Scientists 3D-print a ‘brain’ to learn the secret behind its folds


By 3D-printing a fake gel brain and watching it “grow,” scientists at Harvard University have discovered how the human cortex develops its creepy, classic folds.

The discovery, published in the journal Nature Physics, may solve a longstanding mystery about the structure of our gray matter and could even help shed light on certain disorders that may be linked to underfolding or overfolding of the brain.

The researchers have “demonstrated that physical forces — not just biochemical processes alone — play a critical role in neurodevelopment,” Ellen Kuhl of Stanford University, who was not involved in the study, wrote in a commentary. “Their findings could have far-reaching clinical consequences for diagnosing, treating and preventing a wide variety of neurological disorders.”


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Think of the brain, and you might conjure up a pink, wrinkly object roughly the shape of a partly deflated basketball. But not every species’ brain has these telltale wrinkles — smaller animals such as rats have smooth, pink thinkers. Human fetuses don’t start developing these folds until about week 23 of gestation and don’t put the final touches on the branch-like network of creases until after they’re born.

Scientists have long realized that the brain’s folded structure has some major benefits. Among them: It allows for far more connectivity across the cortex (the surface layer of our brain that consists of “gray matter”) than a smooth surface would.

“Each cortical neuron is connected to 7,000 other neurons, resulting in 0.15 quadrillion connections and more than 150,000 km of nerve fibres,” Kuhl wrote.

But what causes these folds to develop has had scientists a little stumped. Many researchers have tried to identify the cellular or biochemical processes at work, but Lakshminarayanan Mahadevan, a physicist and applied mathematician at Harvard University, decided to study the physics of the structure itself, and develop a mathematical model of its behavior.

“I have a longstanding interest in trying to understand how the body or bodies of animals organize themselves,” Mahadevan said. “I approach these problems from a mathematical perspective.”


Researchers have tried to get at this question for decades, Kuhl wrote. Some 40 years ago, another group of Harvard researchers suggested a physical model where the differences in growth within the brain’s tissues could explain fold formation.

That model “challenged the conventional wisdom” that the brain’s shape and patterning was the result of “purely biological phenomena,” Kuhl wrote. “To no surprise, this rather hypothetical approach was perceived as highly controversial.”

Part of the problem was that there seemed to be no good way to answer this question, she added. Experiments with human brains can be “ethically questionable,” and experiments with rats or other small animals wouldn’t work because their brains are smooth. And usually, an experiment in non-living material wouldn’t show you how the brain develops these folds because non-living tissue doesn’t grow.

For the new study, Mahadevan and his colleagues built a physical model that solved that last problem with some clever use of materials. They used magnetic resonance imagery from a smooth fetal brain at 22 weeks’ gestation and 3D-printed a cast to make a fake brain out of gel. This was the “white matter” of the brain, which they covered with a thin coat of another, more rubbery gel to mimic the layer of “gray matter,” or cortical tissue.

The researchers then submerged the brain in a liquid solvent that caused that stretchy cortex-like layer to start expanding . Sure enough, brain-like folds began to emerge in the once-smooth surface.

Here’s what seems to be happening: The cortical tissue wants to keep growing but it’s anchored to the limited real estate of the white matter below it. As the cortex expands, that strain eventually causes the tissue to collapse, leading to the gyri (round features) and sulci (deep grooves) that cover the surface.


“It’s an elegant example of simple rules making complex outcomes,” said Mriganka Sur, a neuroscientist at MIT who was not involved in the study. “There’s always beauty in nature.”

The next step, Mahadevan said, is to link these large-scale structural changes to the process that may be playing a role on a molecular level.

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“In the end, all of them are related,” he said. “If I think about the shape of the folds in a fetal brain then yes, there are molecular processes: There are biochemical processes which cause cells to move, cause cells to divide, cause cells to change shape and cause cells to change in number.”

Ultimately, the research could help researchers better understand a variety of different neurological disorders, scientists said.

“Making these connections can help us identify topological markers for the early diagnosis of autism, schizophrenia or Alzheimer’s disease, and, ultimately, design more effective treatment strategies,” Kuhl said.


For example, certain disorders like autism and schizophrenia are thought to be related to neurons having too many or two few connections with each other, Sur said. Perhaps the degree of folding could be affecting the degree of connectivity “in ways that we don’t yet completely understand.”

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