Sometimes to really find out how brains work you have to get too close for comfort, so we’re looking for brains that have escaped their warm, cozy skulls and made their way into jars and freezers. We even meet something that is very like a brain, but was never inside a skull in the first place. Not AI, but tissue, grown in a lab, for science.
Sometimes to really find out how brains work you have to get too close for comfort, so we’re looking for brains that have escaped their warm, cozy skulls and made their way into jars and freezers. We even meet something that is very like a brain, but was never inside a skull in the first place. Not AI, but tissue, grown in a lab, for science.
Follow the show:
Katie Jensen:
Have you ever seen a brain outside of a body?
[musical effect]
Katie Jensen:
I’m not talking about that animal brain you dissected in biology class. I’m talking about a real-life human brain.
[musical effect]
Dr. Gustavo Turecki [preview]:
Inside the body has a lot of blood around. It has the membranes that cover the brain which are called the meninges. And then the tissue itself has two colours that are appropriately termed “gray matter” and “white matter.” So, when you look at the brain from the outside, what you’re going to see is mostly a gray organ.
[music]
Katie Jensen:
To the naked eye, a brain doesn’t look particularly complicated. The real magic happens when we use scanners, like MRI, to get cozy with our thinking cells. But sometimes that’s not good enough. Sometimes we really want to take it apart and sink our fingers into the cells that control our bodies and minds—for science. But we can’t just open the skull of a living person, take their brain out, play around with it, and stick it back in when we’re done—not without upsetting them.
So. If we want to discover more about the organ that makes us who we are, we have to figure out a way to see it, feed it, and keep it outside its natural cranial habitat. We’ve gotta get that skull out of the way.
[music beats]
Katie Jensen:
So, let’s go find some brains in the wild. We’ve got a list of places we can see a brain outside of the skull, and we’re going to check them out with the help of a few of our favourite researchers.
Running a lab that keeps thousands of frozen brains in Tupperware containers—check.
Feeding drugs to little brains that were grown by scientists in petri dishes—check.
Taking microscopic pictures of a brain with might be the world’s thinnest deli slicer—check.
I’m Katie Jensen. This is Playing With Marbles.
Let’s take a walk together, to one of Canada’s largest mental health research facilities: the Douglas Mental Health University Institute of Montreal.
[outdoor sounds]
Katie Jensen:
If you make your way down the main boulevard, sitting amongst the acres of lush green space is a smattering of brick buildings. Some of them have been there since the late 1800s. Back then, this Institute was known as the Protestant Hospital For The Insane. Despite the spooky name, it was intended to be the most progressive mental health institute in Quebec. This was the first place that anti-psychotic meds were used in North America.
If we open the door to the Perry Building, our surroundings shift from Victorian hospital to modern research institute. Dr. Gustavo Turecki is the scientific director of the Douglas Research Centre. He’s the best tour guide we could ask for.
Dr. Turecki can lead us through the pavilion to a heavy door. Beside it, a plaque that reads “Douglas-Bell Canada Brain Bank.”
[electronic sound]
[music]
Dr. Gustavo Turecki:
The Brain Bank, it’s a place where you get in and then basically have a corridor with a lot of doors. And what you hear when you get in, it’s noise from the freezers that, ah, make a lot of noise because have like dozens of freezers. It’s a very noisy place because of that.
Katie Jensen:
As Dr. Turecki walks down the corridor, researchers in white lab coats bustle past, disappearing through doors. Some carry plastic containers.
[music]
Katie Jensen:
But back to Dr. Turecki’s tour.
Dr. Gustavo Turecki:
And then each room on your left, you know, would have all these freezers. They’re one besides the other one. That’s where all the frozen tissue, it’s stored.
Katie Jensen:
The tissue Dr. Turecki is talking about here is, of course, brains. Real brains, that were in real people.
[music]
Katie Jensen:
And this lab is one of the few brain banks in North America that specializes in housing not just healthy brains—or at least healthy apart from being dead—but brains afflicted with mental health disorders like depression and schizophrenia.
