It sounds like something out of a 1980s horror movie, but medical researchers are now able to transplant human “mini-brains,” also known as brain organoids, into animals like rats. As gruesome as it may sound to implant human brain tissue into animals, this research provides a way to safely research diseases and health problems we struggle to understand, including genetic disorders that affect the brain.
Recently, a new paper called for the creation of a framework that researchers can use to make ethical decisions about brain organoids. Digital Trends spoke to Dr. Isaac Chen, lead author of the paper and an assistant professor of neurosurgery at Penn Medicine, about the ethical issues involved in this research, as well as its potential benefits.
The process begins with taking a sample of stem cells from a human. These pluripotent stem cells have the potential to develop into other types of cells, such as neurons, as required within the body, and the scientists use this natural pathway of development to grow the organoid. The cells are grown as a colony, and they naturally ball up into a group to create a small organoid, about the size of a pea.
The stem cells can either be grown into region-specific organoids, which are modeled after a particular brain area such as the cortex, or into whole-brain organoids. The organoids are special in that, as they develop, they start to show features of a real organ. For example, the human cortex has a distinct layered structure, and cortical organoids also start to develop up to six layers. This makes the organoid structurally similar to a real brain, making it ideal for research purposes. The organoid can then be implanted into an animal’s brain and tests performed.
This technique has been used for some remarkable findings. In 2017, Chen and his team transplanted a human cortical organoid into the area of a rat’s brain that processes visual information. They learned that the organoid was able to integrate with the rat’s brain, and that the organoid produced signals in response to visual information presented to the rat’s eyes. Even though human neurons and rat neurons are quite different — human neurons are capable of much more complex computations than rat neurons, for example — the implanted human neurons were able to communicate with the neurons in the rats’ brains.
It’s not surprising that this research raises serious ethical questions. Do animals become more human when we implant human brain cells into them? Could we accidentally create human-like experiences or emotions in animals? And if so, what moral rights should be conveyed on an animal which is in some way partially human?
Chen believes that researchers should start pondering these questions now, while the implantation techniques are still in their infancy. He considers the differences between region-specific and whole-brain organoids to be relevant, as region-specific organoids can only affect a small area of the host’s brain. “It’s highly unlikely that a region-specific organoid is going to be able to create brain functions outside of the region that it represents,” he told Digital Trends. “The likely outcomes [of a transplant] are rather limited.”
The matter of whole-brain organoids is somewhat different, however, as they do have the potential to interact with more brain regions. But that doesn’t mean they have the same capabilities as full brains. “Even putting a whole-brain organoid into an animal’s brain at this point in time is unlikely to generate a higher-order thought process within that animal,” he explained. “There are so many fundamental differences between a rat brain and a human brain. The structure of those two brains is very different.”
Chen described a thought experiment in which we can imagine replacing an animal’s entire brain with human neurons that replicate the structure and integrate into the nervous system. This is a long, long way from being possible right now, but it allows us to think about the ethical issues involved. If a rat had the same brain structure as before, but built out of human neurons rather than rat neurons, would it have the same capabilities as a regular rat? Or might the human neurons give the animal more human-like experiences and capabilities?
The scale of the cerebral cortex in a rat is different.
“Much of the reason we as humans are able to talk, to think, to rationalize, to do all of these higher-order functions is based on the cerebral cortex,” Chen said. “The scale of the cerebral cortex in a rat is different. A human brain has upward of 16 billion cortical neurons, as opposed to a rat, which in total has only 200 million neurons. There’s a huge difference. There are also more complex connections in a human brain between different areas of the cortex and between the cortex and other structures. You don’t find those same type of connections in a rat brain.”
That means that even if a rat’s brain was swapped for human cells, while it might possibly be slightly smarter than a regular rat, it wouldn’t be human-like in the ways we normally think of. “A rat brain itself, even made of all human cells, wouldn’t give the ability to think or to be creative, the things that we attribute to humans,” Chen said.
What can we do with organoids?
As is stands right now, implanting whole-brain organoids is more likely to impair an animal’s abilities rather than enhance them. That means ethical considerations in organoid research should be the same as for any other animal experimentation — focusing on whether the animals are kept in engaging environments, whether they have the opportunity to socialize, and minimizing any pain or discomfit they experience, for example. But in the future, organoid research could develop in profound ways.
Currently, brain organoids have around the level of development you’d see in a fetus. The organoids can’t yet respond to environmental stimuli and develop in the same way a human brain does, though Chen believes that organoids approximating the brain development of a small child could be feasible within the next five years.
Another area of future expansion for the field relates to the brain activity demonstrated by the organoids. A recent paper showed some evidence of more complex network activity in organoids, after looking at the oscillatory waves they produced. “That type of theme is what we’re going to see more of, where people are interested in understanding more about what is developing in terms of activity,” Chen said. “Not just at the level of single cells, but as the cells mature, how they start talking with each other within the organoid.”
These developments would allow researchers to use organoids to model complex neuropsychiatric and neurocognitive conditions like schizophrenia, depression, or attention deficit disorder. The advantage of organoids as research targets, Chen says, is that “they are much more accessible and you can do more interventions and experiments on the organoids than you can with a human brain. There’s so much that we can do with the organoid model. The hope is, as we learn more about how these organoids develop and work, that we will gain new insights about how the human brain itself functions.”
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