New research establishes an unexpected connection.
- A study provides further confirmation that a prolonged lack of sleep can result in early mortality.
- Surprisingly, the direct cause seems to be a buildup of Reactive Oxygen Species in the gut produced by sleeplessness.
- When the buildup is neutralized, a normal lifespan is restored.
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.)
Image source: Tomasz Klejdysz/Shutterstock/Big Think
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."
Dr. Kate Biberdorf explains why boiling water makes it safer and how water molecules are unusual and cool.
- University of Texas professor and science entertainer Kate the Chemist joined Big Think to talk about water molecules and to answer two interesting and important questions: Why does boiling water make it safe to drink, and what happens to water when you boil or freeze it?
- According to Kate, when water is heated to a certain temperature (100°C/ 212°F) the hydrogen bonds break and it goes from a liquid to a gas state. Boiling for a minimum of 5 minutes kills any viruses and bacteria that were in the water.
- "Water is a freak and so it is one of my favorite molecules ever," Kate says. "It has these unique properties and we are surrounded by it constantly. We also are made of water. We have to drink water to survive...It's a really, really fun molecule to investigate."
Add some color to the internal structures and you've got some eye-popping imagery.
- By manipulating light refraction in organ tissue, it can be made transparent.
- Coloring internal structures is as "simple" as slipping dyes between tissue cells.
- A new method paves the way for fully 3D imagery of mature human organs.
As science dives deeper into the physiology of human organs, and in particular the human brain, it has become clear that viewing such organs in three dimensions and in microscopic detail is of critical importance if we're ever to understand how they work. Of course, organs are solid, and seeing what's going on inside them has proven a challenge to say the least. Now a new system, the SHANEL method, has been announced. It provides a practical solution for doing just this, and the glimpses it gives us inside the human brain and other harvested organs are stunning.
All of the videos below are by Zhao, et al.
Making tissue transparent
SHANEL addresses two problems. The first is transparency: You can't simply look through the tissue encasing and surrounding the structures we're interested in observing.
Scientists have attempted for some time to explore the brain by slicing it into thin sections. However, reassembling such sections into a 3D model can take years, and the final assemblage is likely to exhibit distortions introduced by the tissue-slicing process.
In the last 10 years or so, scientists have been refining a process called "optical clearing." Its goal is not to remove all the tissue hiding organs' secrets, but to make it transparent.
What causes tissue to be translucent, that is, not transparent, is light scattering. Tissue is made primarily of water surrounded by lipids and proteins, all of which refract light to different degrees. Using a refractive index (RI), for example, water has an RI of 1.33, proteins more than 1.44, and lipids more than 1.45. Together, light bouncing around these components render the tissue translucent.
Various optical cleaning methods have been developed that remove, modify, or replace tissue components using either solvents or water-based methods to normalize their RI values and "clear" the tissue in preparation for microscopy.
While progress has been made in clearing rodent organs and human embryos, say the developers of SHANEL, "Adult human organs are particularly challenging for this approach, owing to the accumulation of dense and sturdy molecules in decades-aged human tissues." In their announcement they report a case in which clearing even an 8 mm-thick slice of human brain took 10 months to clear, and another where 3.5 months were required to clear just a 5 mm-thick human striatum sample. Clearing entire organs or larger segments of them has been out of the question.
SHANEL stands for "Small-micelle-mediated Human orgAN Efficient clearing and Labeling," (we'll get to the labeling in a moment.) It uses a new, small micelle — a detergent aggregate of surfactant molecules in a liquid colloid — that can permeate centimeters-thick mammalian organs and clear them. A key ingredient of it is the zwitterionic detergent known as CHAPS. CHAPS' unusual chemistry contains a structure of both hydrophobic and hydrophilic faces, resulting in much smaller micelles that can permeate tissues more effectively than other detergents.
