For 56-year-old David Virden (BA ’71), it started with a hoarse voice and a weak leg — two seemingly benign symptoms that marked the start of a dizzyingly swift downward spiral.
Within a year, the competitive cyclist and father of three would be walking with a cane and unable to speak. Six months later, he’d require a wheelchair. Soon after, he’d lose his ability to swallow and breathe on his own. All this while his sharp mind and “larger than life” spirit remained intact.
“It was terrible to watch, just awful,” recalls Christine (Godshall) Virden (BA ’71), who bid her husband goodbye on Aug. 29, 2008, 22 months after he was diagnosed with amyotrophic lateral sclerosis (ALS).
“He was still the same person on the inside, but nobody knew it on the outside.”
DU researcher Dan Linseman and PhD student Heather Wilkins are investigating the root causes of ALS. Photo: Wayne Armstrong
Such stories are par for the course among the roughly 6,000 people diagnosed annually with ALS (Lou Gehrig’s disease), an insidious illness in which motor neurons in the spinal cord and brain self-destruct, leading to paralysis and death within two to five years. With only one minimally effective drug on the market, a dearth of research funding and relatively little interest among pharmaceutical companies in finding a cure, ALS historically has been considered a death sentence. “There’s not much help out there, except helping you die,” says Jody Hubbard, who lost her “soulmate,” Floyd Hubbard, to ALS just 10 months after he was diagnosed. “Hope is not a word we heard much.”
But in the first-floor lab of DU’s Seeley Mudd Science Building, one professor, a dozen students and 100 sick white mice are working hard to change that.
Armed with $2.4 million from the National Institutes of Health and the U.S. Department of Veterans Affairs and a stack of proposals for more grants from various agencies, researcher Dan Linseman has devoted the last three years to unraveling the mysteries of Lou Gehrig’s disease. The bulk of his work aims to identify some of the intra-cellular mechanisms by which apoptosis — or programmed cell death — occurs in ALS, in the hope that drug makers might someday use the information to develop better treatments. (The only approved drug extends life roughly three months.)
But well aware of the lack of time patients face, he’s also looking at more accessible potential remedies, such as antioxidant compounds in certain nutrients, that could provide relief even sooner. Meanwhile, he’s also exploring the role that environmental factors, such as exposure to toxins or rigorous physical strain, might play in fueling the disease.
“The more we can figure out about what is killing the motor neurons, the more likely we will be able to mitigate this disease,” says Linseman, an assistant professor of biological sciences at DU and a senior researcher with DU’s Eleanor Roosevelt Institute. “I would never say ‘cure.’ But if we could say to someone, ‘You have ALS, but you’ve got six to 10 years ahead of you and the first five won’t be so bad,’ that would be a big advance.”
An underdog of a disease
After eight years of working for the Upjohn pharmaceutical company (which he left after being assigned to investigate hair loss remedies), Linseman returned to school at the University of Michigan to get a PhD in neuropharmacology. He landed in Colorado in 2000 on a postdoctoral fellowship with the VA Medical Center, where he began researching apoptosis, specifically in Parkinson’s disease. But in 2006, he shifted his focus to ALS.
“Parkinson’s and Alzheimer’s have a lot of people working on them and have tons of funding and a lot of approved therapies that at least mitigate the symptoms,” says Linseman, a 44-year-old father of two. Meanwhile, “ALS strikes people in their 50s, in the prime of their lives, when they are most productive at work and have their families, and it strips away all of their dignity. It has one drug that doesn’t work very well, and there isn’t nearly as much funding.”
In 2008, the National Institutes of Health allocated $43 million to ALS research, down slightly from 2006, when $44 million was granted. That’s compared to $152 million for Parkinson’s and $169 million for multiple sclerosis, which has similar rates of incidence (roughly 8,000 new cases annually). Many family members lament that because ALS patients die so quickly, there are fewer of them affected by the disease at any given time (roughly 30,000) so researchers and drug companies have little incentive to invest in treatments for them. That means doctors can offer little solace when delivering the grim news.
“We left the office that day stunned and in a fog, like, ‘Where do we go from here?’ There aren’t any options,” says Jody Hubbard of the day her husband got the news. “It’s frustrating. There’s no money in it, so it doesn’t get much attention in the research world unless someone takes it to heart.”
In the past decade researchers have pinpointed mitochondrial oxidative stress as a key culprit in ALS (as well as many other neurodegenerative diseases). In essence, mitochondria inside the cell — in the process of making energy — also produce potentially harmful byproducts called free radicals that can eat away at cells, doing damage. In a healthy person, a built-in antioxidant called glutathione comes to the rescue, mopping up those toxic free radicals before they can wreak havoc. But in the ALS patient, it appears, there isn’t enough glutathione to do the job.
Starting with this knowledge base, Linseman — in concert with several undergraduate and graduate students — is working to move the dial forward, trying to better understand the molecular mechanisms of oxidative stress and the pathway between it and motor neuron death.
