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Miniature brains that show electrical activity akin to “a primitive type of thinking” could revolutionise how some drugs are tested and reduce the need for animals in research, according to scientists who have developed the structures. Human mini-brains, made from the neurons of a full-sized brain, will be mass-produced to replace animals in drugs testing, in a move that is likely to transform research and development in pharmaceuticals.

These tiny mini-brains contain all the cell types found in a real brain.

Researchers often rely on animal models like mice to evaluate how new drugs will affect the human brain or to better understand how the brain functions. But in recent years, scientists have turned to “mini-brains”—tiny lab-grown balls of brain cells—to test pharmaceuticals or better understand the causes of some diseases. While many of these brains are sophisticated enough to mimic the structure of the human brain, they also have limitations: They take several months to grow, and each one varies slightly, which inhibits researchers from getting rapid, consistent results from their experiments.

Now, researchers at the Johns Hopkins Bloomberg School of Public Health have developed a technique for making mini-brains more quickly and consistently, which they believe could allow mini-brains to replace animal testing for a variety of experiments. Dr. Thomas Hartung, a professor of environmental health sciences and one of the researchers behind the project, presented the work on Saturday at the annual meeting of the American Association for the Advancement of Science (AAAS) in Washington, D.C.

The cells were working together as they would in a real brain.

Like other mini-brains, these are made from pluripotent stem cells—ones capable of producing any cell or tissue the body may need—that have been isolated from skin. But while others are isolated to a single plane (or as Hartung describes it, “like pan-fried eggs sunny side up”), the cells in these mini-brains are kept suspended by being constantly shaken as they develop. After eight weeks, the mini-brains were each just 350 micrometers in diameter but when hooked up to an EEG, they showed activity—indicating to the researchers that the cells were working together as they would in a real brain. And while the initial batches contain 800 mini-brains each, Hartung believes the system could expand to grow thousands per batch.

It was an otherwise normal day in November when Madeline Lancaster realized that she had accidentally grown a brain. For weeks, she had been trying to get human embryonic stem cells to form neural rosettes, clusters of cells that can become many different types of neuron. But for some reason her cells refused to stick to the bottom of the culture plate. Instead they floated, forming strange, milky-looking spheres.

“I didn’t really know what they were,” says Lancaster, who was then a postdoc at the Institute of Molecular Biotechnology in Vienna. That day in 2011, however, she spotted an odd dot of pigment in one of her spheres. Looking under the microscope, she realized that it was the dark cells of a developing retina, an outgrowth of the developing brain. And when she sliced one of the balls open, she could pick out a variety of neurons. Lancaster realized that the cells had assembled themselves into something unmistakably like an embryonic brain, and she went straight to her adviser, stem-cell biologist Jürgen Knoblich, with the news. “I’ve got something amazing,” she told him. “You’ve got to see it.”

Lancaster and her colleagues were not the first to grow a brain in a dish. In 2008, researchers in Japan reported1 that they had prompted embryonic stem cells from mice and humans to form layered balls reminiscent of a cerebral cortex.

The Johns Hopkins team created the iPSCs by reprogramming the skin cells of a patient with a specific disease or non-disease background. For example, Hartung and his colleagues are very interested in autism because cases of the disorder are doubling every 10 years in the US. ‘This cannot be explained by genetics because genes are not changing that fast, so there must be environmental factors,’ he said.

As a result, the team is making mini-brains from the cells of autistic children, and this allows them to then test the effects of various compounds on that disorder. ‘This is the first time that you really can test gene–environment interactions on a personalised basis,’ Hartung explained. ‘I could imagine similar applications for even testing whether an individual would react favourably to a certain drug or not.’ While such a possibility would be far too costly at the moment, he believes that these mini-brains could facilitate personalised medicine in the near future.

Around five labs in the world have developed similar brain models, but the Johns Hopkins model is different because it is better standardised, according to Hartung. Many of the other models take up to nine months to develop, and they are all unique, Hartung said. ‘These were the Ferraris, the Maseratis – the beautiful almost brain-like structures,’ he remarked. ‘We only produce mini-brains – mini-coopers – but they are all the same, and this allows us now not to compare different brains, but to compare different drivers.’ He stressed that their mini-brains can be used to compare different drugs and toxicants to better understand their various effects.

Hartung is now applying for a patent on the mini-brains and is also creating a spin-off called Organome to produce and sell them. He said nobody should have an excuse to still use animal models, which come with ‘tremendous limitations’, including cost and time.