‘Minibrains’ raise hopes, ethical questions
PHILADELPHIA: Qian Xuyu yanked open an incubator door at the University of Pennsylvania to reveal rows of cylindrical tubes swirling, like shaken-up snow globes, with a strange and exotic flurry. The pale, peppercorn-sized spheres were lab-grown globules of human brain tissue, or, as Qian occasionally refers to them, “minibrains.”
“Minibrain” is a controversial nickname, loathed by some scientists who fear it conjures alarmist images of fully functioning brains trapped in vats, while the reality today is balls of cells that can’t think or feel.
But the term vividly evokes the aspirational goal of this fast- moving area of research: to mimic the complexity of the human brain and illuminate the biology of the human mind, one of science’s darkest black boxes. As the technology, which scientists refer to in journal articles as “cerebral organoids,” improves, the more the “minibrain” title fits.
Today, organoids that resemble different regions of the human brain are routinely spun up from stem cells in large batches in laboratories around the world. Researchers have refined their recipes since the technique was first described five years ago, but the process is surprisingly hands-off: after a few nudges from scientists, stem cells grow into spheres with about a million neurons through a naturally occurring choreography that mirrors early brain development in the womb. At Day 100, Qian’s minibrains resemble a portion of the prenatal brain in the second trimester of pregnancy.
“People are more worried about if they reach a certain level - if it’s really like a human brain. We’re not there; we’re very far from there,” said Song Hongjun, who leads the laboratory at Penn’s Perelman School of Medicine, where Qian works. “But the question people ask is, ‘Do they have consciousness?’ The biggest problem I have so far is I think, as a field, we don’t know: What is consciousness? What is pain?”
At the moment, minibrains are far from anything approaching moral personhood in a dish, and the technology may never come close. But the rapid pace of progress on organoids has led scientists and ethicists to call for a public ethical discussion that can move in tandem with the research.
The disembodied brain, after all, is a long-standing trope of cultural fascination and even philosophy, ranging from the serious metaphysical thought experiment called the “brain in a vat” to the screwball sci-fi comedy “The Man With Two Brains,” in which Steve Martin finds himself falling in love with a charming woman’s preserved brain.
“If, at the sunset of life, the brain is what you examine to know if someone has died, at the beginning of life is there a point where you might say, ‘Look, the brain is at the beginning of life?’ “said Insoo Hyun, a bioethicist at Case Western Reserve University. “Many people don’t understand where the science is now, and where it could go in the future - including, I think, the researchers.”
Organoids offer a powerful tool for scientists studying the mysteries of the brain, which by some estimates is the most complex object in the world. Unlike cancer, which researchers can study by growing cancer cells in a dish, the brain and its disorders have been largely offlimits, except through hard-to-get post- mortem tissue that offered only a snapshot or by trying to study much simpler animal brains.
More than a decade ago, scientists discovered it was possible to create stem cells by reprogramming a person’s skin cells. They could use the procedure to create any cell type in the body and study the basic biology of specific diseases that afflict people, ranging from Down syndrome to diabetes.
Sergiu Pasca, a neuroscientist at Stanford University, dreamed as a medical student of understanding the biological basis of autism and schizophrenia. Now, his lab uses stem cells from people who have those conditions to grow cerebral organoids.
“This gives us aspects of human brain development that were previously inaccessible. Most of the work we’re doing right now is to study really the hidden biology of the human brain,” Pasca said.
By creating organoids from people with a genetic disease that causes autism and epilepsy, he was able to watch how brain cells migrate during early development.
Pasca and his colleagues saw clear differences - one type of neurons jumped around in an abnormal and inefficient way in the organoids from the patients, giving the researchers a window into a critical part of development that could have long-term consequences.
After the Zika virus was officially linked to brain defects in infants, Song and his wife and close collaborator, Guo-li Ming, sent minibrains to collaborators, who exposed them to Zika. They saw the virus infect a kind of stem cell called a neural progenitor that generates new brain cells, wreaking havoc.
Ryan Salinas, a clinical fellow in Ming’s lab, grows organoids from patients with a deadly brain cancer, in the hopes they might provide a better tool for testing the effectiveness of drugs.
At the University of California at San Diego, stem-cell scientist Alysson Muotri is attempting to “Neanderthalise” a brain organoid as part of his larger search for the biological basis of modern humans’ sophisticated social abilities. He used geneediting technology to introduce a mutation found in Neanderthal genomes to a modern human stem cell. The early, unpublished results, he says, are an organoid that, instead of being smooth and spherical, is lumpy like popcorn - suggesting that the gene mutation significantly influences early brain development.
Five years ago, an ethical debate about organoids seemed to many scientists to be premature. The organoids were exciting because they were similar to the developing brain, and yet they were incredibly rudimentary. They were constrained in how big they could get before cells in the core started dying, because they weren’t suffused with blood vessels or supplied with nutrients and oxygen by a beating heart. They lacked key cell types.
Still, there was something different about brain organoids compared with routine biomedical research. Song recalled that one of the amazing but also unsettling things about the early organoids was that they weren’t as targeted to develop into specific regions of the brain, so it was possible to accidentally get retinal cells.
“It’s difficult to see the eye in a dish,” Song said.
People are more worried about if they reach a certain level - if it’s really like a human brain. We’re not there; we’re very far from there. — Song Hongjun, who leads the laboratory at Penn’s Perelman School of Medicine