Jean Mary Zarate: 00:04

Hello and welcome to Tales From the Synapse, a podcast brought to you by Nature Careers in partnership with Nature Neuroscience. Im Jean Mary Zarate, the senior editor at the journal Nature Neuroscience. And in this series, we speak to brain scientists all over the world about their life, their research, their collaborations, and the impact of their work. In episode six, we meet a researcher and author who was fascinated by the evolution of our brains and how they develop in the womb.

William Harris: 00:39

Hi, my name is William Harris, people generally call me Bill. I'm a professor emeritus at Cambridge University. Im a developmental neurobiologist, and Im the author of Zero to Birth, How the Human Brain is Built.

A developmental neurobiologist is basically someone who studies how brains develop. Its usually done in the laboratory. Its a field at the intersection of developmental biology and neuroscience.

Its carried out usually at the level of experimental animals and cells in petri dishes and things like that, rather than on human embryos.

So myself, you know I worked on fly embryos, I worked on salamander embryos, frog embryos, fish embryos. There are tons of fascinating questions about how the brain is made.

I myself got interested in it when I was a graduate student, and I was studying some mutant fruit flies. And these mutant fruit flies, they didn't see the world properly, they made visual errors. So lots of people had isolated, weird mutant flies that didn't see properly.

And when we traced the genes that were defective, mutated in those animals, we usually found that they operated at some point in the development of the visual system.

So that, you know, all these genes work to build the brain. And thats what really got me interested in it. And from that point, I just got more and more interested in how this most complicated organ develops.

And my main questions were, like, you know, wiring up, how does it get wired up? Thats what I spent most of my career doing.

I am a Canadian. I grew up in Canada, and played a lot of ice hockey. That's why there's a lot of ice hockey references in the book, analogies or metaphors in the book.

At the age when I went to university, I went to University of California at Berkeley. I was a graduate student at Caltech. My PhD supervisor was a famous guy named Seymour Benzer. And he worked on behavioural mutants of flies. I did postdoctoral work at Harvard Medical School, in the laboratories of David Hubel and Torsten Weisel, who studied the visual cortex of mammals, and how that developed.

And then I had my own career starting at the University of California, San Diego, in the biology department. And about 25 years ago, I moved to the University of Cambridge, where Ive been since.

I wrote the book because I wanted to do something useful with the perspective I had from 40 years of research and teaching of developmental neurobiology, teaching to university students.

I thought I could offer a glimpse into the field for people who wondered about such things, and have never, ever studied the subject.

I found it really difficult to make such a complicated scientific pursuit fascinating. But I tried to instill in the book some of the stories of the discoveries that have been made.

You know, how exactly were these discoveries made? And I added some colour, because I think people like to know this by trying to tie these discoveries to medical progress in neurology and psychiatry and psychology. Because so many of the things that go wrong during brain development lead to neurological or psychological syndromes.

William Harris: 05:14

Well, human brains are really different from those of every other species of animal. In fact, the brains of every species of animal are different from each other because theyve been tuned through millions of years of evolution to their particular lifestyle.

For example, an insects brain is geared to an insects world. And a human brain is geared to human affairs. But what we found out is that the instructions for making a human brain are written in the human genome, so it's largely genetic.

If you transferred a little bit of mouse embryonic brain tissue into a culture system and a human, then a brain into a culture system, theyd make, you know, a little bit of mouse brain or a little bit of human brain. Theyre genetically instructed to do that.

But what way, what way are the brains different? For example, our brains are about 10 times larger than expected for an animal of our size.

Human brains are about four times as large as chimpanzee brains, even though we weigh about the same as they do.

The architecture of human brains is different and human-specific. And the best example is the cerebral cortex, the covering of the brain where higher functions are. You know, in humans its 75% of the mass of our brain is cerebral cortex. Whereas in others, in monkeys, its only about 50%. And in most mammals, its, you know, 20% to 30%.

So its really taken over the dominant role in humans. So certain areas have enlarged, in comparison to other animals, and certain areas have not enlarged, may have shrunk.

So another key difference is the way brains develop. Just one of them, for example, is the fact that humans are born immature. Because their brains are getting bigger and bigger, they, you know, there, it seems that they constrict. Well, theres a squeezed point in evolution where, you know, in the embryo, you couldnt get an animal with a bigger brain and deliver it safely.

