Last update: Sep 2020
Why isn't high regeneration potential a more common feature?
Wouldn't it be useful if humans could regrow lost limbs the same way newts can? Why is it that so many organisms do not have the ability to regenerate large chunks of their bodies? To answer this question, we have to turn to evolutionary biology.
It is possible that regeneration was lost over the course of evolution due to it being a neutral trait (giving no selective advantage) in some species. For example, if sublethal predation affecting a particular species is low, the chance of it losing an arm, leg, etc. (without dying) decreases. Thus, there is no evolutionary advantage in retaining the ability to grow those structures back. Moreover, some structures may be too costly (energy, food) to regenerate.
There is also a possibility that regeneration could contribute to lower fitness in some way. There could be an energetic trade-off between regeneration and another vital biological process. Regeneration entails extensive cell growth and/or reorganization, which requires transcriptional control of numerous genes and various epigenetic modifications. However, if some of those growth-associated genes are not controlled tightly enough, cancerous cells could easily form. Weighing the advantage of high regeneration potential against the risk of tumorigenesis, it is possible that the net evolutionary advantage belongs to animals that cannot regenerate so well, but at least have a decreased risk of developing cancer thanks to that.
Note that those are some of the possible explanations, but the consensus on the matter has not been reached, as it has been extraordinarily difficult to collect data that would decisively support one hypothesis or another.
How does retinoic acid affect limb regeneration?
Retinoic acid is required for growth, for example, in human fetal development. It plays a role in the two-signal model for limb patterning, where it creates proximal to distal gradient, opposed by the FGF distal to proximal gradient (Fig.1, arrows on the left). The two molecules create a concentration gradient that specifies the positional values of limb bud cells. Intercalary (lengthwise) growth re-establishes positional values. When the surface of a limb cut is treated with retinoic acid, positional values change significantly (towards proximal). Thus, as shown in Fig.2, the proximal segment (arm, followed by a hand) is formed where normally there would be a distal segment (hand only).
Figure 1. Retinoic acid (RA) and FGF in limb regeneration. (Delgado, 2016)
Figure 2. Treatment with retinoic acid (B) shifts the positional identity of cells to more proximal values in amphibian limb regeneration. (Maden, 2002)
What is the difference between morphallaxis and epimorphosis?
In morphallaxis, the whole organism can be reconstructed from a fragment of its body through the reorganization of cells within it. It results in a smaller version of the original organism, e.g., if we cut a hydra into 3 equal pieces, each of the small 3 hydras formed will be 1/3 the size of the original hydra, and if we cut planaria (flatworm) into two unequal pieces, the 2 planarias that form will correspond in size to the piece they originated from (Fig.3). Morphallaxis does not require food intake and is associated with a decrease in body weight. It corresponds to the Wolpert's French flag model part where after cutting a flag in the middle, two smaller flags with the original three-color pattern are formed.
Epimorphosis constitutes the replacement of a lost organ through cell proliferation, as in newt growing a new arm after the old one was removed from its body. Epimorphosis requires food intake and results in the return to the original body weight. It corresponds to the French flag model part where a flag with identical size and pattern to the original flag is formed.
Figure 3. The process of regeneration in planaria (morphallaxis) and newt's limb (epimorphosis). (Bando et al., 2018)
Why do growth and differentiation not happen at the same time?
Let's answer this question using the example of myoblasts.
Myoblasts are cells that develop into muscle cells. In the presence of growth factors, myoblasts continue to proliferate (divide) without differentiating. However, once growth factors are gone, myoblasts fuse and make muscle fibers. Proliferating myoblasts’ have their genes controlled by the FIID transcription factor. When they start differentiating, FIID is replaced by TRF3 and TAF3 transcription factors. Since different transcription factors that do not work at the same time are involved in growth and differentiation, both processes cannot be happening at the same time.
 Alexandra E. Bely, Evolutionary Loss of Animal Regeneration: Pattern and Process, Integrative and Comparative Biology, Volume 50, Issue 4, October 2010, Pages 515–527, https://doi.org/10.1093/icb/icq118
 Wolpert, L. and Tickle, C., 2011. Principles of Development. 4th ed. New York: Oxford University Press.
 Bénazet, J. D., & Zeller, R. (2009). Vertebrate limb development: moving from classical morphogen gradients to an integrated 4-dimensional patterning system. Cold Spring Harbor perspectives in biology, 1(4), a001339. https://doi.org/10.1101/cshperspect.a001339
 Galloway, J. L., & Tabin, C. J. (2008). Classic limb patterning models and the work of Dennis Summerbell. Development (Cambridge, England), 135(16), 2683–2687. https://doi.org/10.1242/dev.021188
Figure 1. Delgado, I., & Torres, M. (2016). Gradients, waves and timers, an overview of limb patterning models. Seminars in cell & developmental biology, 49, 109–115. https://doi.org/10.1016/j.semcdb.2015.12.016
Figure 2. Maden M. (2002). Positional information: knowing where you are in a limb. Current biology : CB, 12(22), R773–R775. https://doi.org/10.1016/s0960-9822(02)01290-3
Figure 3. Bando, Tetsuya & Yokoyama, Hitoshi & Nakamura, Harukazu. (2018). Wound repair, remodeling, and regeneration. Development, Growth & Differentiation. 60. 303-305. 10.1111/dgd.12566.