Ep 3: Debugging our memories

Transcript

Dr. Costa-Mattioli  [0:00]

I’m sitting on an almond tree, [I’ve] been sitting in the countryside in South America under a big tree.

Peter [0:12]

And what do you think the microbes in your gut are thinking right now?

Dr. Costa-Mattioli  [0:16] 

They cannot think because they have no brain!

Peter [0:19] 

So you can open up your eyes now or take the blindfold off. The almond was correct, there are a couple of nuts in there. And the reason why I chose that kind of mixture was because a lot of people think there are certain foods that we can eat to improve our memory. People feel like walnuts are good for memory, blueberries with their antioxidants and dark chocolate have some capacity to improve our memory. But I was wondering how you feel about food being a treatment option moving forward to alter our microbiome or to improve our memory.

Dr. Costa-Mattioli  [0:47] 

I think this is a great option. For centuries, we’ve been discussing the idea of using food to treat a variety of disorders. Now, we are in a position in which perhaps we can use different foods to treat essentially different disorders. So I think this is clearly a great avenue. We know very little, but it’s very interesting. And you know, one of my last point of my website is to perhaps consider the idea to develop […] food therapies that we could use to modulate specific microbial communities in a way to affect the brain or other centers, which are not just specifically brain related, but could improve the quality of life of people as well.

Peter [1:35]   

Really cool. We are what we eat.

Peter [1:52]

Hi, my name is Peter, and I’ll be your host for The Gastronauts Podcast. Here at Gastronauts, we are committed to understanding communication in the body. In particular, how our gut talks to our brain. We will be taking a deep dive into the mind and motivations behind leading scientists and their work, and hope that by getting to know the individuals behind the research, we can understand how different scientists think and why they’re so passionate about their work. So come join me as we explore inner space on The Gastronauts Podcast.

This week, we have a memory expert, who has not only uncovered a pathway that cells use to encode memory, but also discovered specific bacteria in our gut that are capable of regulating social behavior. Dr. Mauro Costa Mattioli’s career path is quite the fascinating one. He studied microbiology as an undergrad at the University of Republic in Montevideo, Uruguay, later traveling to France, where he studied at Pierre and Marie Curie University, and the University of Nantes for his PhD, where he worked on understanding strategies that viruses used to escape immune attack. After completing his PhD, he traveled to McGill University in Montreal to work in Dr. Sonenberg’s lab, where he first got curious about memories, and in particular, the role of protein synthesis in memory formation. So Dr. Costa-Mattioli, thank you so much for being on today.

Dr. Costa-Mattioli [3:43] 

Thank you for having me.

Peter [3:44] 

The first question I wanted to ask has to do with memories- memories are such an integral part of our life; they’re very powerful; they’re the core of our existence and define our experience. Seeing as you’re an expert in this field, could you tell us a little bit about how you and your lab views memory? Is it something that simply stored and retrieved? Or is there a little bit more to it?

Dr. Costa-Mattioli [4:04] 

So […] I am a molecular biologist, and I was interested in the mechanisms which are required to form a memory. And as you pointed out, you know, memories are, you know, essential for survival in animal species, but, you know, it makes the […] core of our identity. So we were interested in trying to identify what are the key components, which essentially make an animal memorize a particular event, which is meaningful. When I joined lab of Nahum Sonenberg at McGill University, we tried to work [out] those mechanisms, which are now they have become sort of the gold standard or key for memory formation.

Peter [4:45] 

Could you tell me a little about these mechanisms?

Dr. Costa-Mattioli [4:47] 

So the major question that we were interested is how a short term memory is converted into a long term memory. And we know that protein synthesis is required for this process. Indeed, this is the molecular process that baptizes a long-term memory. If you were to baptize, what a long term memory has to have molecularly to be long term is a requirement for protein synthesis. But we didn’t know the mechanisms underlying this. And when I joined the lab of Nahum, Sonenberg at McGill University, I thought I was in the ideal place to try to answer that question. And, I decided to switch fields and go from […] virology and microbiology to neuroscience. And we have discovered what appears to be sort of like a switch for memory formation, the mechanisms by which the synthesis of proteins takes place. And if you were to turn it on, now the animals has any has memory, and if you were to turn it off, now the memories actually impaired. In the last 10 years or so, there are many investigators around the world that they have built upon these [findings] and actually reproduce and greatly […] enhance those findings, which they go from, you know, rodents, rats, mice, to even chicks, and hopefully they will make it to humans.

