli works. And people have studied that E. coli for a long time.

And then another member of this Cancer Research UK Grand Challenge Microbiome Award is Cynthia Sears at Johns Hopkins. She’s studied a bug called enterotoxigenic Bacteroides fragilis. I know it’s a mouthful. And in both mouse models and humans, there’s an association with potentiation of colon cancer. And she’s done a lot of nice mechanistic work studying how that bacteria works as well.

Now beyond single organism, which mechanistic or reductionist scientists like to study in the lab, there are more complex ways that the microbiota interact. So these microbes exist in a network or community. They talk to each other figuratively.

They cometabolize and generate stuff. They kill each other. They enable each other to live at different surfaces by changing the metabolic environment so it’s more favorable in terms of oxygen levels and carbon or food sources.

So in many cases, it’s perhaps overly simple to think about it as one organism contributing to a disease as complicated as colon cancer. It can be a variety of organisms over time or in combination that are potentiating tumorigenesis, influencing a colon cancer to grow and spread in different ways.

And then the flip side of all this is a really hot area in science, and tumor immunology, and cancer immunology. And that area is born out of the idea that the configuration of microbes in someone’s colon can influence how responsive they are to different cancer therapeutics, especially those checkpoint inhibitors. So that extends beyond colon cancer and is applicable to many malignancies like melanoma, renal cell cancer, lung cancer where those checkpoint inhibitors. are based.

NOAH LEAVITT: So when you talk– you just talked about the complexity of cancer itself but also all these microorganisms. So I think when it comes to, for example, prevention for cancer risk, I mean how does that complexity make the challenge prevention so much more difficult?

WENDY GARRETT: I think one way it makes it difficult is that it informs sort of the need for special types of studies, called prospective longitudinal studies. And that means that you need to involve populations of healthy people, and follow them really closely over time. And unfortunately, within a large enough population, some of those individuals will develop pre-malignant lesions of the colon, called adenomas. And some of those individuals, over time, will develop colon cancers. And we need to understand that path, and that path from a microbiome perspective.

And so we’re very, very lucky at the school to have something now called the Harvard Chan Center for the Microbiome and Public Health. And that center, co-directed by Curtis Huttenhower and myself, grew out of a grant called Biomass that was funded by Massachussetts Life Sciences Center, which is investing in the state of innovation within the commonwealth. And through the aegis of that award, along with my co-PIs, which include Eric Rimm and Shelly Tworoger, who was formerly at the school, and Curtis Huttenhower, and Andy Chan, with the support of the Department of Nutrition, the Department of Biostatistics, and of course the support of the Department of Immunology and Infectious Diseases here at the Chan School, we began a collection from the Nurses’ Health Study. And I’m sure you’ve heard about that amazing cohort of very dedicated health professionals that have been followed for decades, and filled out surveys, and generally provided lots of their health and lifestyle information, and also samples.

And what this wonderful series of cohorts is now providing is a stool sample, through this Biomass grant that’s funded by MLSE. And this study, with time– and with funding; we’re really looking for funding for this effort– will enable us to begin to ask those critical-to-prevention questions about prospective longitudinal studies around the microbiome in colon cancer. And really, when you’re looking at a population of 30,000-plus individuals, we can look at many things beyond colon cancer.

We can look at a whole host of malignancies– if you’re interested in breast cancer, or lung cancer, we can look at neurological diseases like Parkinson’s disease. But really I think, for prevention studies in the microbiome, you need that idea of a large population-scale study. So not one person, although that’s great. Not 10, not 100, but tens of thousands, that kind of scale.

So there’s this great quote that I absolutely love. It’s from the Canary Foundation. And I think, also, it appears in a publication from a meeting hosted by the National Cancer Institute at the National Institute of Health. And that is, “for every $1.00 spent on prevention, there are about $1,000 spent on late-stage treatment, per individual.” And so the time is really near for us to make an investment in this idea of prevention for cancer. And I think the microbiome is a really exciting place for us to put a nickel down– or more, especially regarding cancer.

NOAH LEAVITT: It’s so funny you mention that quote. Because one of the questions I had wanted to ask you is actually the same that I asked Tim, was that at the recent [INAUDIBLE] Symposia, Sanjiv Gambhir made a really similar point, where he said early detection is the key to cancer survival, yet most of the health care industry’s efforts are directed at later stages of the disease, the treatment.

So what you just talked about is an effort in the right direction. But how can public health– whether it’s pushing the health care industry, pushing other scientists, how do you shift that focus to invest in prevention to potentially save lives, and also maybe reduce health care costs later on down the line?

WENDY GARRETT: I think it’s a whole cultural shift in biomedical sciences and in medical education. And that shift is underway. So the idea is not only teaching medical students, and maybe premed students, and public health students– which I think are already well aware of the issue– about disease, but also teaching about health, and how to maintain health, and thinking about cultural barriers and socioeconomic barriers to engage in surveillance.

