Chronic pain, affecting tens of millions of Americans alone, is debilitating and demoralizing. It has many causes, and in the worst cases, people become “hypersensitized”—their nervous systems fire off pain signals in response to very minor triggers.
There are no good medications to calm these signals, in part because the subjectivity of pain makes it difficult to study, and in part because there haven’t been good research models. Drugs have been tested in animal models and “off the shelf” cell lines, some of them engineered to carry target molecules (such as the ion channels that trigger pain signals). Drug candidates emerging from these studies initially looked promising but haven’t panned out in clinical testing.
“These models don’t tell you what the drug is doing to the whole functioning neuron,” says Elizabeth Buttermore, PhD, a postdoctoral fellow in the F.M. Kirby Neurobiology Center at Boston Children’s Hospital. “They haven’t been holding up.”
Last month in Nature Neuroscience, Buttermore coauthored a report with Brian Wainger, MD, of Boston Children’s and Massachusetts General Hospital, describing a new model that appears to capture pain physiology in a dish, using skin cells as their raw material. Their model, also a technical breakthrough in stem cell research, offers new opportunities to understand how pain is produced and to discover new analgesics.
A nimbler way to make neurons
Labs all over the world are beginning to reprogram skin cells into cells resembling embryonic stem cells, known as induced pluripotent stem (iPS) cells, and transforming those, in turn, to their cell type of choice. But Buttermore, Wainger and colleagues found that they were able to bypass the somewhat cumbersome step of creating iPS cells.
By adding just five signals (namely, transcription factors) to skin cells from mice and from patients with an inherited pain disorder, they were able to create nociceptors—specialized pain-sensing neurons. Two of these signals hadn’t been known before and were found by examining mature nociceptors from mice.
In tests, the lab-created mouse nociceptors closely resembled “natural” neurons. They functioned, responded to different pain triggers and became hypersensitized to pain just like their real-world counterparts. The lab-created human nociceptors still have some hoops to jump through, but by early measures, they appear to “beautifully model” patients’ neuropathies and pain hypersensitivities, says Clifford Woolf, MB, BCh, PhD, senior investigator on the project and director of the Kirby Center.
The nociceptor model is already revealing new aspects of pain physiology and could ultimately provide a much more realistic platform for testing new drugs. Woolf, who also co-leads the Harvard Stem Cell Institute’s Nervous System Diseases Program has already found this to be true for amyotrophic lateral sclerosis (ALS).
The nociceptor project’s success was a long time in coming. The team had first tried to make nociceptors from embryonic stem cells. “We spent three years trying to recapitulate the developmental steps involved, and it turned out to be a total bust,” said Woolf.
But he refused to pull the plug, and the approach that finally worked turns out to be the most expedient and the most clinically relevant: Skin cells can be collected directly from patients, making it easier to model their different kinds of chronic pain—neuropathies caused by genetic mutations, diabetes or even chemotherapy, which can sensitize patients to pain.
“We’re trying to get to clinical trials with more success,” says Buttermore. “Hopefully, we’ll avoid drugs that don’t work.”