Peter [6:00] 

That’s really interesting. I want to touch up a little bit on the differentiation between long term and short-term memory. How do you explain the difference between the two- is it encoded differently? You did mention that protein expression is important for long term memory formation; how about for short term memory? Is it so much so that […] a buildup of protein formation takes time, and that’s why this is long-term specific?

Dr. Costa-Mattioli [6:20] 

So what we know is that the machinery that gets engaged, you know, have the ability to synthesize a protein, seems not to be activated when a short term memory process takes place. So you could think about in a very naïve way, that in the case of a long term memory, you have these proteins, which are synthesized that will be […] building blocks that will allow now the connections between brain cells to last for a longer time. Whereas in the case of a short-term memory, those connections, you don’t require them to be you know, stable, because eventually […] they will wind down as the time goes by. So the machinery get engaged for a short term memory is different than the one that gets engaged for a long term one.

Peter [7:05] 

So short term memories don’t turn into long term memories, how they’re encoded within the brain are two separate process.

Dr. Costa-Mattioli [7:11] 

Well, short-term memories could be converted into a long-term memory and the […] activation of these protein synthesis mechanisms could take place. So for instance, in some of the experiments that we have done, we have given these animals […] a short term memory training protocol. And because protein synthesis is taking place in those animals to start with, now, this short-term memory can be converted into a long term memory, and vice versa, we can essentially convert a long term memory into a short term memory, if we turn the switch off.

Peter [7:48] 

That’s really cool. [A] couple more questions on […] memory in general, I have a lot of […] experience trying to remember things, and I have difficulty remembering some things that I feel like I should remember. Other times when I’m not trying to remember something, you know, it pops up in my head. But I do feel like I’m better able to remember information when I am an active participant rather than someone who’s passively listening. For example, when I try and explain something that I’ve learned with someone else, like talking through the process helps me remember the information better. Is this simply a matter of […] reinforcement or repetition? Or do you think that there’s an effect of social behavior and its impact on memory? Or do we even have a good understanding of this?

Dr. Costa-Mattioli [8:34] 

We might have, but I don’t have it perhaps. So I’m not sure whether we’ll be able to answer that question. But we know that, of course, when you are more engaged and you are more focused, you are not distracted. So if you were to have a distraction, you know, let’s say the TV on or someone is talking to you on the phone, and you are trying to read a book, the way that information is going to be storing your brain is going to be much less because you know, you have that behavioral interference, and so on. The other thing is that we have memories, which gets stored in the brain very, very effectively, in some cases, even without repetition. [This is] when there’s a very strong emotional component. If you have a very strong emotional component, you know, when we learn we need repetition. It’s practice that makes perfect, right? And that practice, I think it needs to be space, you know, it’s not like you need to wait until the last day to study for your exam and spend all night reading. If you were to take several days in advance, and you read it, you know, several times in a repeated fashion you give it space, you go for a drink and so on… the possibility that information will be stored, we can store it way more efficiently. But for those memories, [where there] is a very strong emotional component, you receive information only once and that the information gets stored, we don’t know very well, how this is taking place.

Peter [9:48] 

Is emotion encoded at the cellular level? Or is it kind of a brain region level? I totally agree that […] more emotional experiences have been more memorable? And do you think that is working on a cell to cell level? Or do you think […] certain brain regions are potentiating signals?

