A man can do what he wills but cannot will what he wills.
Arthur Schopenhauer
Have you ever felt that they don’t value your work as much as they should? Have you felt that they’ve gotten used to you just doing things right? If so, you’ll agree that it’s not nice. Well, you do the same thing! You undervalue the work your brain does inside your skull day in and day out, from the time you get out of bed until you get back into it! Just stop to think about how many things your brain ponders when someone asks you how you are doing. It’s a vague question, too vague. But yes, it’s true that the answer can be simple. Sometimes, if you don’t feel like talking, a couple of words is enough. Doing well. Doing bad. Getting by. But it doesn’t mean that your brain is a lazy ass! The reality is that there is a great deal of processing behind these simple words. Then, what do you mean when you say you’re fine?
When you are asked how you are doing you are asked about your current state. That’s to say, whatever you are experiencing at the very moment you are asked the question. Where you are, what you see, what you hear, how healthy you are, how cold, hot, hungry or thirsty you are. But your current state is also everything that happened to you lately with your loved ones and friends, how was work, how well or badly you slept the night before, or how badly you need holidays.
But there’s so much more to it than that. It turns out even these factors influence each other. For example, if you’re extremely cold, you’re probably not as thirsty as if you were hot. Or if you have a problem with your boss, you might not feel like eating as much. And if you’re walking past the window of a chocolate shop, it might whet your appetite even if you weren’t hungry before you walked by.
In short, how we are depends on many things. For example, it’s not as simple as I need nutrients, so I’m hungry, or conversely, I just ate, so I’m not hungry. Our final answer is the result of an infinite computation of multiple factors. Your brain is responsible for the integration of all the information to give rise to an overall state. It integrates visceral signals that come from inside our body, but also signals that come from our perception and our interaction with the world. It’s exciting. It really is. But I can’t tell you as much about it, because I haven’t been studying it for years like Mark Andermann. Mark Andermann’s lab, at Harvard University, tries to understand how our dietary needs can influence what we perceive (or not) in the environment. And conversely, how what we perceive can influence what we need.
Let me tell you a little more about Mark before getting down to business. Mark Andermann grew up in a family of doctors. He was unsatisfied with the current level of understanding of the brain, in discussion with his sisters, parents and grandparents, all of whom were treating patients. He became a physicist at McGill University. He did a summer project on human neuroimaging at Montreal Neurological Institute that Wilder Penfield had founded 90 years before. It was an inspiring time for Mark, because it was when he realized that neuroscience was an opportunity to connect with many kinds of people at different levels: clinicians studying the brain, engineers, physicists, and even philosophers. What all of them had in common was the eagerness to understand the 2 kg of matter that we harbor inside the skull.
Juan Garcia Ruiz: You try to understand how our needs are shaped by what we perceive. How would you explain this research topic to a child?
Mark Andermann: Sometimes when you see food you become hungry. So sometimes when people ask me about what I do, I tell them that I study that. The way neuroscience had built this idea was slightly different: when you need calories, you become hungry. And then when you see food you get a desire to eat it. What I think is that there is really an interesting dialogue between our experience of the world and our feelings of hunger. Our brains are designed to get everything we need. But the brain knows that we won’t necessarily have access to everything all the time. So when the brain suddenly encounters food, it prioritizes it and seeks it. About a decade ago, we started studying the hypothalamus, one of the most ancient parts of the brain that we share with lizards. That part of the brain is related to the drive to seek food. What we discovered together with other groups was that when a mouse sees a picture of food, that very exposure could modulate the hypothalamus. So there was no distinction between parts of the brain that control our drives and that perceive the availability of that food in the world: they were all working through the same brain circuits.
JGR: Let’s see it now the other way around, the way neuroscience built this idea. If we perceive what we need (instead of we perceive, therefore we desire) and our nutritional needs change during the day, could this mean that the focus of our perception changes accordingly?
MA: There are parts of our brain that are there to defend against starvation that only care about calories, whether they’re from fats or from carbohydrates. But there are other reasons that might explain why in the morning you want to have more bread and carbohydrates, and in the evening you want to have more fats. And that’s possibly because fats are easier to store while carbohydrates are easier to burn right away when you know you’re going to need them. As soon as the brain needs something, it will pay attention to that specific kind of thing. Even a baby can do this. There’s something called the wisdom of the body, that was coined to define how a baby would discover from eating broccoli which mineral was missing. And then next time the baby misses that mineral, it will look for broccoli. One of the most interesting outcomes is that when it comes to processed foods, where instead of broccoli you have a package with broccoli powder in it, we can no longer understand the relationship between the food we eat and the ingredients that it provides to our body. So we no longer are able to make the same kinds of learned predictions that we evolved to make.
