Rachel Tompa
So, Saskia — I want to start with a softball question for you. What’s taking you guys so long to figure out the brain?

Saskia De Vries
Uh Yeah, so that’s really the big question. I think there’s a lot of factors to it. You know, a lot of it is that we’re poking around in the pile of tissue that, you know, it’s you have to kind of figure your way around the tissue and figure out how to access things. It’s kind of well-hidden by this really big piece of bone. And so, gaining access to the brain, and then gaining access to the brain in an informative way are two challenges that are related, but aren’t exactly the same thing. And so there’s been a lot of technology and even in recent years, there’s, I think, been a huge like acceleration of technological advances that have really helped us to better map the brain and better access neural activity in a variety of different ways. But these are recent, right? And so, for years, we were going in with these wires to record from single cells and you go in kind of essentially blind where you’re putting this wire in the brain, and then you just kind of like maybe here’s a cell, maybe this is a cell and you know, it really is a little bit like you know, fishing in the dark a little bit.

Rob Piercy
Poor Saskia. If that was your softball question, I’d really hate to hear what your hardball question is.

Rachel Tompa
Yeah, I like to put my interview subjects on edge right off the bat, that’s my technique. That was Saskia De Vries, Ph.D., a neuroscientist at the Allen Institute. We’re talking today about why it’s so hard to understand the brain. I have a tough question for you too, Rob — how does your brain work?

Rob Piercy
Now this is all about context – if you’re talking about my brain before two cups of coffee or after, I would give you two completely different answers.

Rachel Tompa
How many cups of coffee are you running on right now?

Rob Piercy
I’ve had the requisite two, so I think we’re good to go here. I guess my question back to you is: are you going to tell me how my brain works?

Rachel Tompa
Sorry to disappoint you, but no. I have no idea how your brain works.

Rob Piercy
Neither do I… I’m Rob Piercy.

Rachel Tompa
I’m Rachel Tompa, [Ph.D.]

Rob Piercy
And this is Lab Notes, a podcast from the Allen Institute.

Rachel Tompa
When I think about my organs, not that I think about them that often, I feel like I have a good sense about how my heart works. It’s a muscle, it contracts, blood pumps in and out, voila my body gets oxygen. Now I’m sure if any cardiologists are listening to this that’s a massive oversimplification. But the brain — I can’t really sum it up. Information gets converted into electricity, and then it bounces around in my skull, and then… somehow… I have a thought?

Rob Piercy
A lot of things are complicated and hard to explain though. I don’t understand quantum physics, but smart physicists out there get it. Do neuroscientists understand how the brain works?

Rachel Tompa
That’s the thing, they do not — not yet. We’ve talked to scientists in the past about the big mysteries they’re trying to solve about the brain — and there are a lot — but for today’s episode, I wanted to ask them why there are so many mysteries. Why don’t we understand the brain yet?

Stephen Smith, [Ph.D.], another neuroscientist at the Allen Institute, has this perspective on it.

Stephen Smith
The numbers get out of hand really quick for brains. The number of synapses in one human brain is equal to the number of stars in 5000 Milky Way’s. And then every synapse has something on the order of 100,000 molecular switches in it. And these 100,000 switches, protein molecules in every synapse, communicate a lot with one another, they interact a lot. And then that’s in one synapse, and then the, the human has something between 10 to the 14th, and 10, to the 15th synapses. Now, okay, so there’s a lot of complexity. And then to make matters worse, it is intricately arranged in very tight quarters. So the synapse again, there’s a billion of them per microliter of brain volume in a human. remember that each one of those synapses has somewhere between 10 and 100,000, switches in it. So here I go, trying to dazzle you with numbers. It’s a hard problem. And maybe, in two words, the problem can be summed up as it’s complicated.

