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?

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