Human-mouse hybrid brain appears! Stanford University 7-year research published in Nature

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Brain-like organoids from humans have now been successfully combined with mouse brains in the hands of scientists.

And if you touch a mouse's whisker, these brain cells can react normally.

The results of this study from Stanford were published in the latest issue of Nature.

How deep is this "human-mouse hybrid brain" combination?

In the own words of the corresponding author, Stanford neuroscientist Sergiu Pasca :

It is like adding a new transistor to the circuit.

What the hell does this happen?

Integrating human brain-like tissue into the rat brain

To make this clear, we have to start with

organoids.

Organoids are a collection of cells cultured from human stem cells such as embryonic stem cells and induced pluripotent stem cells.

In recent years, organoids have been a major academic hot spot in the field of neuroscience because these three-dimensional micro-organs contain some key characteristics of their representative organs and can be used to simulate human development and disease in vitro.

In other words, with the help of organoids, scientists can directly observe various structures of the kidneys, intestines, and even the brain in a petri dish to explore the underlying neural mechanisms.

Convenience is convenience, but organoids also have many limitations.

For example, although brain organoids can imitate the human brain, they are difficult to establish neural connections like a real brain, and cannot be integrated with other neural circuits that control behavior.

Researchers at Stanford University aim to break through this limitation.

Their experimental plan is:

First, use human stem cells to cultivate a brain-like structure similar to the cerebral cortex.

Then, it was transplanted into the somatosensory cortex of the brain of athymic rats that were 2-3 days old. This area of ​​the rat's brain receives signals from the whiskers and other sensory organs and passes them on to other brain areas.

The number of newborn rats participating in the experiment was approximately 100. They are all implanted in the same part of the brain organoid so that scientists can better monitor its development.

At first, these human brain tissues were only about 5mm long, but after 6 months, they occupied 1/3 of the rat cerebral hemisphere.

The reason why these human brain tissues can grow is because rat endothelial cells quickly entered them and formed blood vessels. Blood vessels provide nutrients and signaling substances to human cells and carry away metabolic waste products.

The researchers also observed that resident immune cells in the rat brain also appeared in the transplanted human brain tissue.

Not only that, experimental results show that neurons from organoids successfully established a working mechanism in the rat brain and integrated with the rat's own neural circuits.

In other words, these human brain tissues have been mixed with the rat brain and

become part of it!

By this time, the researchers found that human cells in the somatosensory cortex of mice also responded when they touched their whiskers.

In addition, the researchers also specially processed some human brain tissue so that individual neurons can be activated by blue light of specific frequencies.

The rats implanted with these human brain tissues participated in a new training: ultra-thin optical fibers were implanted in their brains. When these optical fibers emitted blue light, they could drink from the tap. to the water.

The results showed that the rats learned to associate blue light with drinking water. This showed that the implanted human brain cells were actually involved in the work of the rat brain.

It is worth noting that the researchers mentioned that brain organoids transplanted into rat brains are more complex in form and function than brain organoids cultured in vitro.

What does it mean?

Scientists expressed the hope that through such experiments, they would

further explore human neurodegenerative diseases and mental illnesses, etc., and then develop some effective new drugs. The epilepsy, Alzheimer's disease, Parkinson's syndrome, and amyotrophic lateral sclerosis that we often hear about are all neurodegenerative diseases.

In order to gain a deeper understanding of brain tissue activity in patients with neurological-related diseases, this research lasted for 7 years.

In one experiment, researchers implanted brain organoids grown from stem cells of patients with Timothy Syndrome (TS) into a part of the brain of mice. side, and another time implanted into a healthy human brain organoid for comparison.

​

（

TiMosey syndrome is a rare genetic disease, and patients are prone to arrhythmia)Five to six months after implantation in mice, they observed that the diseased cells were smaller and engaged in electrical activity that was completely different from healthy brain cells.

Moreover, the dendrite morphology at the terminals of TS neurons has been significantly changed.

Further analysis found that at a similar differentiation stage, the dendritic branching pattern of TS t-hCO in rat brains was abnormal, while the dendritic branching of TS t-hCO cultured in vitro did not show this pattern. situation.

The researchers noted that the branching patterns in the rats' brains were abnormal, consistent with their previous research on the disease.

It can be seen that the effect of revealing disease phenotypes by implanting human brains into rats is quite good.

Overall, this research has attracted the attention of many people in the biological and medical circles.

Madeline A. Lancaster, member of the Medical Research Council of Cambridge, UK

commented:

The study is overall quite progressive. , providing a new way to understand diseases involving brain cell dysfunction.

It is worth noting that this research has also raised new ethical issues. The outside world is worried that these "human and other biological hybrids" will seriously damage animal welfare and even create "rat men".

But in fact, it seems that no major problems have occurred so far, and the mice have not become smarter due to the implantation of human-like brains.

A report released last year by the National Academies of Sciences, Engineering and Medicine stated: "Brain organoids derived from humans are still too primitive to form consciousness or human intelligence."

This article Corresponding author Professor Pascal said that judging from their experimental process and results, rats tolerated human brain organoids very well, and the transplantation did not cause problems such as epilepsy.

Despite this, there are still many skeptical voices in the academic community.

Arlotta, a member of the National Academy of Sciences panel, held a different view. She felt that with the development of science, new problems are likely to arise.

She said that the topic of "the integration of human organs with other organisms" should be continuously paid attention to and must not be discussed just once and then ignored.

Especially for primates such as monkeys and orangutans, they are more similar to humans, so human brain-like organs are likely to develop more maturely in their bodies and have a greater impact on animal behavior.

In this regard, Professor Pascal said that they will not conduct such research in the future and do not encourage others to conduct such research.

In addition, some researchers pointed out the limitations of this study:

Although the results of implanting the "mini human brain" into rats were better than other previous animal experiments, Due to spatiotemporal and cross-species limitations, highly reducible human neural circuits cannot be formed even when transplanted at early stages of development.

Bennett Novitch, a member of UCLA’s Biomedical and Stem Cell Research Center, also commented:

Using rats implanted with human brain tissue to test drugs is feasible for small studies, but it is not suitable for pharmaceuticals. Still not feasible for companies because of the need for speed and scale.

Research Team

The team that conducted this study came from the Department of Psychiatry and Behavioral Sciences and the Department of Comparative Medicine at Stanford University.

Common act: Omer Revah, Felicity Gore, and Kevin W. Kelly.

Omer Revah, Ph.D. in Physiology and Computational Neuroscience from Hebrew University. After graduating from his Ph.D., he worked as a postdoctoral researcher in the Department of Psychiatry and Behavioral Sciences at Stanford University. He is currently an assistant professor at the School of Veterinary Medicine at Hebrew University.

Felicity Gore is currently engaged in research in the Department of Bioengineering at Stanford University.

Kevin W. Kelly currently works in neuroscience and genomics in the Department of Psychiatry and Behavioral Sciences at Stanford.

Corresponding author Sergiu Pasca

is currently a professor in the Department of Psychiatry and Behavioral Sciences at Stanford University.

Paper address:

​https://www.nature.com/articles/s41586-022-05277-w​

参考链接：
[1]https://www.nature.com/articles/d41586-022-03238-x
[2]https://www.washingtonpost.com/science/2022/10/12/brain-tissue-rats-stanford/

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