There are over 3,000 different specimens inside these walls—some neurodivergent, some not.
[sound of freezers operating]
Dr. Gustavo Turecki:
On your right, you would have the room where we do dissections. So, when the brain comes in, ah, needs to be processed right away, labeled, and stored, so that’s in the dissection room. And then we will have some parts of the brain that are taken out so they can easily be, ah, used later on for study. You know, some areas that are very small, when they freeze it’s very difficult to identify.
[music]
Katie Jensen:
Researchers at the Institute have access to tissue from a mountain of specimens, all carefully labeled and stored at non-perishable temperatures.
You can imagine it would be a great resource for looking at obvious physical problems—like the blood clots we see in stroke—but Dr. Turecki’s research focuses on suicide and abnormal mental health, things you can’t see by simply pulling out a piece and looking for blockages.
Dr. Gustavo Turecki:
So, let’s say I am a psychiatrist and I treat patients with depression, and I’m interested in trying to better understand what causes depression. So, you come to my office because you are depressed. I cannot ask you, “Can I get a piece of your brain to study?” It’s not an organ that we can sample. Differently, for instance, from sampling blood. If you came, you know, with diabetes, I will get a sample from your blood and then measure sugar levels in your blood. You know? But I cannot do that with the brain.
So, the only way for us to study the brain, it’s for us to have access to it after the person died. So, a brain bank, it’s basically a repository of brain tissue from individuals who donated the brain. And then we can have easy access to brain tissue, to study many different things, the composition of the brain, we will study functional changes at the cellular level, at the connectivity level, and in many other ways to study. So, this is really essential to advance neuroscience.
[music]
Katie Jensen:
And until researchers can figure out how to cut little chunks out of your brain without hurting you, we’ll have to rely on brain banks to better understand mental health in living people.
Personally, I’m in favour of keeping my marble intact.
[music]
Katie Jensen:
And in the spirit of open science, the Brain Bank shares their samples.
Dr. Gustavo Turecki:
We process about a thousand requests per year of scientists around the world who want to have access to the tissue. So, as you can imagine, that’s a lot of work.
So, we need to store the brain in a way that it’s easy to identify, that we have access to the information easily about the brains, and we can dissect the tissue easily.
[music]
Katie Jensen:
All right. So, let’s pretend we’re one of these researchers and we’ve just been given a new specimen to work with. The file says this person suffered from Generalized Anxiety Disorder and had a history of depression. We want to know what causes symptoms, on a structural level, inside the brain.
Dr. Gustavo Turecki:
Now we are able, for instance, to take individual cells and interrogate each individual cell for what was going on in that particular cell at the functional level. Yes. So, we can see, for instance, what genes were turned on and what genes were turned off, and then look at that and compare with a brain from an individual who was not ill. So that would tell us quite a lot, because it would give us some insight into what was different between someone who was ill and someone who wasn’t ill.
[music]
Katie Jensen:
But this type of diagnosis-fishing isn’t perfect.
Dr. Gustavo Turecki:
The challenges are, of course, is that the brain as a whole is a big organ and we don’t know exactly where in the brain the problems are. So, we have to go step-by-step, region-by-region of the brain. You know? And then try to better understand. And that, it’s really a tremendous amount of work.
Katie Jensen:
The Brain Bank is helping researchers piece together the puzzle of why certain brains develop mental illness and why others don’t.
But mental health disorders don’t exist within the vacuum of research labs. They’re part of people. The goal of this research is not just to understand how brain cells work but to improve, and possibly even save, lives.
Dr. Turecki has been figuring this out through trial-and-error. He does spend a lot of time conducting research with the Brain Bank. He also takes on living clients in his psychiatry practice. And he gives them a more wholistic understanding of the brainsicles he has to work with.
Dr. Gustavo Turecki:
Working with patients, it’s essential, because it gives you insight into possible hypotheses that then you’re going to explore later on with the brain tissue.
You know, if you have a… an idea that you want to explore later—you’re going to look at the brain tissue, you’re going to test that idea—and then, let’s say, maybe you were correct. And so, you had this idea from actually observing and working with patients who are affected with an illness, and then you test it.
