Currently viewing a development environment

Why scientists are transplanting artificially grown “brains” into living brains

Scientists are making major strides in growing fully functional "mini brains" -- but what are the ethics of such science?

Yewande Pearse


LA Biomed

Science is awesome, but it can involve doing some pretty strange things. From showing that blood from a young mouse can reverse the signs of aging in an older one by joining the mice together, to hijacking the circulatory system of a mouse with no immune system to grow an artificial ear on its back - science can get freaky. 

Now, scientists are transplanting "mini-brains" into the little brains of mice. Before you write us off as crazy cackling scientists in basements, let me explain why.

"Mini-brains," or brain organoids, the latest development in stem cell technology, are organized 3D cell structures made up of different brain cells, which resemble the complexity of the human brain. Human stem cells can be grown into brain organoids in 40 days, offering neuroscientists an unprecedented opportunity to more accurately model human brain development and disease. Until now, scientists had two choices: to study the brains of other mammals and extrapolate similarities with the human brain, or study the cells that make up the brain in a dish, which  although informative, can only tell us so much about how the human brain  works as a whole.

However, unlike our own brains, which last a lifetime, these mini-brains are relatively short-lived. The human brain has the advantage of a circulatory system, allowing it to survive and function. By supplying brain organoids with a special cocktail of factors, they can grow in a dish, develop and survive, but  only to a limited degree. But, by transplanting brain organoids into the brains of living mice, one group of scientists has shown that artificially grown organoids have the potential to resemble a real human brain even more closely when they  are sustained by a living blood supply. 

The group were able to show that the transplanted organoids can fully integrate into the mouse  brain, survive for up to 9 months, and develop to a level of maturity, which had not before been seen.

By  tagging the transplanted organoid and creating a  glass window in the skull, the group was able  to keep track of where it was in the mouse brain. The first thing they noticed was that compared to organoids kept in a dish, the organoids that had been successfully transplanted into the mouse brain shared more features with a human brain. The normal human brain has a network of cavities, which are filled by cerebrospinal fluid and is also formed up  of distinct layers of neuronal cells, which mature over time. In the  dish, organoids develop a cavity and begin to form different cell layers  like in a real brain, however, the cells that make up the layers do not  fully mature. When the researchers compared the different cell types  present in the implanted organoids vs. those that were formed in a dish,  they detected a higher number of mature neurons and also other cell  types, such as the star-shaped support cells of the brain, called astrocytes, which are not usually found in lab-grown organoids. 

The  human brain is made up of billions of neurons which need to communicate in order for our brains to function as a whole. The point at which two neurons meet is called a synapse and chemical signals are transported between neurons, across these synapses. Not only were the scientists able to show that the transplanted organoids developed mature neurons,  but also that these neurons were able to form synapses with each other,  and with resident neurons in the mouse brain.

The scientists' findings were staggering. They had predicted that providing organoids with a constant blood supply would allow the organoids to fulfill their true developmental potential, but they needed proof. By injecting a red  fluorescent dye (which can only be detected under a specific wavelength  of light  using a special microscope) into the mouse brains, which could  enter the blood stream, they were able to see the flow of blood through the blood vessels and saw that the blood vessels did indeed run throughout the  organoids.

By this point, it seemed like organoids with a living blood supply looked more like a human brain in terms of structure than they had ever looked in a dish because they were able to survive long enough to develop properly. However, the question still remained as to whether the neurons and their synapses were functional. Neurons are electrically excitable cells that receive, process and transmit information through electrical  and chemical signals. Calcium plays an important role in the transmission of electrical signals from one neuron to the next. Changes  in the levels of calcium at the end of neurons can be measured using calcium-sensing proteins that light up red. When the scientists looked through the glass window in the skulls of the mice, they were able to see that neurons did have fluctuating levels of calcium, suggesting that  neurons in the brain organoids were active. To be sure, they used electrodes to directly measure the electrical activity of the implanted organoid at different places and during different times of development, and discovered that the neurons were able to electrically stimulate each  other and respond to stimuli from the external environment.The researchers had succeeded in creating fully functional brain organoids. Then things got really interesting.

In their earlier experiments, the scientists had detected connections between neurons from organoids and neurons from the mouse brain, but they could not tell  whether or not the neurons could actually communicate with one and  other. Optogenetics is an extremely clever technique that uses light to  control neurons. By using this technique, the researchers were able to  specifically stimulate the neurons in the organoids by turning on and  off a light. When the light was on, the neurons of the organoids became  electrically active. When they used electrodes to measure the activity  of neurons outside the organoid in another part of the mouse brain, they  were able to detect electrically activated neurons there too, showing  that organoid neurons could signal to host neurons.

