A New Understanding of Inflammation in the Spine

Research on the mysterious ways that ALS destroys the nervous system highlights the role of the immune system in doing both good and harm.

Irregular patterns of bright colors against a black background
Inflammatory patterns in spinal interneurons at different stages of ALS  (Tom Maniatis / Columbia Zuckerman Institute)

Inflammation has become a lucrative buzzword in health marketing. The meaning is usually unclear, but the vague implication is that this is something to avoid. Turmeric and yoga and sugar substitutes and the like are marketed as things that decrease inflammation. Even Harvard Medical School’s consumer-facing website has a page titled “Foods That Fight Inflammation.”

At the same time, other checkout-aisle products promise to “boost” the immune system—the arbiter of inflammation. This is confusing. Maybe the hope is that anti-inflammatory foods and immune-boosting foods cancel out, and the buyer makes it out unscathed.

The reality of the immune system is much more interesting. Inflammation is the basis for many symptoms of disease, but it also exists to keep humans alive. And strategically manipulating inflammatory processes—both amplifying and attenuating them at precise times—holds promise for treating all sorts of diseases.

Among the most interesting and illustrative is amyotrophic lateral sclerosis, or ALS—the disease popularly associated with Lou Gehrig, Stephen Hawking, and the Ice-Bucket Challenge. According to new research, ALS is turning out to have more to do with inflammation than previously imagined. And it is turning out to actually be not one disease, but many different diseases.

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.

So, of course, that inflammatory process could be a good target for treatments.

When the proteins start to clump inside motor neurons, the cell’s “housekeeping” process, called autophagy, is activated to clear them out. In the beginning, autophagy is effective in that. But at some point, it ends up leading to the death of the nerve cell. This is the finding of the new research this week, which comes from Maniatis’s lab and is published in Proceedings of the National Academy of Sciences. It offers insight into the role of our own immune processes both in fighting ALS and in making it fatal. In a group of genetically manipulated mice, the Columbia team found that inhibiting autophagy in motor neurons slowed progression of the disease and prolonged life by an average of 20 percent.

The effect was greater than Maniatis expected, and it was the result of targeting only one gene. “There are now five genes involved in autophagy that, when bearing certain mutations, can cause ALS,” he explained. His team is in the process of systematically studying how deletion of genes changes the interaction between autophagy and disease in various cases.

While autophagy in motor neurons seems to be required to maintain nerve functioning early in disease, it appears to promote the progression of the disease through the spinal cord later. The inflammatory process means that not only is ALS many different diseases, but, at a cellular level, it is not even the same disease in the beginning as it is in the end.

It is through understanding this complexity that treatments will emerge. In this case, the point seems to be that different stages in the disease process might require essentially opposite drugs. As Maniatis put it, “Early in the disease, you can imagine you’d would want to stimulate autophagy—to increase the efficiency of the motor neurons to fight these protein aggregates. But late in disease, you would want to diminish autophagy.”

How to do that could depend on which genetic mutations are influencing the process in an individual person. This could mean many different therapies for what outwardly appear to be the same disease. ALS progresses in a very similar way in every mutation, which has challenged the notion of how any disease should be defined and studied. Based on the symptoms in people? Based on the cellular pathology? On genetic mutations?

There are interesting similarities here between the emerging understanding of ALS and the emerging understanding of Parkinson’s disease, which I wrote about last year after Muhammad Ali died of what appeared to be a textbook case. Though the two disease patterns look dramatically different outwardly, ALS and Parkinson’s appear to both be fundamentally a result of how tiny vesicles are transported in nerve cells. In the latter case, the vesicles contain dopamine, not protein aggregates. Several different genes are now known to affect different points in this process, all of which cause symptoms that are currently called “Parkinson’s disease.”

Though people tend to have the same clinical course, with the slow, rigid motions like the world saw when Ali carried the Olympic torch in Atlanta in 1996, cases differ at cellular and genetic levels. As James Beck, vice president of scientific affairs at the Parkinson’s Disease Foundation, told me at the time, “All these diseases have different causes, but a similar phenotype. That is, essentially, that they respond well to synthetic dopamine.”

To account for this complexity, some neurologists have begun using the term “Parkinson’s-disease syndrome” to refer to a constellation of symptoms that tend to come along with one another, as opposed to a single disease. In that vein, ALS could potentially be regarded similarly.

These fundamental questions of what defines health and disease, self and other, require enormous sets of genetic and clinical data in order to analyze and understand patterns. This work is the essence of Columbia’s Precision-Medicine Initiative—of which Maniatis’s lab is a part. The program has the same name as the unrelated, much larger federal Precision-Medicine Initiative, which was started under President Obama, in which researchers across the country are in the process of collecting the genomes of 1 million volunteers and uploading them to a cloud where scientists and nonscientists can collaborate to solve complex problems like these.

The goal is to understand the uniqueness of any given person’s disease, and to start breaking down the pathological buckets into which we sort ourselves. Even at this early stage, though, it seems clear that the solution will not involve simply fighting inflammation or boosting the immune system.