So, humans are born with a growing brain, and its gonna get bigger, but its as big as a mother can manage at that time. But it means that the brain is still immature when the human is born, compared to when a monkey is born. And it takes a longer time. And then it matures for a longer time postnatally too. So they spend a lot more time, humans, spend a lot more time than our closest relatives in, in learning about the world outside the womb, and that having an effect on the maturation of the brain.

We call the brain this collection of neurons thats in the head region. There are certain really circular symmetric animals like jellyfish, and they dont really have a front and a back.

And they dont have what we call a brain. They do have a nervous system, and neurons that connect to each other. But we call that a nerve net, because there isnt one centralized group where most of the neurons are.

So in evolutionary time, when bilaterally symmetric animals evolved 500-600 million years ago, and started to move in a forward direction, (you know, there was a front and a back end), it made sense to collect things at the front end that the animal was going to engage in first with the world.

So sensory apparatus, move there, smell, taste, vision, and the capacity to process the information that comes in through those senses was handled by a growing collection of neurons, which we ended up calling the brain.

If you wanted to break it down, what happens in what trimester, you could kind of think of it like this....

You start as a fertilized egg, and this egg divides and one cell becomes two, two four, four eight, eight 16 and so on. You get this ball of cells. Now, every one of those cells has the potential to make a whole human being, theyve got the genetic instructions to do everything to make a brain.

But at some point in early development, only about three weeks post-fertilization, some of the cells, some of those cells become committed to make the brain. They become the Adams and Eves, if you will, of the brain.

And they arrange themselves into groups that are the founders of different regions of the brain. There are hundreds of different regions of the brain. But these are the neural stem cells, theyre still dividing, theyre proliferating.

And theyre going to make a brain of the right size and proportions. Theyre going to make a brain with 100 billion neurons by birth.

William Harris: 11:08

Then in the second trimester, growth slows down a little bit, and some of the first neurons are generated from the neural stem cells. And connections start to be built between these first neurons. So for example, in the second trimester, you can already see some movements in the human embryo. And thats because muscle cells have connected.

Well, neurons in the spinal cord have connected with muscle cells. And neurons in the brain have connected with those motor neurons. So babies begin to kick their whole leg, move in slightly coordinated ways, bring their hands to their mouths, things like that.

You can see that connectivity is happening in the brain. I likened it to how a team is formed, and I give ice hockey analogies in the book, because thats my, that was a sport I had played and still coach.

So a coach will have tryouts and select the best players for different positions. The brain does the same thing. Maybe two neurons try out for every position, one makes it thats a little bit better at communicating, and the other one doesnt, and the one that doesnt has to commit suicide. So they go through a process called, in the business, apoptosis, where they break their own cells apart. But the survivors, once they survived, they have to last your whole life.

William Harris: 12:49

And then, in the last trimester, these neuron production grinds to a halt. The wiring up process is still going on. And this period of competition between neurons for survival, and then synaptic territory, that continues. And the neurons have to connect with each other in really precise ways and get fine tuned.

And this is still happening in the embryo, but it means that, you know, that when youre older, for example, and youre hungry, youve got neurons in your hypothalamus that will sense hunger, you know, sense the nutrition level in your brain, and neurons in your retina that can see a visual image and, you know, maybe its, this is kind of the example I give in the book, maybe its an English muffin, a picture of an English muffin that you can interpret, you learn to interpret.

And then you learn to, you know, the olfactory circuit in your nose has learned to interpret the smells received as melting butter on a freshly toasted muffin.

And then the neurons in your frontal cortex organize these pieces of information and integrate them, and send signals to the motor cortex. And the motor cortex then sends signals down the spinal cord to your motor neurons that organize a sequence of actions so that you can reach out and grab this muffin and bring it to your mouth and take a tasty bite. So a lot of that circuitry has been refined during the third trimester. Not all of it, but a lot of it.

We dont even really know how many types of neurons there are in the brain, but 1000s at least. Given that its the most complicated organ that we have, its not surprising that there are lots of different cell types. Its even been shown by recent science that every neuron in the brain has a distinct molecular identity from every other neuron in the brain. And it has a particular job.

Obvious for people are things like the rods and cones of our eyes, but the red, green, and blue-perceiving photoreceptors in the retina. So thats the three types of photoreceptors, the cone photoreceptors. And theres one type of rod cell. And then those four different photoreceptor types send their information to about 20 different next-order cell types. And they send their information to another 40 different next-order cell types, and so forth.

