Banbury Workshop – Bringing Ideas of Evolution and Development to the Fight Against ALS

May 29, 2013

What causes ALS? Why are some motor neurons susceptible to the disease process, while others seem entirely resistant to it? Are there developmental or evolutionary differences between neurons that affect their susceptibility? Does the disease spread within the nervous system on the basis of proximity to affected neurons or instead on the basis of susceptibility regardless of proximity?

In trying to develop new treatments for ALS, finding answers to these and related questions is crucial. In April, through the sponsorship of the Greater New York Chapter, The ALS Association brought together more than two dozen scientists from a wide variety of backgrounds to begin to address these questions and to foster a wide-ranging discussion intended to bring out new ideas and encourage new collaborations in the hunt for better understanding the disease and, ultimately, development of new therapies.

“A key question in ALS is whether the disease takes advantage of differences among motor neurons that have arisen either through evolution of the nervous system or its development during the lifetime,” said ALS Association Chief Scientist Lucie Bruijn, Ph.D., who convened the meeting together with co-organizers Martin Turner, M.D., Ph.D. of Oxford University, UK, and Jeffrey Macklis, M.D., D.HST, Harvard University, USA. “We know these differences exist; what we don’t yet know is what role they may play in susceptibility.”

The structure of the meeting was designed for maximum conversation and cross-talk among scientists who are often isolated from each other, despite all having an interest in the motor system and, in particular, both “upper” (cerebral cortex) and “lower” (spinal cord) motor neurons, which both degenerate in ALS. Each session included presentations on evolutionary, developmental, physiologic, and clinical phenomena. Experts in each discipline challenged one another and explored new ideas and speculations about ALS as a genetic, cellular and organismic disease.

Does ALS Spread?
A central question that has emerged in ALS is what accounts for the pattern of progression of the disease once it begins. Does it spread from cell to cell, or affect individual neurons randomly, or selectively target the most vulnerable neurons? If it does spread, it may do so along networks of neurons that are connected through functional and developmental pathways. William Seeley, M.D., of the University of California at San Francisco, argued that this phenomenon characterizes ALS and most of the other neurodegenerative diseases. “Systems that can be detected in the healthy brain form the basis of degeneration in disease,” he said.

John Ravits, M.D., of the University of California at San Diego, proposed instead that spread occurred by physical proximity in the nervous system, with the disease process beginning in a random location but then moving on to affect neurons adjacent to the site of onset.

An alternative was proposed by Dr. Macklis, who co-chaired the meeting, and who is an expert on the development of the cortical motor neuron system and other types of cortical neurons implicated in cognition, which have emerged as important in forms of ALS that include behavioral and cognitive changes, including dementia. “There is not just one type of corticospinal (cortical) motor neuron,” he emphasized. In fact, there are hundreds of distinct types of related motor and combined motor-cognitive cortical neurons, based on differences in their molecular building blocks, connections, and developmental history. “This might create selective vulnerability, and the known ALS genes might act on that vulnerability,” he said.

He likened our currently very primitive observation of that selective vulnerability to the different heights of sand bars in a bay, with the lowering tide representing an increase in other causal elements such as stress that affect the entire system. As the water level drops, each sand bar is revealed at a different time. What looks like spreading within the system may instead be the progressive “exposure” of new molecularly and/or developmentally related neuronal subtypes in an increasingly compromised or stressed system.

There are not yet enough data to know whether one or the other model, or all, are correct. But the implications are significant. “Spread implies that unaffected areas can be protected,” noted Jeremy Shefner, M.D., of SUNY Upstate Medical University in Albany, NY. “Selective vulnerability may be harder to protect against.” If the selective vulnerability model is correct, it becomes that much more important to understand the resilience of certain types of motor neurons that remain intact long after other types have degenerated. These include the motor neurons that control eye movements and those that regulate the action of other motor neurons to produce very fine control (so-called gamma motor neurons).

Is All ALS Genetic?
The question of the ultimate cause of ALS was brought to the fore by Ammar Al-Chalabi, M.D., Ph.D., of Kings College, London. He pointed out that virtually every case of ALS in Finland is associated with a mutation in either the C9ORF72 gene or the SOD1 gene. That relative genetic homogeneity is likely due to that population’s origin from a small group of founders, which carried these ALS mutations and not others. Extrapolating from the Finnish results, it seems likely that ALS elsewhere similarly has an overwhelmingly strong genetic basis, from these and other genes.

But it is also the case that not everyone with a mutation develops the disease. This may be due to environmental factors, which expose some but not others to triggers that expose the underlying susceptibility. It could also be that there are additional genetic factors, that either increase or decrease risk, that affect who ultimately develops ALS. “Could there be a set of protective genes, and should we be looking for those and their effects?” asked Robert Brownstone, M.D., Ph.D., of Dalhousie University in Halifax, Canada. In some cases of ALS, more than one gene-causing mutation has been found, suggesting that both are contributing to the disease in that person.

The meeting was filled with provocative conversations on a range of other issues. These included whether there was a relationship between various subtypes of ALS and crucial human adaptations (e.g., bulbar onset and human language) proposed by Andrew Eisen M.D., University of British Columbia, Canada; the role in ALS of interneurons, which regulate motor neurons; and the role of non-neuronal cells such as astrocytes, of which there are also many types.

“Progress against this disease will come from bringing together the best ideas from many different sources,” Dr. Bruijn said. “Our commitment is to leave no stone unturned, no angle unexamined, as we search to better understand ALS and to develop new treatment strategies to fight it. This meeting, which will lead to new collaborations and new research directions, is part of that important effort.”

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