Human cells in a rat's brain could shed light on autism and ADHD

Researchers at Stanford University School of Medicine transplanted human brain tissue into rats, which became a functional part of their brains.

The outcome of this study will boost the understanding of brain disorders and enable the discovery of new drugs to treat them.

The study took seven years to complete and entailed substantial ethical debates regarding animal welfare and other issues. It was published on Wednesday in the journal Nature. The research into illnesses like autism, epilepsy, schizophrenia, and intellectual disabilities will be the study's most direct applications.

The implanted human brain tissue was produced in the lab using a method that lets researchers transform skin cells into what are known as embryonic stem cells, the cells from which all others arise as the embryo grows.

In the lab, scientists can nudge these cells down the developmental pathway, growing them into any of the 200 or so types of cells in the human body.

Researchers created clumps of these cells that resemble parts of the brain. The lumps, known as organoids (tiny structures grown from stem cells that mimic the human brain or other organs), resembled the cerebral cortex, the outermost layer of the brain associated with some of its most advanced processes, including language, memory, thought, learning, decision-making, emotion, intelligence, and personality.

The researchers used syringes to inject human brain tissue into the brains of two- to three-day-old rat pups. Then, rat brain cells moved to the human tissue and connected there, incorporating the human cells into the structure of their brains.

"We don't remove that part of the rat brain. Essentially what happens is that the rat tissue is pushed aside," said Sergiu Pasca, professor of psychiatry and behavioral sciences at Stanford, who led the study.

When implanted, the human brain tissue was about one-fifth of an inch long. However, it quickly grew and, after six months, made up nearly one-third of the rat's brain. The left and right hemispheres of the brain are divided into two sections, each of which performs a separate function.

Deep inside the rat's brain, human and rat cells are connected in the thalamus, the area critical for sleep, consciousness, learning, memory, and processing information from all senses, except for the smell.

"Overall, I think this approach is a step forward for the field, and offers a new way to understand disorders" that involve the malfunction of brain cells, said Madeline A. Lancaster, a group leader at the Medical Research Council Laboratory of Molecular Biology in Cambridge, England, who did not participate in the study.

"Ethically, there may be concerns about animal welfare, and so just like all animal experimentation, the benefits should always be weighed against the risks to the animal," Lancaster said. "But I do not have any concerns around whether the human transplants would cause the animal to become more 'human,' since the size of these transplants are small and their overall organization is still lacking."

According to Pasca, researchers held in-depth conversations concerning animal care with ethicists to prepare for the trials. He said there was no evidence that the rats in the study had pain or seizures or showed any signs of anxiety.

The first brain organoid was created in 2008 by Japanese stem cell pioneer Yoshiki Sasai; however, Lancaster claimed that because they lacked the blood circulation system found in humans, their applicability has been limited. Organoid cells were strained and eventually died as a result of this shortage.

"This study overcomes this limitation by transplanting organoids into the rat brain where the organoids can become vascularised," Lancaster said. "The result is much more mature" structures, connections, and activity from the transplanted tissue inside the rat.