When a post-doc in Dr Thomas Scammell’s lab said he’d found that narcolepsy patients have many more histamine neurons than healthy controls, Scammell initially thought the post-doc must have made a mistake. Another person in Scammell’s lab at Boston’s Beth Deaconess Medical Center was assigned to repeat the cell count. The second count confirmed the first, and, since then, another lab has found that sufferers of the sleep disorder indeed do exhibit a huge increase in histamine neurons.
“We found something completely surprising and unpredictable,” Scammell tells Sleep Review in a phone interview. These results could have a large impact on how future research studies look at the brain circuitry in patients with narcolepsy.
Much of the funding for this and several other research projects in Scammell’s lab comes from unrestricted grants from Wake Up Narcolepsy (WUN). WUN has supported Scammell’s work for five consecutive years, totaling $120,000 at the end of 2014. The investigative freedom these grants allow is key to making unexpected discoveries such as this finding of 94% more histaminergic tuberomammillary nucleus neurons in people with narcolepsy, Scammell says. “Other funding sources may consider some of this research outside the bounds of acceptable scientific risk,” he says. “For example, we would have needed some strong evidence in advance that there was an increase in those cells before we got that funding from the NIH.” In contrast, Wake Up Narcolepsy’s grants, he says, “allow us to explore in a more creative way.”
WUN also helped fund Scammell lab research that tried gene therapy to rescue mice with narcolepsy. “When hypocretin/orexin neurons die off, can we get other neurons in the brain to make it?” Scammell and his team asked. The results found that the mice that underwent the gene therapy exhibited improvements in wakefulness and locomotion. “This is a good proof of concept,” Scammell says. “When gene therapy is more mature, it might be a good concept to explore in people.”
Mice are involved in much of Scammell’s research. “The nice thing about narcolepsy research in rodents is we can do very specific manipulations of pathways in the brain. We can ask more mechanistic questions,” he says. For example, last year, Scammell’s lab was able to show in mice that by turning off or injuring two parts of the brain—the medial prefrontal cortex and the amygdala—cataplexy can be lessened. “It’s really hard to study cataplexy in the lab because when a person is in a research lab, they’re not as likely to have the heartfelt emotions that are the common triggers of cataplexy,” Scammell says. The research with rodents may lead to the identification of new targets and new therapies for narcolepsy.
Scammell predicts that future narcolepsy research will include investigations into why the disorder results in insomnia, which is counterintuitive as, in most other cases, if a person is very sleepy during the day, he will sleep very well at night. He also predicts research will delve deeply into what exactly is killing off the hypocretin/orexin-producing cells.
Ultimately, the holy grail for narcolepsy research would be the creation of a drug that mimics the effects of hypocretin/orexin. “It would be for narcoleptics what insulin is for diabetics,” Scammell says. With the help of more unrestricted grants for Scammell’s lab and other labs in the coming years, this holy grail could become attainable.
Sree Roy is editor of Sleep Review. CONTACT [email protected]