Stephen Smith
What I said, could be said about all living things, it could be said about bacteria, I mean, the numbers aren’t quite as astronomical. But we really don’t understand bacteria all that well. So, you know, the simple way of putting it is we don’t understand brains, because they’re part of life and life is complicated. And we still don’t understand that very well. Try as we may have. However, you know, that’s the sort of glass half empty view of it, we understand it a lot better than we did a year ago with each passing year.

Rob Piercy
Maybe your assertion that you understand how your heart works isn’t accurate then.

Rachel Tompa
Right, Stephen’s really taking me down a notch there. I also asked Saskia whether the brain is more complicated than other organs.

Rachel Tompa
I guess for my, you know, mostly lay person’s perspective, I feel like we have a general understanding of like how the heart produces a heartbeat, and how it moves blood around your body. But we don’t have a general understanding of how the brain produces thoughts and behaviors.

Saskia De Vries
Well, I think even just like, the difference between those sentences is we know how a heart produces a heartbeat. We don’t know how a brain produces a thought, I don’t even know how I would define what a thought is. Right. And so, I think one of the challenges there is that how do we measure a thought? And so let alone how the brain is creating that thought, how do we measure that thought, how do we measure memory in the moment, right. And so, I think that’s a little bit part of the challenge is that kind of the output of the brain is more abstract than the output of the heart or the kidney. Our ability to access the brain while animals or humans are engaged in the world, is really, it’s really difficult.

Rob Piercy
So, the brain is hard to study in action, and it’s hard to define what it does in a tidy sentence, I get it. But it’s also legitimately complicated. Bacteria might be complicated, and the human heart is pretty complicated, but the brain is really, really complicated, right?

Rachel Tompa
Yes, totally. Like Stephen was saying, it has a lot of parts — the human brain has somewhere around 86 billion neurons, which are not the only cell in the brain — but they’re thought to be the main conveyers of information. We also have this ridiculously huge number of synapses, the connections between neurons. And there’s so much variability among all these cells and all these synapses, it’s not as if we just had some way to perfectly model a single neuron and all its connections 86 billion times we’d be able to recreate our brain on a computer, it’s so much more complex than that.

Here’s Christof Koch, [Ph.D.], Chief Scientist of the Allen Institute’s MindScope Program.

Christof Koch
It’s by far the most complex system humanity has ever been confronted with. So if you’re just looking at, you know, besides the universe as a whole, but if you’re looking at entities like bodies, and stars and trees, and rocks, and microbes and viruses and planets, in its complexity, organisms in general, and in particular, the brain sort of being by far by any metric, the most complex piece of highly organized active matter in the in the universe, it’s no question about it. And all these successful scientific theories that we have, they typically deal with highly simplified systems, like elementary particles, or periodic tables, or being able to predict solar eclipses. Those are all puny, simple systems, in comparison, even with a very small brain, let alone a big brain, like ours.

Rob Piercy
Is it just a completely Sisyphean task then, to try to understand the brain?

Rachel Tompa
Hang on, I have an additional complication for you. Describe to me what it looks like when you’re picturing a brain.

Rob Piercy
Ok, umm – I’m visualizing – I’m holding up two fists right now together in the shape of a brain. Something about that size. And it’s gray and it’s wrinkly, just kind of this ball of gray matter.

Rachel Tompa
That sounds a lot like a human brain, and it makes sense that that’s the first image that pops into our heads, because that’s our brain and we’re naturally curious about ourselves. And the brain is really, more than anything, what makes us who we are. It’s maddening in some ways that we don’t understand it yet. How can we understand who we are without understanding the biology of this organ? There are some scientists who think the focus on the human brain, or even on the mammalian brain — because many neuroscientists study mouse or rat brains — is too limiting. So, get ready to hear about some really different brains.

Rob Piercy
I feel like we need to play some spooky music here now

Rachel Tompa
Robyn Crook, [Ph.D.], is an associate professor at San Francisco State University, and a 2021 Allen Distinguished Investigator. The animal she studies is very different from a human.

Rachel Tompa
How complicated is the octopus brain?

