Monica Sosa is an experienced scientist, but she can hardly believe what is happening in front of her. A small plastic cage was placed on the experimental platform in front of her. A few weeks ago, the mice in it were still semi paralyzed and had to drag two hind legs everywhere. Now, the mouse can run around and even jump like an acrobat. In fact, after the mouse was injured, Sosa gave it no treatment other than pain relief**
There is no definite precedent in this regard. Mammals, from small rodents to humans, are often unable to recover from severe spinal cord or other central nervous system injuries. But now it seems that the African spiny mouse is an exception.
In recent years, scientists have found that African spiny mice have extraordinary regenerative ability and can overcome serious injuries to skin, heart, kidney and spinal cord. This rodent, which is very similar to experimental mice, is mainly distributed in arid habitats in African countries such as Kenya, Somalia and Tanzania. No one expected this, including American scientists who found in 2012 that they could regenerate large areas of damaged skin.
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Monica Sosa, who studies nerve regeneration at the University of Porto in Portugal, and her colleagues recorded the extraordinary spinal cord repair ability of African spiny mice in a paper published earlier this year, "we were all stunned". Within a few weeks, the African spiny rats recovered from paralysis.
Besides mammals, a considerable number of species have the ability to regenerate important parts of the body. Regeneration is a special form of wound healing, which will more or less replace the lost tissue and avoid too many scars, so that the body parts with problems can work normally as before. For example, salamanders, flatworms, zebrafish and some jellyfish can regenerate relatively large and complex parts of the body. According to a study published in 2020, newly hatched alligators can reproduce their severed tails. However, from a genetic point of view, these animals are not as closely related to us as the African hairy mouse.
Many researchers believe that these regenerative animals may carry biological secrets, help open a new medical revolution and promote the treatment of severe limb trauma and degenerative diseases. In this field, researchers may make more than one breakthrough. Of course, we are not absolutely sure about this. The study of these animals raises ethical concerns because scientists must deliberately harm them to understand their reactions. After decades of research on some of these animals, scientists still haven't found a way to regenerate key parts of the human body.
The story tells how researchers discovered the extraordinary regenerative ability of African spiny mice and whether they can eventually help millions of patients with chronic failure.
It was 2011 and Ashley Seifert was still working at the University of Florida (now an assistant professor of biology at the University of Kentucky). He was standing in the garden of a retired veterinarian in Florida. The veterinarian, Elliot Jacobson, owns an outhouse full of pet snakes. However, Seifert is not interested in snakes. He was informed that Jacobson also owned a small group of African spiny haired mice. These animals are hard to get, although they are sold as pets in the United States. As early as the 1990s, Jacobson obtained these stinging mice from someone at the Phoenix Zoo and kept them all the time. Finally, he was happy to give all 40 African spiny haired mice to Seifert. These animals form the basis of Seifert's related research.
But Seifert was on a mission. A colleague accidentally mentioned the African spiny mouse in the conversation, which made him realize that this kind of mouse may have amazing abilities. There is a report circulating in academic journals that there is a strange mouse in Africa, which sometimes molts suddenly. What Seifert wanted to know was whether mice that could do this also had extraordinary wound healing abilities.
Seifert first came into contact with these animals in Kenya. During a local research trip, he managed to capture some individuals. Having never been in contact with the African hairy rat before, he soon found that even a very gentle grip could cause the animal's skin to fall off, along with the thick, spiny hair covered on it.
By observing the reaction of African hairy mice after their skin fell off and the recovery of their ear skin after being punched with a small hole in the control experiment, Seifert made some incredible discoveries: African hairy mice look full of vitality in the process of recovering from such damage. The wounds on their ears are not only healed by the formation of scar tissue, but go further and form new tissue including hair follicles, body fat and cartilage. After healing, the wound just lacks a layer of muscle.
"I was really shocked. Through the microscope, I could see new hair growing out," Seyfert recalled. He took skin samples from the African stinger and analyzed them in the laboratory. In the same study, Seifert and colleagues also found that the skin of African spiny mice was extremely fragile. They calculated that the skin strength of mice (MUS) species was 20 times that of African spiny mice. The team published the results of this work in 2012. After a glimpse of the regenerative capacity of the African spiny mouse, Seifert developed a more in-depth research plan and soon carried out the research using the research group obtained from Jacobson.
