Sledge, George W. Jr. MD
Surfing the web recently I came across a photo of a brown bear (charmingly named Palle-Jooseppi by his Finnish keepers) emerging from five months of hibernation, then promptly lying down for a nap (http://now.msn.com/living/0224-bear-hibernating.aspx). Such is the power of suggestion that I immediately started yawning.
GEORGE W. SLEDGE JR....Image Tools
Sleep is one of nature's great mysteries, occupying a third of our lives but nowhere near that much attention, outside of that lavished on it by pharmaceutical companies. In 2008, sleeping medication prescriptions topped 56 million in the United States, and surely the number has only gone up since then. Who wouldn't have wanted to sleep through the last few years?
I'm a bit of an insomniac myself. One night a week my brain will refuse to shut off, and I will enter the next day short of soothing rest. Usually this occurs when my mind is racing, focusing on something irritating and (typically) beyond my control. I then become progressively crabbier until I crash and burn early the next evening.
I know I'm not alone in this. Sleep disorders are common in our society, occurring in close to 1 in 5 of the general public. My favorite free medical textbook, Wikipedia, lists (in addition to primary insomnia) disorders such as bruxism, delayed sleep phase syndrome, narcolepsy, cataplexy, periodic limb movement disorder, obstructive sleep apnea, and a dozen or so others. There are just so many ways to mess up your sleep patterns.
Whenever I read these lists I suspect that I have had several at some time or other. My self-diagnoses include nocturnal myoclonus, primary insomnia, maybe a little obstructive sleep apnea (my wife and I both accuse each other of snoring), night terrors, shift work sleep disorder (as an intern), and jet lag on many a trip. I also toss and turn a great deal, so that my bed looks like a combat zone in the morning. I don't think they've named the “he woke up because his feet were cold because his blanket ended up on the floor” sleep disorder yet, but if they ever do I'll be the case study.
I've never suffered from somnambulism, or sleepwalking, but a good friend of mine had it, and occasionally woke up at a bus stop at 4 am in his pajamas. His parents got used to picking him up at odd hours. Fortunately he lived in New Orleans, so he didn't freeze to death, and his behavior wasn't even considered all that unusual.
What Is ‘Normal’?
What is a “normal” sleep pattern? This turns out to be an interesting historical question. As recently as 200 years ago, sleep patterns differed significantly from ours. Roger Ekirch, a professor of history at Virginia Tech, wrote a wonderful book on the subject called At Day's Close: Night in Times Past. Ekirch documents, through analysis of hundreds of primary sources, that our ancestors commonly had a “first sleep” followed by a period of wakefulness, followed in turn by a “second” or “morning” sleep. This pattern, a function of living in a night that was both long and dark, disappeared with modern home and street lighting systems.
In other words, we all sleep abnormally, at least in historical terms, though some more abnormally than others. My cancer patients frequently complain about their sleep, or lack thereof, particularly in the months following chemotherapy. As many as 45% of cancer patients complain of sleeplessness in some series, though like everything else in the quality-of-life realm, we do a poor job documenting the problem, and an even poorer job of understanding.
Sleep disorders in cancer patients cluster with other problems (fatigue, pain, depression, loss of concentration, and other cognitive dysfunctionality), making it hard to tease out cause and effect. The correlation between fatigue and sleep loss in particular is a vexing chicken-and-egg question, or so the literature would suggest.
Does any of this matter from a cancer standpoint? If you don't get a good night's sleep, will your micrometastases wake up? We don't really know, but if you mimic obstructive sleep apnea in mice by exposing them to intermittent hypoxia, their tumors grow at a more rapid rate. That hypoxia can make tumors grow is no surprise, but of course sleep apnea is only one of many sleep disorders.
Dread of Sleep
I have had patients who suffer from another sleep disorder, somniphobia, or the dread of sleep. This has been a particular problem for some with advanced cancer: they are literally afraid that if they fall asleep they might not wake up. But I don't know that somniphobia, or any other sleep disturbance, shortens a cancer patient's life.
There is another interesting connection between sleep and cancer. Investigators at Brown University working with C. elegans, that scientific workhorse of the nematode family, demonstrated last year in Current Biology that upregulation of Notch signaling (by osm-11) puts worms to sleep. Maybe not the sort of sleeping you and I do, but what passes for sleep in worms. Which begs the question: do worms dream?
And, it turns out, the C. elegans osm-11 gene being studied is closely related to human DLK1 (Deltalike1), an atypical Notch ligand that is expressed in the parts of the brain associated with the sleep-wake cycle. The Notch system is big in cancer these days, with involvement in both the cancer stem cell and angiogenesis fields, and Notch inhibitors are being developed for clinical use.
Will Notch inhibitors affect the sleep of cancer patients? Do sleepy cancer patients have altered Notch or DLK1 expression? Who knows? What we do know is that the patent office has received several applications for DLK1: I saw one posted on Patentdocs on January 12, 2012 for “Treatment of Delta-Like 1 Homolog (DLK1) Related Diseases by Inhibition of Natural Antisense Transcript to DLK1,” with sleep disorders listed among the potential applications.
Back to insomnia: there's a gene for that. Researchers at Rockefeller University (reporting in Neuron in late 2011) screened 21,000 fruit flies (Drosophila melanogaster, a little higher up the food chain than C. elegans) for flies that sleep poorly (317 minutes per day vs. the usual 927 minutes: flies know how to sleep). The insomniac fruit flies have mutations in a gene called—you guessed it—insomniac (for a pretty picture of fruit fly brains with tagged insomniac, see http://bit.ly/insomniacfruitfly).
Mutant flies live only two thirds as long as normal flies: they, like us, need our beauty rest, you might think. But not so. Knock out insomniac only in the neurons, and the flies have a normal lifespan, but are still night owls. I can see a new therapeutic application for college and medical students in the wings.
We are not even sure why people (or other organisms) sleep. One theory is that sleep affects synaptic plasticity, learning, and memory. Another recent study suggests that it also enhances complex decision-making through positive effects on frontal lobe function. That seems as reasonable as any other theory under consideration. I'll sleep on it. Maybe I'll be smarter and wiser tomorrow morning. Meanwhile, I'm yawning again.
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