Two things made research on the neuron possible at the cellular level, notes neuroscientist and AAAS Fellow Scott Brady — the squid, and video-enhanced contrast microscopy, which debuted in the early 1980s.
Brady ought to know. Now professor and head of anatomy and cell biology in the College of Medicine at the University of Illinois at Chicago, Brady published a groundbreaking paper as a post-doc, in 1982, with his mentor Raymond Lasek and VEC co-inventor Robert Allen, that provided a glimpse into the bonanza scientists would gain from being able to watch the movement within a squid's axon in real time. Brady and other researchers quickly put the new method to work to discover kinesin and other motor proteins responsible for propelling organelles back and forth along the axon.
Throughout his career, Brady has been involved in cellular-level breakthroughs that have increased our understanding of the nervous system — and are also helping to unravel the mysteries of neurodegenerative diseases like Alzheimer's, Parkinson's and Huntington's diseases.
This was just what Brady had in mind when he decided as a boy he wanted to become a scientist. A soft-spoken, understated man, Brady recalls launching his life's work with the neuron as a deliberate excursion into the unknown. "It sounded so cool to discover things no one had ever done before," he says.
A neuron can be a meter long, extending, for example, from mid-spine to the end of a toe. It contains motors that transport organelles — different kinds of proteins and other materials — back and forth along the axon, a thread-like extension between the cell body and targets that can include other neurons, muscles and other tissue. This cargo is not floating. It's on microtubules that serve as tracks, and the neuron makes decisions about how to deploy these materials, including some made with information gathered far away from the cell body. And the neuron needs to live as long as we do — up to100 years or so — because if it dies, it will likely not be replaced, as a standard cell would.
This singular, specialized system has fascinated Brady from his first acquaintance with it. "Most people come to study the brain because they are curious about how we think, but I looked at the neuron, and said, 'What remarkable cells,'" he recalls. "How does something in the cell body know we need more of this protein down in our toes? And how does it get it to the right spot?"
The system doesn't always work the way it ought to, though. In neurodegenerative diseases, neurons die in huge numbers, slowly robbing sufferers of their ability to function. And so the day came, Brady recalls, when his work on the mechanics of the neuron converged with that of other researchers who were looking for the causes of these devastating maladies.
"Cell death is a very late event," Brady says. By the time it occurs, "the game has been over for a long time, because what's been happening is that you've lost the connection between the neuron and its target. Neurons and the nervous system are all about connections. If the neuron is there, but it's not connected to anything, it's not going to do you any good."
The squid once again is a critical contributor in Brady's research into neurodegenerative diseases. It has a nervous system much like our own, but because it is an invertebrate, "it never developed the trick of making myelin, the cellular sheath that wraps axons," Brady says. Instead, the squid has axons that can be "easily seen with the naked eye."
Scientists use the squid to understand what's happening in the neuron, and then test their ideas about it on mice, to see if they can elicit the same symptoms that appear in people who have a neurodegenerative disease.
With Huntington's disease, a devastating inherited disorder that leads to a loss of physical control and cognitive functioning, for example, a genetic anomaly causes toxic changes to an essential but scantily understood protein, Huntingtin. What causes the disease, which usually presents in middle age, is that the toxic version of Huntingtin "inhibits both directions of transport," Brady says. The symptoms may appear so late because the neuron scrapes by for decades on what it is able to move, but finally shuts down as advancing age makes the process more difficult, he says.
Another question Brady has worked on is: Why does stress damage some people's brains, but not others'? Specifically, why does chronic stress cause shrinkage in the neurons of men, but not nearly as much in most women?
It turns out, Brady and his colleagues have found, that glucocorticoids, which cause stress, naturally go up when a woman gets pregnant. They suppress the immune system, making it less likely to attack the embryo. But women have a special mechanism that kicks in when glucocorticoid levels go up, shifting their expression of glutamate receptors to ones that can tolerate high levels of glucocorticoids. Men don't have that adaptation, so when life gets stressful, they get slammed.