It was about a decade after Seifert's findings were published that a small number of other researchers became interested in African spiny mice. For example, a well-known paper published in 2021 describes how African spiny mice recover from severe kidney injury, which can lead to systemic organ failure in other mice.
The researchers speculate that the ability of African spiny mice to shed their skin is to avoid predators trying to catch them. However, the ability to regenerate in the wild may have other benefits, such as allowing them to tolerate a large number of parasites. Whatever the reason, the most surprising thing is that they have evolved this ability, which is rarely seen in other mammals. But in a recent unpublished study, Seifert found that a rodent closely related to African spiny mice - bristly mice - seem to have a similar ability to regenerate.
Since 2012, many scientists have carried out research based on Seifert's work. Their findings surprised Seifert. Sosa and his colleagues' paper on spinal cord regeneration in African spiny rats was particularly impressive: in their experiment, the spinal cord of about 10 African spiny rats was completely cut off; All but three individuals regained full mobility - even after a second spinal cord transection.
"I lost my chin because I can't believe they can recover like this after a complete cross cut," Seifert said.
It is worth noting that clean surgical incision may be easier to recover than spinal injury in field environment. In the wild, injuries to the spine and its surroundings may be more difficult to heal. However, the fact that axons - connections between nerve cells - appear to regenerate in African spiny mice is of concern.
Like Seifert, Sosa heard of the African spiny mouse by chance. A researcher from the University of Porto happened to describe their regenerative ability and mentioned that the laboratory of the University of Algarve had an African spiny mouse group about 550 kilometers away on the south coast of Portugal. Sosa sent some students to know the situation.
With permission, they made some incomplete cuts in the spinal cord of African spiny mice, but when they returned for examination later, they could hardly tell which individuals were injured because their tissues regenerated very well.
Obviously, the experiments described above are very invasive, and some people question the ethics of these studies. Notably, in Sosa's study, mice without short spines failed to recover from the same spinal cord injury.
In countries such as Portugal or the United States, scientists must be strictly approved by the ethics committee when doing such experiments. Sosa stressed that all experimental mice were given painkillers and that their overall health was taken into account at each experimental step.
"Sometimes people think that scientists use animals just to get the results they want - that's not the case." "In this experiment, the complexity of the spinal cord cannot be replicated by any cell culture or other model," she explained
Of course, the researchers who conducted experiments on living African hairy mice said that whenever possible, they also hope to develop cell cultures for such experiments, rather than using only live animals.
In defending such experiments, scientists often argue that such work could lead to life changing drugs or other treatments for millions of people. However, from the beginning, it was not clear whether this would happen. Therefore, a question worthy of consideration is: is there any precedent that animal regeneration research may promote, and how to promote medical progress?
It is undeniable that most of the work in this field is very elementary. Researchers are still trying to verify the cellular mechanisms behind the regenerative ability of different species. At present, scientists have made some crucial understanding. Take vitamin A as an example. Animals, including humans, can produce retinol and retinoic acid with the help of vitamin A, namely vitamin A. These substances seem to help some animals do some very incredible things.
Take sea cucumber whose intestines can regenerate as an example. A 2019 study showed that retinoic acid is involved in this complex process and seems to help zebrafish grow fins again. In fact, retinoic acid has been studied for decades and has been used in the treatment of various skin diseases, including psoriasis. Many scientists believe that there are still many deficiencies in our understanding of vitamin A, especially considering their role in the regeneration of some animals.
Then there is the example of islet cells. In patients with type 1 diabetes, the immune system attacks islet cells, preventing them from producing the right amount of insulin. Over the past decade or two, doctors have successfully transplanted islet cells from deceased donors to patients with type 1 diabetes. But studies in (spineless) mice suggest that in the future, we may be able to stimulate the pancreas to regenerate these cells. However, it is still unclear whether the method that proved successful in the African lancet will play the expected role in humans.
Regenerative animals can also promote medical research in other ways. According to a paper published in 2019, zebrafish can be used to regenerate spinal cord injury, so it can be tested as a drug for zebrafish to regenerate spinal cord injury.
"Some creatures do very well in regeneration," said Johnny king of the Max Planck cardiopulmonary Institute in Germany. "I've always felt that animals that can do this are very exciting."
