Watching paralysis take hold of someone with ALS is like watching a massive stroke in slow motion. It starts with discrete problems in some fast-twitch muscle fibers, which grow weak, break down, and eventually stop working altogether. A person with minimal symptoms knows that they will become paralyzed, and that the progression will be rapid and fatal.
The degree to which neurological conditions are terrifying has to do with how they mix certainty and mystery, and it’s rare to find a disease that brings them in worse proportions than ALS. The average life expectancy after diagnosis is three years. In that window, the immune system effectively switches from defending against a foreign process to destroying the self. The new research sheds light on how that dichotomy breaks down.
The unpredictability of ALS has long been in whom it’s going to affect. As we learn more about the disease, its complexity only grows. Doctors practicing medicine today were taught that ALS is a disease of motor neurons. This turns out to be true, but very incomplete: It is also a disease of protein clumping, and one facilitated by other cells in the nervous system. Scientists have only recently come to understand that what we currently call ALS acts through many different types of cells.
When it was first described and brought into public consciousness as Lou Gehrig’s disease, ALS was thought of as just that—a disease, a discrete pathological process that killed motor neurons. The process seemed for a long time to be simply sporadic, regularly affecting people with no family history and no other health problems. No one could tell patients what caused their disease, and not a word could be said about how to prevent it.
Despite myriad advances in modern science and medicine, ALS remained largely a mystery for decades. But the notion of what ALS is began to morph with the recent advent of high-volume genetic studies. Not one but multiple genes have now been identified that dispose people to the clinical symptoms that constitute ALS.
How is it that one disease can be caused by many different genetic mutations?
The real difficulty is not knowing which genes cause disease, but figuring out how they do, explains Tom Maniatis, chair of biochemistry and molecular biophysics at Columbia University Medical Center. Some ALS-causing genes encode proteins that are prone to clumping, while other genes can exacerbate that clumping, and still others can disrupt the pathway that helps cells dispose of those clumps. “You can’t tell just by watching people’s clinical course which process is happening at the cellular level,” Maniatis explained. “There are complex physiological events happening in very similar ways almost irrespective of the cause of the disease.”
ALS has long been seen as a disease of motor neurons because those are the cells that die, and their death is what causes the impairment of movement and ultimately the death of the person. But it is now clear to him that other cell types within the spinal cord play fundamental roles in the process. The spread of the disease is really a consequence of how cells around the nerves (astrocytes and microglial cells) respond to the dying motor neurons. It’s once that inflammatory process is triggered that the disease becomes debilitating.