JGR: I see, so with processed food we can maybe realize that we are eating something that we were lacking but there’s physically nothing we can associate that to?
MA: Yes. It’s very hard to relate a candy bar package to all the calories inside, because it’s not proportional to the size of the food. I think a lot of modern food decisions are challenged by the fact that we don’t really have an easy mapping of foods or a correct sensory processing of food calories and food composition.
JGR: You study food perception and needs in rodents. Our case as human beings is a bit different because we don’t need to hunt or to look for food in nature. We have supermarkets. Is our perception, as human beings, shaped by our needs like it is for other species like mice? I guess we don’t need to struggle to get what we need so we don’t need to engage our perception as much as animals that hunt for example.
MA: It is not an easy question. The easy availability of food is only about 200 years old phenomenon, but our brains haven’t really changed much in 200 years or so. That doesn’t mean that there isn’t cultural transmission and other environmental factors that we can learn over our lifetime about food availability. And that may affect what we care about and what we perceive for sure, that’s true. But when it’s late at night and you’re very tired, all the basic instincts that evolved before supermarkets take over. And then there’s another layer that we’ve developed particularly well as humans to say “no, no, I can wait until later even if I see the food now, this isn’t what I’m supposed to be eating”. But those circuits can be weak unless parents and schools train them early in life.
JGR: You focus your research on the way perception interacts with our nutritional needs. But are there other needs that you consider as crucial as nutrition? Are social needs at the same level?
MA: Ultimately, I think there are two needs that rule them all: one is survival and the other is procreation to extend your genes. All other needs extend from that. So there’s a need to find temperatures that are sustainable for survival. There’s a need to find enough calories to survive, obviously. And there’s a need to sleep, which we don’t understand very well, but we’re beginning to understand. So these are fundamental needs that are derived from the need for survival. I believe, and it’s a bit controversial, that social needs are essentially survival needs. Social needs are real. If you’re in social isolation, it’s like removing food. There are behaviors that even animals make that only happen when you’ve had an accumulating amount of deprivation of social interactions. So we see that as a need. But we see it as a need that’s very much selfish in the sense that it helps individuals survive in hard situations like when there’s aggression, and it also helps to ensure that offspring will survive. It’s very hard to see any of this other than in a biological utility perspective.
JGR: Needs are not only shaping what we perceive, but also what we learn and remember. Is that right?
MA: Over the course of evolution, parts of the brain, like the cortex, have expanded a lot more than the core of need drivers in the hypothalamus, in the bottom of the brain. But that expansion hasn’t occurred so that we can watch Pokemon. The expansion is simply to help us meet our needs better. And one way that we can do a better job of meeting our needs is to become more sophisticated in how we search for food. So if we have very good memory that allows us to think about where we found a source of food not only a day ago, but even a month ago, we will have a greater chance of finding that source of food again. That’s how memory helps us to survive. Similarly, we have ways of learning that depend on what we need. It is the case for flies. If they are starved, they can learn about sources of food while they won’t learn about potential situations where they can be punished, because what really matters to them at that moment is calories. So everything about how we learn depends on what we need.
JGR: How could your research impact society?
MA: The feeding research we’ve done in mice can impact society in three ways. The first way is psychological. Many people are criticized by society as having a weak will, as if they just weren’t strong willed enough to not eat this food. But we are showing that there are very powerful circuits controlling this. I can point to specific neurons and say, “look, in this mouse that just ate a whole Thanksgiving dinner, you can turn on 10,000 neurons, and they will eat another 10% of its body weight: the mouse has no control once those neurons are on”. And I think that’s helpful as a way to see this as something more than just your will, which is actually a flawed idea.
The second way this research is helpful is that as we are identifying the specific neurons that drive us to need food and to seek it, we are also getting a list of all of the proteins and all of the receptors in those cells. We know that those cells are conserved in humans, because they’re so ancient: they’re present in lizards, mice and humans. So that allows us to go to a drug company and say, “here’s a list of receptors, please make drugs that are better and more specific, with fewer side effects, because the receptors are in these neurons and not in others”.