Dr. Costa-Mattioli [10:05] 

Well, we have specific regions, you know, let’s say that instance reward that ultimately […] will essentially have connections with another brain regions that control memory formation. But you know, the circuitry or the cell level, I think there’s much to do on this. We need to try to figure it out whether it’s specific circuits, that essentially, they are connecting, you know, those brain areas to the memory areas. So yeah, I think there is a circuit specificity that determine these specific circuit that gets activated. But to be honest with you, I don’t think that we don’t we don’t know much about.

Peter [10:39] 

Yeah, so tagging off of that. What do you think are some really important questions with regards to memory that the field still needs to answer?

Dr. Costa-Mattioli [10:46] 

So I mean, I think there are many. Some of them, you know, from the more fundamental standpoint is, I mentioned to you that it’s been probably 50-60 years that we know the new protein synthesis is required for memory formation. We don’t know, what are the subset of proteins which are required for this process. We don’t know whether this synthesis proteins needs to take place in neurons or different types of neurons (excitatory or inhibitory neurons). We don’t know what makes memories to become fractured. […] Our focus has been trying to enhance memory. But erased memories are very important aspect as well. And those memories that you retrieve became fractured, and you can essentially erase them. Can we generate mechanisms to target specifically those bad memories, like those associated with PTSD, and get rid of them? So there are these two […] situations, you know, enhancing memory and erasing memory. And [if] we were able to essentially find mechanisms associated with retrieval […] we could […] could help people with cognitive problems as well.

Peter [11:55]

So understanding […] the retrieval aspect of memory, in addition to the repression of memory, fundamental biology that underlies those. Thank you for sharing that knowledge with us. I want to kind of move on to the second aspect of some of the work in your lab: understanding how these gut microbes or the microbiome can influence the brain function. And I think this is kind of like a nice, coming full circle for you. I know that you did microbiology as an undergraduate. And then you’re now studying the microbiome and microbiology again, and how that impacts the brain. I was wondering what prompted you to kind of go into the microbiome field from being very heavily focused on memory […]

Dr. Costa-Mattioli [12:34] 

I will say serendipity. We were not originally looking to look into the microbiome, so the project that we started, actually aimed at looking at how diet could affect behavior. And specifically, the positive that was driving this project was interested in in microglia. So a particular result that led us to think about the microbiome was that animals that […] have social deficit, [with] moms that were given a high fat diet, were put together with normal animals. And when we do that experiment, and we measure the behavior later on, the behavior of the social animals completely disappears. In other words, the animals become normal. At the moment is when, you know, we start to think about how diet affects the microbiome. So just by looking at that hypothesis, and testing that hypothesis, we end up with that surprise that yes, there’s a particular bacteria that it gets eliminated by the diet in the mom. And ultimately, that bacteria is required for social behavior. Because if you were to put it back in the animals, which are social, the behavior is completely normal. So in my wildest dream, I could have conceived the idea that a particular microbe in the gut were to be required to reverse or to affect our behavior, which is […] brain driven? And today, we know that a maternal high fat diet, essentially can change the offspring microbiome, even in humans.

Peter [14:01] 

That’s really neat, so these autism-like phenotypes are seen in the children of obese mothers. And why do you think the case is that the babies will have this kind of predilection, as opposed to the mothers?

Dr. Costa-Mattioli [14:12] 

It’s like everything in life should you know. You have a particular critical period where the brain or the gut, or the gut-brain connection becomes vulnerable. So if you do the high fat diet manipulations, if you can think about it, you know, the babies are in the womb, this is the time when an animal is way more vulnerable. And if you were to do the same insult, when the animal is adult, you know, the synaptic connections are already formed. So the possibility that you will have an impact in the mom is actually lower […]

Peter [14:45] 

So the networks are a little bit more hardwired at that point; there’s less room for change or impact. So I think this microbiome field is really picked up steam lately, how it can affect anything from depression to obesity to how we process a lot of the drugs that we take, what do you think some of the biggest things that the public gets wrong about the microbiome [are]? And what do you wish some people knew more about this field and the effect of microbiome on our health?

