Scientists are about to find a way to put humans into hibernation; Maybe this is the only way for humans to reach Mars.

One day in 1992, neuropharmacologist Kelly Drew was working in a laboratory at the University of Alaska Fairbanks near the North Pole when his colleague Brian Barnes, a professor of animal physiology, changed the course of his life and possibly humanity forever. Gave Barnes told Drew to reach out and brace himself for an exciting surprise. A few moments later, a sleeping arctic squirrel was in Drew’s hands. This squirrel was tightly curled up like a bullet, and its body was so cold that Drew thought it was dead, But Barnes happily told him that the frozen squirrel was in perfect health.

The polar ground squirrel, which had settled in the palms of Drew’s hands, had fallen into hibernation. This small animal, which holds the record for the longest hibernation, spends eight months of the year in hibernation, and during all this time, the internal temperature of its body reaches below minus 3 degrees Celsius; His brain waves become so weak that they are barely noticeable, and his heart beats only once per minute. However, it is completely alive and healthy, and with the arrival of spring, it can raise its body temperature to 37 degrees in a few hours and resume its normal life.

On that fateful day, a big question stuck in Drew’s mind; What is going on in the brain of the polar squirrel that allows it to survive in these harsh conditions? And this question started thirty years of research to bring humans a few steps closer to achieving hibernation and reaching Mars.

The big problems of traveling to Mars

Currently, three major organizations, including NASA, China National Space Agency, and SpaceX, are in a breathtaking competition to send the first human to Mars by 2040; But to win this competition, they need to solve a series of challenging problems first.

The most important problem facing the engineers who are trying to open our feet of us humans to the red soil of Mars is that we need a lot of care and maintenance. We, warm-blooded animals with high-functioning brains, burn large amounts of food, water, and oxygen during the day to survive. This high consumption makes it extremely difficult to design a light spacecraft suitable for a round trip to a planet 226 million kilometers from Earth. . By examining the eating habits of the astronauts of the International Space Station, it can be estimated that a four-member crew needs at least 11 tons of food to complete the 1100-day round trip mission to Mars. The weight of this food alone is about ten times more than that of the Perseverance rover, the largest cargo ever to reach Mars. Now, to these 11 tons of food, add all the other essentials, including the equipment needed to settle on Mars, so that the weight of a spacecraft when it leaves the Earth’s atmosphere for Mars is easily more than 330 tons, that is, more than the weight of two blue whales. Mature, go beyond. As you read this, it’s impossible to imagine where such a gigantic spacecraft will get the fuel it needs to make the round trip to Mars.

If you’ve read Arthur C. Clarke’s science fiction novels or at least seen Stanley Kubrick’s “2001: A Space Odyssey,” you can guess the solution to the spacecraft’s weight problem; That we need to reduce the crew’s metabolism to such an extent that they only need to use minimal resources during their 1,100-day journey. In the movie Space Odyssey, we see astronauts hibernate in coffin-like chambers, and in this state, their hearts beat only three times per minute. Their body temperature is slightly below 3 degrees Celsius.

John Bradford, one of the chief executives of SpaceWorks, the Atlanta-based engineering firm that manages NASA’s ambitious research projects, has devoted a large part of his 21-year career to answering the question of what allowed Kubrick as an artist. Ignore it in his film; How exactly can we safely “shut down” the human body so that it is only one step away from death and then be able to revive it whenever we want?

In search of answers

In the first days of his research, Bradford thought of hypothermia therapy as a way to turn off the human body. Hypothermia therapy is a medical technique that lowers the body temperature of people who have suffered a cardiac arrest, usually by injecting cooling fluids to 32 degrees Celsius. As the internal temperature decreases, the body’s metabolic rate decreases to such an extent that the cells can continue to work with approximately 30% less energy and oxygen, thus giving the damaged tissues a chance to repair.

Patients are usually only kept hypothermic for a day or two, as the cold causes severe shivering that can only be controlled with sedative injections and strong neuromuscular blocking drugs. However, Bradford was able to identify a few rare cases in which patients remained hypothermic for up to two weeks. This issue sparked this question in his mind: Why can’t we keep the human body in hypothermia for more than two weeks, and how long can we keep the coma?

