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Out of sight tenants

Juan García Ruiz
July 4th, 2021 · 9 min read ·
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Over four and a half billion years ago, the first life forms began to emerge from hydrothermal vents at the bottom of the oceans: prokaryotic microorganisms, the ancestors of bacteria. This occurred only two hundred and sixty thousand years after the origin of the Earth. In contrast, the first homo sapiens did not emerge until much later, about three hundred thousand years ago. In relative terms, if we imagine that one hour has elapsed since the formation of the Earth until today, the first prokaryotes appeared 0.2 seconds after the formation of the Earth while the first homo sapiens appeared 59 minutes and 59 seconds later. Our passage on Earth is insignificant from a temporal point of view if we compare it with that of bacteria, which have lived almost the entire history of the Earth. Bacteria are no longer those insignificant microorganisms that we only think of when we have an infection. But it doesn’t end there. Bacteria have not only lived much longer than humans, but they are also part of us (or we are part of them). Let’s face reality: there are more bacterial than human cells in our body. In a way we are like mythological beings, except that unlike the centaur or the faun, we often forget our other half (and we do exist).

To better understand our relationship with our prokaryotic tenants, we talked to John Cryan, Professor at the University of Cork in southern Ireland, where he is also Vice President for Research and Innovation. John was trained in neuropharmacology and focuses his research on stress-related disorders and the brain-gut microbiota axis.

Juan García Ruiz: What exactly is your current research about?

We are working on trying to understand the relationship between the microbiome, which is the strains of bacteria we have in our gut, and the brain and behavior. We want to answer to two big questions. One is understanding how microbes can communicate with the brain, and applying state of the art neuroscience tools to try to disentangle these routes of communication. Secondly, we try to translate our findings in animal models to the human condition so we can understand what works best to our gut.

JGR: Why is this research so important for society?

JC: This is really important because if we place this research in an evolutionary context, the microbes were there first. There never has been a time where the brain existed without microbial signals. Understanding how this coevolution has occurred and to what level have signals from the microbiome been able to shape our brain circuits is essential for understanding every aspect of our lives, because if our microbes are shaping our brains, they are controlling all of our decisions and therefore they impact everything that we do.

JGR: What’s the estimate number of microbes we have in our guts?

JC: We have more microbes than human cells, the ratio is about 1,3 to 1. That would also include virus, archaea and whatever else. In terms of genes though, we are more than 99% microbials. That’s very humbling, it’s 20 years of the human genome project and we are only dealing with 1% of all the genes.

JGR: How do we study the microbiota-gut-brain interaction in the lab?

JC: We have to be a bit reductionist so we can look at every part individually. We study the microbiome itself by looking at its genomes, its metabolites, its functional capacity. Then we look at the next layer for the microbes, and we study the gut epithelium to try to understand how it’s interacting with the immune system within the gut, the enteric nervous system, the vagus nerve, the hormones and so on, and see how all of this can have confluence to the brain. We study most things in the brain with traditional tools, in models and in humans, and we eventually integrate human brain imaging techniques.

JGR: Now that you mention the metabolites, is there a way to tell microbiota molecules from the human version of the same molecule?

JC: It’s a great question. There are some metabolites that are made by the host and are also made by the microbes, but then there are some that are only made by microbes, so we can figure out which ones they are.

JGR: What do we know about the interaction between the microbiota and the brain so far?

JC: We know very little overall. We are really at the beginning of it. From my research I know that the microbiome in early life is very important for sculpting brain development. So in our models we take away the microbiome and we interfere with brain development processes, that’s really clear. We know the microbiome is involved in functions such as prefrontal cortical myelination patterns, adult hippocampal neurogenesis, the integrity of the blood brain barrier, and the functioning of microglia, which are the brain immune cells. What we don’t know is how. But it doesn’t stop at early life. We also think that the microbiome is contributing in some ways to some of the neuroinflammatory effects that occur with aging. Knowing this, we can either target the microbiome to improve developmental processes or to slow down aging.

JGR: How variable is the microbiota in human?

JC: The way I see microbiome is almost like a signature of what happened to you in the last proximal and not so proximal time. It’s variable. It’s very influenced by the environment we are living in and the diet. If you eat a lot of very nice Portuguese pastries, you will have a different microbiome than if you drink a lot of Irish Guinness.

JGR: I guess if it’s influenced by the environment and the diet, we can also influence our microbiota by changing our habits, right?

JC: Yes, that’s the good news! There’s nothing you can do with your genome, except blaming your parents and your grand-parents. Unlike the genome, you can potentially change your microbiome. That gives the patients great agency of their own health, in terms of taking control.

JGR: Our interest for the brain-gut microbiota and publications about this topic have skyrocketed in the last years. It is possible to find all kind of relationships between microbiota and psychiatric disorders in the literature. As an expert in the field, are you sceptical about some of the findings?

JC: I think it’s good to be sceptical on this field. There’s a lot of healthy scepticism. Extraordinary claims needs extraordinary evidence. Have we got the extraordinary evidence? Probably not yet, but we got really intriguing evidence that is starting to build. In the autism field in particular we see it quite remarkably, but we cannot forget that autism is a genetic disorder, so the microbes are not the whole answer, but they are maybe playing a role in shaping it. Some of the data that has been shown in that regard is quite interesting. I think it’s early days. We have to always look at the evidence. The microbiome field is trying to go from correlation to causation. How do we get a causation? We need to do a lot of more basic research, a lot of human research, and a lot of longitudinal research to get there.

