The study of how organisms evolved and diversified, called phylogeny (phylo = race or kind and gene = origin), may bring up memories of sitting in biology class looking at elaborate tree-shaped diagrams and incomprehensible latin labels. But there is so much more to it. If we take a closer look, it becomes clear that phylogenetics can be an extremely useful tool for uncovering the secrets of regenerative capability and directing our search for regenerative medicine strategies.
Phylogenetics was first developed in the 19th century as a way to group all living beings according to shared traits. At the most basic level, phylogenetics can take one or more morphological characteristics (e.g., vertebrates versus invertebrates) and use them to construct a tree based on whether or not the trait is present in different species or groups. It can help to answer questions about long extinct ancestors of today’s species and determine the evolutionary pathway that led to the present diversity. While traditional phylogeny is largely obsolete, with the advent of molecular techniques for characterizing the genome it has become a powerful tool for studying differences in functional molecular profiles.
What does all of this have to do with regenerative medicine?
Researchers have documented regenerative ability across the animal kingdom and designed a phylogenetic tree. If we look at the most extreme form of regeneration in vertebrates, replacement of a whole appendage or tail, we see that this actually emerges frequently in many groups. Amphibians such as salamanders, newts and axolotls display an impressive ability to replicate near-perfect copies of their limbs if amputated, but we also see tail regeneration in lizards, who are our nearest regeneration-competent relatives.
It is curious, however, that looking within these groups shows that not all species of a group can regenerate. For example, some lizards can regenerate a tail, whereas other species of lizard cannot. Why is this? Did the common ancestor of all lizards have the ability to regenerate, and then this trait was lost in some subsequent species? Or did regeneration arise separately within different lizard groups, but was not present in the common ancestor?
By looking at which species can regenerate and which cannot, we can make inferences about why this ability was lost or gained during evolutionary history. Some researchers have suggested that it’s all about tradeoffs: regenerating a full appendage takes a huge amount of the body’s energy and resources, so if there is no evolutionary advantage to re-growing it, it is unlikely to evolve.
Another example of a trade-off is the interesting link between the immune system and regenerative capability. Mammals are unable to regenerate multi-tissue structures and instead form a scar after injury. But studies comparing the mammalian immune system and that of amphibians have shown that amphibians have a weaker immune response when challenged with injury or infection, and a less-diverse population of the immune cells responsible for inducing antigen memory. This suggests that although our scar-forming immune response following injury is not conducive to regeneration, our evolutionary trade-off is that we have a more effective defense against pathogens than regenerative-competent species.
Now for the big question: can we use phylogenetics to develop regenerative medicine therapies for humans? By understanding the evolutionary history of regeneration, we can make inferences about the key molecular mechanisms involved. If we know species A can regenerate and expresses factor A, and species B cannot regenerate and does not express factor A, then we might assume factor A plays a role in facilitating regeneration. We may then be able to target candidate factors with a therapeutic drug strategy to improve regeneration in humans.
This strategy is illustrated with an important protein involved in scar formation: transforming growth factor-β (TGF-β). Researchers noted that TGF-β is highly expressed in mammals following injury, but not in regeneration-competent species such as amphibians. Furthermore, when researchers inhibited TGF-β in the mammalian skin after injury they found that, amazingly, it can actually prevent scar formation.
Although administration ofTGF-β only prevents scarring and does not stimulate regeneration, it’s an encouraging step in the right direction. While traditional phyologenetics has become outdated, adapting it to a molecular approach and combining it with observational studies on regenerative processes can help researchers develop new targets to tackle in the quest to achieve human regeneration.
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