Finding the cause and the cure for a deadly disease is a little bit like investigating a murder. Clinicians collect clues from their patients, bring them back to the lab, and try to reconstruct the crime and identify the killer. For amyotrophic lateral sclerosis (aka ALS or Lou Gehrig’s Disease), this investigation has lasted over a hundred years – since neurologist Jean-Marie Charcot first described the disease in 1874. But it’s only in the last two decades that ALS researchers have started to find major breaks in the case, revealing genetic clues to the origin of this deadly neurodegenerative disease. At a special ALS gathering at the University of Chicago, Medical Center neurologist Raymond Roos told nearly 200 patients and caregivers that the case may finally be cracked soon.
“I think the field is on fire now,” said Roos, the Marjorie and Robert E. Straus Professor of Neurology. “I think it’s astounding and exciting what’s going on with respect to neurodegenerative diseases and absolutely ALS. We have all these things piling up now and we are continuing [to look]. Should we be optimistic about the future? Yes.”
Wednesday’s gathering, put together by the Greater Chicago Chapter of the ALS Assocation, was a unique two-part event featuring both a symposium for researchers of the disease and a luncheon/health expo for the patients and their families. In one room of historic Ida Noyes Hall, 14 Chicago scientists studying the origins of ALS and developing new treatments for what is currently an incurable disease shared their latest results. Meanwhile, patients and their families learned about medical devices and advocacy opportunities, and shared stories of how they cope with their disorder.
The day’s scientific component demonstrated both why the ALS investigation has taken so long, and why Roos thinks there is cause for optimism. The central mystery of ALS is why it selectively targets the motor neurons of the nervous system, the extremely long cells that deliver instructions from the brain to the muscles of the body. As the motor neurons die off, the patient experiences a progressive paralysis, losing the ability to maintain balance, walk, and eventually, breathe. Figuring out what causes this specific population of neurons to perish will point the way to treatments that slow or even reverse the progression of the disease.
For suspects, scientists have looked to genes. Roughly 10 percent of ALS cases are inherited through generations of families, indicating a genetic cause. While this population might be only a small minority of cases compared to the more common “sporadic” cases, they could be a foothold along the path to understanding both types of ALS.
“Those are very important even though they make up this small group, because they open a window,” Roos said. “If we can identify the gene that’s mutated, we can figure out what the function of that gene is. The hope and assumption and, I think, the reality, is that information will guide us into understanding the non-inherited, sporadic form.”
In 1993, scientists discovered the first ALS-associated gene/suspect, called SOD1. Though mutations of this gene explain only 20 percent of the familial 10 percent, they have been an important clue into exactly what goes wrong inside a motor neuron during the disease’s tragic march. The morning’s sessions zoomed in on these details, describing how a faulty SOD1 can kill off a cell through to the aggregation of cellular proteins, the interruption of the cell’s highway-like transport system (presented by UIC’s Gerardo Morfini and Scott Brady), and the creation of a “toxic channel” (as told by UCMC’s Michael Allen). The damage caused by SOD1 mutants might not even be limited to the motor neurons themselves, as Roos presented research demonstrating its toxic activity in the cells surrounding those neuronal types.
The path from what goes wrong to the creation of new potential therapies for ALS was explained by Richard Silverman, a chemist from Northwestern University. By screening for compounds that prevent the type of protein aggregations observed in the motor neurons of ALS patients, chemists hope to design new drugs that will slow the damage and hopefully, the physical symptoms they produce. Silverman detailed the incremental design of two new compounds in his laboratory that, in animal studies, produce an extension of life that is two to three times longer than seen with the only drug currently approved for use in ALS, riluzole.
But to throw a further wrench into the investigation of ALS (and to strain the credibility of the crime scene metaphor), SOD1 has recently been joined by several other genetic and biological suspects implicated in the disease. Genes such as TDP-43 and ubiquilin-2 have generated further excitement in the field, with the latter explaining some of the observed overlap of ALS with Alzheimer’s-like dementia. Because each of these mutations explains only a percentage of familial cases, no one expects a single gene to emerge as the lone gunman. Instead, the researchers hope that the deranged activity of these genes will merge into a shared pathway that explains both familial and sporadic ALS.
“We’re starting to essentially find some common threads for a variety of different familial ALS mutant genes that all seem to converge,” said Brady, professor of anatomy and cell biology at UIC.
The two halves of the event merged at the luncheon, where Roos (who was honored with this year’s Iron Horse Award from the Greater Chicago chapter), ALSA scientific director Lucie Bruijn, and other experts updated patients and their families on the latest research and clinical advances for the disease. Due to the rapid progression of ALS (an average of 3 to 5 years between onset of symptoms and death), many of the patients in the room will not themselves reap the rewards of the research currently underway. But that tragic fact made it even more inspiring and touching that the patients work so hard to raise awareness of ALS and funding for the research, hoping to prevent future generations from suffering from this terrible disease.
“It really is all because of you, and because of your drive and your energy that we have the commitment to make a difference in this disease,” Bruijn said. “Sometimes it takes ten years to get from the lab to the clinic. It’s a long time, it’s frustrating, but the fact that we’ve got clues to get there is phenomenal.”
(Image: SOD1, the first genetic suspect in amyotrophic lateral sclerosis. From Wikimedia Commons)
(Other participants in the scientific symposium were James Brorson of the University of Chicago, Brian Kay of University of Illinois at Chicago, and P. Hande Ozdinler, Charles J. Heckman, Mingchen Jiang, Manuel Marin, Han-Xiang Deng, and Teepu Siddique of Northwestern University.)