And then maybe, you know, you were correct. And then that observation may lead to treatments, may help you better treat that particular condition. So, to circle back and have an impact in the clinic.
[music]
Katie Jensen:
So maybe we’ve convinced you to donate your own brain. Lucky for you, they’re currently accepting donations. But there are a few things to consider first.
Dr. Gustavo Turecki:
We don’t take donations from people who are alive.
Katie Jensen:
That should be a no-brainer.
[music]
Dr. Gustavo Turecki:
So, there are two ways, basically, that we recruit brains: either when people consented before they died; or we work through a collaboration with the coroner’s office, where families post-mortem, immediately after death, consent for a donation. So, for instance, let’s say people who want to give their organs to science; and then we approach the families, families give the consent, and then we get the brain.
[music]
Dr. Gustavo Turecki:
So once the brain arrives in the Brain Bank…
[door-knock sound]
Dr. Gustavo Turecki:
… they are dissected. Yes. So that they can be properly stored. And then the tissue can be retrieved later on. So, the tissue is processed in a way that facilitates that.
So, half of the brain, it’s fixed in formerol. It’s a way to process the tissue for some types of experiments. And then the other half of the brain is frozen, and it’s kept in freezers—it’s minus-80 freezers—where the tissue is preserved in a way that can be used for other types of studies.
When scientists contact us, they want, let’s say, to study certain molecules, so they would need frozen tissue; when they need to study something else, they would need fixed tissue.
[music]
Katie Jensen:
So, your donated brain will be used for all sorts of research, possibly around the world, for years to come. Who knows, maybe your noodle will be a brain sample that helps cure depression.
But if you’re not ready for that sort of commitment and you still want to help Dr. Turecki’s research, you can always donate to the Brain Canada Foundation. Tell them I sent you.
Brain banks are great. We love brain banks in this house. But there are some limitations to doing research on brains in jars. The big one is that they’re dead.
So, if a researcher wants to test out a new drug to see if it can help with depression, for example, dead brains don’t get better. There wouldn’t blood or electrical activity to move the drug around the tissue. So, we have to take a different tack.
[music]
Dr. Liliana Attisano [preview]:
Up until now, we’ve mostly studied neurons using animal models, because that’s all we had accessible. And it just became increasingly clear that a human brain, or even neuron, is not the same as a mouse brain or a neuron.
[music]
Katie Jensen:
That’s Dr. Liliana Attisano. She and her team of scientists in Toronto were looking to improve the ways we can experiment on live brains without using animal models or potentially hurting humans.
Dr. Liliana Attisano:
And so, we decided to apply sort of this new technology where we can make human-based brain neurons that we can study in the lab.
[music]
Katie Jensen:
Pause. They make brains? Like mini-brains?
Dr. Liliana Attisano:
“Mini-brain” conjures up this, ah, image of something that looks exactly like our brain, growing in a dish that maybe can, ah, think and respond. And it’s not really a tiny version of our brain. What we are recreating in three dimensions is different parts of the brain. They would never function together to (laughs a bit)… to develop thought. So, we just try and avoid that perception that there’s cognition in what we’re growing in a dish, because that doesn’t exist.
Katie Jensen:
So, they aren’t achieving sentience. No tiny-brain uprising coming out of Dr. Attisano’s lab anytime soon.
[music]
Katie Jensen:
Instead of calling them “mini-brains,” because that’s not entirely accurate, Dr. Attisano’s team has landed on the term “brain organoid.”
Dr. Liliana Attisano:
An organoid is defined as a memetic of a tissue that displays different cell types that are organized in some manner that reflects what a true tissue would look like.
Katie Jensen:
So, you could have a liver organoid or a kidney organoid. But they’re making brain organoids—growing a bunch of neurons and sticking them together with glial cells, a.k.a. “nerve glue.” It’s kind of like a deconstructed hamburger at a fancy restaurant: it takes the same but it looks different.
