Mickey Mouse, Mrs. Frisby from the Rats of NIMH, and Remy of Ratatoullie are all rodents who act like humans. These childhood characters are anthropomorphized versions of important laboratory species that scientists study to understand why humans get disease. However, findings from animal models do not always translate to humans because of the genetic differences existing between our genomes.
Scientists have now created for the first time, mice that harbor human glial cells from birth. The brain is composed of several cell types, but neurons and glial make up the majority of the cells in the brain. Neurons send electrical impulses or “messages” to other cells in the brain, while glial cells are considered the “support cells”. Both glial and neurons are essential for proper brain function. Unlike previous reports in which adult mice were grafted with mature human glial cells, the human glial mice developed in the Goldman Laboratory at the University of Rochester, had human precursor glial cells introduced into their brains as newborns. By having the precursor cells introduced at such a young age, the glial cells were able to develop with the mouse, which resulted in a majority of the mouse glial cells being of human origin.
Much to the surprise of all involved, the human glial cells proved a dominant force in the mouse brain, dividing, maturing and overpowering the mouse glial cells. After one year, most of the glial cells in the mouse brains were human. The human precursor glia cells differentiated into additional types of support cells for neurons, which increased the neuron functioning efficiency. Due to the increased functioning efficiency, human glial mice performed significantly better on behavioral tests that measured memory and learning compared to wild type control mice. In a test designed to measure memory of a sound and the associated electric shock, the mice with human glial cells performed four times better than their wild type counterparts.
The researchers claim that these mice are not “human-like”, and that their increased scores on the behavior tests are due to the increased size and efficiency of processing that the human glial cells confer to their host’s brain. The neurons, which are considered the memory forming and learning cells of the brain, remained of mouse origin. The researchers have progressed towards testing their method in rats, but have decided against monkeys, due to ethical concerns. Ethical concerns are more pertinent when dealing with monkeys due to the increased similarity in physiology, molecular biology, and genetics shared between humans and monkeys.
The potential that this method offers for studying the role of glial cells in human neurological diseases, especially those associated with aging, is game changing. Being able to study a select population of human glial cells throughout an entire mouse brain could help elucidate what role that glial cells play in specific neurodegenerative diseases. This can be especially useful if one just injected disease affected glial cells into an otherwise healthy newborn mouse, eliminating the complicating effects of the disease affected neurons, which are present in current mouse disease models.
With the advances in genome engineering using CRISPR/Cas9 technology, one could engineer a specific mutation in human glial precursor cells and study their function in the context of the mouse brain as the mouse ages. By understanding the effects that a diseased glial population would have on the brain, new therapies could be tailored to specific cell populations. A reverse of this approach would also be possible in which normal human precursor glial cells are injected into diseased mouse models to observe if healthy human glia ameliorate disease symptoms and progression or even cure disease. This reverse approach was tried on mice that were unable to produce enough myelin (similar to multiple sclerosis patients). Myelin is a protective neuron coating made from glial derived cells called oligodendrocytes. When these mice were injected with human glial precursor cells, the injected cells differentiated into oligodendrocytes, which specialize in making myelin, and significant improvement in the symptoms occurred. The Goldman lab is hoping to begin a multiple sclerosis clinical trial with this human glial precursor cell treatment in 2015.
Although this study suggests a promising use of human glial precursor cells as therapeutics, its implications must be viewed with caution. Injecting human brain cells into animals and then experimenting on these animals creates several concerns. The animals are not able to “voice” any feelings or thoughts that may arise from these changes due to the lack of a voice box from which to form words. Our current methods for detecting animal thoughts are rudimentary. As scientists, there is a risk that while studying these animals, we could cause changes to an animal’s perception and behavior that we do not yet understand. These changes could alter the way in which an animal views its environment, and may result in increased stress levels. This arguments are all currently hypothetical, but they do ask an interesting basic science question: how much of our brain function and perception is altered when the glial cells originate from a “smarter” species? The current guidelines in place for animal studies are adequate for traditional animal models, but with new studies planned on these human glial mouse models, additional guidelines may be necessary.
I do not imagine that Mickey Mouse has actually been created in a laboratory, but thoroughly understanding the changes made in the rodent brain with the addition of human cells would be extremely useful when considering the transfer of this technology to other animals (cats, dogs, monkeys). This new technique has the potential to be extremely helpful in understanding many brain diseases, and should be further explored.