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Podcast: Ask the crab
A chat with Eve Marder

Dr. Eve Marder
I have a perverse side in me.

Vivien
Hi and welcome to conversations with scientists, I’m Vivien Marx. Just so you know, this is not an X-rated podcast. You just heard a comment from neuroscientist Dr. Eve Marder from Brandeis University. She studies how neurons and circuits of neurons work to generate behavior such as walking, or swimming or food digestion and how the circuits change over the lifetime of an animal. For much of her work she studies lobsters and crabs specifically the 30 neurons of the stomatogastric ganglion.

[0:40] Eve Marder
I often tell my people that they should go ask the crab how it does it right, because the crab knows the answers. I say, don't fall in love with your own ideas. Just ask the crab.
Vivien
You will hear more about the crab and about the brain in this episode of this podcast called conversations with scientists. Today it’s about brain models called organoids.
Just first ever so briefly about this podcast. In my reporting, I speak with scientists around the world, and this podcast is a way to share more of what I find out. This podcast takes you into the science, and it's about the people doing the science. You can find some of my work, for example, in Nature journals that are part of Nature portfolio. That's where you find studies by working scientists. A number of those journals offer science journalism, such as pieces by science journalists like me. Ok back to Dr Marder.
I spoke with her ages ago about organoids and using organoids to study the brain.
In talking to a neuroscientist, one way to get off on the wrong foot is to ask them about the mini-brains in the dish on their lab bench. It’s not that the blob in the dish doesn’t somehow look like a piece of living tissue that could be a piece of brain.
Or that this blob isn’t relevant to studying the brain. It is. Organoids are grown from stem cells that were coaxed to become neurons. They differentiate and grow into a three dimensional object. And these objects are becoming more complex and more dynamic in labs around the world.
Some labs are connecting organoids and making assembloids. But these are not mini-brains in a dish. They are a model of the brain.
Actually according to Eve Marder, they are biological theory.

[2:35] Eve Marder
I think the only way to think about organized in my mind is to think of them as biological theory, in a sense, because what you're doing is you're constructing something which is not the same as the real brain. But if you do it extremely well. And if you ask the right questions that might lead you to insights that could lead you to do better or more insightful questions in the real brain

Vivien
Theory in biology, as Eve Marder has written in one of her columns in the journal eLife is what she calls “disciplined dreaming.” The discipline aspect comes from, as she points out “the challenge of creatively marrying the rules of mathematics and physics with what is known of fundamental biological principles.”
So how does this connect to organoids. I noticed that some stem cell researchers and neuroscientists had quite disparate views of organoids. So I asked Eve Marder about this.
[
3:35] Eve Marder
There are many experimentalists who distrust theory in general, and because they think theory, by definition, is not real. And then there are many people who misunderstand the role of theory because as far as I'm concerned, theory is to suggest new ways of thinking rather than to replicate what's already known. So I wrote a piece, a little piece called Theoretical Musing that I can send you, which is about theory, but I think there are some analogies between the reactions to the experimental community to organoids, which it's not quite the same, but it shares some of the same features of the distress between people who are really studying what actually is, and people who are trying to build things to gain insight into how things might be, because I think the only way to think about organized in my mind is to think of them as biological theory, in a sense, because what you're doing is you're constructing something which is not the same as the real brain, but if you do it extremely well, and if you ask the right questions that might lead you to insights that could lead you to do better or more insightful questions in the real brain.

Vivien
The real brain is hard to study especially for scientists who want to watch and learn from the developing brain of a person. After all, a fetus growing in his or her mother’s belly cannot be observed or perturbed.
And to understand neurodevelopmental disorders for example, physician scientists are eager to understand exactly what might be going awry in those early phases of development. So maybe organoids are perfect to study the brain as it develops.

