What Keeps Steven Hayes Up at Night?

Question: What keeps you up at night?

Steven Hayes: What keeps me up at night in a positive way is the possibility that we might contribute to the development of human culture in a way that, years from now, people who will never know our names may be able to live more empowered lives. And if you ask like what is the name of your great-great-great-grandfather, you probably don't even know if you get three or four greats out. So it's not that we're immortal; we're going to die very, very soon. It's not that what we produce is going to live on; it will not. But the changes that we can make in the culture can be there for people that we will never meet, that will never know us, and that's what keeps me up at night. It's what excites me about science, that we can learn ways of being with each other. And the behavioral sciences have not been enough of a part of cultural development. The physical sciences have; the behavioral sciences have not. And I would like to see if we can bring some things into human culture that would humanize and soften and empower people.

What keeps me up at night in a negative way is, if we don’t solve these problems of the human heart and of the human head, of human psychology, there is no technological solution so great that it can prevent the world that is coming, and a world of suitcase bombs or of the ability to pollute the planet in a way that it cannot recover, of global warming and the rest. We've created through science and technology a different world that has frightening sides to it, and psychology and behavioral science has to be part of this, because if you take something like the so-called war on terrorism, if we go out another 20 years and it isn't just planes into buildings, but it's a suitcase bomb in the middle of New York, there's not enough soldiers and there's not enough bullets to kill enough people to make us safe. I think we're going to have to find a way to humanize the culture itself.

And it isn't just them; it's us. When we fly planes over countries, dropping bombs on the evil ones, I think we're doing something very similar to what's being done when the infidels are getting their comeuppance with planes going into buildings. So it's gotten to the point where if we are not healthy psychologically as a human society, we will not have a planet to live on. And that's what keeps me up at night, when I see so little focus on the behavioral side of these problems, and the idea that just politics, or just physical science, is going to solve this. Or just the military; it's not true. We have to solve this, and we've got to solve it in our own heads and in our own hearts, one at a time. And I think psychotherapy actually tells us a little bit about what we might need to do to soften the culture and make it more possible for us to live together as human beings on this planet.

If we don’t solve problems of the human heart and head, there is no technological solution so great that it can prevent a world of suitcase bombs.

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Image source: Vaccaro et al, 2020/Harvard Medical School
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We don't have to tell you what it feels like when you don't get enough sleep. A night or two of that can be miserable; long-term sleeplessness is out-and-out debilitating. Though we know from personal experience that we need sleep — our cognitive, metabolic, cardiovascular, and immune functioning depend on it — a lack of it does more than just make you feel like you want to die. It can actually kill you, according to study of rats published in 1989. But why?

A new study answers that question, and in an unexpected way. It appears that the sleeplessness/death connection has nothing to do with the brain or nervous system as many have assumed — it happens in your gut. Equally amazing, the study's authors were able to reverse the ill effects with antioxidants.

The study, from researchers at Harvard Medical School (HMS), is published in the journal Cell.

An unexpected culprit

The new research examines the mechanisms at play in sleep-deprived fruit flies and in mice — long-term sleep-deprivation experiments with humans are considered ethically iffy.

What the scientists found is that death from sleep deprivation is always preceded by a buildup of Reactive Oxygen Species (ROS) in the gut. These are not, as their name implies, living organisms. ROS are reactive molecules that are part of the immune system's response to invading microbes, and recent research suggests they're paradoxically key players in normal cell signal transduction and cell cycling as well. However, having an excess of ROS leads to oxidative stress, which is linked to "macromolecular damage and is implicated in various disease states such as atherosclerosis, diabetes, cancer, neurodegeneration, and aging." To prevent this, cellular defenses typically maintain a balance between ROS production and removal.

"We took an unbiased approach and searched throughout the body for indicators of damage from sleep deprivation," says senior study author Dragana Rogulja, admitting, "We were surprised to find it was the gut that plays a key role in causing death." The accumulation occurred in both sleep-deprived fruit flies and mice.

"Even more surprising," Rogulja recalls, "we found that premature death could be prevented. Each morning, we would all gather around to look at the flies, with disbelief to be honest. What we saw is that every time we could neutralize ROS in the gut, we could rescue the flies." Fruit flies given any of 11 antioxidant compounds — including melatonin, lipoic acid and NAD — that neutralize ROS buildups remained active and lived a normal length of time in spite of sleep deprivation. (The researchers note that these antioxidants did not extend the lifespans of non-sleep deprived control subjects.)

fly with thought bubble that says "What? I'm awake!"

Image source: Tomasz Klejdysz/Shutterstock/Big Think

The experiments

The study's tests were managed by co-first authors Alexandra Vaccaro and Yosef Kaplan Dor, both research fellows at HMS.

You may wonder how you compel a fruit fly to sleep, or for that matter, how you keep one awake. The researchers ascertained that fruit flies doze off in response to being shaken, and thus were the control subjects induced to snooze in their individual, warmed tubes. Each subject occupied its own 29 °C (84F) tube.

For their sleepless cohort, fruit flies were genetically manipulated to express a heat-sensitive protein in specific neurons. These neurons are known to suppress sleep, and did so — the fruit flies' activity levels, or lack thereof, were tracked using infrared beams.

Starting at Day 10 of sleep deprivation, fruit flies began dying, with all of them dead by Day 20. Control flies lived up to 40 days.

The scientists sought out markers that would indicate cell damage in their sleepless subjects. They saw no difference in brain tissue and elsewhere between the well-rested and sleep-deprived fruit flies, with the exception of one fruit fly.

However, in the guts of sleep-deprived fruit flies was a massive accumulation of ROS, which peaked around Day 10. Says Vaccaro, "We found that sleep-deprived flies were dying at the same pace, every time, and when we looked at markers of cell damage and death, the one tissue that really stood out was the gut." She adds, "I remember when we did the first experiment, you could immediately tell under the microscope that there was a striking difference. That almost never happens in lab research."

The experiments were repeated with mice who were gently kept awake for five days. Again, ROS built up over time in their small and large intestines but nowhere else.

As noted above, the administering of antioxidants alleviated the effect of the ROS buildup. In addition, flies that were modified to overproduce gut antioxidant enzymes were found to be immune to the damaging effects of sleep deprivation.

The research leaves some important questions unanswered. Says Kaplan Dor, "We still don't know why sleep loss causes ROS accumulation in the gut, and why this is lethal." He hypothesizes, "Sleep deprivation could directly affect the gut, but the trigger may also originate in the brain. Similarly, death could be due to damage in the gut or because high levels of ROS have systemic effects, or some combination of these."

The HMS researchers are now investigating the chemical pathways by which sleep-deprivation triggers the ROS buildup, and the means by which the ROS wreak cell havoc.

"We need to understand the biology of how sleep deprivation damages the body so that we can find ways to prevent this harm," says Rogulja.

Referring to the value of this study to humans, she notes,"So many of us are chronically sleep deprived. Even if we know staying up late every night is bad, we still do it. We believe we've identified a central issue that, when eliminated, allows for survival without sleep, at least in fruit flies."

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