What's Wrong With Growing Blobs of Brain Tissue?

Last week, Rusty Gage and colleagues at the Salk Institute announced that they had successfully transplanted lab-grown blobs of human brain tissue into mice. Gage’s team grew the blobs, known as brain organoids, from human stem cells. Once surgically implanted into rodent brains, the organoids continued growing, and their neurons formed connections with those of the surrounding brains. It was the first time such transplants had worked: Until now, organoids had only ever been grown in dishes.

To be clear, Gage’s mice weren’t running around with human brains, nor did they have a human mind trapped inside their heads. The biggest brain organoids are lentil-sized and contain 2 to 3 million cells; a human brain is 20,000 times bigger and contains around 172 billion cells. Even the biggest ones don’t have the full set of cells needed for a working brain. On their own, their neurons don’t form networks like those in our heads. They don’t sense, learn, or make memories. They are emphatically not brains in jars. They’re not mini-brains either, in the same way that a leaf is not a mini-plant and a doorknob is not a mini-building.

They do, however, capture some of the architectural features of parts of a brain, which is why they’re useful. Scientists can use them to understand how brains develop, and how they differ in disorders. For example, one group of researchers made organoids with a genetic mutation that’s linked to microcephaly—a condition where babies grow up with small brains. Those organoids were also smaller than usual, and the team could work out why. Another group, led by Hongjun Song at the University of Pennsylvania used organoids to confirm that the Zika virus can affect the fetal brain and cause microcephaly, and to pinpoint which cells it infects.

“There are many issues why psychiatric disorders have been hard to crack, but one is that we don’t have access to the functioning human brain,” says Sergiu Pasca, a neuroscientist at Stanford University. Imaging technologies are still relatively crude. Animal brains are smaller than ours, and grow differently. Organoids, though also limited in their own ways, “allow us to capture aspects of human brain development that were previously inaccessible,” says Pasca. They might even allow scientists to replace brain tissue that’s been lost through injury or disease.

But Gage’s experiment, which was first announced at a conference last November, shows that the ethical discussion around organoids has yet to catch up with the fast-moving technology for creating them. They are getting bigger and more complex. They’re being transplanted into animals. “It does raise visceral reactions and for this research to progress, the public must be comfortable with it and understand it,” says Nita Farahany, a bioethicist at Duke University. “At some point, these models could become so good that they could approximate the whole brain. The closer they get to the human brain, the sharper the ethical issues.”

At what point would an organoid be worthy of moral status? Of respect? “At what point is it reasonable to at least discuss the question of sentience? Or conscious experience? Pain? Pleasure?” asks Christof Koch from the Allen Institute, “We’re not there, but we have to start thinking about these possibilities.” Farahany, Koch, and 15 other leading ethicists and neuroscientists have now outlined some of those issues in a new paper, based on a workshop they held last May. (The debate was vigorous: “Every one of the authors wordsmithed every line of this paper,” Farahany says.)

Over the last decade, scientists have managed to coax stem cells into many different kinds of tissues and organs. And along the way, they started realizing that these cells have an incredible capacity for self-organization. You don’t need to carefully orchestrate every step of their growth; you just need to give them oxygen, nutrients, the right molecular triggers, and some kind of scaffold so they make the right shapes. And voila—organoids. There are heart organoids, liver organoids, gut and kidney and pancreatic organoids—none of which pose many ethical conundrums.

That changed when, in 2012, Jürgen Knoblich from the Austrian Academy of Science fashioned the first brain organoids. “The brain is what people most closely identify with self and personhood, with the capacity for consciousness and agency,” says Farahany. So the act of duplicating the brain, even in part and even imperfectly, cannot help but create an instinctual unease.

Brains don’t work in isolation, though. They exist within bodies. They come wired up to eyes, ears, and other sensory organs, which provide inputs that are vital for wiring the brain correctly. “An animal deprived of visual inputs never learns to see,” says Koch. “And organoids don’t have any inputs. They won’t see or hear or smell. They can’t recall anything because there’s nothing to recall. They can’t think in any way, shape, or form.”

Thinking, however, is hard to define neurologically. Is a neuron that responds to incoming electrical signals by producing an electrical signal of its own “thinking”? “A computer can do that,” says Song. “An organoid can probably do that too. Whether that is thinking is semantics. We don’t even really know exactly how humans think.”