Let’s learn about how to make brain organoids.
First off, you need multiple years of experience researching stem cells. Everybody got that? Yes? Okay, great.
[music]
Katie Jensen:
Let’s move on to step two. We need to grow some brain cells. How do we do that?
Dr. Liliana Attisano:
We start with the pluripotent stem cells—same as you would start with the first step of a… an embryo.
Katie Jensen:
Quick biology refresher. Pluripotent stem cells are a building-block cell that can morph into any type of cell: a blood cell, a bone cell, in our case a brain cell.
Dr. Attisano’s team gets ahold of these stem cells by converting them from skin cell samples.
Next up, we need to feed these stem cells the right type of nutrition to make sure they take on the characteristics of brain cells. Finding this concoction took a really long time to figure out. We’ve only known how to feed stem cells, in this way, since 2013.
As the stem cells get fed their favourite brand of nutri-juice, they start to grow and form into different layers, like the layers in the cortex of a real brain. To the naked eye they look like little white blobs. Kind of like a marble, actually.
[music beats]
Katie Jensen:
But the really interesting stuff happens under the microscope.
[music]
Dr. Liliana Attisano:
I guess it’s sort of like a teeny tiny, round ball or an oblong-shaped tissue sitting in a dish. So, it’s not like in vivo, because there’s no blood, there’s no immune system—at least not yet.
[music]
Katie Jensen:
After that, according to Dr. Attisano, they just kinda do their own thing.
Dr. Liliana Attisano:
Well, we basically just let the cells figure it out themselves. So. And then just nudge them along the way. I’m quite serious. So, we just, ah, provide it the right environment and it will just execute the normal program.
[pulse sound]
Dr. Liliana Attisano:
The first step of embryogenesis is formation of what are called the “three germ layers.” And then you put them in an incubator and you just let them shake. And you can, ah, start analyzing them after a month, or six months, or nine months. It… they just keep growing and maturing.
[expanding music]
Katie Jensen:
But even if you’re a stem cell master chef, it’ll still take six months to a year to learn how to make the special sauce.
[busy commercial kitchen sounds]
Dr. Liliana Attisano:
It’s a little bit like an art. So, you might read the protcol and, you know, count 2,000 cells, and place them in this dish. But even how you transfer them is something that you can’t put down on paper. So, it’s a little bit of technical knowledge that you have to develop over time.
Katie Jensen:
Now we can give these organoids new drugs and experimental treatments, to see how the neurons might react. But a brain organoid is not a human being. It’s like saying a few skin cells are the same as your face.
It’s still something though. And researchers can also create organoids that have diseases like Alzheimer’s.
Dr. Liliana Attisano:
I think one of the challenges for many neurodevelopmental disorders and psychiatric disorders is we really have no way to explore them the way we would other diseases or cell types.
And so, what we can do is, for example, we could take skin cells from patients with particular disorder—so, for example, Alzheimer’s or Parkinson’s—we can take their cells and convert them into brain organoids and then study how they differ compared to, ah, those generated from a normal patient that doesn’t display the disease.
And then we can, you know, manipulate it at the molecular level—add things, stimulate them—in different ways that we can’t… you know, obviously we can’t experiment on a… a human the way we would like to (laughs a little) to answer these kind of questions.
So, it’s extremely powerful.
[music]
Katie Jensen:
Dr. Attisano is also looking into how to make these brain organoids more like a brain—not just in cellular form but in structural form as well.
Dr. Liliana Attisano:
I mean, in terms of the organoids, what’s really needed is getting one step closer to the in vivo situation. So, for example, I’m working with the team that is trying to introduce blood vessels into the brain so that we can study the blood-brain barrier and increase nutrient flow, so that we get closer to what it really looks like in the brain.
The next step is adding in some kind of immune system.
So, in other words, getting a more advanced model that comes closer to in vivo, so that we can really do reliable drug testing. So, wouldn’t it be great if rather than testing any new compounds in animals—which is what we have to do now—could be done in a dish in a highly reliable manner? I think it would be a huge advantage.
