Origins of Regenerative Medicine: The Mythical and Historical Foundations

For millennia humanity has searched for the key to immortality and to uncover the tools necessary to prolong life and delay death. This endeavor has been arduous, met with challenges, dead-ends, and false hope. Still, humans have not relented in their quest. Today the hunt for answers to secure a longer, better quality of life continues within the field of regenerative medicine. As we age our body’s healing capabilities become less efficient. Modern day regenerative medicine is focused on addressing the challenges of repairing, restoring, and delaying degradation of the body and its various systems. But how did we get here? Where did the idea of regenerative medicine come from? How does it work, and does it prolong life? In this blog series, we will explore the origins of regenerative medicine, examine the trials and tribulations of early attempts, and explore what the future may hold.

The key to prolonging life may lie within our own bodies

The concept of regeneration, the natural process of replacing or restoring damaged or missing cells and tissues, is a popular notion in terms of prolonging life because it is an inherent property to varying degrees in most living organisms. Less complex organisms, such as plants or small sea creatures, have extensive regenerative capabilities while more complex organisms like mammals have much more limited abilities. For example, tiny freshwater animals with multiple head-like structures growing off a central body stalk known as hydra can form two whole bodies after being cut in half.¹ Though more complex than the hydra, the Mexican salamander can regenerate both form and function of almost any limb and organ. In contrast, humans are one of the most complex creatures on the planet and therefore have a more limited regenerative capacity with which we are only able to form new skin, regrow hair, and repair bone fractures.¹ The one exception is the liver which can undergo a process called compensatory hypertrophy wherein if part of the liver is removed or destroyed, the remaining portion will grow to the original size allowing the liver to continue functioning at full capacity.¹ Exploitation of this intrinsic regenerative property is especially appealing compared with other approaches to prolonging life that require artificial or synthetic replacement or treatment of damaged tissues. Tapping into our body’s own regenerative abilities would also allow us to enhance healing pathways we already had by making them more efficient or repairing them if they are malfunctioning. The fascination with the idea of tissue regeneration and how to harness its power is so strong that it has been woven through our history and storytelling.

The promise of regenerative medicine began in ancient myths

Greek mythology is laden with the idea of tissue regeneration along with ties to immortality. Let’s first examine the legend of Prometheus, the Titan god of fire as introduced around the 8th century B.C.E. As punishment for bringing fire to mankind, Zeus had Prometheus nailed to a mountain in the Caucasus Mountain range where each night an eagle named Ethos came to peck at his liver. Because Prometheus was immortal, his liver would regenerate each day, only to be pecked at again each evening until he was rescued by Hercules. ^2,3 You see, the Greeks were aware of the regenerative capacity of the liver, hence they named it hepar after hēpaomai meaning ‘to repair oneself’. ²

In another display of stories about regenerative capabilities and their link to immortality, the Greeks regaled the world with the legend of the Lernean Hydra. Also called hydra, this creature was a very large monster reminiscent of a water snake that had nine heads, one of which was immortal. Sound familiar? Hercules was tasked with slaying the hydra; however, for each head he eliminated, two more would burst from its place.^4,5

More recently, we have the reimagining of Prometheus’ story in Mary Wollstonecraft Shelley’s novel Frankenstein: or, the Modern Prometheus. Published in 1818, Shelley details the story of Victor Frankenstein, a mad scientist who could regenerate life in a creature made from pieces of human corpses that were no longer living.⁶ Since its publication, the story of Frankenstein and his creature has been retold repeatedly in books and movies through much of the 20th and 21st centuries. While Frankenstein’s scientific endeavors do not exactly work out in his favor, spoiler alert – the creature kills him, the story itself serves as yet another example of how the concept of regeneration continues to enthrall us all.

Could the regenerative capabilities of myth become more than just stories?

In our search for prolonging life, humankind has been trying to manipulate the process of repair and regeneration to delay death for centuries. Survey data of mummies from prehistoric Peru have shown evidence of cranial trepanation, one of the oldest surgical interventions known to man, followed by alloplastic reconstruction of the skull with shells, gourds, and silver and gold plates as early as 3000 B.C.E.² Historical documentation as far back as the 6th century B.C.E. describes various reconstructive procedures for different types of defects performed by Sushruta, an Indian physician known as the father of surgery in the classical medical system of India.⁷ In the 4th century B.C.E., Greek philosopher Aristotle studied and wrote about the ability of animals to regenerate. He hypothesized that animals in the early developmental stages have a higher potential for regeneration and made detailed descriptions of the regeneration of salamander limbs and deer antlers. Aristotle was a man ahead of his time when he theorized that biological forms originate from undifferentiated matter into differentiated tissues, organs, and beings. This theory would later become known as epigenesis, and the undifferentiated matter previously identified by Aristotle would turn out to be cells.² Many years later in the 13th century C.E., a painting entitled The Miracle of the Moor’s Leg depicted a transplantation involving the replacement of a patient’s diseased lower extremity with a healthy one by Saints Cosmas and Damian. ²

Setting the stage for one of the biggest scientific endeavors our civilization has ever seen