That final letter in SHANEL, as noted, stands for "Labeling," which is another problem that's vexed scientists and for which SHANEL provides a new solution. While seeing inside organs is a large part of the battle, another is developing a means of marking molecular structures so they can be differentiated from other components of the organs. This is generally done using a method called "permeabilization," that sneaks dyes and such between tissue cells to mark the desired objects. SHANEL's smaller, micelles greatly improves scientists' ability to reach and make desired targets visible in imagery, as the videos here show so dramatically.
Just the beginning
For now, SHANEL's inventors assert they can clear "human samples ranging from 1.5 cm thickness to whole adult human organs," adding, "We also show that the technology works on other large mammalian organs such as pig brain and pancreas." Going forward they expect to "pave the way for cellular and molecular mapping of whole adult human organs, including the human brain."
We imagine you agree they're already creating some pretty amazing imagery.
Scientists figured out how a certain treatment for skin cancer gives some patients a visual "superpower."
- In the early 2000s, it was reported that some cancer patients being treated with chlorin e6 were experiencing enhanced night vision.
- Using a molecular simulation, researchers discovered that a chlorin e6 injection under infrared light activates vision by changing retinal in the same way that visible light does.
- Researchers hope that this chemical reaction could one day be harnessed to help treat certain types of blindness and sensitivity to light.
In the early 2000s, it was reported that a certain kind of skin cancer treatment called photodynamic therapy, which uses light to destroy malignant cells, had a bizarre side effect: It was giving patients enhanced night time vision.An essential component to this therapy is a photosensitive compound called chlorin e6. Some people being treated with chlorin e6 were upset to discover that they were seeing silhouettes and outlines in the dark. Researchers think they might finally know why this happens.
The chemistry of vision
Rods and cones photoreceptors in a human retina.
Photo Credit: Dr. Robert Fariss, National Eye Institute, NIH / Flickr
"Seeing" happens when a series of receptors in the retina, the cones and rods, collect light. Rods contain a lot of rhodopsin, a photosensitive protein that absorbs visible light thanks to an active compound found in it called retinal. When retinal is exposed to visible light, it splits from rhodopsin. This then allows the light signal to be converted into an electrical signal that the visual cortex of our brains interprets into sight. Of course, there is "less light" at night, which actually means that light radiation is not in a domain visible to humans. It's at higher wavelengths (the infrared level) that retinal is not sensitive to. Hence, why we can't see in the dark like many critters can.
But the vision process can be activated by another interaction of light and chemistry. As it turns out, a chlorin e6 injection under infrared light changes retinal in the same way that visible light does. This is the cause of the unforeseen night vision side effect of the treatment."This explains the increase in night-time visual acuity," chemist Antonio Monari, from the University of Lorraine in France, told CNRS. "However, we did not know precisely how rhodopsin and its active retinal group interacted with chlorin. It is this mechanism that we have now succeeded in elucidating via molecular simulation."
"Molecular simulation" is a method that uses an algorithm that integrates the laws of quantum and Newtonian physics to model the functioning of a biological system over time. The team used this method to mimic the biomechanical movements of individual atoms – that is, their attraction or repulsion to one another – along with the making or breaking of chemical bonds.
"For our simulation we placed a virtual rhodopsin protein inserted in its lipid membrane in contact with several chlorin e6 molecules and water, or several tens of thousands of atoms," Monari explained to CNRS. "Our super-calculators ran for several months and completed millions of calculations before they were able to simulate the entire biochemical reaction triggered by infrared radiation." In nature, this phenomena occurs within fractions of a nanosecond.
The molecular simulation showed that when the chlorin e6 molecule absorbs the infrared radiation, it interacts with the oxygen present in the eye tissue and transforms it into reactive, or singlet, oxygen. In addition to killing cancer cells, "singlet oxygen" can also react with retinal to enable a slightly enhanced eyesight at night, when light waves are at the infrared level.
Now that researchers know why the "supernatural" side effect occurs, they may be able to limit the chance of it happening to patients undergoing photodynamic treatment. Thinking further out, the researchers hope for the possibility that this chemical reaction could be harnessed to help treat certain types of blindness and sensitivity to light.
Ultimately, researchers say that this has been a big flex for the power of molecular simulations, which can give us astonishing scientific insights like this.
