Origins of Regenerative Medicine: Bringing Myths and Legends of Regeneration into Reality

Disclaimer: The following text includes information pertaining to cell-based therapies and stem cells. Please note that this information in no way reflects any current product offerings or product claims provided by StimLabs LLC. The inclusion of this information within the text below is only for educational and historical purposes and does not reflect the products, goals, or opinions of StimLabs, LLC as a company.

From Prometheus to Frankenstein’s creature, regeneration has been a constant fascination preserved in our storytelling, culture, and scientific endeavors. In our previous post, we left off at the end of the 19th century when scientists had just begun exploring transplantation; however, they’d encountered a challenge. Transplanted allografts were failing at an alarmingly higher rate than autografts for reasons that were yet unknown and causing strife within the scientific and medical communities.

In investigating the mystery of allograft rejection, scientists discovered the key to successful solid organ transplantation. Progress made in the field of transplantation would go on to spark innovation in other disciplines of regenerative medicine like tissue engineering and cell therapies. Let’s take a look at how these early disciplines were established and how they allowed humankind to bring the regeneration of Greek myths and legends a little closer to reality.

How twin cows solved the mystery of transplant rejection

It took a series of trials and tribulations in multiple countries to solve the riddle of allograft transplant rejection with decades devoted to understanding this phenomenon. Our story begins in Chicago in 1916 with a researcher by the name of Frank Lillie. Lillie was studying twin development in cattle and found that anatomies of the placentas encasing the fetuses were partially fused, allowing for shared circulation wherein blood could be exchanged freely between the twins.1 Thirty-three years later in Wisconsin, Ray Owen discovered that when twin cows shared a common blood source in utero, they exchanged red blood cells and other cell types that would allow them to carry similar immunological makeups throughout their lives.1 Okay, who cares, right? Just stay with me. While these twin cow studies were being carried out, scientists at the Rockefeller Institute in New York, coincidentally where a statue of Prometheus and his fire still resides today, firmly established the critical role of the lymphocyte, a type of white blood cell that is part of the human immune system, in allograft rejections.1 Their research concluded that most allograft failure events were due to immunological rejection coordinated by lymphocytes when they were exposed to tissues from other subjects. Because of erroneous beliefs regarding the mobility of lymphocytes, this breakthrough in transplantation was ignored which partially hindered advancements in the field.1

However, lack of progress did not result from a lack of trying. Experimental transplantations continued with strides being made in solid organ replacement. Particular attention was paid to kidney transplantations because treatment options for kidney failure and renal disease were limited.1 During World War II, researchers circled back to the idea of immunological rejection and twin cows. In 1949, researchers in the United Kingdom Peter Medawar and Rupert Billingham discovered that twin cows could accept donated allografts taken from each other. At first, this discovery was baffling but when their colleague, Hugh Donald, suggested they read Owen’s publication from a few years earlier, all became clear. With all of the evidence laid out, Medawar and Billingham reasoned that cells exchanged between twin cows in utero due to shared blood supplies gave the twins similar immunological makeups and that these similarities were sufficient for the twins to tolerate allografts taken from one another! These findings all together supported what the Rockefeller scientists had initially hypothesized – that the immune system was responsible for transplant rejection.1

Meanwhile, in other parts of the world, researchers were experimenting with various types of tissues as potential allograft sources. One tissue type, in particular, stuck out – amniotic membrane. In Maryland in 1910 amniotic membrane allografts used in skin grafting showed superior results when compared to xenograft or cadaveric coverings. Though these amniotic membrane allografts were more successful than other allografts, it would be decades before researchers understood why.2 In 1953, still reveling in his discoveries regarding the immunological rejection of allografts in twin cows, Medawar hypothesized that the reason allografts made from amniotic tissues were successful was their immune-privileged status, meaning they do not incur immunological responses as a strategy to protect a growing fetus from the maternal immune system during pregnancy.3,4

Shortly after these pivotal discoveries, the first successful human-to-human kidney transplant was performed in 1954 when a living donor gave a kidney to his identical twin.1,5 Once the concept of immunological rejection was accepted, the scientific community began exploring irradiation and drugs to suppress the immunological reactions of patients receiving transplants. Irradiation of the immune cell-containing bone marrow allowed for successful transplantation between unrelated donors and recipients and was the standard of care until the late 1970s when sufficient chemical immunosuppressants became available.1

Despite all the milestones accomplished in the field of transplantation, these successes were not without drawbacks. Transplantation comes with two major hurdles that still exist today. The first is that transplantation requires long-term immunosuppression which can be tricky to navigate as patients age and requires constant monitoring to ensure that they are not being under- or over-immunosuppressed.6,7 Additionally, today, there is an increasing demand for organ transplantations resulting in donor and organ shortages.7 To address these hurdles, scientists began to investigate whether tissues and organs could be created in a laboratory.