The third way that this research helps society is the most surprising one. We and other groups found that when a mouse is hungry, those neurons that promote feeding and foraging do that partly by suppressing pain and anxiety. Because obviously, if you’re in pain or anxious, you’re not going to forage. This inspired us to actually speak to psychiatrists who treat patients with eating disorders like anorexia nervosa. And we’re pushing a new idea forward now in mice. We feel hunger as something aversive. In Spanish you even say matar el hambre(to kill the hunger). But when an animal or a human has previous history of high anxiety, hunger is perceived as a kind of self-medication. We think that dealing with the anxiety before it spins out of control may prevent the development of anorexia nervosa der. In a sense, studying all this in the mouse was necessary to pinpoint the specific neurons that were involved, because we can now target those circuits without the side effects of people weighing less than 100 pounds. So we can just target the anxiety and pain circuits without targeting the hunger circuits directly.
JGR: What are the specific questions that your team is trying to answer right now?
MA: I received training on the study of external senses like hearing, touch and vision. Then I started to realize that we have a limited understanding in how our brains sense signals related to hunger and thirst, so I decided to focus on that. The reason why it’s so poorly understood is because while we’ve used televisions to study vision and fancy sound systems to study hearing, we have no equivalent way of controlling the signals that go from our body to our brain. At least until very recently. What we’re trying to understand as a lab is how the brain senses all of the signals in the body in a holistic way. By holistic, what I mean is not just from the heart, the stomach, or the bladder, but from all of the regions of the body including even the bloodstream, and not just through nerves that innervate the body and send signals to the brain. We think that there are regions in the brain that are integrating all possible information about the body and using that as a kind of context. For instance when you’re in the supermarket, you get really hungry for the food you see. That’s a spatial context. But a lot of the signals from the body together create an interoceptive context. That context is critical for understanding drives, but also for understanding addiction and withdrawal states.
JGR: To study the motivation of an animal to do something, I guess first you need to create a need. I can imagine that’s not the most difficult part, since you can easily create a state of hunger for instance to study its motivation to eat. But I wonder how you manage to study the consequent perception. I mean, you cannot just ask an animal: hey, what are the sensory cues you attending to right now? So how do you approach that matter?
MA: That’s a fantastic question. It’s exactly why I got into this field. A brilliant Postdoctoral Fellow, Yoav Livneh, worked with me and with Brad Lowell on this for several years. He started with these neurons that I mentioned in the hypothalamus. When you turn them on in a not hungry animal the animal starts to eat. But what happens if there’s no food around? The animal searches for food.
Then, if you present an animal with pictures or smells of food, there are some brain regions in the cortex that become active. But only when the animals are hungry. They are no longer responsive to pictures of food if they are sated. But if you turn on just about 10,000 neurons in the hypothalamus, now the cortex starts to become responsive to food pictures again.
So even though we can’t ask the mouse if it is attending to the food, we can actually see that the mouse’s brain is reacting to it. Once we knew that those hypothalamic neurons were somehow affecting the whole brain and making it look like the response to food that you’d see in a hungry brain, we could start studying the pathway from the hypothalamus to the cortex. What I mean by that is that we tried to understand the flow of information that goes from a first neuron that talks to a second neuron, that talks to a third neuron, and so on until it reaches the cortex. This was important for us, because it allowed us to go beyond what was known in humans.
JGR: How does our brain process food cues?
MA: There are several brain structures involved. For instance, the amygdala works as a flashlight that cares about things that are very salient, and processes whether they are good things or bad things. It is like turning up the volume on a speaker to make the rest of the brain hear what’s going on at this moment, because it’s an important moment. What we have found is that the hypothalamus neurons that are specifically there to encourage the brain to seek food, they affect the amygdala in a way that is like opening up a gate. So first food pictures come in through our eye into our visual system and they reach the visual cortex. Then, to get to the motivation centers of the brain, these visual signals must pass through the amygdala. But in a sated state they can’t pass. Somehow there’s like a gate that hypothalamus neurons and thalamus neurons can open according to the needs of the body. Then the information can flow to what’s called the insular cortex, which is this region that cares about food when we’re hungry.
We also did some studies where we recorded in the mouse’s visual cortex. When we showed a mouse pictures of food, then we saw from the mouse’s brain activity that the mouse was daydreaming about that same experience even in the dark. If you expose the mouse to other pictures not associated with food, it will also daydream about those but less often. This daydreaming might be important for making the memory of the food experience stronger, so that the next time they see the food they know how to react.
JGR: What are the black boxes of your field of study?
