The ability to transplant clusters of human neurons into the brains of newborn rats is a striking feat of biological engineering that may provide more realistic models for neurological conditions such as autism and serve as a way to restore injured brains.
The clumps of human cells, known as "organoids," grew into millions of new neurons and wired themselves into their new nervous systems according to a study published on Wednesday. The rats were able to receive sensory signals from their whiskers once the organoids were in their brains.
Dr. Sergiu Pasca said that he and his colleagues were using the transplants to learn more about the biology behind the disorders.
More complex models of the human brain are needed to tackle the biology of these conditions.
In 2009, after training in medicine in Romania, Dr. Pasca joined the research team at the university. He and his colleagues bathed volunteers' skin cells in chemicals that changed their appearance. They were like embryo cells, which can be used to make any tissue in the body.
The researchers added more chemicals to encourage the cells to become neurons. They could observe the length of the neurons as they were shot down.
Dr. Pasca and his colleagues carried out the same experiment again, this time using skin cells from people with Timothy syndrome, a rare form of autism that causes serious heart problems as well as impaired language and social skills.
Dr. Pasca was able to see differences between Timothy syndrome neurons and typical neurons. They made more signaling chemicals such as dopamine.
A limited number of clues can be found in examining single cells. Dr. Pasca thought he could learn more by studying the brains of thousands of people.
Dr. Pasca was able to mimic the condition inside the brain with a new chemical recipe. The skin cells became progenitor brain cells, which in turn became tangles of neuron found in the brain's outer layers.
He and his colleagues connected three organoids: one made of cortex, another of the spine and a third of muscle cells. The muscles contracted when the cortex organoid was stimulated.
Organoids aren't mini brains. Their brain cells are not functioning for one thing. They aren't as active as normal brain cells. There are a number of limitations to these models.
Organoids were put in living brains because a petri dish limited their development. Fred Gage and his colleagues at the Salk Institute for Biological Studies were able to transplant human brainoids into adult mice. As the mouse brain suppled the human neurons, they continued to grow.
The back of the brain has been used by Dr. Gage and other researchers to implant organoids. The mouse's own cells responded in a similar way to the flashes of white light that the animals saw, according to a study published online in June.
Organoid transplants were being worked on by Dr. Pasca and his team, but they chose to use young rodents instead of adults. The scientists injected an organoid the size of a poppy seed into a region of the brain called the somatosensory cortex after a rat was born. Rats are sensitive to signals from their whiskers.
About a third of the cortex on one side of the rat brain is made up of human cells. The organoid's cells grew six times faster than in a petri dish. The cells were just as active as the human brain.
Human organoids wired themselves into the rat brain. They connected to distant ones even though they were not close to each other.
Humans are sensitive to the rat's senses. The rat's organoid crackled in response to the researchers blowing puffs of air over it.
They used a water fountain in the rats' chambers to see how organoids affected their behavior.
The rats were trained to drink from the fountain when their organoid was stimulated. Rats were receiving messages from the human organoids.
There are provocative ethical questions raised by these experiments. Before starting the work, Dr. Pasca consulted with experts at the Center for Law and the Biosciences atStanford, who urged him to pay special attention to the animals.
"You're not just worried about how many mice are in a cage, or how well they're fed." This is a new way of doing things. You don't know what to look for.
The rats did not experience pain, became prone to seizures, or suffered a loss of memory. According to Dr. Pasca, the rats are well-equipped to accept human material.
The human organoids did not make rats more human according to a University of Southern California neuroscience researcher. They didn't score better on learning tests than other rats.
They are rats and stay rats. It should be reassuring from an ethical point of view.
If human organoids were to be placed in a close relative of humans, that might not be right. She said that setting guidelines to operate in the right ethical framework would be a good opportunity.
The similarity between humans and primate might allow the organoids to grow more and play a bigger role in the animal. He said that it wasn't something that they would encourage doing.
He is studying neurological disorders with the implanted organoids. In one experiment, Dr. Pasca and his team implanted an organoid from a patient with Timothy syndrome on one side of a rat's brain and a different organoid without the disease on the other side.
The rats had organoids. There were more dendrites in the Timothy syndrome neurons than there were in the other ones. The dendrites weren't as long.
Dr. Pasca wants to be able to observe differences in the way rats behave when they carry brain organoids from people with a neurological condition. Experiments that show how certain genes change the way the brain works could be useful.
A researcher at the University of Pennsylvania who was not involved in the research thinks that the repair of injuries to human brains may be possible.
Dr. Chen wanted to grow brain organoids from a patient's skin. The organoid can grow in the patient's brain after being injected.
He said that the idea is out there. It is just a matter of how to take advantage of it.
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