Dr. Costa-Mattioli [15:13] 

This is an emerging field. This is a field that, as the audience is learning, we are scientists that we are doing the science we are learning. This is a field, if you were to think about it was sort of inconceivable, you know, if 10 years ago, 15 years ago, a microbe in the gut, which could affect our behavior […] couldn’t be conceived, right? Today, you know, we are even thinking about ideas of using some of those single bacterial species with the possibility to perhaps, in humans, have an impact. So because the field is emerging, and we are starting, of course, we understand the other side, which is the audience of those, specifically, parents of kids that have autism, that they go under rush to the supermarket, and they buy any kind of […] probiotic with the hope that this is going to work. From our own work, we know that we have a specific species, and a specific strain to be specific, which actually are active, whereas others, they are not. And if you ask me why it is so I don’t know yet. Scientists, which are being working in the brain, as a main driver of those pathologies, they have benefit of 20-30 years of research. And I think we need a little bit more of time to essentially see whether any of what we are doing here could be translated or could be applied into humans. For the time being. Everything that we do in my lab is with animal models, and we have great fun. Whether this is going to be translated into human therapies remains to be seen.

Peter [16:52] 

So all the yogurts and the probiotics that are being advertised in the supermarket right now, not really something I should jump on the shelf for if I’m trying to improve my microbiome, or it’s just not proven at this point?

Dr. Costa-Mattioli [17:03] 

Well, so first, I don’t know I mean, but it is a function of the yogurts that you buy, and so on, and you can perhaps you can improve your microbiome. They say you can digest much better, or you don’t have as much constipation. But whether this is going to affect the brain, I have absolutely no idea whether this will be the case. So there are, you know, some probiotics, which perhaps they can help you, especially some of those probiotics, help constipation in young kids, that apparently they are apparently alleviate stomach discomfort, and so on. But for the brain, I don’t think that we have any indication yet. And it remains to us to see whether these could be used for humans. We are tackling the problem from a completely different angle. We are not doing what some other people are doing. This is a different way of thinking perhaps how to treat the disorder, and whether we will be this is going to be effective or not, I can answer that.

Peter [18:04] 

How important do you think different perspectives or tackling problems from a different viewpoint are in science? And how would you recommend someone who is a young new scientist with an idea that they think is somewhat radical, very different from what is going on currently- how do they go about pursuing an idea like that?

Dr. Costa-Mattioli [18:20] 

So it’s not about [being] radical, or have a completely different view. The answer is to have the right answer. But the problem is that we don’t know what the right answer is, right? So what […] fascinates me is ideas that not many people will conceive, rght? And which could be right [or] could be wrong. But if they are right, these open a completely different avenue on which you can, in this particular case, tackle the brain. Perhaps some behaviors could be ameliorated by using microbial based treatments, and others they would have to go with a more conventional route that will essentially affect directly the brain.

Peter [19:06] 

Thank you for those perspectives. I wanted to transition a little bit to some more personal questions. I know you have received numerous awards: the Alkek Award for Pilot Projects and Experimental Therapeutics; you are awarded the Eppendorf Science Prize for Neurobiology for your essay on switching memories on and off; and you’ve been named-dropped on Jeopardy for one of the questions. I was wondering what is the accomplishment that you’re most proud of? And what continues to motivate the research that you do?

Dr. Costa-Mattioli [19:34] 

That’s a great question that I asked myself every day and frankly speaking, I don’t believe I have discovered anything so far. I believe that she has been playing around with a few things and some of them they have become have been important and some others they don’t, I believe that the times are headed the best to come. This is what essentially makes me wake up very early in the morning and makes me go to bed very late at night, some of those ideas and concepts. So I’m not by any means [settled]. And frankly speaking, I was speaking with someone just a few days ago, and I was telling the person that I really felt that there was not much that I have done, because there are these people that they have [had such] great accomplishments. So I think, I hope, the better is still to come.

Peter [20:28] 

That’s very humbling to hear. You have done so many things that have been so successful, and you have such a great experience and I was wondering if you could think about what a common mistake graduate students do, or someone who’s just entering the scientific field, what is something that they frequently make a mistake of. And how would you go about trying to help them fix this?

