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Making Motor Neurons
Perhaps the newest means to study ALS will finally provide the scientific nutcracker researchers have long been searching for: dishes of human motor neurons grown from ALS patients. Until now, "never have we ever, ever been able to isolate a single motor neuron from a [nonfetal] source that could survive," says Kevin Eggan. He has perfected the molecular recipe for making the cells, a recipe that promises a nearly unlimited supply of motor neurons that can be used for basic physiological studies of the cells and for screens of potential new drugs.
The recipe builds on two decades of work centered in the laboratory of developmental biologist and HHMI investigator Tom Jessell of Columbia University. Jessell became fascinated with motor neurons early in his career, as they're fundamentally different from the 10,000 other types of neurons. Motor neurons send long axons—up to three feet long—outside the spinal sheathing to every muscle in the body. "They're the sole means of communication between the central nervous system and the body," he says. "So in this feature they are distinct from all other CNS neurons."
Working with chicken and mouse embryos, Jessell figured out the sequence of genetic switches that turn on and off in embryonic nerve tissue to produce motor neurons. Building on that work, a postdoctoral fellow in Jessell's lab, Hynek Wichterle, discovered in 2002 that adding two small molecules to embryonic stem cells coaxes them to generate motor neurons with high efficiency. Wichterle and Jessell told Eggan about the advance over coffee, and the young Eggan—who was then deliberating a career path—decided to work on motor neurons and ALS. "Hynek's work distilled 20 years of developmental biology into a simple and reproducible molecular recipe for making a motor neuron," Eggan says. "These cells were not like motor neurons, they really were motor neurons. They were electrophysiologically active; they made synapses with other cells."
After Eggan landed a faculty position at Harvard, he and his colleagues had some early successes in making human motor neurons, but the difficulty in obtaining a sufficient supply of human embryos slowed the work. Then in 2006, while attending a stem cell conference in Whistler, British Columbia, Eggan heard about a second advance that would prove crucial to pushing the work forward. Shinya Yamanaka of Kyoto University told attendees that he had reprogrammed ordinary skin cells to act like embryonic stem cells. Yamanaka called the new cells induced pluripotent stem (iPS) cells. "I was sitting in the back row and this wave of realization washed over me," Eggan says. He visualized a path to an unlimited supply of motor neurons carrying all the genetic mutations found in ALS patients. Step 1: Obtain skin cells from patients. Step 2: Reprogram those cells into iPS cells. Step 3: Apply Wichterle's recipe to grow those embryonic-like cells into motor neurons.
Now, after collecting skin cells from several dozen ALS patients and transforming them, Eggan is confident that the resulting cells "are real, functional motor neurons. We had to go to great lengths to show that," he says. The Harvard Stem Cell Institute is preparing to provide the cells to qualified researchers.
Valerie Estess, director of research for Project ALS, which helps fund Eggan's work, calls the advance "ALS in a dish." She says that, already, researchers at Harvard and at Columbia University are using the cells to screen for potential new treatments. "We can now model ALS more accurately," she says. "We hope that the drugs that emerge from the screens are contenders."
Of course, that's the ultimate goal for ALS researchers—to provide treatments for patients who now have few options. Yeast, worms, flies, mice, and, now, human neurons in a dish all offer platforms to quickly test drug candidates against the range of defects that lead to ALS. "It's great to have an arsenal of models to study disease," says NINDS's Gubitz. "Every model mirrors a specific aspect of disease, and they're much more powerful when combined."
And so with this solid foundation for discovery, ALS researchers expect an avalanche of advances in the coming years. Says Bonini: "You can't predict where the big breakthroughs are going to come from, which is why it's important to take many different approaches. It's really important to cast a wide net." Because, in the end, "the whole reason we're doing this is to make an impact for patients."