Robyn Crook
Yeah, I mean, there’s lots of different ways to evaluate neural complexities aren’t there. And so, in terms of the number of neurons, the octopus nervous system as a whole has half a billion neurons. So that’s larger in in just sheer cell number than a lot of the, the non mammalian vertebrates.

Rachel Tompa
To put that in perspective for us mammals, many small rodents have around 100 million neurons. The lab mouse has a bit less than that, around 70 million.

Rob Piercy
So, octopuses have more than five times as many neurons than a mouse does? I guess that’s not so surprising, given just how intelligent they are. I think we’ve all seen those stories and YouTube videos of octopuses who escape their tanks. There was that famous one from a few years back where it gets out of the tank and then makes its way to drain so it can get back to the ocean. They’re really intelligent creatures.

Rachel Tompa
Yeah, I think we all cheer for the octopus when we see those stories.

Can you describe a bit what the cephalopod or the octopus nervous system is like? When I was reading about it, one thing I was struck by is just how many neurons they have in their arms – so, that’s pretty different from us, right?

Robyn Crook
It is. So, it’s, it’s the all cephalopods have a centralized brain. They have a very large visual system. So, the mass of the central brain is actually dwarfed by the optic lobes, which are these very, very large centers that are associated with each eye. Most of the visual information is processed there, the central brain does a fairly small job. But the really remarkable thing is the degree to which there is peripheral control of the arms, for example, in octopuses, so two thirds of the neurons in the octopus nervous system are actually in the arms, they’re not in the central brain, then the arms have a series of repeating ganglia all the way along them, and those are responsible for receiving and processing input from each sucker. And then the whole arm has a ganglion kind of like where we might imagine our shoulder joint to be. And that communicates processed information from the arm up to the brain and back. And the arms are quite autonomous. So, we know from from a lot of different studies, that a lot of the behaviors that the arms perform, so the rhythmic crawling behavior, the grasping of prey, the coordination among the arms to some degree, is performed without input from the central brain, which seems very extraordinary. But in the mammalian nervous system, a lot of processing happens in our spinal cord that we are not aware of. So, in some ways, the arm is quite analogous to the spinal cord, in in its degree of peripheral control, I think we don’t, as humans, we don’t necessarily appreciate how much of our nervous system is working in the spinal cord without our conscious awareness, because we’re just not thinking about it. So, in a lot of ways, an octopus has one brain and eight spinal cords.

Rob Piercy
OK, that’s just wild.

Rachel Tompa
I know, I think we could do a whole episode on the mysteries of our spinal cord and the octopus arm.

Rob Piercy
But let’s get back to my brain for a moment. I still want to know how it works, and it sounds like it’s really different from an octopus brain.

Rachel Tompa
Yes and no. Robyn had an interesting perspective on what octopuses might teach us about ourselves.

Rachel Tompa
Will better understanding the octopus brain tell us anything about the human brain? Or is that just way too human-centric a question?

Robyn Crook
I mean, I think it? I think it would, because I think that, you know, when we study the human brain, we tend to study it from the perspective of being the most perfect brain there is, you know, when we use laboratory rodents, when we use other mammals, to study aspects of neuroscience, were typically approaching that from the perspective of them being simpler, more approachable models of the human brain. But the human brain is obviously not the only one that’s out there. It’s not the only one that does complicated things. And I think sometimes trying to get at the real fundamentals of brain function, are hard to grasp. If you never look beyond one group of animals, it’s hard to know if this is a fundamental truth about brain structure or brain function, if we never bother to look at a different animal to see if in fact, it isn’t fundamental. And perhaps it’s something very specific to humans. The brains that are present in octopuses and humans are obviously completely different. And so, if we find similar things, similar circuit function, similar molecular underpinnings and similar anatomical structures, that are performing similar computations to produce similar behaviors, I think that says something really interesting about the constraints on our brain, and about the way that our brain has come to be. So absolutely, I think we can learn something about mammalian brains from octopus brains.