Dr. Costa-Mattioli [20:47] 

So there are a few rules that you know that I set in into my mind, right? So the first one is trust no one. So as a grad student comes to a lab and start to work on a project and the believe that the project supposed to work in a similar way that the Cell or the Nature paper that was published by another graduate student, [but] you have to see it with your own eyes. So this is a clear thing that student has to go and see when your own eyes and if the experiment doesn’t work one, two, three or four times, this is the moment where you need to go and be vocal and, and tell people that perhaps you’re not doing things the right way and get all the help to see whether you can build your story and continue with this. The other important thing is you need to be curious and curiosity might not just be driven by your PI. [You should be driven by a] specific aspect of the biology that you are doing that your PI is not thinking [of]. You need to go to the office and say, guys, what I’m interested in this, because this is a way more important question than doing what you’re telling me to do, right? So I think those are, a few [pieces of] advice that I will give to entering grad students. Never get discouraged. Never get discouraged. […] This is a marathon, this is not a sprint, for some people could be a sprint, but for the majority of us it’s a marathon. This is something that takes time. Your PhD takes time […] Now that I’m thinking [about it], I will tell you what I think is the more important factor. The more important factor is learning to fail. And if you learn to fail, because in science you fail every single day, every single day is a failure. The majority of the experiments that you do, they don’t work. If you learn to fail, or how to fail, or how to cope with that failure, things become much easier because you don’t go back depressed, because you know! You know at the onset that  things are not going to work. And when they work it’s sort of a gift.

Peter [22:56] 

So it all comes down to- the first thing you said was, trust no one, but trust your own experiments. And that invariably is going to lead to a lot of failure. It is not easy to repeat what other people have done, maybe they did something slightly differently, maybe they thought about something that they didn’t write down in the protocol. But going through that process, learning a little bit about it, is what you think is kind of essential to the growth of someone as a scientist and something that they should take with them moving forward.

Dr. Costa-Mattioli [23:21] 

I take it seriously because you go and you do an experiment, you find a paper that was published, you go you do it in two minutes, the experiment didn’t work. This is the easy thing. Of course, it’s not going to work because you didn’t optimize it. For every single of the experiments that we do, we need to essentially optimize the protocol, find that particular window, where the experiment essentially [can live]. Give the experiment a chance to be successful. Right, so from the moment that you have a story, which is strong, and you believe in it, this is where your PhD starts.

Peter [24:12] 

I’ve seen in some of your other interviews that you reference Eric Kandel influencing your decision to delve into the neuroscience field. What advice do you have for someone who is trying to delve into a field that is slightly different? I know previously, you’ve done a lot of work in virology and microbiology. And then having heard this talk from him, you felt like your lab was really well positioned to move into understanding the mechanisms that are driving memory. So how do you go from someone who is a microbiologist, a protein lab to someone who studies memory or what advice do you have for someone who is trying to make a career job.

Dr. Costa-Mattioli [24:47] 

As I said, I mean, in retrospect, you work it out. But the shift was risky. So I was reading a book by Francis Crick the other day, which he was just saying that before, of course, the discovery of the DNA structure, he just knew physics. He had absolutely no idea about biology, but he had an ability to turn into things and turn these things to work. So there’s a lot of determination in going and a lot of cojones, as well, because you need to move from area in which you are comfortable with. For most of the scientists, I will say when they reach the age of 30-35, they are established already. The possibility to change their career to a new direction is very low. In my case, I am interested in biology. And if you come to my lab, and you […] show me something that gets me excited, I don’t care where this is going to bring me because I’m interested. That’s my thrill. Now, in that process, you’re required to get to know the field and there’s a lot of learning. The way that I have done it is consulted and learn from experts in the field, the best that I could find in electrophysiology, the best that I could find in behavior, and just go and reach out to them.