Those with an active imagination might picture the organoid taking over, creating some sort of "hybrid-consciousness." They wouldn't be foolish for thinking  so. Consciousness is a difficult term to grasp. It is a topic that still  has scientists scratching their heads. In fact, most scientists believe  that the origin of consciousness lies outside the realm of scientific inquiry. One thing that scientists can agree on though is that consciousness needs the brain, and that the neural circuits of which the brain is comprised are essential for certain aspects of consciousness. Therefore, if consciousness can be boiled down to neural connections then experiments like this raises interesting question about  whether consciousness can therefore be grown in the lab and it's  ethical consequences.

In a 2016 interview, organoid pioneer Madeline Lancaster at the Medical Research Council  Laboratory of Molecular Biology in Cambridge, England said of her 3D  brain tissue structures, “Just to be clear, they are not really human  brains.” At the time, she was able to recall 16 labs around the world  who had adopted her technique. But did she foresee that a year later, other labs would be injecting them into mouse brains? If neural networks  are at the root of consciousness and if we don't fully understand how consciousness arises because of them, do we need to consider the ethical implications of producing brain organoids, which are becoming better and better at forming functional connections? The president of the Allen Institute for Brain Science in Seattle, Christof  Koch, has concerns, saying in an interview last year "We are entering totally new ground here... the science is advancing so rapidly, the ethics can't keep up."

In reality, scientists develop techniques with noble intentions - to understand how our bodies work. Not to create "freaks of science." But in the process, techniques are developed which have further potential - potential that might be considered unethical. 

Animals are used in research without us fully understanding their consciousness, so why should we worry about creating artificial 3D brain-like structures? Maybe we shouldn't. This is something we, both the scientific community and the public, need to work out. A variety of 3D organoids including a colon, small intestine, liver, retinal cells (cells in the eye), and pancreas have been implanted into living organisms, in some cases, to repair and rescue tissue damage (colon, liver, and pancreas). Meaning that organoids may have potential for cell therapy. Stem cell therapy is  already being tested in a number of clinical trials, and organoids could be the next step. We are not that many steps away from organoids reaching a human brain, therefore, it is worth considering how they  impact the brains of other living creatures.

Comment Peer Commentary

We ask other scientists from our Consortium to respond to articles with commentary from their expert perspective.

Max G. Levy

Science and Health Journalism and Chemical Engineering

This is a wonderful, intriguing piece. I wonder how the scientists selected the specific brain region to receive the transplant? We know, of course, that the brain’s physiology/function differs from location to location. I’m also curious how the organoids would grow in place of a removed brain portion. Could this be used to replace parts of the brain, for example to remove an amygdala and inject cells in its place?

Yewande Pearse responds:

I am glad you enjoyed the piece! Thank you for your question - it’s a great one. They transplanted the organoid into the retrosplenial cortex - which is involved in a range of functions such as episodic memory, navigation and spatial learning. They suctioned out a small bit of the tissue using a blunt-tip needle attached to a vacuum line to create room for the organoid. The organoid grew into the cavity created, but they only removed a small portion of the whole structure. It’s unclear if this would be the case if the cavity was larger, or as you say - a whole structure was removed.

I think the use of organoids as a stem cell therapy is promising, but more in terms of providing a “tool-kit” of different cells at this point, rather than actually replacing specific structures. This is because they are not perfect yet, they still lack a lot of the important features to perfectly replicate e.g. an amygdala. However, the more sophisticated they become, the more feasible this might be in the future and researchers are definitely considering this in stroke and traumatic brain injury research.

Just a final thing that you might also find interesting that I didn’t include in the piece. They don’t explain why they chose to transplant into the retrosplenial cortex, but they did carry out some relevant learning and spatial memory tests to assess the impact of the organoids on behaviour. They found that learning was not affected too much but that memory was impaired. This was probably because of the trauma of the surgery though, rather than the organoid itself, but more tests are needed to properly look into this.

Max G. Levy responds:

Oh that’s really cool! I didn’t realize that they actually did behavioral tests afterwards. That’s very exciting, it would be fascinating to see a controlled study on behavioral effects, but I imagine that it’s hard to have a control for a surgical operation. Looking forward to more progress on this front, thanks for sharing!