So for colon cancer– and it’s not perfect, but it’s pretty awesome– we have colonoscopies. We have screening tests that are invasive colonscopy and non-invasive. And the idea there is if we can catch a precancerous lesion, like an adenoma in the colon, we can stop that process– we can intercept. That’s another big term in the prevention biomedical sciences, devoted to cancer field. We can intercept that cancer before it gets big, before it grows too much, before it spreads and becomes what we refer to as late-stage disease.

So that’s what’s so exciting about the [INAUDIBLE] Family Center, because it’s a wonderful investment that’s going to enable science here at the school, around prevention, and at Dana Farber, and across the Boston ecosystem, and hopefully beyond. It’s going to enable science, it’s going to enable education, it’s going to enable faculty recruitment, which touches on both– both the education access and the science– and it’s going to enable translational science around cancer prevention. So I think it’s a very exciting time for cancer prevention, for population health and for the microbiome. And it’s great to see sort of this confluence of all this positive energy that’s definitely being channeled through the Center.

NOAH LEAVITT: Yeah, and I spoke to Tim a lot about the center, and kind of the interdisciplinary nature of the Center, and what he’s hoping to accomplish. And it seemed interesting because I feel like the microbiome is a really kind of cool example of that. So could you talk a little bit– I mean, you mentioned, for example, the work you’re doing with Eric Rimm, who’s from nutrition, and you’re bringing all these kind of diverse groups together. So how– I guess, why is microbiome research maybe such a good opportunity to do that, to bring people with your perspective, but maybe people from population health sciences?

WENDY GARRETT: I think since microbiome sciences began to call itself that, or became sort of inherently self-aware, it had this realization that cross-disciplinary was the way to go. You need computational biology. You need pipelines like cancer genomics, to not only sequence the omic information related to the microbiome, but to analyze it.

You need biologists that know how to cultivate microbes. You need immunologists that know how to interrogate the cellular immune response and how microbes interact with immune cells. You need cancer biologists and other disease modelers that think about the confluence of the immune system, microbes, and whatever disease system they’re studying.

You need people that think about translational models, be it preclinical models in mice, or other rodents, or non-human primates, or that work with different iterations of cell culture, be it traditional cell culture, be it organoids, which is a little bit more complex, or be it from patient-derived organoids, which is really exciting, which can exist in culture, or actually in mouse models as well. So, so many different ways of thinking, ways of solving problems scientifically, are needed to think about the data, to interrogate the data, to test hypotheses.

And I was remiss in leaving out the population sciences aspect. We need epidemiologists. We need people that think about biostatistics and ways to evaluate data in a rigorous way around microbiome sciences. So the science has so many needs to be robust, to repeat, to identify real signals in the data, that it’s inherently cross-disciplinary or transdisciplinary.

And we’re so fortunate here at the Chan School that we have that spectrum of people. We have the population health scientists. We have the epidemiologists, of which there are many different subtypes– nutritional epidemiologists, infectious disease epidemiologists, et cetera. We have the computational biologists. We have the biostatistics department here. And we have the experimental bench folks here in the Department of Immunology and Infectious Diseases, and Genetics and Complex , Diseases, and Environmental Health.

NOAH LEAVITT: Do you feel like you bring– I mean, you touched at the beginning that you’re a physician scientist, that you have training as an oncologist. Do you feel like that gives you a potentially unique perspective on all of this as well, that you kind of have– you yourself are cross-disciplinary in some way.

WENDY GARRETT: I think the physician scientists training track is transformative. I think it’s very important that it be cultivated. It may be maintained throughout the pipeline, that we continue to recruit into that pipeline, and we continue to maintain that educational pipeline, and we continue to nourish those careers after someone attains the degree. It’s so wonderful to have the broad-based medical education and the postgraduate clinical training as well. So that internship, that residency, that clinical fellowship.

You learn so much about different things. And the science-based PhD education is wonderful as well, because it enables you to delve deeply in a field, to think very rigorously about scientific questions, to learn the tools to test a hypothesis and carry sort of years of research within a PhD to fruition and completion. So I think the two disciplines complement each other very well. But I did it. So I believe in it. And–

NOAH LEAVITT: You’re biased.

WENDY GARRETT: I’m a little biased. Of course there are people that don’t do both degrees and are highly successful scientists or highly successful physicians. And there are people that do both with one degree. But I’m a believer in the MD-PhD pathway, and careers that are enabled– that you can do both.

NOAH LEAVITT: You mentioned a few minutes ago, kind of this ultimate goal, I think, of translational potential. So when it comes to the microbiome and colon cancer, I mean, what could that look like from the spectrum of prevention and screening, all the way down the line to more targeted treatments or better treatments? What might that look like in the future?

WENDY GARRETT: Oh, it looks like a lot. So let’s say we could monitor you from a saliva sample or a stool sample, and also from knowing your genetics, that you were at increased risk for colon cancer. What if we knew that a certain configuration or a certain signal in your stool sample told us that you were an elevated risk? That would be good to know.