[5:50]Eve Marder
I have a perverse side in me, which is why I still study lobsters and crabs and things like that. But that perverse side of me, which I'm very proud of, finds organoids extremely intriguing. And then the conservative neuroscience reductions in me still believes that they're made up so that there are things you're going to see in organoids that may be not terribly useful in terms of understanding how things work in the real brain. And there are other things that are going to be revealed in organoids that could open up whole new lines of investigation because you see something you never would have otherwise imagined in that way.
And I'm perfectly capable of maintaining two belief systems which seem to be mutually system. At the same time, I learned that from my mother, who was very able to always do that. But I think both are true in the sense that organized tell you a lot about the potential of biological materials themselves, but they are not going to tell you how the actual brain did it they're going to tell you potentially could give you insight into many of the fundamental mechanism. But the way those fundamental mechanism are called into play during normal brain development might be different in important ways and possibly unpredictably important ways.
So I think it's a fabulous thing for people to do, and it should be thought of. I think in the same way that I think really good theory is incredibly instructive in revealing in neuroscience because you can do in theory things that you could never actually do experimentally. And likewise, with the organizers experiments you could do that are not feasible in the same way in a normally developing brain.

Vivien
As scientists embrace these multiple sides to their scientific personality, they can consider how and when they might use organoids.
For anyone looking to develop treatment of neurophysiological or neurodevelopmental disorders, the answer might be ultimately about drugs. Perhaps organoids are a great way to test drugs for all sorts of brain disorders and could be a boon to pharmacology. Here’s Eve Marder.

[8:35] Eve Marder
Part of me believes very deeply that all the pharmacology that we need to do should be done in human cells. If you're looking for Therapeutics, for someone who's interested in Therapeutics for human physiological or neurophysiological neurological disorders, I would rather see all of that pharmacology done in human cells, whether it's human slices, whether it's organized, I just don't care, but I'd rather see it at human cells, and I'd rather see it as close to physiological temperature human cells for potential treatments. Okay.

Vivien
Human cells for potential treatments, ok. Some researchers are looking into fundamental principles about how the brain works. And organoids might help them do so.
But they will need to be careful about the conclusions they draw. They might be thinking about taking their findings and eventually applying them for therapeutic purposes. With that goal in mind, when they are studying a research organism or use neurons from animals, scientists need to be extra careful, says Eve Marder.
Some researchers are looking into fundamental principles about how the brain works, and organoids might help them do so. But they will need to be careful about the conclusions they draw, and they might be thinking about taking their findings and eventually applying them for therapeutic purposes. With that goal in mind, when they are studying a research organism or when they use neurons from animals, scientists need to be extra careful, says Eve Marder.

[9:45] Eve Marder
There's a real puzzle in biology, which is how do you know when you've come across a really fundamental general principle? And how do you know when you're studying the idiosyncrasies of a particular species or a particular part of the brain or particular neurons or a particular whatever? And so the really, really best intuitive scientists are very good at having a sense that, yes, they're studying a particular part of the brain in a particular species, and yet they can suss out or articulate the general principles, and other people are trapped by the idiosyncrasies of their preparations.
Now, one of the places that more less than perfectly instructive work has happened, is it the real level of pharmacology? Drugs do different things in different species, drugs with different things and different cell types. Drugs do different things at different temperatures. Drugs do different things at different PHS. So in thinking about Therapeutics, if I were thinking about looking for a new drug to work on a calcium channel, for a human, I would really like a test to any of the cells, whether it's human slice cells or human culture cells or organized or whatever it is.
Just because if you're going to give a drug to humans, you should know what it does to human cells. And I don't really care what it does to mouse cells. And I don't really care what it does to rat cells. And I certainly don't care what it does to mouse cells measured at 20 degrees.

Vivien
When using cells or organoids for Eve Marder, it's about being mindful watchful careful about these conditions when hunting for fundamental principles that might one day be part of development of a therapeutic. Experimental conditions can vary from lab to lab and might vary from experiment to experiment. But scientists will want to try to make these conditions as stable and consistent as possible.

[11:45] Eve Marder
Yes, experimental conditions make all the difference in the world. Organized, done with human tissue at least have the advantage that they're human. I mean, they're not a human brain, but they're human.

Vivien
Some researchers, such as the lab of Sergio Pasca at Stanford University, construct assembly and link organoids together. They might, for example, stimulate a motor neurons to make a muscle Twitch in an organoids. In a lab dish.

[12:20] Eve Marder
There are trillion of ways to build a circuit to do X. And if all you're looking for to make the muscle Twitch, the fact that you've got a circuit that when you fire some pieces with the muscle moves tells you nothing about the organization of the circuit in the animal. That's where I'd say you have multiple solutions. You just found a evolution that will do that. It doesn't tell you anything about the organization of the circuit in the animal. And if you really want to understand the spinal circuits in the animal, he's got to study the spinal circuits in the animal.

