Sleepy dogs and collapsing mice paved the way for a new science of sleep.
In the late 1990s, Dr. Masashi Yanagisawa at the University of Texas Southwestern Medical Center discovered two brain chemicals in rodents that seemed to be instrumental in stimulating hunger. He called them “orexins,” a play on “orexis” the Greek word for appetite.
At the same time, Dr. Emmanuel Mignot at Stanford University School of Medicine was hunting for the root cause of an inherited form of narcolepsy in Doberman pinschers, Labrador retrievers and Dachshunds.
In back-to-back studies published in the summer of 1999, these two lines of research unexpectedly converged, breaking open the neurobiology of sleep and identifying a root cause of the sleep disorder narcolepsy, which affects an estimated one in every 2,000 people in the United States. A new narcolepsy drug based on these insights was approved in August.
On Wednesday, Dr. Yanagisawa, now at the University of Tsukuba in Japan, shared the Albert Lasker Basic Medical Research Award with Dr. Mignot, for their work into the nature of sleep. The prestigious prizes are often called “America’s Nobel.”
“Their work has cracked open a molecular dissection of sleep regulation, reinforced the immune system’s involvement in human narcolepsy, and pointed toward new treatments for this illness and other sleep disturbances,” the Lasker citation said. The field is now a major target of pharmaceutical companies, but their basic science research was supported largely by philanthropy and federal funding.
Thirty years ago, it was far from clear that these scientists were studying the same problem.
Dr. Yanagisawa was fascinated by basic science: There were dozens of receptors on the surface of brain cells whose functions were unknown. He wanted to decipher the function of these “orphan” receptors, and one of his first successes yielded short chains of amino acids, called peptides, that bound themselves to two brain receptors. When researchers injected the peptides into rodents in large doses, they ate more. He called them orexins. (Another group simultaneously discovered the same brain chemicals and called them hypocretins.)
Next, they genetically tweaked mice to knock out the gene that carried the code for orexin, expecting the animals to be skinny and disinterested in food.
To Dr. Yanagisawa’s disappointment, the mice looked normal, at least until scientists started videotaping them at night and reviewing hours of infrared footage. That’s when they discovered that the mice were abruptly collapsing multiple times a night and plunging into brief bouts of REM sleep.
Dr. Mignot, on the other hand, had come at the research question from the opposite direction, hoping to find the root cause of narcolepsy.
In humans and dogs, narcolepsy not only causes excessive sleepiness, but episodes of cataplexy; positive emotions cause muscles to go slack. The dogs, Dr. Mignot found, lacked a particular receptor that was activated by the same brain peptide Dr. Yanagisawa had discovered.
“In two different species, this was such a dramatic and beautiful convergence, which makes everything in the story very convincing,” Dr. Yanagisawa said.
Science awards highlight the contributions of individuals, but the story of orexin shows how it is often propelled forward by intense personal competition.
Dr. Yanagisawa and Dr. Mignot began to hear each other’s footsteps as they neared similar conclusions.
“Overall, it kind of pushed both of us to be faster,” Dr. Mignot said.
Dr. Mignot’s group found that people with narcolepsy lacked orexin in their spinal fluid, while another group at the University of California at Los Angeles studied the post-mortem brains of people with narcolepsy to show that they lacked the cells that produce orexin.
The first drug to block orexin — a treatment for insomnia — was approved in 2014. Finding a way to mimic the molecule was a bigger challenge, and the first drug to do it is expected to be available this fall.
This is not the end. Dr. Mignot is continuing research into the cause of narcolepsy, which is thought to occur when the immune system errantly attacks the neurons that produce orexin. Dr. Yanagisawa is trying to figure out precisely how sleepiness builds up and how the body regulates the switch between wakefulness and sleep.
The approved drug targets only one of the two orexin receptors. Scientists are hopeful that if the other can be targeted, it could open up more therapeutic avenues. And orexin deficiency may not be the only cause of narcolepsy; a study published earlier this year highlights the loss of a different type of brain cell in narcolepsy patients.
The Lasker Medical Research Awards began in 1945, and they often augur a future Nobel Prize.
Other winners this year include the actor and Parkinson’s disease advocate Michael J. Fox, who was awarded the Lasker-Bloomberg Public Service Award. The Lasker-DeBakey Clinical Medical Research Award was shared by three Japanese scientists — Kunihiro Hattori, Takehisa Kitazawa and Tomoyuki Igawa — for the invention of a drug called a bispecific antibody, to treat the rare bleeding disorder, hemophilia A.
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