In 2013, Bradford convinced NASA’s Advanced Innovative Concepts to fund a project to make human hibernation possible. Bradford told them that if the astronauts could be kept frozen for most of the trip to Mars, their vital resources could be reduced by 60 percent. He also hypothesized that hibernation could protect astronauts from serious physical and mental harm, from harmful radiation to the psychological dangers of isolation and extreme boredom.

A drug that suppresses shivering stops breathing

But a fundamental problem was still there; Medicines used to stop shivering frozen people also stopped them from breathing. Thus, sleeping astronauts must breathe through tubes inserted into their trachea for weeks or months. In addition, using the serum to inject fluids into the body was frightening because the syringe needle increased the possibility of infection in astronauts.

The ideal and dream way to solve this problem was to use a pill to fall into a long sleep and be able to breathe without the need for a tube. Although this extraordinary method seems science fiction, some aspects of it were familiar to Bradford; Because many animal species go to sleep for a long time every winter, and in the state of unconsciousness, their body’s desire for food and oxygen is greatly reduced. When these animals return to their alert state in the spring, they show no signs of muscle atrophy, malnutrition, or other diseases caused by prolonged immobility. Bradford concluded that it is possible to discover the secret of their hibernation by observing and examining these animals.

The beginning of NASA’s hibernation research

And so it happened that Bradford went to the very small community of hibernation researchers, Scientists who had devoted most of their lives to the study of bears, bats, and lemurs, whose hibernation was an essential part of their survival. Their research focused on the molecular changes of these hibernating animals and the reduction of their body metabolism. Since many hibernators are genetically close to us, it is possible that by changing our brains and bodies, we can also hibernate.

By the time Bradford decided to enlist the help of hibernation researchers, Kelly Drew of the University of Alaska had been researching the arctic ground squirrel for more than 20 years. When Bradford first contacted him in 2015, Drew had just made a major discovery and taken the critical first step toward giving humans the power of optional on/off.

When his colleague Brian Barnes put a frozen arctic squirrel in his hands, Drew began studying this animal using the microdialysis technique. In this procedure, small tubes are placed under the living creature’s skull to sample the brain’s neurochemicals, and usually, a wound is created where the tubes enter the skull. However, Drew was amazed at the absence of scarring in the sleeping squirrels after microdialysis. This gave him the idea of the protective properties of hibernation. “Hibernation seemed to protect the brain from damage,” he says.

The discovery of the protective properties of hibernation in animals made Drew’s research more vital in finding a way to induce hibernation in humans.

The main obstacle to the realization of winter sleep in humans is the heart’s sensitivity to rapid temperature changes.

During his time in Fairbanks, Hauck became fascinated with the study of bears. In 1960, he published a paper entitled “Possible Use of Hibernation in Space Travel,” in which he pointed out, for the first time, in precise and scientific detail how the fledgling US space program could benefit from his research. Huck said in this article that winter sleep is just a few steps away, and the main obstacle to its realization is the sensitivity of the human heart to rapid temperature changes.

Hibernations have learned how to overcome this sensitivity, and several labs are currently investigating ways to implement this in humans.

In this article, Hawk also mentioned the potential of hibernation to slow down the aging process.

Because they use much less energy during the year, hibernators live longer than mammals of the same size that do not hibernate.

Hawk estimated that if humans, like bears, could keep their internal body temperatures about 13 degrees cooler than normal, “the aging process would occur at half the normal rate.”

In the early 1960s, Hawk and his colleagues exposed a species of large squirrels called marmots that were hibernating to sudden extreme cold. They discovered that marmots’ brown fat, also present in the human body, produces heat in response to this extreme cold. Hawk research team concluded that brown fat, which warms the body by burning energy stored in cells, could be the secret to humans surviving in the frozen state of hibernation.

But Hawk died in a tragic accident in 1970, and as the Cold War got colder, hibernation research fell out of fashion. With the Pentagon and NASA cutting off funding for this research, biologists looked at hibernation as a field without a future. And since it takes a year to collect data on an animal’s hibernation cycle and compare it to their normal physical activity, research in this area is painfully slow.

However, Kelly Drew was so fascinated by the arctic ground squirrel that he dedicated several decades of his life to research on animal hibernation.

