Gabriel de Cool (1854 – ?, French) - The Muse, 1895
The New Yorker has a long article about the development of a new insomnia drug. It starts with the discovery of a novel neurotransmitter—discovered independently by two different groups of researchers in the 1990s, named by some hypocretin (because it is produced in the hypothalamus), by other orexin (meaning appetite-stimulating, because of its observed effects). Orexin/hypocretin was first thought to regulate appetite, but attention soon turned to sleep. Orexin receptors are only present in a few thousand nerve cells in the hypothalamus, a tiny number compared to the billions of neurons across the brain. But these neurons have connections all over the brain, and they appear to act as an “awake switch.”
Orexin comes along and tells the brain, “hey, be awake, don’t fall asleep.” Soon after the discovery of orexin’s effects on rats’ appetite, it was discovered that rats lacking orexin receptors (“keyholes”) acted similarly to human narcoleptics. They have disturbed sleep patterns, and tend to fall asleep suddenly or fall into a heap, their muscles inert, at intervals during the day. Human narcoleptics were found to lack orexin (“keys”). This novel discovery led to the possibility of new medications. Orexin agonists (which activate the receptors) could become new treatments for narcolepsy or daytime sleepiness. And orexin antagonists (which block the receptors) could become new sleep aids. The search for the next blockbuster drug was on.
The article gives a fascinating look into the evolution of pharmaceutical research. Here is a description of how scientists came up with the zolpidem molecule, the active component in the popular sleep aid Ambien:[Jean-Pierre Kaplan] and Pascal George—a younger colleague whom Kaplan described as “sympathetic and brilliant”—started by building wooden models, including ones for Valium, Halcion, and zopiclone. Colored one-inch spheres, representing atoms, were connected by thin rods, creating models the size of a shoebox. This was a more empirical, architectural approach than is typical in a lot of pharmaceutical chemistry. Kaplan and George tried to identify what these molecules had in common, structurally, that allowed them to affect the brain in the same way. Kaplan told me that their thinking wasn’t wildly creative, but it was agile: “You know, at that time it was maybe clever, because you have no computer. Now it’s routine work.”
Then a couple of decades later, pharmaceutical giant Merck is trying to find a drug to block orexin in order to help patients sleep:
Merck has a library of three million compounds—a collection of plausible chemical starting points, many of them the by-products of past drug developments. I saw a copy of this library, kept in a room with a heavy door. Rectangular plastic plates, five inches long and three inches wide, were indented with hundreds of miniature test tubes, or wells, in a grid. Each well contained a splash of chemical, and each plate had fifteen hundred and thirty-six wells. There were twenty-four hundred plates; stacked on shelves, they occupied no more space than a filing cabinet.
In 2003, Merck conducted a computerized, robotized examination of almost every compound in the library. At this stage, the scientists were working not with Renger’s animals but with a cellular soup derived from human cells and modified to act as a surrogate of the brain. Plate by plate, each of the three million chemicals in the library was introduced into this soup, along with an agent that would cause the mixture to glow a little if orexin receptors were activated. Finally, orexin was added, and a camera recorded the result. Renger and his colleagues, hoping to find a chemical that sabotaged the orexin system, were looking for the absence of a glow.
But drug development isn’t just science. Politics and marketing also enter into it. Everything from the color of the pills (“reds are culturally not acceptable in some places”) to the packaging (“the U.S. prefers everything in a thirty-count bottle”) to the dose. The final hurdle is approval by the Food and Drug Administration—America’s final arbiter on what drugs are allowed to be marketed and sold, and for which diseases—and other regulatory bodies in other parts of the world. It’s good that such hurdles exist, because otherwise dangerous drugs—such as thalidomide, which caused severe birth defects—would enter the market much more frequently. However, there is a question of balance: at what point do potential downsides outweigh the benefits? The FDA has turned to a more conservative line: dosages should be as small as possible.
This poses a problem for Merck. Their orexin antagonist, their potential superstar new sleep medication, suvorexant, is effective (as measured by objective measurements) at a dose of 10 milligrams. However, at this dose, patients don’t experience any subjective improvement in sleep quality. At higher dosages, both objective and subjective measurements agree that the drug is effective. But the FDA argues that such higher doses run a higher risk of side effects, and recommends the lowest dose, the dose which doesn’t make patients feel any better even if they’re getting better sleep as determined by objective measurements. This leads to an absurd situation where the FDA is arguing the drug’s effectiveness (at the lowest dose) while the drug company is arguing its ineffectiveness. If the FDA will only approve the lowest dose, this poses a problem for marketers:How successfully can a pharmaceutical giant—through advertising and sales visits to doctors’ offices—sell a drug at a dose that has been repeatedly described as ineffective by the scientists who developed it?
Regardless of marketing and backroom tactics and FDA meetings, the research into orexin continues on. And that’s the really interesting part from a scientific perspective. Just a little more than a decade ago we discovered a completely new piece of the brain puzzle. We still don’t understand sleep. That’s the big thing. More basic research—the kind of research that just tries to figure out how things work, without regard for practical applications such as drug development—is needed. We don’t know why we need to sleep, we don’t know the exact significance of the different sleep phases. We do know that sleep is vitally important, that a specific cycle of brain states throughout the night is needed to perform well the next day. But why must we sleep at all? Why is resting awake not good enough? We have some ideas—memory consolidation, ridding the brain of certain toxins that can build up during wakefulness—but we’re not sure.
Sleep remains a mystery. Orexin is likely to play some part in the solution. And that’s exciting, whether you have sleep troubles or not.
Illustration for Alexander Pushkin’s Eugene Onegin - Lidia Timoshenko
"Stay single. I only say this to you because when you’re young and in love, everyone thinks they’ll be the exception. Sure, maybe Mom and Dad slept in separate beds and then separate rooms. Maybe the older couples you know bicker or fight; maybe they don’t talk at all if they ever did. But at your age, you can’t imagine it will ever be you. But it will be, which is bad enough. But what’s worse is how much you’ll feel like a failure because when the person who knows you best loses interest, that really takes something out of you. Like surgery almost. And you really start to wonder if you’ll ever be whole again. Anyway, i’m babbling. Excuse me, gentlemen."
Marta1901 wins our Photo of the Day with a Lomo remake of Alice in Wonderland. - http://bit.ly/1cNG6wB