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One lost garden leads to one whole branch?

New research reveals how mice of a certain breed are able to regrow their limbs. Will we be able to complete missing body parts in the future?

An image that won fourth place in the Worcester Institute's scientific photography competition
An image that won fourth place in the Worcester Institute's scientific photography competition
They were first discovered fourteen years ago: the mice capable of regrowing their limbs. This week the understanding of how they do it was received for the first time, which may lead to practical applications in humans as well. Will we be able to complete missing body parts in the future?

In 1996, a routine scientific experiment was conducted on a group of laboratory mice. As part of the experiment, the researchers marked the mice so that they could differentiate between them, and for that they pierced small holes in the earlobes of the mice, in a routine procedure that is less painful than piercing a hole for an earring in the human earlobe. After a few weeks, when the researchers wanted to check how the mice were affected by the treatment, they discovered to their surprise that they were unable to differentiate between the marked mice and the unmarked ones, because the holes in the mice's ears had completely fused.

This phenomenon has not been previously recorded in mice, and is different from the recovery process that occurs in most mammals. When we are injured, scar material is secreted in the injured area, which supports the damaged tissue but does not restore its abilities. A damaged mouse heart will never fully recover, just like the human heart, and many of us carry pale scars on our skin - evidence of past injuries. How, then, did that small group of lab mice manage to completely restore their ears? This was the question that occupied a number of laboratories around the world, who studied the unique mice that were called healers - 'healers'.

The first clue to solving the mystery came from the insight that those healing mice are mutants, in which the gene known as P21 has been damaged. This gene is one of many that control the cell division cycle. When a normal cell wants to replicate itself and divide into two new cells, it first of all makes sure that its DNA is normal, and not damaged by the effects of radiation or particularly problematic mutations. This test is important, because DNA contains the cell's operating instructions. If the DNA is damaged for some reason, the cells formed after division may become cancerous and form a tumor inside the body. For this reason, P21 is one of the genes that checks that the DNA is in order before division. If the DNA is not normal - P21 stops the whole process, and sometimes also tells the cell to commit suicide. In the preventive war against cancer, you can never be too sure.

When the healing mice are injured, their defective P21 gene is unable to stop cell division. The cells in the area of ​​the injury do not form scar tissue, but a structure known as a 'blastema', which usually appears in amphibians after an injury. The cells in the blastema divide at a rapid rate and undergo changes that help them replenish the tissue with cells of the right type and in the right location. In this way, the healing mice are able to complete their ears, renew the cartilage in their joints, and even partially regrow severed fingers.

It is known, therefore, that the P21 gene is defective in mice endowed with an extraordinary healing ability. But is this gene responsible for the ability to heal, or maybe it's just a coincidence? To find the answer, the researchers created genetically modified mice, in which the P21 gene is silent, similar to the original healing mice. The genetically engineered mice were also able to restore the ear tissue after it was perforated, thus proving that the paralysis of the P21 gene does indeed provide the mice with an extraordinary ability to heal. These results were published last week in the prestigious scientific journal PNAS. It is interesting to note that similar mice were already created in previous experiments in other laboratories, but until now the researchers did not attach importance to the fact that those mice are able to heal the holes in their ears.

Apparently, the healing mice were a blessing, but isn't there also a curse on the side? After all, P21 is supposed to protect the cells from cancerous division. Doesn't its absence increase the risk of cancer? Surprisingly, it seems not. Although in the mutant cells there is an expected increase in the damage caused to the DNA, these mice do not suffer from cancer more than other mice. In fact, the researchers actually saw an increase in the number of cellular suicides. Professor Helen Haber-Katz, who is responsible for the research on the healing mice, believes that this is exactly the process we see in creatures naturally endowed with the ability to self-heal, such as amphibians. In these creatures there is an increase in the rate of cell division, side by side with the suicide of some of the new cells, and this mechanism allows them to regenerate their organs without getting cancer during the process.

This is all well and good in mice, but can the results in the laboratory be translated to human benefit? If we had asked the question twenty years ago, the answer would have been negative, because we would have had to genetically engineer an entire embryo from the moment of fertilization, in order to achieve complete paralysis of P21. But science is advancing rapidly, and in the late nineties a new method was discovered to control gene expression in cells, using small molecules called siRNA. These molecules are designed in advance, and if they are inserted or produced inside the cell, they are able to temporarily immobilize the gene against which it was produced. Only recently, an Israeli researcher developed 'nano-submarines' - tiny fatty globules capable of locating individual cells in the body and injecting siRNA molecules into them. It is possible that in the future it will be possible to use a similar invention in humans to immobilize P21 in cells in the area of ​​injury. If such a procedure succeeds in causing the wounds to heal, the cartilage to regrow and the heart muscle to recover, we will have another small victory for medical science - and a big victory for hundreds of millions of patients around the world.

Link to the original scientific article
Link to the news release
Link to the article about the siRNA molecules

9 תגובות

  1. The main problem is that mice do not spontaneously develop cancer, so nothing can be concluded about the significance of p21 paralysis and cancer risk.

  2. It says "P21 is supposed to protect the cells from cancerous division. Does its absence not increase the risk of cancer? Surprisingly, it seems not"
    Hence, whether he is asleep or not, it does not matter even that he is one of the genes that check that the DNA is correct before division, and perhaps luckily for us it is because he is only "one of them" and the rest of the genes complete the task.
    And if it is a gene that can probably be discarded, wouldn't it be worthwhile in the evolutionary process to prioritize the restoration of the organs over its not so important role? But apparently those evolutionary branches did not succeed for one reason or another that should be ascertained or their turn to grow has not yet come and it is the role of science to direct us up those branches and create evolution ourselves.

  3. 1. "In a routine procedure that is less painful than piercing a hole for an earring in the human earlobe"

    May I ask on what basis they determined this?

    2. Is it possible to get clarification regarding the attached photo? A photo of what? And how does this relate to the article?

    Thanks in advance.

  4. I did not understand what the illustration on the left has to do with the content of the article

  5. What is interesting is that P21 is supposed to stop cell division if the DNA is damaged but its paralysis does not increase the chance of cancer, it is written that there is even a high number of cell suicide even when this mechanism is not active, so what actually causes them to commit suicide if the mechanism responsible for it paralyzed?

    Is it really a net profit when the garden is paralyzed? And if it is about profit then the question raised above regarding natural selection is very relevant.

  6. I estimate that the gene has important effects on mammals at least (if not also on reptiles and birds) the more complex the genome, the higher the chances of "replication errors".
    I assume that even the local and controlled treatment that Roy mentioned can have unexpected results

  7. There is no such thing as a "P21 gene with a negative contribution" a gene has an effect .. in relation to the environment and other genes it can have a negative effect on the statistical total .. but sometimes it helps

  8. Age, if the gene is permanently silenced (damaged) it probably causes a high increase in the amount of mutations in the daughter cells, most of which are harmful to the daughter cells and in these cells it is found. Second: the defective gene allows the division of cells that have mutations and as a result, it finds itself in cells with a genetic defect, which probably cannot survive, in most cases (most mutations are harmful and not beneficial). These mutations greatly reduce the survival of these daughter cells and also the continued existence of the said defect in the gene. The result of all this is that a gene with such a defect cannot spread in the population because of the (indirect) damage it does not prevent in the daughter cells.

  9. If the P21 gene has a negative contribution, how did it survive all evolution until today.
    According to the laws of natural selection, the gene was supposed to deteriorate and stop functioning.
    When the generation of the defective gene has a better ability to heal and survive.

    This is not about changing the gene to a more suitable form, these are only about a defect that will cause it to stop functioning.

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