So by the time the image leaves the retina, the neural signal leaves the retina, its been seen by hundreds of different types of neurons, each doing a different kind of processing job.

There are lots of different types of neurons, some are numerous and tiny, and some are large, and few.

And one of the ones thats large and fewer are the dopaminergic neurons in the forebrain, whose degeneration is linked to Parkinsons disease. They're dopamine-secreting neurons. And they have exons that spread out across the cortex and many other areas of the brain. And they tone the brain, allowing people to initiate movements and things like that.

When they degenerate, then you develop Parkinsons disease. So different neurons, you can find out their function because when they when theyre gone, it reveals a defect, colour blindness, Parkinsons disease, and many other syndromes and neurological disorders are caused by defects in the formation of particular types of neurons.

William Harris: 17:03

Well, although the nervous system has started to fire up, its active before birth. And these prenatal activity patterns work, kind of like, test TV test patterns, if you remember those.

And theyre important to start to begin to tune brain function. But its only after a baby has been born that the outside world can have and does have such an influence on the activity patterns of the brain.

And so the outside world begins to fine tune the circuitry of the brain. The baby learns what its mother's face looks like, and many other things, the smell of coffee, or a muffin.

The babys brain, we say its over-wired. That means too many connections, there are too many connections. But its also under-connected because the connections arent very strong at the beginning.

And these connections need to continue to mature in the outside world. Synapses do continue to change to some extent throughout life, which is how people learn new things and forget other things.

William Harris: 18:28

Its interesting to think about the brain and the way the brain develops in two basic stages. One is building everything. And then the next stage is refining things. During the building phase youre constructing, adding more and more and more.

And during the refining phase, youre getting rid of stuff. For example, you might build a building, you might have scaffolding, and you put it up, and then you have to take it down at the end.

You may have brought in way too many bricks to build the building and have to discard some of those bricks at the end because they werent fit for purpose.

Well, the brain has a construction phase, and a destruction phase, or a decluttering phase. So first, you know, by the time a baby is born, it has more neurons than it will ever have in the rest of its life.

Neurons are dying at a faster rate than they are being born in a baby. In fact, neuronal birth has ground to a halt pretty much at the time of birth. But neurons are dying in vast numbers.

An adult human only has about half the neurons that it produced during its development. But once the brain has gone through this initial period of cell death, when its refined, got rid of the neurons that don't work so well, those neurons have to survive the rest of a lifetime because they dont divide anymore. And we dont have any neural stem cells left.

But what the survivors do is they continue to work against and with each other to gain or lose synaptic territory, and synaptic influence. And that continues on throughout life.

So, you know, a neuron might have a branch that goes to another area, and that branch might get pruned away, because someone else has taken over that territory. Those kinds of things happen, largely in childhood, but also, to a lesser extent, in an adult human.

William Harris: 20:45

My career, and particularly writing this book, has influenced the way I look at certain things, particularly my grandchildren, and one of my grandchildren features in the book a couple times.

One is about, you know, how people learn to be afraid of spiders, and whether epigenetics is involved or not.

And another is learning to speak. So babies are born with the potential to understand language. And their brains are already wired, so that they will be capable of getting it, but they cant speak yet.

So how does that happen? We talk about that in the book. But it wasnt my research so much, but it was really writing this book that changed my outlook, because I started to think about those things from a human perspective, instead of a fish brain perspective.

When I was researching, I was thinking about fish brains and fish retinas, writing a book starting to think more about human brains.

And I learned a lot about the connections between evolution and development in the brain. So how animal brains are like ours, and how theyre different from ours.

And the way its changed my outlook has, certainly, its increased my respect for what animals brains are and what animals are up, when I look at an animal.

And its also increased my respect for humans, because each one of us is born with a very unique brain. The developmental mechanisms that are used to make a brain ensures that your brain is going to be very different than my brain, its gonna be very different even if you had an identical twin brother, or sister that, you know, was grown in the same environment and had the same genes.

Theres a little bit of randomness thats thrown in. Probably our brains are the most unique things about us. We have unique faces, but our brains are even more unique. Just you cant see them.

23:06: Jean Mary Zarate

Now thats it for this episode of Tales From the Synapse. I'm Jean Mary Zarate, a senior editor at Nature Neuroscience. The producer was Don Byrne. Thanks again to Professor William Harris, and thank you for listening.

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