In the 18th century A.D., theories about how regeneration occurs began to develop and stimulate debate, thus driving continued curiosity and initial trials and errors. Up to this point Aristotle’s epigenesis theory held strong; however, a newer concept known as pre-formation was gaining momentum. Under the idea of pre-formation, tissues and organs with regenerative capabilities existed as miniature versions at the point where they would grow into their full-sized counterparts, if necessary. For the first half of the 18th century pre-formation was the dominant theory but was later dismissed and the theory of epigenesis was reinstated. ² The 19th century A.D. was marked by rapid growth in the development of regeneration theory, including the role of cells when the cell theory was described in three parts. The first part stated that all organisms, plant or animal, are made of cells. The next part stated that cells are the basic building blocks of life and the last part stated that all cells come from pre-existing cells that have multiplied. Parts one and two were established in 1838 and 1839, and part three was later confirmed in 1858. ^2,8 The Cohnheim hypothesis was developed in 1867 and postulated that cells necessary for the regeneration of wounds came from the bloodstream. ² Two years later in 1869, the term “stem cell” would appear for the first time in scientific literature describing a single cell that can develop into an entire organism. Unbeknownst to scientists at the time, stem cells would go on to play a dominant role in the development of regenerative medicine. ⁹

By the end of the 19th century, the scientific and medical communities had begun to dabble in the art of transplantation as a means of replacing damaged or destroyed tissues and organs. In its infancy, transplantation began with the replacement of skin. While transplanting skin was not necessarily a new trick, the latest iterations involved the use of “free” or detached tissue grafts that could be moved to parts of the body requiring healthy tissue. Early transplantations typically utilized replacement grafts taken from a patient’s own tissue known as an autograft, or that of another person known as an aIlograft.¹⁰ In 1869 the first skin autograft transplantation was performed by Jacques-Louis Reverdin.^10,11 Reverdin went on to perfect his technique to treat burns, ulcers, and open wounds.¹⁰ Pretty awesome, right? But…there’s always a but, transplantation was not without its tribulations. For starters, in those early days the majority of graft transplantations were unsuccessful for reasons that were not immediately clear to physicians and scientists.¹⁰ Records of the time indicated that allografts were far more likely to fail than autografts; however, clinicians and scientists in favor of allografts often attempted to minimize the failure rates as complications unrelated to the tissue source.¹⁰ But what was the reason for these allograft failures and what made them less successful than autografts? The mystery of allograft failures would daunt researchers for decades until one day a pair of twin cows would turn the discipline of transplantation on its head.

The twentieth and twenty-first centuries would see an explosion of development, discovery, and beginnings, including transplantation, tissue engineering, and cell therapies and their evolution into modern day regenerative medicine. These next two centuries would bring with them many pitfalls and technological limitations; however, these would be far outweighed by the knowledge gained, progress made, and the number of lives that would be changed by regenerative medicine therapies.

To read more about how regenerative medicine continued to evolve through the 20th century and into the 21st century, look out for the second post in this Origins of Regenerative Medicine series coming soon!

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1. National Institute of General Medical Sciences. (2020, April). Regeneration. https://www.nigms.nih.gov/education/fact-sheets/Documents/fact-sheet-regeneration.pdf. Accessed 2021, September 21. 2.   Polykandriotis, E., Popescu, L. M., & Horch, R. E. (2010). Regenerative medicine: then and now–an update of recent history into future possibilities. Journal of cellular and molecular medicine, 14(10), 2350–2358. https://doi.org/10.1111/j.1582-4934.2010.01169.x 3. Britannica, T. Editors of Encyclopaedia (2021, August 30). Prometheus. Encyclopedia Britannica. https://www.britannica.com/topic/Prometheus. Accessed 2021, September 21. 4. Crane, Gregory R. (ed.) The Labors of Hercules, /Herakles/Perseus Digital Library. Tufts University. https://www.perseus.tufts.edu/Herakles/labors.html. Accessed 20 Sept 2021. 5. Crane, Gregory R. (ed.) The Lernean Hydra, /Herakles/Perseus Digital Library. Tufts University. https://www.perseus.tufts.edu/Herakles/hydra.html. Accessed 2021, September 20. 6. Britannica, T. Editors of Encyclopaedia (2020, March 10). Frankenstein. Encyclopedia Britannica. https://www.britannica.com/topic/Frankestein. Accessed 2021, September 21. 7. Singh V. (2017). Sushruta: The father of surgery. National journal of maxillofacial surgery, 8(1), 1–3. https://doi.org/10.4103/njms.NJMS_33_17 8. National Geographic Resource Library Encyclopedic Entry. (2020, April). Cell Theory. https://www.nationalgeographic.org/encyclopedia/cell-theory/. Accessed 2021, Nov 1. 9. Boston Children’s Hospital. History of stem cell research – a timeline. https://stemcell.childrenshospital.org/about-stem-cells/history/. Accessed 2021 October 11. 10. Barker, C. F., & Markmann, J. F. (2013). Historical overview of transplantation. Cold Spring Harbor perspectives in medicine, 3(4), a014977. https://doi.org/10.1101/cshperspect.a014977. 11. Health Resources and Services Administration, U.S. Department of Health and Human Services. Timeline of Historical Events and Significant Milestones. https://www.organdonor.gov/learn/history . Accessed 2021, October 8.