JGR: What is the most astonishing discovery you have done or experienced during your professional career?

JC: For me an eureka moment was when we found that mice that grew up without microbes showed a very high hypermyelination in the prefrontal cortex. These mice can actually live longer. I described it a little bit like those studies that looked at how nuns living in convents, in enclose orders, can live into their hundreds. It’s kind of the same. If you are not exposed to anything, you have no stress of children, no stress of anything and all you do is pray all day, then you are more likely to live longer, but this is not as much fun! So anyway, discovering that there was hypermyelination in mice without microbes is a remarkable finding because it opens up so many questions. Could we target myelination process in the brain by targeting the microbiome? Or could we somehow understand what is going on in relation to myelination, conductivity of neuronal signals and behavioral changes we find in these mice, which are social deficits? Hypermyelination is also occurring in some autism cases. Not very often, but it’s still interesting. That’s pretty cool, you can look down to the microscope and see this, that’s impressive!

JGR: Considering your great research career I have many questions. What led you to do research?

JC: I guess I have always been curious. I probably didn’t do real research until I went to university. I studied general science and got very interested in biochemistry. I just got softly into it. I like to see things change, so I like studying behavior. Besides I wasn’t a very good biochemist. I remember I was amazed when a friend of mine who was doing studies with drugs at the time showed me what a mouse looked like on extasy. I started to do research on the serotonergic system and behavior. So everything I do is contextualized by how is this affecting behavior. Even though that I cannot see the microbes, I can really see the output and I am very fascinated by that.

JGR: You have hundreds of publications and a very high h-Index. Especially for young researchers, getting started to publish can be tricky. Do you have a piece of advice?

JC: The hardest thing for a young researcher is focusing on the output. You should think about writing a paper as a five figure plan and have this in your head at the beginning. The data can take you in different places and you should always be agile and aware of that. If you focus on how to get there, then you will not be long building paper after paper after paper. I think publications are a sign that you are being productive and that you are output-oriented. Whether you want to stay in academic research, or move into industry, or project management, having a paper shows that you can deliver an angle and wrap something up. One of the biggest problems we have that I try also to tell young people is that sometimes you just have to let it go. Meaning two things: there is an aspiration to try and solve everything, and sometimes you just need to get the finding out there. For instance take myelin paper: we could have spent years and years figuring out the mechanism. It’s been five years and I still don’t know what’s happening. We could have delayed the publication till then, but I thought it was too important to wait. But the other thing I mean by let it go is that sometimes things just don’t work, so don’t hold on to these things, be flexible, be imaginative. I never worked on microbes really until I came back to Ireland. My colleagues here were doing it for different reasons and I started getting in collaborating with people here. I could have been very snobby and say: “well no I won’t work on that, I am working on stress, the brain” and so on. I think instead we should be open, that’s how wonderful things can be crafted.

JGR: What’s the best advice you got from someone?

JC: I worked in the industry so I spent four years working in Basel, and they were very wonderful years. But my PhD supervisor had said to me once: never work for industry. I was a bit perplexed because he had worked in industry. Then he rephrased it and he said: “work for yourself while you are in industry and as long as you are meeting the industry goals and you keep that you are a scientist, and that you are creative and curious, it doesn’t matter who’s paying your salary”. I think that now really amazing innovation is going on in industry, we see it with the COVID-19 vaccine and various other things. Some of the brightest scientists I know work in industry, so we need to also be aware of that.

JGR: You have participated in the writing of the bestselling The Psychobiotic Revolution. Can you talk us about this project?

JC: We wrote this book and for us is now like the new New Testament, it’s like our Bible to the world to tell them that we should be thinking more holistic about the microbiome. We tried to get people excited about science. It was published by National Geographic, so it was a very exciting adventure. We translated it into a language so the everyday person could read it. Also in different languages. We recently published it in Polish, in Chinese and in Spanish: La revolución psicobiótica (N. of A: pronounced with amazing Spanish accent). Not French, for the moment.

JGR: In addition of the co-writing of The Psychobiotic Revolution, you have edited three books, you are a professor, you are on the editorial board of more than 15 journals, you have received numerous awards for your research and you still have time to do Ted talks. Are you a human being?

JC: Yes, and don’t forget that I also have kids! People ask me this sometimes. I am very passionate about what I do, I really love what I do. That makes it all easier. Secondly, I am not really a perfectionist, so I am able to let things go. I feel passion about communication in science, we need to be able to get messages out there, to inform policy and to inform the public about what’s going on. Therefore I can get funding. Then I have an amazing team of people who work with me, many Spanish, from Madrid, Barcelona, Mallorca. So you know we have a very Spanish-Catalan view of the world here. That’s quite exciting. I guess I am output-oriented and I try to train people to be outoput-oriented, so we can achieve a lot! We try for excellence and push ourselves. But there’s a lot of fun, you enjoy, you make discoveries. Every paper I publish I still get excited about it!

JGR: Do you have a message you would like to share with the readers?

JC: My message is going to be for researchers. Research is about understanding that what they will be working on in ten years has probably not even been discovered now. Be open to these discoveries coming down the line. Secondly, break down the barriers we create in research and medicine. Because we talk different languages when we talk about the brain, the gut, or immunology and microbiology. Let’s break down these compartmentalisations. Finally make sure that the research has some impact from a whole planetary perspective. Embed research within the systemic development goals of the United Nations. It’s really important to use what we do to help create the innovation situations that makes us moving forward.

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