From its inception, neuroscience has made use of animal models to model the brain. Experiments with a wide variety of animals, from fruit flies to macaque monkeys, have been conducted to understand the functioning and behavior of neurons. Although these studies provide valuable information about both the normal functioning of the brain and its diseases, they also have some limitations. The features that make us different from animals make it difficult to transfer data from animal experiments to humans. For example, although Alzheimer’s disease has been treated many times in mice, there is no effective treatment for humans. Because the developmental process of this disease differs significantly in animals and humans, current animal models are not sufficient to provide the answers we seek.
Advances in technology over the past few years have led to the development of new models for studying the activity of human neurons and their communication with each other. These include ex vivo tissues, organoids, and chimeric models (animal tissues modified with human genes or cells) from human donors. These new technologies, in which induced pluripotent stem cells are also used, create excitement in the scientific world. The main advantage of these methods is that they provide new avenues for investigating human brain cells, including the particularly sensitive developmental period. Despite the expected benefits, the use of new brain models may cause some practical and ethical problems.
Experimental Human Brain Model
What comes to mind when you hear the word “brain on a plate” or “experimental model of the human brain”? Of course, a brain that pulses, thinks and feels in a liquid-filled jar at full scale as if it came out of a science fiction movie is not an example of a brain model. Many people may not even realize that they are made of human brain tissue when they first look at the experimental models we are talking about. In one example, tissue the size of sugar cubes, obtained with the permission of patients who have undergone brain surgery, is used. With this example, an attempt is made to classify the cell types found in the human cerebral cortex more precisely. Brain tissue is transported from the operating table to the laboratory by ambulance and can be kept alive for a few days with oxygen support. With these studies, our understanding of the molecular, morphological and anatomical properties of living nerve cells has increased.
Mini Brains and Brain Model
Tissue models from adults do not reveal much about brain development. Three-dimensional, self-organizing “mini-brains” or organoids obtained from induced pluripotent cell cultures are used for this. Thus, it is studied how cells come together as the brain grows. Organoids are not brains at full scale and function, but rather potato ball-like masses 4-5 mm in size than any organ. Despite their small size, organoids are a good tool for both brain development and for investigating genetic aspects of diseases.
While animal models are invaluable in understanding the brain, it is clear that there are limits to what we can learn about humans. On the other hand, it is not possible to conduct controlled experiments on the living, real human brain. The contribution of different genes to brain development is a phenomenon that takes place in the womb and this period cannot be studied experimentally. Organoids, while primitive, provide an opportunity to ask and test new questions.
In chimeric models of the brain, the animal brain is “humanized” by the addition of human genes and cells. This model is used to investigate issues such as the involvement of microglia cells in Alzheimer’s disease. Previously, microglia cells were sorted into a vessel and studied. However, when cells are cultured, their gene expression changes. The longer it is cultured, the greater the change. When these cells are implanted in the mouse brain, the gene expression is very similar to that in the human brain.
With the new methods mentioned above, our understanding of the contribution of genes to brain development and diseases has increased. These methods cannot fully replace classical animal models, but provide new opportunities to investigate phenomena that we might not otherwise understand. However, there are certain limitations. Organoids reach a maximum size of 4-5 mm even after months of development. Without vital vasculature and other supports, they cannot achieve normal patterns of cell organization and architecture. Although various cell types can be produced in organoids, they do not reach the cellular and structural complexity of the normally developing brain.
Different studies are being conducted to improve the properties of new brain models. On the one hand, techniques are being developed to increase the ex vivo survival of living tissue donations. On the other hand, improvements are continuing so that organoid and chimeric models can better mimic normal development. However, as the models get closer to the normal human brain, ethical issues may arise. For example, at some point it may be questioned whether these brains feel.