MA: I think one of the frontiers is that we have studied many motivational drives separately in isolation, but we haven’t studied how they compete with each other. We don’t really understand how it is that we change from one goal to another. This idea requires us to merge many different fields and to ask questions more holistically. Similarly, we are not just feeling hungry. We are not just feeling pain. We are feeling all those things. So how is it that we actually perceive one at a given moment and not another. The field has focused in general on both vision and other sensory systems of the cortex. But we and others are discovering that an important part of perception is this shutting down of information transfer right at door into the brain. And that’s a frontier idea, because there’s a lot to be done to understand it.
JGR: If you had infinite funding, what unreasonable experiment would you do?
MA: That’s a great question. I don’t really feel limited by funding. What I think is challenging is the politics of research. I feel limited by the fact that we need to find projects that have outcomes within 3 to 4 years. And some of the questions that I have described, if someone could work on them for 10 or 15 years with no pressures from the world outside, I think it would be much more successful.
But I want to actually answer your question. I used to believe that recording from more and more neurons was not necessarily a good idea. But more recently we published a paper showing that if you record from 6000 neurons at the same time, you can decode the mouse’s thoughts in a way that you could not do very well with 600 neurons. So newer microscopes that allow you to go from 600 to 6000, or even 60000 neurons, are going to change the way we think about the brain.
JGR: What’s the best advice you were given during your career?
MA: I was very lucky to have a PhD mentor named Chris Moore. His advice to me was to be courageous and not to be fearful of risk because if you take risks, individually you will fail a lot but collectively you will have a chance to succeed. But if you don’t take risks then definitely you will fail.
JGR: It’s nice and rare that you got this kind of advice from your supervisor.
MA: I was his first student, so perhaps he was operating at the level of peak optimism.
JGR: What makes a good scientist?
MA: I think that science is hard and not always appreciated by society or by governments. But it is an incredible privilege to get up in the morning and know that your job is to figure out how something works. To me the scientists that I believe are the most fulfilled and probably the most productive, are the ones who are so appreciative of the gift of being able to focus their life on discovery that they see this as the number one payment.
JGR: I am going to try to challenge you by playing devil’s advocate. Research is expensive. Sometimes it requires the use of animals. And yet sometimes it is hard to see the point, especially when you see that there’s a lot of effort made that seems to be vain when it comes, for instance, to curing diseases. But not only in terms of clinical research: it is hard to make sense of fundamental research because it doesn’t bring immediate outputs. What’s your opinion on that matter?
MA: I think it is the responsibility of the government and of scientists to educate taxpayers that certain basic economic realities should motivate them to fund science, rather than trying to convince taxpayers that understanding of knowledge is so valuable that they should pay for it. Even though I believe that’s the most important reason, it is easier to just go by the facts. And the fact is that at least in the United States, every dollar invested in federal research has saved in the past half a century many dollars in health care costs. Even though only a tiny percentage of the projects ever funded ended up resulting in a medication or a cure, statistically it is an extremely good investment. In terms of giving people the ability to convince parents and friends of the value of research, it is important to educate yourself on situations like the development of AIDS therapies. Because the therapies basically came from people that were studying very strange viruses that were not particularly relevant to anything. And they stumbled upon something that ended up being the foundation for incredibly important therapies. There are many other examples including the discovery of insulin, that really came from training people to just care about how the world works and as a byproduct helping society. I think the other reason to care about research is to consider science as a guiding light that continues to teach generations of people how to think about evidence. Without science, this critical thinking could fade and then we would be in big trouble.
JGR: Is there a book you would like to recommend to the readers?
MA: One of the earliest books I was given by my PhD advisor was called Anatomy of a scientific discovery by Jeff Goldberg. It is the story of the discovery of endorphins, which are these natural chemicals released by our body when we go on a long run and in other situations. They’re natural painkillers. What the story details is this incredibly challenging struggle to purify enough of these molecules to understand them. In the process, it illustrates the joy of the scientists that were doing the work, and it is clear that they were savoring the journey.
JGR: Do you have a final message you would like to share?
MA: I think that the one thing that I want to clarify is that I am a white male, and I grew up very sheltered. A lot of the words that I said about the importance of just being inspired and pursue joy in science, I am very aware I can say them because I am very privileged because my family could support itself without worrying about where the next paycheck was coming from, which allowed me to take risks in my training and afterwards. I think there is definitely an awareness that the same fuel that can inspire people to stay in science, is not a fuel that society allows everyone to partake in. That’s why I think there is a bigger role for understanding science in all these other ways, so there’s not only just people like me that can say how satisfied I am with my career. It should be something really available to everyone.
