This Editorial by in Development
The regenerative biologist Richard Goss wrote a half century ago: ‘If there were no regeneration, there would be no life. If everything regenerated, there would be no death. All organisms exist between these two themes.’ (Goss, 1969). Tissue regeneration is on display in natural phenomena known to most professional and lay biologists, such as the renewal of tails dropped by lizards to distract predators, or the reproductive fission of flatworms that creates a new head and tail and turns one animal into two. Humans are often casually referred to in the literature or in discussion as unable to regenerate. However, tissues like liver, blood, skeletal muscle and intestinal epithelia possess tremendous regenerative potential. Other tissues such as pancreas, heart, brain and kidney lie lower on this spectrum. With regenerative capacity described as shades of gray rather than black or white, virtually all tissues have some low or latent regenerative capacity that might be stimulated by experimental or therapeutic manipulation.
The field of regeneration has been intertwined with developmental biology from its onset, so to consider tissue regeneration as nothing other than central to developmental biology undervalues both disciplines. Viewed through a regenerative biologist’s lens, fertilization triggers the most spectacular regenerative event of all – the growth and morphogenesis of an entire organism from a single cell – and the terms ‘regeneration’ and ‘reproduction’ were once used interchangeably by biologists. A rich history of luminary scientists who shaped biology in multiple ways over their careers included regeneration as a topic of their investigations. Thus, any student who readies themself with scissors or scalpel today against worm, fish, frog or salamander will be repeating an exercise from centuries ago. René-Antoine Ferchault de Reaumur described experiments examining appendage regeneration in crayfish in 1712 (Reaumur, 1712), building on observations of Jean-Baptiste Du Tertre decades before and contributing with others to debates on predestination, the existence of miniaturized tissue reserves or germs, and the nature of the soul. A founding father of laboratory animal model systems, Abraham Trembley brought hydra from the field into his university in the early and mid-18th century to bisect and disorganize (Trembley, 1744). Vertebrate regeneration fell under the magnifying glass of Lazzaro Spallanzani who, in the 1760s, described regeneration not only in snails and worms, but also in amphibians, most notably salamanders – cementing limb regeneration in newts and axolotls in the pantheon of regenerative events (Spallanzani, 1769). At the turn of the 20th century, Thomas Hunt Morgan explored regeneration in a host of creatures from flatworms to killifish. Descriptions of his experiments and those of others, showcased in his classic Regeneration, were profoundly thoughtful and rigorous, challenging controversial views on the extent to which regeneration is a product of adaptation (Morgan, 1901).
Over the past two decades, regenerative biology has grown exponentially as a field, making this an exciting time indeed. Transgenesis and knockout technologies for mice applied initially to fields of embryology, immunology, cancer and neuroscience found a willing partner in regeneration. Key regulators of events such as skeletal muscle regeneration, liver regeneration and axon regeneration began to emerge, and source cells for regeneration in many tissues were implicated by genetic lineage tracing. The past decade has seen the use of these techniques, most recently accompanied by genome editing, perfuse additional model systems, many of which have been reinvigorated from the classic era.
This is a crude and filtered representation of a great history, but we are supremely fortunate today to have available dozens of animal model systems and injury contexts, and methodologies some of us could not have dreamed of two decades ago. Lineage-tracing experiments, complemented by molecular trajectories inferred from single-cell RNA-sequencing, have rooted out cellular subpopulations and states, and enable conclusions on developmental plasticity during regeneration. New imaging platforms and cell tracking software facilitate direct visualization and quantification of cell behaviors in live regenerating tissues, either in accessible surface tissues or by intravital imaging to probe internal tissues. CRISPR-Cas9-based tools have brought genetics to the masses, facilitating mutant creation and analysis in familiar species and those new on the scene. Induced pluripotent stem cells can be used to generate ex vivo regeneration models for human tissues, or can be a source of resident stem cells for engineering applications such as skin or corneal therapy.
The current and next generations of regeneration scientists have many key questions to attack and goals to consider. Among these, to what extent do gene regulatory networks of regeneration overlap with those involved in initial development, growth or homeostasis of tissue? Why does wound healing trigger regeneration in some contexts but scarring in others, and what roles do inflammatory cells and fibroblasts play? How do we genome- and epigenome-edit for safe, effective regenerative therapies, and can regeneration programs be harnessed for particularly ambitious goals such as a functional blastema for mammalian limb stumps? What is altered during senescence to impact physiological regeneration and injury responses, and how are these targets best modulated to slow aging? And, as Morgan wondered, can we understand how and why regeneration has been retained or lost during evolution? Addressing questions like these will not only require the innovation of new tools and technologies, but continued inclusion of new animal species in which we study regenerative events.
Which takes us (finally) to the point of this editorial. When we started our laboratories, given the miniscule size of the community, talks on regeneration represented a small fraction of coverage in conferences centered on developmental biology, tissue disease or animal model systems. Poster presentations were sprinkled among various session themes, and we liked to joke that our regeneration talks were relegated to those necessary, end-of-conference sessions. Now, thanks to recognition and embrace of its re-emerging importance by major societies such as the Society for Developmental Biology, the International Society for Stem Cell Research and others, regeneration is a cornerstone and plenary topic of many meetings worldwide. Yet, no formal community for regenerative biologists exists – nor has one ever to our knowledge – and regular meetings are infrequent, every 2 or 4 years. We are thus pleased to launch the International Society for Regenerative Biology (ISRB) this year, to promote research and education in the field of regenerative biology (isrbio.org). This effort will formalize an inclusive and integrated community of scientists that studies all aspects of regeneration in invertebrate and vertebrate model organisms. The ISRB will support and enhance key existing meetings, while organizing its own main conference and virtual events such as webinars. Another function of the ISRB will be to convey the importance and impact of regeneration research to the greater scientific and lay communities, by highlighting regenerative biologists and their discoveries and through outreach activities and educational resources. It will promote regenerative biology by giving awards for discoveries and service, and by advocating for research and community funding. One of us (K.D.P.) will serve as Founding President, and the other (E.M.T.) will serve as President-Elect. Regular elections will fill positions for other Officers, and a diverse Board of Directors will advise and oversee operations.
We recognize that regenerative biologists have existing commitments with societies, and we emphasize that ISRB will complement and collaborate with these societies rather than compete with them. A primary role for the ISRB will be enabling cross-species comparisons to understand the commonalities and divergences in regenerative capacity and the mechanisms of regeneration – toward an integrative framework. We envisage the ISRB as the central society to promote and help achieve this next frontier for our field. Regular opportunities will be available for investigators using different models and injury contexts, but with the common goal of understanding how and why regeneration works, to share their discoveries and form new collaborations. Junior scientists will be a focus of the ISRB and will be provided with opportunities for interactions, visibility and career support.
Our first meeting will be virtual and concise, consisting of exciting scientific talks and an open community discussion on April 8-9, 2021 (isrbio.org). Some of these talks will be chosen from abstracts of unpublished work submitted by graduate students and postdoctoral researchers. We await our first in-person conference at a stimulating location in 2023, most likely to be hybrid with virtual features. We warmly and eagerly encourage you to join as a member, and, if you are a group leader, to encourage your group members to join. Participate in the launch meeting this April to see great science, and get involved! This has been a long time coming.
We thank A. Dickson, H. Roehl, K. Echeverri and S. Eming for comments on the manuscript.
Goss, R. J. (1969). Principles of Regeneration. New York: Academic Press.
Morgan, T. (1901). Regeneration. New York: Macmillan.