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A comprehensive knowledge of brain function would have enormous impact in every field of medicine, including psychiatry, physiology, pharmacology, and language development. In the field of neurobiology alone, deciphering how the brain functions could advance medicine into an era where brain and spinal injuries might be stopped or even reversed before they resulted in paralysis, coma, or death. But how to get at the brain and study it while it is functioning is a formidable task for basic biomedical researchers.University of Calgary Heritage researcher Dr. Sarah McFarlane is undaunted.
A recent arrival to the U of C, Dr. McFarlane's main interest is how the nervous system develops, a focus that developed from her doctoral studies at McGill University in Montreal. There, while working with the electrical properties of nerve cells (also known as neurons) she became intrigued with the flexibility of the developing nervous system. Later as a post-doctoral fellow at the University of California's San Diego campus, she delved deeper into the properties of the nervous system with investigations of developing visual systems.
It is well known that a change in the embryonic environment produces changes in the development of nerve cells, resulting in completely different cells with different functions. "Even with identical twins," explains Dr. McFarlane, "there are differences. They will have the same copies of genes, but they don't turn out exactly the same because their nervous cell development is not 'hard-wired'. This plasticity arises from the fact that the environment in which cells grow influences what they become."
The fact that nervous system development isn't "hard-wired" that it has this amazing plasticity led her to concentrate on a central research question: "How do you get a functioning brain with all the right cell types; and not only that, but the right cell types connected to each other in the midst of all these endless opportunities for change?"
Dr. McFarlane's approach is to study the most basic structures of life cells, protein messengers the actions of which start and influence nerve system development. To measure the effects of induced changes, she had to find developing, living brain tissue to work with, in the least invasive way possible, in order to see nervous system development in its natural environment. This was a double bind since brains are protected in skulls and developing embryos are protected in the uterus. A small South African toad called Xenopus solved both these problems.
Xenopus has three key characteristics that make it vital to Dr. McFarlane's investigations. It lays eggs that can be easily worked with in a petri dish. Its eye tissue, as with humans and most other animals, is an out-pocketing of brain tissue accessible, visible brain tissue. Finally, Xenopus' visual system develops within three days, so results from testing can be determined very quickly.
The major cell types that make up the visual system in Xenopus are also found in our retinas and brains. In a developing visual system, human or otherwise, the first dividing cells, precursor cells, are indistinguishable from each other. But two things happen: as growth continues, cells begin to differentiate into separate types with separate functions. As they differentiate, connections are made between cells for communication. This is all done by growing nerves that pick out just the right signals from the chemical soup of their environment.
Dr. McFarlane says, "At the tip of the growing nerve there is something called the growth cone, and it acts like a hand groping in the dark for a light switch. It feels out the molecules it needs to grow and connect through its three-dimensional environment. These growth cones are very active. With the right equipment, you can see them move in real time."
As the embryo matures, nerves connect, connections (synapses) form, and the growth cone recedes. This is one of the major problems in the attempt to repair the central nervous system after injury. Injured cells must reconnect, yet the signal molecules that direct axons (the long distance nerve processes that carry electrical signals throughout the nervous system) may no longer be there. The signals are important for developing neurons, but probably also for re-making neurons and their connections in an adult brain after injury. In fact, inhibitory signals may have taken their place.
"If you have brain injury, you don't just want to make neurons, you want to make a specific type of neuron. And you are going to have to know what are the signals to make that specific type of neuron," says Dr. McFarlane.
She takes a number of approaches in her quest to identify the chemical signals that turn on nerve cell growth. Drugs or proteins added to brain axons in Xenopus's developing visual system can be used to reveal the specific function of specific molecules. Other substances knock out signalling systems from nerve cell growth cones, or prevent eye cells from picking up signals from the brain. Still another method is to introduce molecules that aren't normally found during development. Bits of genetic code can also be inserted into developing eye cells to get them producing molecules they wouldn't normally make, in order to block a specific signal. If cells then behave abnormally, it suggests they need this signal for normal development.
Dr. McFarlane is particularly interested in the role of growth factors that make nerve cells grow and help them survive. She has focused on a family of molecules known as fibroblast growth factors (FGF). From her experiments, she has determined that to become a light sensing cell, an eye precursor cell must receive an FGF signal. Dr. McFarlane is also investigating how FGF may affect cells at various stages of growth. Once the eye is formed, FGF produced by the developing brain promotes the growth of connections between retina and brain. Without FGF, nerve cells fail to make the right connections with the brain's visual centre. "Nature is very parsimonious. If a cell can use the same molecules differently throughout the stages of its growth, it will be more efficient for the cell," says Dr. McFarlane.
Because of the common nervous tissue origin of eye and brain cells, she thinks FGF also helps brain cells differentiate, although understanding the exact mechanisms require further research. The possibility exists that, when FGF's role in the brain is completely understood, it could be used to regenerate specific nerve cells after brain injury. But FGF is only one molecule involved in nerve cell growth.
Dr. McFarlane comments, "In research, if one or two percent of nerve cells are affected, that means something. But for people with brain injuries, one or two percent will not lead to functioning. Only long-term basic research will help us find out more about the specific signals of molecules. The more we find out and piece together, the clearer the picture we'll have of overall nerve system development and function."
Dr. Sarah McFarlane is a Heritage Scholar in the University of Calgary's Anatomy and Neuroscience Research Group. She also receives funding from the Medical Research Council of Canada.
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