Of Mice and Men

What would a mouse with half a human brain look like? A team of scientists in New York and Denmark (Steven Goldman and colleagues at the University of Rochester) have decided to find out.^[1] The intention of this novel idea is not to emulate fiction but to further advance the scientific understanding of human brain diseases by studying them in an organism’s brain (in vivo), rather than in cell culture dishes (in vitro).

A Tale of Two Species

The human brain is made up of complex cell types generally belonging to two categories: either neurons or glial cells. It may be prudent to mention here that communication in the brain is known as neurotransmission and takes place via electrical and chemical signals between neurons and glial cells are noted to be a vital support cell in this process. The neurons allow us to conduct multiple tasks ranging from thinking, moving and coordination and glial cells help that happen. For example, throwing a ball, reading, writing or speaking all increase neuronal activity in specific brain areas. These active regions then need greater blood flow for oxygen and nutrient delivery. It is glial cells that direct and orchestrate that blood flow to and from regions of the brain that need it most.^[2] This is one way that glial cells support brain activity.

Goldman and his team transplanted human glial cells into mice to create a hybrid: a mouse with both its own brain cells (neurons) and human ones too (glial cells). They did this by extracting glial cells from donated human foetuses and injecting them into the brains of mouse pups. After transplantation, the human donor cells in the mouse brains developed into a subtype of glial cells known as astrocytes. Astrocytes are large star-shaped glial cells that anchor neurons and coordinate neural activity. Fascinatingly, within a year of transplantation, these human intruders completely overtook the mouse glial cells. The 300,000 human glial cells injected into each of the mice multiplied, resulting in the expansion of their numbers to 12 million, thereby displacing the original mouse glial cells. The humans had invaded.

Man Power

It turns out that the mice with human glial cells, ‘humanised mice,’ were much smarter than their non-hybrid siblings, as was revealed by using multiple memory and cognition tests. For example, humanised mice reacted four times as often as ordinary mice to a sound they had learned to associate with danger. This suggests that the mice with human glial cells learned more quickly and accurately, as compared to their non-hybrid counterparts. The results indicated that their memory was four times greater. It demonstrates that glial cells, and astrocytes in particular, play an integral role in memory. Perhaps they help to strengthen and support the communication zones between neurons called synapses. Some human astrocytes are ten to twenty times greater in size than their mouse counterparts. Consequently, human astrocytes may be able to coordinate all neuronal signals in a given area of the brain far more proficiently than mice can. For the humanised mice, it’s like an upgrade from an old Nokia phone to the latest iPhone.

Healing Hands

Goldman and colleagues went a step further and injected the human glial cells into mouse pups that had a particular disease in which they were unable to make a substance called myelin. Myelin is a protein which functions to insulate neurons. It is produced by a subtype of glial cells called oligodendrocytes. Just as electrical cables require insulation for efficiency, so do our neural circuits. The experiment proved to be a success, as a plethora of injected human glial cells matured into oligodendrocytes in the deprived mice. This suggests that the host cells are able to detect and compensate for defects by accepting the transplanted recipient glial cells. To explore this issue further, Goldman and his team are grafting the human glial cells into rats. Rats exhibit signs of greater intelligence than mice and in some cases are comparable in intelligence to some breeds of dog. This will enable them to test their hypothesis in a more intelligent animal model. Furthermore, Goldman and colleagues will have to test their hypothesis in increasingly complex animal models such as primates, a necessary step before human clinical trials can be considered.

This work has great implications. It indicates, for example, that if we inject human glial precursor cells into patients with multiple sclerosis, a human condition in which the patient suffers from oligodendrocyte degeneration in the brain and spinal cord, their condition, in theory, may be significantly improved, as the body would regain the ability to produce new myelin. However, it remains to be seen how newly transplanted glial cells may react in a more complex organism such as a human being.

Endnotes

1. Han X, Chen M, Wang F, Windrem M, Wang S, Shanz S, Xu Q, Oberheim NA, Bekar L, Betstadt S, Silva AJ, Takano T, Goldman SA, Nedergaard M (2013). “Forebrain Engraftment by Human Glial Progenitor Cells Enhances Synaptic Plasticity and Learning in Adult Mice.” Cell Stem Cell 12(3):342-53. doi: 10.1016/j.stem.2012.12.015.
2. Atwell D, Buchan A.M, Charpak S, Lauritxen M, MacVicar B.A, Newman E.A. “Glial and Neuronal Control of Brain Blood Flow.” Nature 468, no. 7321(2010): 232-243. doi:10.1038/nature09613.