‘Changing small pieces of the cerebral cortex can generate superhero abilities’: Óscar Marín, neuroscientist

The father of neuroscience, the Spaniard Santiago Ramón y Cajal, invented beautiful metaphors to explain what he discovered with his microscope at the end of the 19th century. Cajal wrote that neurons, the main cells of the brain, were “the mysterious butterflies of the soul” that communicated with each other through “kisses.” More than a century later, the neuroscientist Óscar Marín has added numbers to the poetry: 100 billion neurons inside each skull, with an average of 1,000 connections each. It’s an inconceivable amount of butterfly kisses. The human brain is so complex that it cannot imagine itself.

Marín, 51, directs the Centre for Neurodevelopmental Disorders at King’s College London. On July 15 he formally became a Fellow of the Royal Society of the United Kingdom, a prestigious institution founded in 1660. Geniuses such as the naturalist Charles Darwin, the physicist Albert Einstein, the neurologist Rita Levi-Montalcini and Ramón y Cajal himself all belonged to the group. Marín’s discoveries have illuminated the development and function of the cerebral cortex, that gray substance that is home to our most distinctively human characteristics, such as imagination and thought. His goal is to reveal the causes of “some of the most devastating psychiatric disorders, such as autism and schizophrenia.”

Question. The English artist Stephen Wiltshire, diagnosed with autism and savant syndrome, flew over Madrid by helicopter in 2008 and later drew the entire city from memory. What happens in those types of brains?

Answer. The correct answer is that I don’t know. The development of an organ as complex as our brain allows this range of variability. There is a recipe for generating brains, and there are many deviations from it that are compatible with life. In some cases, they produce brains that we recognize as pathological, and in other cases, like this one, brains that acquire these super-capabilities. My intuition, and this is completely speculative, is that these brains are not very different from neurotypical brains [without autism spectrum disorders], but they have acquired some kind of capacity during development, in this case the capacity to fix very stiff patterns.

Q. There are other people with savant syndrome who hear a song once and can already play it by heart.

A. Yes, it’s perfect pitch, that ability to recreate musical notes without any problem. I think that those cerebral cortexes are not very different from yours or mine. It’s really fascinating that our genome encodes such an enormous variability of behaviors, just by varying small pieces of that incredible puzzle of our cerebral cortex. With changes in no more than a few dozen genes, a practically identical structure is generated, but with a superhero capacity, so to speak.

Q. You have been elected a Fellow of the Royal Society for your discoveries on the migrations and connections of neurons in the cerebral cortex, especially the inhibitory ones.

A. Yes, there are two types of neurons, excitatory and inhibitory, which are like yin and yang. There has to be a very precise balance for the cerebral cortex to work. It was assumed that all these neurons were born in the same place, that they were formed in situ, but we discovered that the inhibitory neurons are not born where the majority of the neurons of the cortex, the excitatory ones, are. They are born in another region of the embryonic brain and migrate a very long distance to reach the cortex.

Q. How long is that trip?

A. In humans, they take weeks to reach their final destination. In other words, the cortex has a kind of population of resident cells—the autochthonous ones of the cerebral cortex, so to speak, which are the excitatory ones—and a very large population of inhibitory cells that immigrate and end up colonizing this area. There are approximately four excitatory neurons for each inhibitory one. Most of the computation is done by the pyramidal cells, which are the excitatory cells. The inhibitors are like an orchestra conductor: they are in charge of controlling the flow of information between the pyramidal cells, which would be the instruments. They coordinate that there is sound when there should be sound and also control their volume: the amount of information they transmit. When the inhibitors don’t work, there is uncontrolled activity in the cortex and epilepsy.

Q. And that conductor arrives from outside the cortex.

A. Exactly. It is a very nice way to generate a new structure in the brain. You have two structures that are working independently, and suddenly, from a mutation, one population of cells becomes migratory and joins the other structure. And that creates opportunities in the way of managing information, opportunities that do not exist if the population is more homogeneous.

Q. What kind of opportunities?

A. It must represent an evolutionary advantage large enough for such a complicated system to have been preserved over millions of years of evolution. The larger the brain, the longer the distance these neurons have to travel and the greater the probability of error: cells not arriving at their destination, not placed correctly or exhibiting problems. It’s a complicated system to understand in terms of efficiency. But this mixture of neuronal types in the cortex must provide a very important evolutionary advantage. The parallelism is that talent is universal. Societies capable of attracting talent from more places are richer and have a greater capacity to generate new things.

Q. This migration of conductors to the cerebral cortex can also cause problems. It could be behind some developmental disorders, such as autism and schizophrenia.

A. Yes, and epilepsy. Almost anything that fails in the cortex can cause these types of problems. Conceptually, the most important change since we started in this business 25 years ago has been that we then thought that any mutation that affected the development of the cerebral cortex would have a more or less homogeneous impact. We now know that because these two populations of neurons have very different origins, they express very different genes. We now know that there are mutations that will affect the development of excitatory cells, which make up 80% of the neurons in the cortex. When there is a problem in the development of these cells, it usually manifests itself in a very visible way, such as macrocephalies or microcephalies. In contrast, people who have autism or schizophrenia usually have brains that are macroscopically very similar to those of neurotypical people.

Q. And what does that imply?

A. Perhaps the problems are much finer. Perhaps there are genes that only affect inhibitory neurons and, therefore, create problems in the generation of these cells, in their migration, in their connectivity. We know more and more about which genes are important in developing these diseases. What we still do not fully understand is when and in what population of cells this deviation from normal brain development occurs. There are probably at least 60 types of excitatory neurons and another 60 types of inhibitory neurons in the cerebral cortex.

Q. The plasticity of the brain is amazing.

A. It’s really fascinating to see how plastic the brain is. You do very radical experiments, where you alter very important things, and yet the developing brain has the ability to adapt. There is a widespread idea that the brain is like a computer. One would understand developmental illness as missing a piece of the computer, so simply putting it back would be enough. Nothing really works like that in brain development. When a piece is missing, or in the wrong place, the rest of the brain will reorganize and rewire itself to try and fill that role. And that is why there are people who walk around without half of the cerebral cortex or without the cerebellum, spectacular things that in an adult brain would not be compatible with life. However, if they do occur during development, the brain will look for ways to compensate for those deficits. That’s why I think it’s going to be very difficult to understand some of these diseases, in which surely what we observe is the final product of an initial change and subsequent reorganization of the brain.