The beginning of the fateful experiments of Kelly Drew for Human hibernation

Every summer, Drew pitched a tent in the northernmost part of Alaska, called the North Slope, to trap arctic squirrels for his laboratory. The US Army Research Office funded his research; Because Drew had convinced them that the results of his research could be used to save severely injured soldiers by quickly and safely cooling their bodies on the battlefield. He told the military organization that he plans to identify the chemicals involved in hibernating arctic squirrels and then test whether these chemicals would have a similar effect on humans.

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Drew, who became an assistant professor at the Arctic Biology Institute in 1993, originally hypothesized that the neurotransmitter gamma-aminobutyric acid, known as GABA, was primarily responsible for hibernation in squirrels. GABA is essential for inducing sleep; It means the lowest level of metabolism for animals that are not able to hibernate. For example, our human metabolism typically drops by 15% when we sleep. On the other hand, hibernation, in all its complexity, is just a deep sleep; It means a state in which breathing is reduced, and appetite and elimination of waste materials are prevented. For example, bears do not defecate or urinate throughout their hibernation.

However, when Drew injected his squirrels with GABA and a host of related chemicals, they did not induce long-lasting, stable hibernation. Years passed like that, and by the time Drew celebrated his 40th birthday, his efforts to find the molecular key to hibernation had largely been fruitless.

In 2005, an undergraduate chemistry student named Benjamin Warlick started working as an assistant in Drew’s lab. One of Warlick’s tasks was to search the databases for new ideas about chemicals that might trigger hibernation in ground squirrels.

Among the papers Warlick found on hibernation, he came across an unknown paper from Japan’s Fukuyama University on golden hamsters that, although written entirely in Japanese, had a brief abstract in English. In this paragraph, it was mentioned that the article’s authors managed to wake up the golden hamsters from hibernation by injecting a drug that blocks the adenosine A1 receptor in the animal cells. Although the paper’s findings contradicted Drew’s research, Warlick sent it to his boss because he thought it was valuable.

Two years passed before Drew could send the entire article for translation. When he finally read the English version of this article in 2007, he had an idea. If blocking the adenosine A1 receptor (responsible for promoting sleep) wakes sleeping hamsters, perhaps activating them in its squirrels causes them to hibernate.

The key to the mystery of hibernation was in an unknown paper in Japanese.

And that’s exactly what happened; When Drew injected his squirrels with the adenosine A1-stimulating drug CHA, the squirrels’ body temperatures quickly dropped, and they went into hibernation. Of course, this happened only when the CHA drug was injected into them in the winter months. Therefore, there must have been something else going on in the brains of squirrels that prepared them for hibernation.

Although Drew was surprised by the effects of CHA on his squirrels, there were two major problems with using the drug; First, it had to be injected directly into the brain, which, well, sticking a needle into the human brain is rarely recommended, especially if it’s in a non-hospital setting. Second, when CHA enters the body, it engages the A1 adenosine receptors of the heart and slows down its heartbeat so much that it eventually stops beating. Consequently, using CHA in humans seemed possible only in very limited cases.

Now, almost 20 years have passed since the day Barnes put that frozen squirrel in Drew’s hands and planted the seeds of hibernation research in his mind, and Drew still hasn’t found a safe and effective way to induce hibernation in humans.

But then he came up with another idea: to mix CHA with another drug that would block its effect on the heart but still involve the brain. CHA is of the “agonist” type, which stimulates the receptors. But the medicine that blocks the nerve receptors is called an “antagonist.” Drew realized he needed an antagonist for adenosine A1 whose molecules were large enough to cross the blood-brain barrier (BBB).

Drew explains how agonists and antagonists behave in the body like this:

If you think of the body as a color map, so that the agonist is red, then red is spread throughout the body because it is stimulating all the receptors. We don’t want this agonist to stimulate cardiac receptors, So we need something to block these receptors. Now suppose the antagonist is blue. We add this to the body, but it’s not supposed to reach the brain. As a result, the whole body turns purple; But the brain is still red.

Adenosine A1 antagonists had been extensively researched, so Drew had several viable options. Finally, he chose the antagonist 8-(p-sulfonyl)theophylline, known as 8-SPT, which is closely related to one of the main ingredients of black tea. Drew decided to inject the 8-SPT and CHA into the abdominal area and conducted several experiments on mice to test the effectiveness of this combination.

