Super-regenerating animals provide clues to medicine

According to Greek myth, the Hydra of Lerna It was an aquatic monster, with a serpent's body and multiple heads, that guarded an entrance to the underworld, near present-day Nafplion, in the Argolic Gulf. This fearsome mythological creature was almost invincible and When one head was cut off, another one stronger than the first or even two would grow., according to the version of the myth, which also tells that she had another head that made her immortal. However, the demigod Heracles he finished her off in the second of the twelve works which he had to complete in penance for having killed his wife, Princess Megara.

In the animal world, there are other much more harmless hydras, but they share with the mythological creature an amazing power of regeneration, which practically makes them immortal.

These are small cnidarians freshwater, related to jellyfish, polyps, corals, and anemones, which live in ponds and streams in temperate and tropical climates. They have a tube-shaped body, a few millimeters in length., with a foot at its base and a head at its apex with twelve mobile tentacles, around the mouth, full of stinging cells, with which they paralyze and capture their prey: mainly, insect larvae and crustaceans.

It is believed that hydras do not age and do not die unless they are deprived of food. Their regenerative capacity allows them to reconstitute tissues and parts of their body when they suffer an injury. For example, If cut into two halves, each one will regenerate the missing end, forming two hydras; the end containing the head will regenerate the foot and vice versa. If cut into several pieces, the middle pieces will form both a new head and a foot.

How does regeneration work?

Regeneration of the head or foot in hydras It is a quick process that is completed in just under a day and a half. It involves the closure of the wound, the establishment of an organizer – a group of cells responsible for maintaining the pattern and morphology of a part of the organism, where a signaling molecule called Wnt plays a key role – and, finally, a phase of morphogenesis. , in which the organizer sends signals to neighboring cells to adopt an appropriate differentiation state to form the head or foot and to structure themselves in space.

Since the number of genes in hydras is not very different from that of other animals with less regenerative potential, Scientists hypothesize that the differences between them are found in the regulation of gene expression: which genes are activated and which are silenced during this process. Epigenetics is the study of the mechanisms that regulate the turning on and off of genes during embryonic development, the adult phase of an organism, and also in regeneration.

build a head

Scientists have compared the process of forming a head in hydras during regeneration and during gemmation. The latter is the asexual mode of reproduction by which a protuberance is formed on the animal's body – a bud – which will grow and develop, giving rise to a new organism. By analyzing how gene expression is modified, they have established that the mechanisms of head formation in both processes are different. In budding, genes are activated gradually, while in regeneration abrupt changes occur- Many are activated at startup, then silenced, and then activated again. Therefore, there is more than one way to construct a head.

Gene regulation

Researchers have identified a complex gene regulation structure in which DNA sequences called amplifiers ('enhancers' in English) that direct the expression of genes relevant to head regeneration. The discovery of this type of complex regulation also in hydras suggests that their evolution would have taken place more than 600 million years ago, before the evolutionary divergence of cnidarians and animals with bilateral symmetry (including humans). ). Therefore, Hydras are a great model for understanding how regeneration works on a molecular scale, before applying this knowledge to medicine.

Why can't mammals regenerate?

Biologists have long wondered why animals like salamanders can regenerate body parts while others, like mammals, cannot. To unravel these differences, Scientists are looking at the molecular level for the factors involved in regeneration and trying to understand whether animals that are very distant in evolution use the same tricks or not.

Alejandro Sánchez Alvarado's group, from the Stowers Institute in Kansas City, has been investigating regeneration in a type of flatworms, the flatworms (also known as planarians). According to this researcher, animals with great regenerative capacity are capable of activating and deactivating certain genes to generate new tissues after an injury. Thus, It is as important to identify the genes involved in the regeneration process as it is necessary to understand how they are regulated.

In 2020, they published in 'Science' A study in which compared two species of freshwater fish that can regenerate their fins, but are separated by an evolutionary distance of about 230 million years: zebrafish (Danio laughed), of Asian origin, and the African fish Nothobranchius furzeri. The researchers cut the tail fins of both fish and analyzed gene activity as they grew back. The objective was to find a type of short DNA sequences called amplifiers or enhancers ('enhancers' in English).

These 'enhancers' are short sequences, of 50 to 1.500 DNA letters (or base pairs), that are found throughout the genome, usually far from the genes, and their function is to increase the level of activation of a particular gene or group of genes. Proteins – transcription factors – that are important for activating genes are bound to them.

In both species of fish, the scientists identified enhancers that participate in regeneration, activating genes that promote the growth of new tissue in response to injury. They were also able to determine which of them were particular to each species, and found that a few were shared by both. Since the two species have different evolutionary histories, separated by 230 million years, the shared genes and enhancers are evolutionarily conserved and would be part of an ancient regeneration program which could also be relevant in other animals.

One of these enhancers regulates the inhibin beta A (inhba) gene, which is known to be important for regeneration in vertebrates. The researchers saw that if the 'enhancer' was removed from the fish, they completely lost the ability to regenerate both the tail fin and their heart. Also They identified that mammals have an equivalent 'enhancer'. But when they introduced the mammalian version to fish that had had their own enhancer removed, they did not regain their ability to regenerate.

The results suggest that changes in enhancers occurred during evolution would explain the loss of regenerative capacity in certain vertebrate species, which would only maintain the potential to respond to wounds; while others would have retained both capacities.

Miniorgans to study and treat diseases

For an organ to regenerate, it is necessary for cells to divide and proliferate, grow and differentiate into the necessary cell types, but also that are arranged in space so that the organ adopts its shape, which is known as morphogenesis.

In the last decade, scientists have attempted to recapitulate these processes in the laboratory by generation of small replicas of human organs, known as mini-organs or organoids, obtained from stem cells.

In the laboratory, stem cells – which have the potential to differentiate into a host of different cell types – are grown under specific culture conditions to allow them to differentiate and organize themselves into three-dimensional structures that, in both their form and function, resemble a real organ or tissue. For example, a mini-kidney or an optic cup (a kind of mini-eye).

In them, scientists study both the normal physiology of the organ and what happens during a disease, since organoids can be obtained from a patient's cells carrying a genetic mutation. The mini-organs are also used to analyze the effect of drugs; and, In the long term, they could be used in regenerative medicine, to replace a patient's damaged tissues. 

In this sense, scientists are inspired by the tissue engineering –which provides materials that serve as scaffolding for the cells and as a guide, enhancing their regenerative capacity–, to obtain organoids that increasingly resemble the real organ physiologically and anatomically.

Different animals, different potential

Hydras are not the only members of the animal kingdom that possess an extraordinary regenerative capacity. Planarians, a type of flatworm, regenerate parts of their organism and even an entire one from a small fragment. Starfish regrow arms that detach from their central disk, and there are species that complete the reverse process: they regenerate an entire body from a lost arm. Crayfish regenerate both legs and claws.

Among vertebrates, Many teleost fish can regenerate their fins, the ventricles of the heart and the spinal cord. Geckos, lizards and lizards lose their tails to escape predators and then grow a new one. In amphibians, tadpoles can regenerate tails and limbs, but they lose this ability when they transform into adult frogs. Others, such as salamanders and newts, are the kings of regeneration, because they completely reconstitute their limbs and tail after an injury, but also the jaws, the lens and retina in the eye, and other internal structures.

There are no mammals that can completely regenerate a limb, but Regeneration of fingertips after amputation has been observed in mice and humans. This phenomenon occurs only when the edge of the nail where it is located is preserved in the cut. a population of stem cells capable of orchestrating the regeneration of the fingertip, including bone, nail and skin.