I mean, right now you have to test a new drug before you give it to a human. You test it in animals. The problem is, humans are not animals and there’s no model that’s similar enough that we can trust results from one species to another.
And so having a human-specific context would be… I think it would be a huge advantage for drug development.
[music]
Katie Jensen:
Brain organoids are still experimental. And at this early stage, they’re really far removed from the realities of what a real brain is like: how it looks, and how it functions.
But there’s a project that’s tackling one whole brain in incredible, delicate, minute detail.
[music]
Katie Jensen:
In our last episode, we met Dr. Alan Evans. He helped develop a type of scanner to check patients for Alzheimer’s disease.
Dr. Alan Evans:
When I came to Canada, I, ah, started to work on positron tomography as an imaging physicist. But I was always at least as interested in the biological uses of these technologies as in the technologies themselves.
[music]
Katie Jensen:
That’s not all. Dr. Evans has projects on the go, and he expects they’ll provide more accurate results when using brain scanners to look for abnormalities in the brain.
One in particular is near to his heart.
Dr. Alan Evans:
One of the projects that we’ve been engaged in—now for about 20 years, which has become, ah, it started out as a labour of love and it’s now become a much bigger enterprise, I guess—is the… the so-called “BigBrain.”
[music]
Dr. Alan Evans:
It started life as a project to deal with the problem of brain mapping.
[music]
Katie Jensen:
That problem Dr. Evans mentions, it has to do with what scientists use as their litmus test.
[music beats]
Dr. Alan Evans:
Brain mapping rests on a standard brain that everybody in the world uses. Their new study—they collect the data and they map the new data onto that brain, into that space, into that three-dimensional space.
[music]
Katie Jensen:
It’s kind of like the brains from the Brain Bank. There, if you have a patient who might be suffering with a mental illness, you can take a sample of a brain with that disorder then look for similarities. But in this instance, researchers use this “standard brain” to look for abnormalities.
[music]
Dr. Alan Evans:
In the past, that standard brain was based on MRI. And MRI has, ah, a spatial resolution of about a millimetre in each direction. A millimetre is a thousand microns.
Katie Jensen:
Or almost the width of a grain of sand. That’s a very thin slice of noodle. However, that’s still too thick to get into the finer details of brain cells. And so, in a joint effort with researchers in Germany, Dr. Evans’ team got to know the brain on a microscopic level.
Dr. Alan Evans:
Our… our German colleagues did the wet work. They took a single brain, and they used a gigantic deli slicer to slice that brain into 7,000 individual sections, each 20 microns thick.
Katie Jensen:
Now we’re getting somewhere. Twenty microns is about a fifth of the width of a strand of human hair.
Dr. Alan Evans:
So that’s 50 times smaller, in each direction, compared to an MRI volume. Do the math: 50 times 50 times 50 is 125,000. So, the BigBrain is the equivalent of 125,000 MRI volumes. It’s a huge amount of data, with near cellular-resolution over the whole brain.
[music]
Katie Jensen:
Researchers then took a picture of each of the 125,000 slices and compiled them into a data set.
[music]
Dr. Alan Evans:
And it’s easy to say that. What it actually involved was years of processing to take these 7,000 20-micron thick slices, which each covered the whole brain. But they’re ripped, and they’re torn, and they’re distorted, and they’re optically imbalanced, and there’s all kinds of problems with them. So, we spent years beating that data to death to restore it to three-dimensional coherence to build the… the three-dimensional BigBrain data set.
[music]
Katie Jensen:
And after years of slicing, and taking pictures, and restoring the data, the BigBrain project finally made its grand public debut in 2013.
[music]
Katie Jensen:
So now researchers have a perfect diagram of a normal brain that they can use for comparisons.
Dr. Alan Evans:
Last time we checked, it had been downloaded by 25,000 groups around the world. So, it became an international standard.
[music]
Katie Jensen:
Seriously! Even you can download the BigBrain data if you want to, at BigBrainProject.org. Yay, for open science!
[electronic noises]
Katie Jensen:
Just make sure you’ve got a lot of space on your computer.