Vivien
Organoids seems to give scientists compelling access to a developing brain. And perhaps organoids can help a lab find out something new about neural development in the brain. Some scientists say findings from organoids will be insightful about the real brain, but others are skeptical. Both sides are true here's Eve Marder.

[13:15] Eve Marder
There are things that you're going to learn studying from organoids that maybe you don't have access to in people. But once you think you've understood something new, you, in a sense, have to be able to go back now. Could you find a new fundamental principle? Absolutely. I would hope so. Could you do a manipulation that will cause you to think about some fundamental problems in new ways? I hope so. But is the way the organization does it the way it happens in utero. Maybe, maybe not.

Vivien
When using organoids, there might be a temptation to believe that findings transfer to what is happening in the human brain, say, during pregnancy, researchers could indeed find something new and something important about neural development.

[14:05] Eve Marder
So that's what I'm saying. I'm capable of maintaining what looks like mutually inconsistent positions at the same time. I'm not going to tell you that organized aren't going to tell you anything about neural development, but I'm telling you that if you're lucky, you're going to learn something completely new, which then you have to go back and see how it plays out, how that mechanism plays out in normal development. And the organizer is not a brain. It's not a developing baby. Things are not timed the same way.
Yes, you have access to the components. And yes, you're making tissue and layers and this and that. And if you're really clever and ask the right questions, you will learn a lot about tissue formation, but it doesn't tell you that that's the way it's actually happening. That's why you have those two conflicting points of view. And you'll have people who will feel very strongly on the one hand or very strongly on the other hand, and they're evangelical on both sides. But actually, both are true. And the real key is to force people to be scrupulously honest about what they think.
The new principles are that they have learned. And I really do think if you're a really clever, intuitive person studying organoids that you're going to discover things that we didn't know precisely because you have access. But then you have to figure out how those things play out.

Vivien
Labs will have various approaches in the ways that they use organoids as they explore any number of questions about the brain in her lab. Eve Marder does not tell her team to definitely use organoids or to definitely not use them.

[16:05]Eve Marder
Usually when someone in my lab wants to do something, I say, oh, sure. Try it, see what happens. And I would also like to say that almost everything new and wonderful we've done was because somebody in my lab either did it without asking me or told me after they did it or mentioned and I said, sure, and I forgot about it and they did something and they saw something. So in honesty, most really good senior scientists benefited enormously from the creativity and the initiative of their junior people, and their job is to encourage that and not to tell those people what the answer that they should be getting is right.
So I often tell my people that they should go ask the crab how it does it right, because the crab knows the answers. And I say, don't fall in love with your own ideas. Just ask the crab, right? Because there's a difference between the way you think things work and the way they actually work. And you have to figure out how to extract that knowledge from the biology. If you're interested in how the biology actually happens, if you're interested in and this played itself out in computational neuroscience and artificial intelligence, if what you're interested in is building a new brain out of Silicon to do things better than the human brain, then you don't necessarily care how the human brain does it.
If you're interested in building models to understand how the human brain does it or how the insect brain does it, then at some point, you have to go back and ask, Is this the way the brain actually does it? So both things are. I'm perfectly comfortable with people who really are all about artificial intelligence, all about trying to build a new generation of intelligent creatures that just don't happen to be biological. And that's fine. And then there are people who want to use computational theoretical methods to understand the nervous system.
And that's quite wonderful. But they, too, cannot be confounded. You have to be clear on what your goals are. And I think in the same way, the organized people, I think have to be clear what their goals are, and they may be a little fuzzy about that. They're probably not being careful enough to say, look, I'm studying the potential mechanism, and I'm seeing things that would be difficult to see otherwise. And hopefully I'll learn new principles. And maybe this will tell us what we should be looking for in naturally developing brain.

Vivien
That was 'Conversations with Scientists.' Today's episode was with Dr. Eve Marder from Brandeis University. And I just wanted to say, because there's confusion about these things, sometimes there was no payment involved to be in this podcast. This is independent journalism produced by me in my living room. I'm Vivien Marx. Thanks for listening.