The combined drug CHA/8-SPT induced hibernation in mice without complications.

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In these experiments, Drew stopped the heart of mice from moving and then brought them back to life by applying CPR. Once the mice were freed from death, one group was given the CHA/8-SPT combination drug, and the other group was left alone to allow their body’s metabolism to repair them at its normal rate. By conducting these experiments, Drew noticed that the mice that received the CHA/8-SPT combination had a better health status than the second group. And perhaps more importantly, the mice in the first group did not develop complications despite receiving the drug. There was no sign of shivering in these mice, and therefore there was no need to inject them with a sedative that would cause problems in their breathing.

Achieved on mice, patented the technique of using the CHA/8-SPT combination drug under the title “Methods and compositions for treating tissue damage by hypothermia”; And the first image he put on his patent form was that of a sleeping arctic ground squirrel, actually a reference to that small but fateful moment in 1992 that changed the course of his life forever.

How did Drew’s research reach NASA?

Familiar with science fiction films such as A Space Odyssey and Planet of the Apes, Drew vaguely knew that his research might one day attract the attention of the space exploration industry. Therefore, he was not surprised when he was contacted by NASA Spaceworks in February 2015. The company had just received funding to advance human hibernation research, and John Bradford invited Drew to join Spaceworks as a senior hibernation consultant.

Drew accepted Bradford’s invitation and soon began testing the CHA/8-SPT combination drug in pigs with anesthesiologist Matthew Kumar. The drug safely lowered pigs’ internal temperature to 30 and 32 degrees, not as much as doctors lower body temperature by intravenous fluids, but close enough.

Meanwhile, University of Colorado biologist Sandy Martin was also researching hibernation. Martin remembers those days:

I thought to myself that what we should do is understand how hibernating animals do this so beautifully and naturally without the slightest harm to their bodies. They don’t even need to use tubes for breathing and feeding.

Martin and his daughter began working on their paper, suggesting several promising avenues for research based on Martin’s genomic analysis of the leopard ground squirrel (a close relative of the arctic ground squirrel). One of the proposed methods was to further investigate a receptor called TRPM8, which plays a very important role in helping leopard squirrels regulate their body temperature during hibernation.

NASA could start injecting CHA/8-SPT in humans as early as 2026

In March 2018, NASA invited Drew, Martin, and a handful of leading hibernation researchers to attend a two-day conference in Mountain View, California; The event was named the first “Space Sleep Workshop.” This conference was a golden opportunity for biologists to convince NASA that with enough funding, they could help humans achieve some degree of hibernation in the next 10 to 15 years. Their timeline matched well with NASA’s plans to send humans to Mars in the late 2030s or early 2040s.

Speaking to NASA officials in this workshop, Martin emphasized that the frequency of hibernation among mammals shows that humans can also achieve it. There are three types of mammals in the animal world: egg-laying monotremes, such as platypus; Marsupials that raise their babies in pouches attached to their bodies, such as kangaroos; And finally, the group of couples that includes us, humans. Martin says:

In all three categories of mammals, there is a species that can hibernate. The simplest explanation for this is that the common ancestor of all three of us was hibernating.

Assuming Martin is right, then all we need to do to deal with humans’ physiological stresses of hibernation is a small genetic change.

Now, NASA accepts that hibernation is critical to making the spacecraft lighter and accepts Bradford’s view that hibernation can solve some of the physical problems astronauts face during long space trips.

Drew is now 63 years old and can’t believe he has spent nearly half his life figuring out the secret of squirrel hibernation. But thanks to the academic research of researchers like Drew, the private sector has also realized the potential of this field. For example, Silicon Valley startup FaunaBio aims to improve treatments for heart and lung diseases by discovering why hibernators survive in stressful conditions that are fatal for most humans.

Hibernation won’t just be for astronauts

If hibernation can one day become a realistic option for humans, even normal people who are not planning to travel to the Red Planet or are in good health could reap the benefits of a long sleep. Earlier this year, a group of UCLA researchers concluded that “the molecular and physiological responses required for hibernation in humans may reverse the aging process.”

Via: Wired