"Molecular simulation is already being used to shed light on fundamental mechanisms – for example, why certain DNA lesions are better repaired than others – and enable the selection of potential therapeutic molecules by mimicking their interaction with a chosen target," Monari told CNRS.Don't hold your breath on night vision eyedrops though.
A recent computer analysis found that millions of possible chemical compounds could be used to store genetic information. This begs the question — why DNA?
- The central dogma of biology states that genetic information flows from DNA to RNA to proteins, but new research suggests that this may not be the only way for life to work.
- A sophisticated computer analysis revealed that millions of other molecules could be used to function in place of the two nucleic acids, DNA and RNA.
- The results have important implications for developing new drugs, the origins of life on Earth, and its possible presence in the rest of the universe.
Simply put, the so-called central dogma of biology asserts that genetic information flows from DNA to RNA to proteins, and once that information is passed to a protein, it cannot be returned as DNA or RNA again. It's dubbed the central dogma because it seems to be universal amongst all living organisms. There are some exceptions to the linear flow described in the popular version of the central dogma — information can be passed back and forth between RNA and DNA or between DNA and DNA or RNA and RNA, but the central players remain the same: DNA, RNA, and proteins.
But what if this didn't have to be the case? Could genetic information be stored in media other than the two nucleic acids of DNA and RNA? New research published in the Journal of Chemical Information and Modeling suggests that there might not be just a handful of alternative molecules for storing genetic information, but millions.
Millions of useful targets
The central dogma of biology asserts that the genetic information is transcribed from DNA to RNA, which then translates that information into useful products like proteins. This new research, however, suggests that DNA and RNA are just two options out of millions of others.
Analogues to nucleic acids exist, many of which serve as the foundation for important drugs for treating viruses like HIV and hepatitis as well as for treating cancers, but until recently, no one was sure of how many unknown nucleic acid analogues could be out there.
"There are two kinds of nucleic acids in biology," said co-author Jim Cleaves, "and maybe 20 or 30 effective nucleic acid-binding nucleic acid analogues. We wanted to know if there is one more to be found or even a million more. The answer is, there seem to be many more than was expected."
Cleaves and colleagues decided to conduct a chemical space analysis — in essence, a sophisticated computer technique that generates all possible molecules that adhere to a set of defined criteria. In this case, the criteria were to find compounds that could serve as nucleic acid analogues and as a means of storing genetic information.
"We were surprised by the outcome of this computation," said co-author Markus Meringer. "It would be very difficult to estimate a priori that there are more than a million nucleic acid–like scaffolds. Now we know, and we can start looking into testing some of these in the lab."
Though no specific analogues were targeted in this paper, it does present a long list of candidates to be explored for use as drugs for serious diseases like HIV or cancer. A more intriguing possibility suggested by the research is that life itself may have taken its very first steps using one of these alternative compounds.
Many scientists believe that before DNA became the dominant means of storing genetic information, life used RNA to code genetic data and pass it down to offspring. In part, this is because RNA can directly produce proteins, which DNA can't do on its own, and because it's a simpler structure than DNA. Over time, life likely started to opt for using DNA for storage due to its greater stability and to rely on RNA as a kind of middleman for producing proteins. But RNA on its own is still a very complicated compound and is fairly unstable; in all likelihood, something simpler came before RNA, possibly using some of the nucleic acid analogues identified in this study.
A galaxy of nucleic acid analogues
Not only does this shed light on how life may have started on Earth, but it also has implications for alien life as well. Co-author Jay Goodwin said, "It is truly exciting to consider the potential for alternate genetic systems based on these analogous nucleosides — that these might possibly have emerged and evolved in different environments, perhaps even on other planets or moons within our solar system. These alternate genetic systems might expand our conception of biology's 'central dogma' into new evolutionary directions, in response and robust to increasingly challenging environments here on Earth."
When we search for extraterrestrial life, often we're looking for signs of RNA and DNA, but this may be an excessively narrow scope. After all, if millions of alternatives exist, there would need to be something very special indeed for life to universally favor using just DNA and RNA.