The dying cells - the same type lost in patients with the devastating neurological disease spinal muscular atrophy - confirmed that the University of Wisconsin-Madison stem cell biologist had recreated the hallmarks of a genetic disorder in the lab, using stem cells derived from a patient.
By allowing scientists the unparalleled opportunity to watch the course of a disease unfold in a lab dish, the work marks an enormous step forward in being able to study and develop new therapies for genetic diseases.
As reported this week in the journal Nature, Svendsen and colleagues at UW-Madison and the University of Missouri-Columbia created disease-specific stem cells by genetically reprogramming skin cells from a patient with spinal muscular atrophy, or SMA. In this inherited disease, the most common genetic cause of infant mortality, a mutation leads to the death of the nerves that control skeletal muscles, causing muscle weakness, paralysis, and ultimately death, usually by age two.
Genetic reprogramming of skin cells, first reported in late 2007 by UW-Madison stem cell biologists James Thomson and Junying Yu and a Japanese group led by Shinya Yamanaka, turns back the cells' developmental clock and returns them to an embryonic-like state from which they can become any of the body's 220 different cell types. The resulting induced pluripotent stem cells, known as iPS cells, harness the blank-slate developmental potential of embryonic stem cells without the embryo and have been heralded as a powerful potential way to study development and disease.
Just one year later, the new work is fulfilling that promise.
"When scientists study diseases in humans, they can normally only look at the tissues affected after death and then try to work out - how did that disease happen? It's a little like the police arriving at the scene of a road accident - the car's in the ditch, but they don't know how it got there or the cause of it," explains Svendsen, a professor of anatomy and neurology in the UW-Madison School of Medicine and Public Health and the Waisman Center, and co-director of the Stem Cell and Regenerative Medicine Center.
With iPS cells, he says, "Now you can replay the human disease over and over in the dish and ask what are the very early steps that began the process. It's an incredibly powerful new tool."
In the new study, the researchers created iPS cells from stored skin cells of a young SMA patient and his mother, who does not have the disease. The cells grew well in the lab, and the group developed a new method to efficiently drive them to make large numbers of motor neurons, the cells that control muscles and that are affected in SMA.
Initially, the motor neurons thrived in both samples. But after about a month, "the accident started happening," Svendsen says, and the motor neurons from the patient-derived cells began to disappear.
"The motor neurons we got started to die in culture, just like they do in the disease. This is the first validation of a human disease that we've modeled in a culture dish," he says.
They can now begin to dissect what kills the motor neurons and why these cells alone are targeted in the disease. Past studies to understand the effects of the SMA-causing mutation have often relied on the easy-to-obtain skin cells, which are not affected in SMA and offer limited insight into how and why motor neurons die, says UW-Madison researcher Allison Ebert, lead author on the new study.