We might think about lifestyle changes. We might think about treatments– which could be anything from a vaccine to a collection of microbes, maybe, that pushed out something bad, to a specific diet. There are sort of a panoply of ideas that would prevent you, hopefully, from developing colon cancer. And maybe you’d have, hopefully, enhanced surveillance, too. So that would sort of be the prevention– let’s stop it by thinking about your microbiota, and making changes in your lifestyle, your diet, and maybe give you something to target that microbe that’s linked to increased risk.

And hopefully, over time, we have a better understanding of, what is it about that microbe that increases your risk? Is it making a toxin? Does it create an environment in your gut where other quote, unquote, “good microbes,” whatever that means, are pushed down or squashed down in their membership? And how do we change that? Or do they make a sticky substance that enables them to stick to places where they shouldn’t? And if we could just block that interaction, we could cast out that potentially naughty microbe that’s going to increase your susceptibility risk.

Or maybe we can give you something– thinking on the flip side– that is beneficial in some way, that keeps oxygen levels down within your microbiota, and keeps balance of whatever to-be-determined healthy microbes are, versus less healthy and good microbes in terms of colon cancer risk.

NOAH LEAVITT: So it’s interesting, because it’s not enough to say, OK, we know this microorganism is associated with this. I mean, that’s helpful. But what’s more helpful is understanding the why, the mechanism.

WENDY GARRETT: I think so. Because that gives us a target, right? So if we know microbes make x, or this collection of microbes make a metabolite, can we design a sponge that soaks up that pro-carcinogenic metabolite? Maybe. What can we do to increase the fortitude of your gut or your barrier function so we don’t have to worry about that microbe getting to the layers of your gut that are below that first cellular layer?

And then we talked about prevention, but how can we think of the microbiota as a way to make therapies work better or be less toxic? A lot of folks think about that, too, whether it’s those immuno-oncology therapeutics, or more traditional chemotherapy, or even radiation. And then if you are unfortunate enough to get a cancer, how do we prevent it from coming back? If we treat you in a standard fashion, how do we bring our knowledge of the microbiota to lower recurrence risk?

NOAH LEAVITT: I mean, I think what fascinates me is that– I think you mentioned this again, that microbiome becomes this, like, umbrella term. But it seems so infinitely complex. So how do you, as a scientist in your lab, with the people you’re working with– how do you choose where to start? How do you identify, these need to be our priorities?

WENDY GARRETT: Yeah. So sometimes we look at a human data set, and we see a microbe that’s enriched, let’s say, in a colon tumor. And there might be many that are enriched. And we would test in a preclinical model which of these microbes increases, let’s say, cell proliferation, or a hallmark in cancer, some change in the immune system that’s linked to cancer growth and spread, some change in the metabolism of a cell type that’s linked to cancer. So we might look at a human data set, and then for hypothesis-generating ideas, and test those ideas in preclinical models.

And honestly we might settle on one bug to study. One model system that we use here at the school is gnotobiotics. So we can have animals– we use mice here– that we use very special ways to raise them, and pay a lot of attention to their husbandry, the food they get, the water they get, the air they breathe.

And we can control what microbes live in them. We can also, just like conventional mice, design their immune system, we can design their genetics, in terms of them harboring– the mice– certain cancer-predisposing mutations. And in the confluence of this controlling the microbes and controlling the genetics of the mouse, we can begin to hopefully improve our models and improve our understanding in terms of what’s important to study with the microbiome for cancer growth.

So those sorts of model systems are very important. And where the hypothesis generation comes from can be starting with a model system, or it can be from gazing into a large human data set.

NOAH LEAVITT: And we’ve talked about, I think, so many different opportunities here, really. So what makes you most excited about the work you’re doing. Is it a particular path for prevention, or is it just kind of the field in general? What most excites you?

WENDY GARRETT: Oh, I think there are many, many, many exciting aspects of microbiome sciences. And sometimes it’s a single bug, like a fusobacterium nucleatum species. Sometimes it’s a kind of microorganism that we might think of as targeting bad actors in the microbiome, that I can become entranced with. Sometimes it’s a metabolite made by a microbe that I find– that’s fascinating. Sometimes it’s the ability to change or alter the genetics of a preclinical model or a microbe. So there are many, many, many, many different facets of the biology and the science intrinsic to studying the microbiota and cancer that I find thrilling, and dazzling– maybe, some days, a little overwhelming.

And what’s so great about a lab and big collaborations like the Cancer Research UK Grand Challenge that’s studying the cancer microbiome is the number of people within a particular lab– or within my lab– that are studying different aspects of cancer in the microbiota, and also the collaborations. So you can become involved in so many different projects that touch on the different science, and learn from your collaborators, and hopefully, in turn, contribute to helping and growing their science.