ALS Problem Solver

by Nora Dunne | photography by Teresa Crawford
Robert Kalb is moving Northwestern’s
Les Turner ALS Center forward.

 

 

 

 

 

 

 

 

 

 

Some of the facts we know about amyotrophic lateral sclerosis (ALS) today: It causes neurons in the brain and spinal cord to degenerate, leading to muscle weakness and, eventually, paralysis. An estimated 20,000 or more Americans have the disease at a given time. Their average life expectancy after diagnosis is three to five years, though some may live much longer. What we don’t know yet: what causes motor neurons to die, how to stop ALS from progressing and how to cure it.

Listen Up:

Hear an interview with Kalb in Feinberg’s podcast series.

 

Despite this grim reality, Robert Kalb, MD, is optimistic about the outlook for ALS.

“ALS is a very hard problem, but I think this is a great time in science to solve the problem,” says Kalb, the inaugural director of the Les Turner ALS Research and Patient Center at Northwestern Medicine.

When Kalb was finishing medical school at Cornell University in the early 1980s, scientists and physicians were translating groundbreaking therapies for hypertension and cardiovascular disease, “but it was a desert for neurology,” Kalb says. “I think that’s what drew me to the specialty in the first place.”

Kalb went on to complete an internship and residency in internal medicine at the Albert Einstein College of Medicine’s Montefiore Medical Center and then a residency and fellowship in neurology and neurobiology, respectively, at Yale New Haven Hospital.

Soon after, he opened a laboratory at Yale, secured funding from the National Institutes of Health (NIH) and began to focus on motor neuron development, studying rats who spent neonatal life at zero gravity on the Space Shuttle. Over time, his interest in motor neurons blossomed into an interest in motor neuron diseases. Today, he studies gene activation and misfolded proteins in familial ALS.

“Never in the history of science have we had such powerful tools for understanding how genes are involved in normal cellular activities and what goes awry in disease states,” Kalb says. “When I see patients with ALS, I pinch myself and say, ‘how could it possibly be that we don’t have a cure for them?’ I don’t know when we’ll have an answer for them, but I really think we can get there.”

Two-fold Mission

Kalb arrived at Northwestern last December, after spending 15 years on the faculty at the University of Pennsylvania.

“Everything was terrific in Philadelphia, but moving to Northwestern seemed like a new adventure and a superb opportunity to make an impact on the lives of individuals with neurological diseases,” he says. “Now I have two missions: The first is to make the Les Turner ALS Center, which is already great, even better. The second is to grow my own laboratory. There is really high-end basic science going on here, and I am excited about the opportunities for collaboration.”

As director of the center, Kalb is responsible for aligning Northwestern’s ALS research with its clinical activities, in partnership with the Les Turner ALS Foundation.

“One priority is to build the translational program so that when a discovery is made in the lab, it reaches patients more efficiently,” he says. “I think this role needed somebody who wears both the basic science hat and the clinical hat to make sure everybody’s working together.”

Mutations in the C9ORF72 gene are the leading genetic cause of ALS. A product of the mutant gene (green) locates to the nucleus of motor neurons (red) where it inhibits the cellular trash disposal unit, nuclear proteasomes.
“Bob is a thoughtful, creative clinician-scientist ideally suited to lead the Les Turner ALS Center during these exciting times,” says Dimitri Krainc, MD, PhD, chair and Aaron Montgomery Ward Professor of Neurology. “I’m confident he’ll bring insights from basic science to the bedside to improve the lives of many patients with ALS.”

Brick by Brick

In his own laboratory, Kalb started studying ALS in tissue cultures and microscopic worms called C. elegans. Though only about 10 percent of ALS cases are familial (inherited), he and members of his team focus on that version of the disease because they are able to recreate it in animal models by manipulating genes associated with familial ALS in humans. Then they explore the molecular mechanisms that go wrong during the disease and search for therapeutic targets that could help patients with any form of ALS.

“We have leveraged the awesome power of the worm to discover new genes and new pathways involved in promoting survival in models of familial ALS,” Kalb says. “Now we’ve taken those findings back into rodent systems, and we are working to target pathways with drugs. Ongoing partnerships with the pharmaceutical industry will accelerate the translation of basic science observations into potential therapies.”

Through the years, his group has found that dysfunctional energy metabolism contributes to neuron death in models of ALS and identified two biological pathways in cells that can be targeted to treat the disease.

Kalb in his new laboratory at Feinberg, with postdoctoral fellow Patrick Riechers, PhD (left).
Currently, Kalb is interested in how cells’ waste disposal systems may be connected to ALS.

“All cells, and motor neurons in particular, create lots of misfolded, or damaged, proteins that are noxious to cells if permitted to accumulate in them,” Kalb explains. “So cells devote enormous resources to clearing that excess. I’m a strong believer that the underlying defect in all neurodegenerative diseases, and ALS in particular, is intimately tied to an inefficient trash disposal unit.”

Interestingly, some scientists studying cancer are going after the same critical pathways.

“In fact, one reason cancer cells stay alive is because they’re incredibly efficient at dealing with trash. The cancer guys want to block that. We in neurodegenerative diseases have the opposite problem: We want to stimulate waste disposal,” Kalb says. “I think there’s a chance that we might all meet in the middle somewhere with the same drugs.”

Despite nearly 30 years of NIH funding and about 100 peer-reviewed publications, Kalb says that his greatest accomplishment is training future scientists.

“Science is such a big, complicated edifice. Very few people in the end make the apex discovery,” he says. “I’ve made observations that are some of the bricks to build that edifice, but helping my graduate students and postdocs move their careers forward, that’s what I’m most proud of.”

Outside the Lab and Clinic

Kalb says that a move to Northwestern would never have been possible without the support of his wife, Marianne Bernstein, an internationally recognized curator of site-specific art shows. They have two grown entrepreneurial sons, one living in San Diego and the other in New York City. Outside of work, Kalb enjoys running, cycling and swimming, as well as reading, especially about history, for pleasure.

Neural progenitors cells differentiated from human embryonic stem cells, from the lab of Evangelos Kiskinis.

 

ALS Discoveries from Feinberg Scientists

Teepu Siddique, MD, is working to determine the causes of and treatments for neurodegenerative disorders, particularly those involving mitochondria and motor neuron function. His lab has identified genetic causes of ALS and engineered the first mouse model for ALS dementia.

Pembe Hande Ozdinler, PhD, explores the mechanisms responsible for selective neuronal vulnerability and degeneration, focusing on upper motor neurons. Her group was the first to isolate these neurons in the brain that die in ALS and give them fluorescent tags so they can be tracked.

Evangelos Kiskinis, PhD, uses neuronal subtypes derived from human stem cells to study the cells primarily affected in ALS. In a recent paper published in Cell Stem Cell, he showed how the process of DNA methylation regulates the development of spinal cord motor neurons.