The stuff we really care about in the brain, like consciousness, are emergent phenomena—they arise from the collective workings of individual neurons, which create a whole that’s greater than the sum of its parts. The problem is that we don’t know at what level these phenomena emerge. A neuron is not conscious. A person is. What about all the steps in the middle? What about 2 million neurons? 20 million? 200 million?

Scientists like Koch have made a lot of progress in identifying the signals of consciousness (or the lack of it) in a living adult brain. Certain kinds of brain waves, produced by the collective electrical activity of large networks of neurons, are a good indicator. Organoids show no such signals. To the rare extent that they show electrical activity, it is chaotic and messy, more like what you’d see in a seizure.

But Farahany notes that signatures of consciousness were discovered in living beings that we already know are conscious. “It doesn’t tell us the necessary preconditions for consciousness in a new organism, or organoid, or artificial intelligence,” she says. “How do you detect consciousness in those when they have never been conscious before? You assume that it will be the same but who knows if it will be?”

This is the critical problem that the field must wrestle with. Everyone agrees that organoids aren’t currently conscious. But how would we know when they reach that point? “I was talking to organoid people just yesterday at a conference, and they want to have it both ways,” says Koch. “They’re getting better and better and they’re closer to real human tissue. Oh, so what about consciousness? Oh, that’s very far away, they say.”

Certainly, organoid research is moving quickly. Pasca recently developed an “assembloid”—a merger of two organoids representing different brain regions. Paola Arlotta from Harvard University, another author of the new ethics paper, created organoids using both retinal and brain cells; when she shone a light on them, they showed some electrical activity—evidence that crude sensing is possible. And then, there are the transplants.

Researchers have long transplanted neurons into rodents, to study and optimize procedures that might one day, for example, replace dying cells in people with Parkinson’s disease. The relocated neurons often die on their own, but organoids might fare better. Transplants also lift one of the major restrictions on organoids—they lack their own blood vessels, which limits their size. In an actual brain, they can grow bigger.

There are still limits, though. A lentil-sized organoid isn’t going to reach human size in a mouse brain that’s no bigger than a sugar cube. But, as Gage’s team found, it will start forming networks with the surrounding neurons, potentially gaining sensory information. “What if you’re implanting into a monkey?” says Koch. “Remember The Island of Doctor Moreau? We have to think about where the boundaries are.”

Even without questions of consciousness or thought, organoids still raise interesting ethical issues. “Who owns it?” says Koch. “If I take a snippet of cells from your arm, make stem cells, and make an organoid in a dish, do you still own it? Does my lab? My university?”

These questions are valid for any kind of stem-cell research, but given the special cultural status of the brain, extra transparency might be warranted. A donor might, for example, want to prohibit their stem cells from being used to make an organoid that’s transplanted into a rodent, in the same way that people can donate embryos to research on the condition that they won’t be used to make a baby.

One can approach the ethics of organoids from the other direction, too. Instead of growing brain tissue, let’s say you carve an equally small slice from a living brain, and use that to study how neurons are connected or which genes they activate. That feels less viscerally unsettling, and scientists have been doing it for a long time, during surgeries for cancer or epilepsy.

The slices “are still alive in the sense that I can get neurons to spike with electrical currents, two or three days later,” says Koch. “But it’s like the tissue is in a deep coma. There’s no spontaneous electrical activity and it’s cut off from its inputs and outputs. And since you have a living donor, you can get permission. The ethical issues are much clearer.”

But research in this field is progressing quickly, too. Scientists are developing ways of keeping the isolated slices alive for longer periods—research that might be useful for treating strokes or traumatic brain injury. “If we could get to a place where brain function is not irreversibly lost, you start thinking about whether death as a concept can be tied to that loss. In a few months, you’ll see some significant breakthroughs. That’s part of the reason for our paper.”

There are more far-fetched possibilities. “Will we ever be able to read out memories?” says Koch. “This is complete science fiction at this point and it hasn’t even been done in an animal yet. But science is advancing rapidly. As it becomes more powerful and mature, with untold promise for therapies, one has to approach these issues in a thoughtful way, and get in front of them.”