Nevertheless, in the field of heart disease studied by Johnny king, he has not found any examples of new therapies that can be developed directly from animal regeneration mechanisms. "My personal view is that as a natural scientist, a scientist who studies basic science, it is very important to understand the natural and biological basis of other organisms," he said As for whether this knowledge will bring significant progress in medicine, that is the "second question".
Penny Hawkins, head of animal science at the Royal Society for the prevention of cruelty to animals, pointed out that some African spiny mouse experiments are invasive, but the results may eventually change medicine. She believes that funding agencies and research institutions should carefully evaluate the real impact of such research in order to minimize harm to animals. "Sometimes you find that such research lasts for decades," Hawkins said. "It's a moral question: to what extent do you think it won't actually benefit us?"
Matt Morgan, an intensive care doctor at the University of Wales Hospital in the UK, believes that scientists must weigh the reasons for conducting invasive experiments on animals. He believes that in general, as long as alternative methods can be used, including cell culture or simulation, this should be done. But he added that we have good reasons to explore various processes in nature in order to bring revolutionary changes to medicine.
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"We must focus on future breakthroughs. Coronavirus disease has shown us this," Morgan said. He was referring to the success of the mRNA vaccine, which was developed on the basis of decades of basic research.
Johnny King praised some of the research done so far using the African hairy mouse. A paper published in 2021 showed that this rodent can regenerate some heart tissue after a heart attack, "the quality of this work is very excellent".
The study was carried out by Kerstin bartscheler of the Institute for developmental biology and stem cells in hubricht, the Netherlands, and his colleagues. They surgically created artificial blockages in the arteries of African hairy mice and mice. Like Sosa's experiment, all experimental animals were given painkillers and carefully observed. Blockage of arteries leads to heart attacks and scar tissue formation in African hairy mice and mice. However, although the heart pumping activity of African hairy mice decreased, the situation improved over time, while the mice deteriorated.
After examining the hearts of these African spiny mice, the researchers found that although these organs did not regenerate in a real sense, the scar tissue on them did have large blood vessels filled with blood. This result is very unusual. There will be no similar situation in the human heart. It seems that this seems to be the key to the recovery of African spiny mouse. The animals later looked quite healthy, running around in their cages as usual, or doing back somersaults, bartscheler said.
"The question is, why do African spiny mice have unusual scar characteristics? Why do they produce new blood vessels?" "We don't know why," she added.
Now, scientists studying African spiny mice are eager to find out how they repair or regenerate all these different tissues in vivo. Among them, the work of Chelsea Simmons of the University of Florida and others shows that the immune system of African spiny mice operates slightly differently from that of humans, which enables them to alleviate or delay the outbreak of inflammation after severe trauma, which may help to promote tissue regeneration.
Simmons pointed out that African spiny mice heal wounds very quickly, which may lead to the fact that they will not form too much (or no) scar tissue, but will regenerate the missing parts of the body. Simmons and Seifert believe that macrophages play a role, but it is still unclear what led to this result. Macrophages devour invading bacteria and help control the immune response to damaged tissues.
Unlike humans and many other animals, when African hairy mice are injured, they seem to deploy only certain types of macrophages that contribute to wound healing without causing excessive inflammation and scar tissue formation. "Macrophages are the main coordinator of increased and decreased inflammation," Seifert explained. "They are like commanders during inflammation."
However, many other things can happen during regeneration. For example, Sosa and his colleagues found a special enzyme in spinal cord regeneration in African spiny mice, but they still don't know which cells or which cells express the gene.
Inspired by the African hairy mouse, solving these complex puzzles is an important step in the development of human regenerative medicine. However, whether it will succeed or not, the study will take time. Media hype about early animal research often angers scientists because media articles often fail to make it clear that the potential therapies so far have worked only in mice and not in humans. "Scientific progress is sometimes so slow that it's hard to know whether the public is ready to understand it," Seifert said.
A review in 2018 found that research on the regeneration of non-human species has made "great progress", but there is still a distance to develop new medical therapies based on this work.
Although the road to developing revolutionary drugs or therapies based on the study of African hairy mice may be long and uncertain, Simmons believes that this possibility is too important to ignore. Because once successful, it is enough to change the lives of many people. This possibility will also bring hope to countless people. And when we go down this path, we will make really amazing biological discoveries from African spiny rats.
"Something happens at the cellular level, causing different organs or tissues to have some unusual reactions," Seifert said. "It's fascinating." (Ren Tian)