Inside their small furry heads, Stanford rats have brains that are a little bit human.
These rodents any aren’t any smarter than their peers. Their memories aren’t better, and they can’t read, write, play Wordle or do much else that we can do.
But their unique brains – a blend of human and rat cells that talk to each other – are working models of disease that could someday unlock the mysteries of autism, epilepsy, schizophrenia and other severe neurological disorders that are not easily studied in people.
The Stanford project, published Wednesday in the journal Nature, represents the most advanced human brain circuitry ever built from scratch — and demonstrates that implanted human neurons can influence an animal’s behavior.
Their effort raises this thorny question: How far we should go to create an animal that is human-ish? The closer scientists get to approximating the human brain, the more useful the research – yet the murkier the ethical waters.
The goal “is to understand psychiatric disorders at the biological level, so that we can find effective therapeutics,” said Dr. Sergiu Pasca, professor of psychiatry and behavioral sciences at the Stanford School of Medicine, who led the research.
While other forms of animal-human fusion are now commonplace — such as implanting the heart valve of a pig into a human — the brain is something different. It’s our soul and the seat of our identify, responsible for thought, speech, judgment, and other advanced cognitive functions.
But when the brain gets sick, there are too few tools to help, because it is so hard to conduct research. And most psychiatric illnesses are distinctly human, not found in other animals.
“I believe we have a moral imperative to find better models to study these conditions,” which are the largest cause of disability worldwide, Pasca said.
In a landmark 2021 report, the National Academy of Sciences said that such research offers promise for understanding the human brain — but that this promise must be carefully weighed against ethical concerns.
“We can’t subject your brain to a variety of nasty stuff and then take it out and look at it. That’s called murder,” said Stanford bioethicist Hank Greely, director of the Stanford Program in Neuroscience, who was hired by the university to evaluate the project’s ethical issues. “This is a good way to learn more about human disease in a way you can’t in humans.”
While the ethical concerns of current research can be addressed by existing oversight mechanisms, the issues will need to be reassessed as the science develops, he said.
The hope, said Pasca, is that human disorders can be successfully studied in the living laboratory of a rat’s brain — so we can stop there. He opposes moving the research into chimps, monkeys and our other evolutionary cousins, citing ethical and animal welfare concerns.
Already, the rats are being used to test potential medicines. In the future, they could be used to advance “cell therapy,” which aims to replace parts of a damaged brain.
The animals offer other research opportunities, as well. They could be used to study how the healthy brain develops, or is harmed by toxic chemicals or social deprivation.
Already, the research has yielded insights about a devastating developmental disease called Timothy syndrome, a rare genetic condition strongly associated with autism and epilepsy.
The Stanford team spotted marked differences in the electrical activity of brains built with Timothy syndrome-derived brain cells. Compared to healthy cells, the Timothy syndrome cells were also much smaller and less capable of sprouting extensions called dendrites, which act as antennae for input from nearby neurons.
“I know of the many concerns and sorrows which are associated with the lives and outcomes of these children,” said genetic researcher Katherine Timothy, who long ago recognized and described the disorder. The research “will help give the medical community a better understanding of abnormal neuronal development,” she said, “and hopefully, in the future, give better ways we might be able to treat and improve neuronal function.”
The field got its start about 20 years ago, when a team led by Stanford University’s Dr. Irving Weissman and Rusty Gage of the Salk Institute of La Jolla created a pint-sized hybrid: a healthy mouse with paws, whiskers and millions of human cells in its brain. But the cells never fully integrated, and eventually died.
Since then, the research has flourished, building on greatly improved techniques.
In this new project, Pasca’s team took human skin cells and turned them into stem cells. Then they used chemical prods to turn the stem cells into a dozen different types of types of brain cells.
They didn’t just create flat, garden-variety layers of cells. Rather, they grew three-dimensional clumps, called organoids. With time and practice, the scientists learned to turn these clumps into “assembloids,” larger and more complex structures of many cell types — more closely mirroring the human cerebral cortex.
Next, these “assembloids” were implanted into the skulls of 100 newborn rats, whose brains had not yet matured. These are special animals, with weakened immune systems that don’t reject the tissue.
Then the magic happened: the human cells thrived, grew and merged with the rats’ brains. They grew blood vessels and sprouted axons. They also grew little knobby spines that received chemical messages from the rat cells’ axons. It is this signaling that enables animals to think and learn.
The human cells grew over time, eventually occupying one-third of the hemisphere of the rats’ brains. Meanwhile, the rats’ neurons wandered over into the implanted human tissue. The animals even built blood vessels to the human cells to supply nutrients and cart away waste.
Remarkably, working mental circuits were formed. The human neurons forged direct connections with the rats’ thalamus, a region deep in the brain that relays multiple sensory inputs to the cortex. When scientists moved the whiskers of the rat, the human neurons responded.
The implanted human cells even controlled the animal’s behavior. In a complex experiment, the rats learned to associate blue-light stimulation of their implanted human cells with the reward of water.
Cognitive tests found that the rats were neither smarter nor stupider. They had no new fears. Their memories didn’t improve, or deteriorate.
“It’s incredible to think that we can finally leverage all these amazing tools that we have today in neuroscience,” said Pasca, “without the need to poke holes in people’s heads and look at their neurons.”
