Elly Tanaka: "Salamanders are extraordinary creatures"

Cardiac regeneration is currently one of the greatest challenges facing scientific investigation. Unlike other animals, such as the salamander or the zebra fish, human beings are incapable of regenerating their tissues and organs, but scientists do not know why. Elly Tanaka, of the Research Institute of Molecular Pathology in Vienna (Austria), spoke on this subject during the CNIC Conference, 2022. For years, Tanaka has been fascinated by the highly regenerative capacity of Ambystoma mexicanum, commonly called the axolotl. “All species of salamander that have been studied appear to be capable of regenerating their limbs,” she affirms.

In the future, will it be possible to regenerate the heart after a heart attack?

Making predictions is always tricky, but we are on the right track.

Are humans so different from salamanders?

I have always been fascinated by salamanders because of their capacity to regenerate. Salamanders are extraordinary creatures. If they lose a digit, they can regenerate it. Likewise, if a piece of their heart or their spinal cord is cut, they can regenerate it. Specifically, my laboratory is working on axolotls, salamanders that live in the lakes of Mexico City. At first, we observed that they were able to regenerate their limbs, but recently, as we published in Nature, we have seen that they also regenerate their internal organs like the heart and brain. 

How can the information provided by your group serve to advance in the regeneration of tissues and organs in humans?

The data we obtained are really important for ongoing research into organ regeneration in humans. Recently, we have seen that stem cells from axolotl brains are similar to the stem cells we encounter in the brains of mammals. We have also identified special genes that are activated in the stem cells of axolotl brains. In future, we’re going to investigate whether we can activate these genes in mice, and -why not?- in humans, and inactivate genes that are not related with regeneration. Humans and mice have these genes; now we have to see which genes are active or not in humans.

In the last 10 to 15 years, we have been able to understand that rat and human muscle cells regenerate in a similar way to those of salamanders and now, the specific factors that make these cells able to proliferate have been identified

Whereas the skin and many other tissues of the human body retain the capacity to repair themselves after a lesion, the same is not true of the heart. What can be learned from these other tissues?

That is a difficult question to answer. We are studying, and it is possible that humans have a larger number of cells that block regeneration than axolotls do. The point is that we don’t know why. One hypothesis is that the axolotl and other salamanders have a different regeneration mechanism to humans, whereas in mammals the mechanism is more related with survival. One of the ways would be to identify and characterise the cells involved in regeneration and attempt to modify them.

Cell therapy and gene therapy are two approaches to the regeneration of the heart that have been tried for some time without successful outcomes. Why?

In the 1970s, the then President of the United States, Nixon, declared war on cancer in the USA and now, more than 50 years later, we have therapies that are very effective against cancer. I hope that within the next 10 or 20 years something similar will have happened in cardiac regeneration which will revolutionise the field in the same way, for instance, as has occurred in immunotherapy for cancer. Of course, the immune system is very important in this aspect, and we see that in animals that are capable of regeneration, in some way the immune system cells help regeneration, whereas in mammals these cells do not seem to help. We have to understand this balance between immune cells.

Although the possibility of a person regenerating an arm or a leg belongs in the realm of science fiction, do you think that salamanders can offer us a new perspective to improve the treatment of human lesions?

We hope so. There are laboratories devoted to studying the spinal cord. My team is working with cultures of mammalian cells to analyse regeneration patterns. I think that the results we are obtaining with salamanders are going to be of great use, not only for spinal cord regeneration.

Is the salamander the most important animal in the field of regeneration?

These amphibians fascinate me. For instance, in the field of heart regeneration, over 50 years ago, the salamander was the first animal in which it was proved that cardiac muscle cells have the capacity to regenerate the heart. For years, investigators have searched for cardiac stem cells, but the results have been very confusing. Recently, in the last 10-15 years, we have been able to understand that the muscle cells of mice and humans regenerate in a similar way to those of salamanders and now, certain factors have been identified that allow these cells to proliferate. And all of these ideas come from studies on salamanders. What we are learning from the salamander is key information to understand what might happen in humans. It is a model that shows us the right path to follow.

You group participates in REANIMA (New-generation cardiac therapeutic strategies directed to the activation of endogenous regenerative mechanisms), the project coordinated by CNIC’s Miguel Torres. What is the purpose of this project?

REANIMA is a group of research scientists working on cardiac regeneration from different approaches. The idea is to identify the molecules in different models and be able to compare them between the various research groups. Soon we will have results, with publication in the medium term. The good thing about this group is that we work on different models, from the smallest, like the zebra fish or the salamander through to mice, pigs and humans.

What we are learning from the salamander is key information to understand what might happen in humans. It is a model that tells us what the right path is

The European-funded RegGeneMems project ends in 2023. What could the results be?

If we want to progress in the bioengineering of human tissues in the future, we have to try to regenerate a larger limb; I mean, when we regenerate limbs in an embryo, they are very small, but if there is an amputation, we need to do it with something larger. This project is about understanding how an adult salamander is capable of regenerating one of its limbs. We know that it uses the same components as an embryo and that the cells need to communicate with each other. The difference is that, in an embryo, the distance between cells is very small; however, in the case of adults, the distance between cells is much greater. What we have seen is that somehow, in larger animals, the factors that these cells use to communicate with each other are able to do it over greater distances. Animals have the capacity to use these factors, even at longer distances. And that is what we are trying to ascertain. How does this happen? The idea is to understand how these factors are capable of communicating over long distances.

But humans have this capacity to generate during their first days of life. So, do we lose the capacity for communication between cells and factors?

Yes, distance is clearly one problem that makes communication difficult, but there are other hurdles. For instance, mammalian cells do not have the capacity to activate these communication molecules because after the first moments of life they are not necessary, therefore the factors deactivate. So, whereas axolotls can reactivate it, this does not happen in mammals.