In a groundbreaking paper in the October 2007 issue of the Journal of Biological Chemistry, he and his colleagues pinpointed a family of “good” proteins — called Bcl-2 proteins — as key in helping usher glutathione into the mitochondria to quell oxidative stress. His team has since identified another group of “bad” proteins (a sort of wicked stepsister in the Bcl-2 family called BH3 proteins) that seem to have the opposite effect, inhibiting Bcl-2 function, keeping glutathione from doing its work and thus fueling oxidative stress. During recent laboratory tests in mice with ALS, Linseman and his students found that astrocytes (helper cells that neighbor motor neurons) were riddled with BH3, or “bad” proteins.
“Astrocytes are normally good neighbors to the neurons, but in ALS they go haywire and secrete toxic substances,” Linseman explains. He believes BH3 proteins could be to blame, essentially turning good neighbors into murderers. “If that were true, and we could figure out the pathways that lead to the increased expression of these proteins in the astrocytes, we could create inhibitors that could block that pathway.”
Promising stuff, but Linseman concedes it could take years before this idea leads to a new drug. So while he works to understand how to get rid of the “bad guys” (the BH3 proteins), he also is exploring ways to reinforce the “good guys” (glutathione and Bcl-2).
Sense of hope
In March, he’ll begin feeding his ALS-afflicted laboratory mice a dietary supplement derived from whey protein, a precursor to glutathione, in hopes that it might slow the progression of the disease. He’ll also be looking at a compound called kuromanin (from black rice) and callistephin (from strawberries). Both are powerful antioxidants that seem to protect neurons from death, even when Bcl-2 is in short supply. Linseman says he’s not ready to endorse any particular dietary supplement, and he stresses that the Food and Drug Administration doesn’t regulate them, as it does drugs. But he’s hopeful.
“That piece is much more straightforward and has the potential to come up with a therapeutic option more quickly,” he says. “I think it will work.”
Aside from looking for new treatments, Linseman is keenly interested in just what causes ALS. Between 5 and 10 percent of ALS patients have some family history of the disease, and of those about 20 percent (or 1 to 2 percent of all ALS cases) are blamed on a mutation of a specific gene called SOD1, or superoxide dismutase. What about the other 98 percent of ALS sufferers?
Linseman believes environmental exposure may play a role. He points to research showing that military veterans, dating back to the Vietnam War, are far more likely to get ALS, and they tend to get it at an earlier age. One study conducted at the University of Texas Southwestern Medical Center found that more than three times as many Gulf War veterans developed ALS as would be expected in the general population. Another study, published in 2005 by Harvard researchers, found that men with any history of military service in the last century are at a 60 percent greater risk than men who did not serve.
“Could it be exposure to heavy metals, pesticides or insecticides?” Linseman asks. There also is a hypothesis that sudden, significant physical exertion (think basic training) could have an impact on motor neurons, he says.
“Think about taking a guy like me, a couch potato, and throwing him into a situation where he is physically going to the max all the time. There is some evidence that could cause delayed damage to motor neurons.”
Linseman currently is applying to the Department of Defense for a grant to see if mice with the mutant SOD gene (which causes ALS) deteriorate more quickly when exposed to certain toxins or extreme physical exhaustion. The other big question: Could such environmental factors cause ALS in a healthy mouse?
If so, that could lead to the development of an entirely new model for studying ALS: Instead of using mice who have the disease due to a faulty gene when studying new drugs (a practice that has proved unsuccessful time and again), researchers could study new drugs in mice that got the disease from something else (like the vast majority of people who have it).
“We only have one animal model for ALS, and that probably influences the outcome of clinical trials,” says Heather Wilkins, 23, a first-year PhD student who is working with Linseman on a paper for the PBS program “Nova.” She notes that numerous drugs that showed positive results in the mice with mutated SOD genes showed no results in humans with the disease. In one case, it even made the disease worse.
“We don’t have a model for the sporadic form of the disease. That’s the problem,” Wilkins says.
Lucie Bruijn, chief scientist with the California-based ALS Association, says that increased funding as a result of the recent federal economic stimulus plan already has helped fuel a surge in interest in ALS, with numerous new clinical drug trials and research projects under way on multiple fronts across the country. She credits Linseman and others like him for “contributing to a better understanding of the disease and its treatments.”
“It is an extremely exciting time for ALS, with so many more scientists who did not work in this area before now working on the disease,” she says.
Linseman too is optimistic, but when asked how soon his work may lead to changes for people suffering from the disease, he is cautious: in his lifetime, for sure. In the next decade, probably. He wishes it could be faster.
“I can only say to them, ‘Hang in there.’ We’re working on it,” he says, looking at a computer screen full of e-mails from concerned loved ones, including Hubbard and Virden.
How does that make them feel?
“Hopeful,” Hubbard says. “Finally hopeful.”