Jun 07 2013
One thing you learn going through medical school and studying all sorts of diseases and pathology is a powerful medical corollary to Murphy’s Law – anything that can go biological wrong with the body, does. Every single function in the human body is associated with a disease or disorder in which that function is impaired or not working, unless such an impairment is incompatible with life.
Pick any cell, protein, enzyme, structure, ion channel, hormone – anything you can think of, and I bet there is either a disorder associated with that thing not working, or dysfunction would result in a non-viable embryo or fetus.
In fact, there are diseases and disorders caused by underlying biological mechanisms we haven’t discovered yet, and studying these diseases offers big clues to healthy biology.
The brain is no exception to this rule. This is an argument I frequently offer to those who deny that anything that can meaningfully be called mental illness exists. The details of the wiring of the brain – which neurons connect to which other neurons, in what pattern, and with what strength of connection – are what largely determine brain function. (There are other factors also, like glia and biochemical factors.)
It does not seem reasonable to argue that any and all patterns of neuronal wiring should be considered healthy and functional, just all part of normal human variation. At the same time I don’t think we should have a narrow concept of what is healthy human brain wiring. I understand the concept of “neurotypical” – there is a great deal of human variation and we should not automatically label anything 2 standard deviations from the median of the Bell curve as “abnormal.”
There has to be a balance in between these extremes (with, of course, no sharp demarcation line). Some patterns of wiring are demonstrably dysfunctional, resulting in self-mutilation, refractory seizures, or severe mental retardation, for example. Understanding what is happening in these extreme cases perhaps will aid our understanding of more subtle or borderline conditions.
A recent study had discovered one part of the developmental process by which axons find their targets and that can go wrong, resulting in dysfunction.
The brain’s development is guided largely by genes, but genes do not contain a blueprint of the brain, telling each neuron exactly how to connect. Rather, the genes encode for the processes by which neurons develop, with the complexity of the brain emerging from these processes.
Neurons send their long axons along distant paths to connect to target neurons. They achieve this through what are known as growth cones – the tips of axons chemically sense their environment and this tells them in which direction to grow so that they can find their target.
The new study presents a mechanism by which the axons steer themselves. Study author Samie Jaffrey explains:
“As a circuit is being built, RNAs in the neuron’s growth cones are mostly silent. We found that specific RNAs are only read at precise stages in order to produce the right protein needed to steer the axon at the right time. After the protein is produced, we saw that the RNA instruction is degraded and disappears.
“If these RNAs do not disappear when they should, the axon does not position itself properly — it may go right instead of left — and the wiring will be incorrect and the circuit may be faulty.”
So RNA activity will, for example, tell the axon to go left, and then turn off. If it doesn’t turn off then later steering of the axon will be faulty, and it won’t reach its intended target. The result is that the wiring of the brain is faulty. This explains previous research that showed that faulty brain wiring was associated with mutations in genes for proteins that are involved in RNA degradation.
I don’t know how this kind of discovery will lead directly to any sort of treatment. Developmental problems need to be prevented – we don’t have the technology for curing them once they occur. Treatments may partially compensate for them through brain plasticity, however. Perhaps such plasticity may be improved in patients with developmental brain disorders due to impaired RNA activation if that problem can be fixed. This would probably require gene therapy, which is a tricky technology not yet fully developed.
It’s hard to predict the downstream effects of basic science, however. Understanding more about how axons steer to their targets may bear unanticipated fruit in the future. Plus, the more we understand about brain development and function the better we will be able to think about it and research it in general.
Meanwhile, we understand one more thing in the human body that can go wrong.
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