Dr. Alan Evans:
It is 7,000 separate two-dimensional images. So, a student usually, or a trainee, will go to that website and, ah, essentially press the button and download all of the… this information. And it takes a long time to download all this information.
Katie Jensen:
But before you go out and buy an external hard drive, Dr. Evans already has a fix. A portal where you can browse the brain without downloading it.
[music]
Dr. Alan Evans:
So, it’s been set up as one of the data sets that we make available to the world through the Canadian Open Neuroscience Platform that’s funded by Brain Canada. With that CONP platform, we’ve built a portal which allows people from around the world to come and download not just the BigBrain but many other kinds of open neuroscience data that we’ve been given by our colleagues to make available to the world.
And of course, this has allowed people around the world to extract all kinds of interesting information about the brain, using the BigBrain itself to analyze, ah, the… the layers in the cortex. And we map all of that into an in silico computer simulation of the human brain.
And of course, this allows us to explore all kinds of aspects of brain development and brain disorder.
[music]
Katie Jensen:
So, thanks to Dr. Alan Evans’ team, and their colleagues in Germany, the general population has access to this very detailed map of a standard brain.
[music]
Katie Jensen:
And with so many people using this map to research the brain, there’s a lot of people reviewing the data. Luckily, Dr. Evans welcomes the open dialogue.
Do you ever hear feedback from any of those 25,000 people about what they want you to do next (laughs) or how they want you to do your work differently?
Dr. Alan Evans:
Yeah. They say, “Yes, but it’s only one brain. Can you collect 1,000 of these to cover age, gender, brain disorder?” And of course, it took years to build one of these BigBrains. And it took 10 years to do it once; maybe to do it a… a… a second time would take only 2 years. But there’s still each time there’s a massive amount of work to develop something like this.
So, we are working on, ah, BigBrain2 and BigBrain3.
Katie Jensen:
This is the final step in the positive-feedback loop we call “open science.” Once you break down the barriers to accessing this sort of data, more people can experiment with it. And then there’s more possibilities for success in finding cures for illnesses.
Dr. Alan Evans:
Science used to be the… the province of, ah, one researcher, two students, and half-a-secretary working together in a cottage industry. Well, that’s changed completely with The Information Revolution. And now science in general, and certainly neuroscience, has become industrial-scaled. Large amounts of data are being collected: imaging, behaviour, genetics, all kinds of information. And it has to be assembled and analyzed.
It’s become more and more apparent that the… the way that you really have to do this, to make progress, is to share the data so that more scientists around the world can get at it. So, you don’t have a single investigator sitting on a precious data set and publishing one paper a year for the next five years. You let of hundreds of scientists get at it. And lots of work comes out of this. And you… science advances much more quickly if you do that.
Katie Jensen:
And in the end, that’s really what all this research is for. Right? It’s to better the lives of those suffering with brain disorders or mental illness.
Because we all have a marble to take care of.
Dr. Alan Evans:
With open science, you can make that data available for a lot of people and therefore get to the cure, whatever the cure might be, faster—because there’s more people looking at the data.
This is all the good reasons to share data. It’s not enough just to describe the clinical outcomes. Of course, it’s the clinical outcome you want to fix, but you’re not going to do it by just looking at the end-stage outcomes. You need to get in and understand the… the brain anatomy and physiology.
[music]
[different music]
Katie Jensen:
Thanks for listening to this season of Playing With Marbles.
The show isn’t over though. We’ll have new episodes to explore more about how brains work and the research around them. So, if you haven’t yet, follow our show on your favourite listening app. And don’t forget to tell a friend.
What do you want to hear next season? Leave a comment on our socials, at Brain Canada, or in a review on your podcast app. We’ll use our frontal lobes to comprehend all of your feedback.
Playing With Marbles is a Vocal Fry Studios production, in partnership with Brain Canada. The executive producer is Jay Cockburn. Our associate producer is Max Collins. I’m Katie Jensen. Thanks for playing.
[music]
[end of transcript]