As a postdoc, I went into their office, and I told them, this is my idea, they told me you’re crazy. It doesn’t matter, because it helps me and they didn’t listen to me and ultimately it paid off. And in the case of that very late switch, you know, from say, memory to microbiome-brain, as you pointed out, to me, it was like a natural transition, because, you know, I knew about evolution. I knew about microbiology and, and during my PhD, I was looking at how particular selective pressure will affect a viral population and how the virus could escape. So I would say that the transition has been smooth. But I have so much to learn, I have colleagues like Jeff Gordon, [sic], and others, which are experts in the microbiome, that every single time I have a chance to read their papers or meet them in conference, I learn so much from them. And I think this is what keeps me going: learning every single day so I feel like a student again. Learning new things. Going to different directions. Some of them are crazy. Some of them are more conservative. But I think this is what science is about. And this is how we do science in my lab.

Peter [27:29] 

Yeah, it’s really nice to see how you’ve kind of kept that curiosity, kept that passion with you, and it hasn’t really subsided. Or maybe it has, but you have kept it with you and its continued with you from your days as a graduate student to a postdoc to now. I was wondering, just one last piece of advice from you that you could give to someone who is going into that new field, starting a new lab, being a PI for the first time, what advice would you give to them to develop their ideas or how you think some of the problems that they may run through.

Dr. Costa-Mattioli [28:01] 

So times have changed from when some of my mentors became PIs to the moment that I became a PI. We have a tremendous pressure for funding, what I see repeated time and time, again, is that people who start the labs, and the first thing that they do is they start to write grants. Of course [this is the case], because they want to have money to run their operation. When you start your lab, if you end up in a great institution like Duke, for instance, they will give you enough money to do science for a few years. And this is the time that I feel that is remarkable, because all you have to do is do your science and show your science. Forget for the first year or two years about grants. Do your science. Do [the] more interesting experiments that you want to do. If your experiments are good, if you’re sinking correctly, that science is going to bring money. And that money should support more science. And if the science is good, is going to bring more money. And this is the cycle that all of us we get into. From the moment that you are in, the cycle is non-stop. But during those first two or three years, you are not in the cycle, don’t get into the cycle until you need to.

Peter [29:22] 

I feel like it’s hard to feel like you’re not part of the cycle.

Dr. Costa-Mattioli [29:25] 

It’s fine, it’s fine. You will be an amazing outsider. Don’t worry about money doing your science. And I think you know, for some of the people that I discussed [earlier], they just told me, oh my God, I didn’t have those first two years in which I was enjoying doing the experiments myself and teaching my post-docs or students. They are so committed. I understand the pressure. The pressure is massive. The funding is actually low. We have great science and unfortunately part of the great science doesn’t get funded. So I really hope that these agencies like NIH, the government, the DOD and so on increase the payment and support those great projects […] because we have other countries like you know, like China or South Korea, which are putting tremendous amount of money in science. And I think you know, the innovation that we have in the US is still top, but we need to keep it away.

Peter [30:26] 

We have to continue to foster [our science]. Well, thank you so much for your time, Dr. Costa-Mattioli.

Dr. Costa-Mattioli [30:30]

My pleasure.

Peter [30:40]

From memories to microbes, we have got the chance to see how Dr. Costa-Mattioli has not let himself be defined by one particular field. It was the refusal to let go of an interesting finding that sparked his curiosity that has made it easy for him to push forward into new fields. I feel like we should take this mentality and try and invest a little bit of time every month to reflect on what excites us about what we do. Perhaps even write it down or share it with someone. If nothing comes to mind, maybe it’s time to rethink our approach to our work. Just some food for thought until next time. And thank you so much for listening. For more of our content, you can follow us on Twitter @gutbrains or visit our website at thinkgastronauts com. The Gastronauts Podcast would be impossible without the incredible team that we have here. Meredith Schmehl is our producer and the music composer. Dr. Laura Rupprecht is our social media manager. And special thanks to the founders of Gastronauts Dr. Diego Bohórquez and the Bohórquez laboratory