Holding Out Hope

A tenacious scientist's quest for the causes of Lou Gehrig's disease

He hit .295 with 29 home runs and 114 RBIs that last year in 1938 — a season most baseball players could only dream about.

They called him the “Iron Horse” because he was known for his durability. But even in 1938, he was feeling tired by mid-season. And for him, a season like that was considered mediocre.

Joe Beckman

Finding a way to eliminate, not repair, mutant nerve cells could lead to improvements in Lou Gehrig's disease treatment, says Joe Beckman (Photo: Karl Maasdam)

The next year started off much worse. “I think there is something wrong with him,” one sports reporter wrote. “Physically, I mean. I have seen ballplayers ‘go’ overnight, but they were simply washed up as ballplayers. It’s something deeper in this case.”

The reporter was right. Seventy years earlier, a French doctor named Jean-Martin Charcot had described a strange disease called amyotrophic lateral sclerosis (ALS), and in the seven decades since, very little had been learned about it. It was only in 1939 that ALS burst onto the world consciousness when Lou Gehrig, one of the greatest baseball players who ever lived, announced he was suffering from the disease, retired and died just two years later.

ALS would evermore be known to most people as Lou Gehrig’s disease. Unfortunately, when World War II was just starting in Europe in 1939, they didn’t know much about it.

Unfortunately, after another seven decades has passed, that’s still true.

Still No Cure

Doctors do not know for sure what causes ALS. They don’t know how to slow its progression. They certainly don’t know how to cure it. Researchers debate among themselves and trade theories in science literature. Dedicated doctors, nurses, therapists, aides and especially family members work to reduce suffering and treat symptoms, but the disease is debilitating, progressive and terminal.

In the middle of this quandary is Joe Beckman, an Oregon State University professor of biochemistry, holder of the Ava Helen Pauling Chair in the Linus Pauling Institute and director of the widely recognized OSU Environmental Health Sciences Center.

Major research programs are under way, and Beckman has been laboring in them for 15 years. The goal is a therapy or cure for ALS. But this disease is not simple. If it were, very smart scientists would have figured it out a long time ago, and that hasn’t happened.

“This is complex, and it’s not certain yet where the right answer lies,” Beckman says.

The complexity, from one perspective, is about whether to restore zinc, remove copper or stabilize “superoxide dismutase” (an enzyme that protects cells from damage). If you think that sounds complicated, consider that Beckman has a stack of scientific studies on his desk about a foot thick, at risk of toppling to the floor, that address this and a lot of other issues.

But if the OSU researchers are right — and they think they are — then at least some research programs may be on the wrong track, and their efforts to stabilize a certain biological function are misguided. Instead of helping, these approaches may lead to the death of motor neurons and progression of the disease. As it progresses, ALS causes lost motor function, paralysis and usually death within a few years.

Beckman and nine other researchers last year published what they believe is an important study that summarizes more than a decade of findings and helps make the case for their theory.

The work was funded by the National Institutes of Health, the Amyotrophic Lateral Sclerosis Association, and other agencies. And it’s been facilitated by the sophisticated mass spectrometry facilities at OSU, which allow detailed questions to be asked at levels never before possible.

Copper May Be Key

Therapies that could remove copper atoms from superoxide dismutase (SOD), the OSU team believes, would allow it to die and be naturally eliminated. In the process, they could form the basis for a treatment for ALS. Researchers say this could stop the progression of the disease, while others in the science community continue to argue that copper is irrelevant.

“With the approach we’re using, we can already remove copper atoms in cell cultures and stop the death of motor neurons,” Beckman says. “We haven’t done this yet in animals, and some researchers who disagree with us point to certain experiments that they say show this won’t work. But I think this issue is more complex than many understand and those experiments are flawed.

“The devil is in the details,” he adds.

Complexity is a word that keeps coming up in discussions about ALS. That’s the sometimes painful process of science, which rarely yields simple findings and unchallenged facts. With ALS, some things are known. The disease results from the death of nerve cells in the brain and spinal cord. It’s less clear what starts that process, how it could be slowed or stopped, and there’s no known way to detect it before it begins.

Which brings us back to copper-zinc SOD, an antioxidant that helps rid cells of harmful molecules known as free radicals. A genetic mutation in the SOD gene leads to a zinc-deficient form of this compound, and some people with this mutation are far more likely to get ALS.

“In healthy people, superoxide dismutase compounds sort of partner together, fighting back-to-back to make each other stronger and help protect other cells,” Beckman says. “In ALS patients, for genetic or other reasons that are not clear, this process breaks down. Zinc-deficient SOD proteins begin to lose their shape and function, and the end result is dead motor neurons.”

Many researchers believe that stabilizing these mutant proteins would help prevent the progression of ALS. “Some neuropathologists look through a microscope at damage from ALS, and they see the tangled globs of misfolded proteins that are hallmarks of the disease,” Beckman says. “They find SOD associated with that, and think that’s the cause of ALS, and believe preventing that damage, preventing that unfolding, is the way to a therapy.”

Beckman’s findings are just the opposite. They suggest the SOD damage is just step in the process and an early one at that.

“We believe that keeping this dysfunctional superoxide dismutase around just makes things worse, creates a situation that is even more toxic to motor neurons and leads to the disease,” Beckman says. “Our studies indicate the best thing is to just let the zinc-deficient SOD go ahead and unfold, fall apart and be naturally eliminated.”

Scientists have found that removing copper atoms from this zinc-deficient SOD allows just that. The SOD is eliminated and does not create a toxic environment. In cell cultures, this has been shown to stop the death of motor neurons.

Therapies that would do this effectively don’t yet exist, but Beckman says they could. It would probably be a drug that helps remove the right amount of copper in cells in the right places, a metabolic balancing act that may be tricky but possible. “The real cure to defective superoxide dismutase is not to try to stabilize it; it’s to get rid of it. Removing copper is a way to do this, and we believe in that direction may lie a cure for ALS.”

Hope for Today

While this work goes on, 30,000 Americans have ALS at any given time, and Beckman provides what relief he can as he makes progress on the research front.

“Joe is a brilliant scientist, but he can also explain these very complicated topics in ways that others can understand,” says Lance Christian, executive director of the ALS Association of Oregon. “He regularly meets with our support groups to help explain the latest research findings. And he’s very patient, never rushed. Even though the science is so narrow and focused, Joe will answer every question, and he understands the larger issues of real people dealing with this disease.”

Beckman says that’s important, and he gets upset when he hears stories about people being told “nothing can be done.”

“There’s a lot we can do for people who are stricken with this horrible disease,” Beckman says. “We can’t cure it yet, but we can provide hope. And we can make sure that patients get all of the special help they may need to watch their nutrition, communicate, breathe, reduce their stress levels. That can improve both the quality and length of their life.”

ALS affects everything from swallowing to maintaining weight, breathing, and in some cases, cognition. Fatigue and depression are common. Most people die from respiratory failure or pneumonia within a few years of diagnosis.

“ALS is such a difficult disease that it not only can kill individuals but can destroy families, with the constant struggles and demands for 24-hour care,” Beckman says. “We have to do everything we can to help people until we can finally figure out exactly what is causing this disease.

“And when we do that, I really believe we can find a therapy for it, at least a way to slow or stop its progression. We’ll see the day when ALS is no longer a terminal illness.”
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See more about Joe Beckman’s research.

 

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