Rachel Tompa
Robyn thinks that to understand the brain, we kind of need to understand this brain-shaped box that evolution guided us and the octopus toward. And maybe we can’t understand fully how our own brains evolved without understanding how these other, really complicated but really different animals evolved their brains.

Rob Piercy
OK, so how are we ever going to understand the brain? Or I don’t know – maybe the question is: are we ever going to understand it?

Rachel Tompa
I think those are two separate and really important questions. Scientists are making progress. We know more about the brain now than we did just a few years ago. At the beginning of the episode, Saskia De Vries was talking about how neuroscience used to involve sticking single electrodes into the brain at random, and the field has moved beyond that. From her perspective, there are two really important recent advances. One is a much better understanding of the kinds of cells that make up the brain. Our brains have neurons and blood vessels and all these support cells called glia, but there are probably more than 100 if not more different types of neurons in the brain. Scientists are really pinning down the details of those types in pretty extraordinary ways in the last few years. You’ve been at the Allen Institute for longer than I have, but we’ve both seen this in the last few years, right?

Rob Piercy
Yeah, we’ve gone from studies that were really cutting-edge at the time, sorting a few thousand brain cells into types, to more recently, studies that map an entire large region of the brain, the motor cortex, and really getting at the precise types of cells that make up that region from several different angles.

Rachel Tompa
The other advance is an improvement over recording from neurons with a single electrode. We know the currency of the brain is, well, electrical currents, pardon the pun. Neuroscientists figured out quite a while ago that they could record electrical signals from individual neurons in a living animal and actually see those neurons in action if the animal looked at a picture, or had some other experience. Now there are technologies that can record from hundreds or thousands of neurons at a time, in a living animal. The one that’s being used at the Allen Institute and elsewhere is called Neuropixels. Here’s Christof Koch talking about this really cool technology.

Christof Koch
I remember you know, when I got my PhD last century, the last millennium, you know, people typically spend, you know, days recalling one nerve cell right? Today with our Neuropixels, you know, we can record 1000 or 5000 at a time, and do this day in day out and make all the data available to everyone. So, the progress has been tremendous. But you have to realize, even though there’s big progress compared to what we want to achieve. There are 100 billion neurons in the human brain in the human cortex has 16 billion, you know, if we want to even record from a tiny fraction of it, you know, even a million neurons out of 10 billion is dilution of one in 10,000. Right? So, we were still very far from understanding for instance questions like, what’s a thought?

Rob Piercy
All of this is just mind boggling. And it’s clear why it’s taking so many scientists so many decades of work to even scratch the surface.

Rachel Tompa
I have another hard question for you. Do you think a human being is even capable of understanding the brain? What if it’s too complicated to understand?

Rob Piercy
That’s a great question and one I have heard brought up before by neuroscientists in this very meta way: can the brain understand itself? I dunno.

Rachel Tompa
Right, I asked Saskia this too.

Rachel Tompa
Do you ever wonder if the human brain is even capable of understanding itself?

Saskia De Vries
Is a singular human brain capable of understanding the brain as opposed to is it is a collection of human brains capable of understanding the brain? And I think that those might be different questions, right? We learn a lot, not just through the neural processes of learning, but through our interactions with other people and through conversations and collaboration. And, you know, me working on one question, and you’re working on another question and us seeing where those questions intersect. I do kind of believe in the collective human ability to understand the human brain. While, it’s not like I think it’s impossible for the human brain to understand the human brain, but I think where that’s going to happen is through that collective work.

Rob Piercy
Scientists coming together for a collective understanding of the brain, I like that.

Rachel Tompa
It takes a village to understand the brain? Something like that.

Rob Piercy
At least a village of brains! I’m Rob Piercy

Rachel Tompa
I’m Rachel Tompa.

Rob Piercy
For more Lab Notes episodes and other science news, visit our website at alleninstitute.org.

Rachel Tompa
Thanks for listening.

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