Tissue engineering brought science fiction into reality

Generally speaking, tissues in their native state consist of cells and an extracellular matrix (ECM). The process of tissue engineering utilizes ECM aspects of tissues for increased tunability and quality control, sometimes with the addition of cells.7-9 Today, tissue engineering is defined as the creation of new tissue for the therapeutic reconstruction of the human body. It relies on the controlled delivery of chemical and mechanical signals to surrounding cells via scaffolds.8 Scaffolds are structures made of natural or synthetic materials that serve as a substrate and guide for tissue repair and regeneration. Ideally, whether synthetic or natural, materials should be biocompatible and able to remodel as damaged tissue is repaired without leaving any remnants that may interfere with regeneration.7

Beginning in the 1970s, researchers studying the nature of how cells grow, proliferate, and work together determined that cells in any given tissue relied upon their surroundings for instructions via signaling. Depending on the signal, a cell might be instructed to form a cluster with other cells, move to a different location via a process called chemotaxis, or even undergo a controlled cell death program otherwise known as apoptosis.10 While signaling instructed cells to carry out various processes, by the mid-1980’s it was clear to some that cells alone would be limited in their capacity to integrate into or regenerate tissue. They needed assistance. With this in mind, researchers Joseph Vacanti and Robert Langer hypothesized that the cells needed a template guide to properly integrate into the tissue, so they began designing scaffolds to integrate cells into the tissue more effectively.10

The term ‘tissue engineering’ was officially coined in 1987, and in the 1990s several research centers hoping to expand upon this relatively new field were established throughout the United States and Europe. By the mid-to-late 1990s, nearly every developed country in the world had a dedicated tissue engineering center.11,12 Tissue engineering gained much notoriety in 1997 when Auriculosaurus, a rodent with a tissue-engineered ear growing off its back, made its debut in a televised special on the British Broadcasting Company. Though small in stature, Auriculosaurus had a large impact on public interest, both positive and negative, surrounding tissue engineering, its ethics, technology, and capabilities.10-12

Today, skin substitutes are prime examples of successful transplants and tissue engineering approaches that can be used in a variety of applications including chronic wounds, burns, and full-thickness skin injuries. One biomaterial used in skin substitutes has gained popularity in recent years. Care to guess what it might be? If you guessed amniotic membranes, you’d be right! If you’ll recall from earlier, amniotic membranes were one of the few successful allograft tissues in the early days of transplantation. Now they are an important source of biomaterial commonly used as a surgical membrane or wound care skin substitute because of their immunological privilege and high tensile strength.13

Tissue engineering remains a major area of focus within regenerative medicine research as a means of treating and improving the quality of life for patients; however, tissue engineering is just one piece of the puzzle. If we talk about tissue engineering, we must also talk about cell therapies because they are another founding sector of regenerative medicine and occupy a significant space in the field.

Cell therapies may be the next step in discovering the elixir of life

The overall objective of cell therapy is to treat damaged or diseased tissues by transplanting new and healthy cells into the tissue. These therapies can rely either on differentiated cells or stem cells.7 Differentiated cells are in their final developmental phase and perform specific functions, i.e., red blood cells, liver cells, skin cells, etc. Using differentiated cells is advantageous because they can be collected from the patient with diminished risk of immunological rejection when used as an autograft. In addition, they may not need further manipulation before implantation and present no obstacles in terms of procuring the cells. However differentiated cells are often limited in their ability to proliferate in a laboratory setting to the volumes that may be required for certain therapies.7,15 Stem cells, which were described by James Till and Ernest McCulloch, are defined by two properties: 1) they can self-renew, meaning they can divide and give rise to more stem cells of the same kind, and 2) they can mature or differentiate into specialized cells that carry out specific functions.16 These stem cells can be proliferated in a laboratory setting to larger volumes and can be obtained in multiple ways including from the patient, a human donor, or even another animal.7,15,17

One example of a currently approved cell therapy is the hematopoietic stem cell transplant (HSCT).15,18 In HSCT procedures a patient’s bone marrow is irradiated to eliminate damaged or dysfunctional cell populations and replaced with donor bone marrow containing functional cell populations. These new and functional cell populations replenish the populations depleted by the irradiation, replacing the diseased cells with healthy cells. Today this procedure is used to treat patients with various blood diseases and cancers like leukemia, anemia, and thalassemia.15

While early cell therapies mostly involved various types of stem cells, today, cell therapies continue to evolve and incorporate different techniques. One up-and-coming technology in the space is cell-based immunotherapies. These therapies utilize gene modification to alter a patient’s cells. These alterations allow the cells to combat various diseases including cancer.19

As impressive as the breakthroughs in tissue engineering and cell therapies are, the industry has just skimmed the surface in terms of the regenerative therapies that could be achieved with the right technology and team.Successes of today are tomorrow’s opportunities for improvements

Today the term ‘regenerative medicine’ is used to describe therapies that intend to repair, replace, or regenerate cells, tissues, or organs to restore impaired function. William Haseltine is largely credited with coining the term at a conference in 1999 while attempting to describe an emerging field that blended knowledge on tissue engineering, cell transplantation, stem cell biology, biomechanics, prosthetics, nanotechnology, and biochemistry.7,11

Despite the relatively young age of the field, the development of regenerative medicine therapies continues to thrive.

Regenerative medicine remains a unique cross-functional field that enlists doctors, biologists, bioengineers, and chemists in the quest for a higher quality of life. Advancements in regenerative therapies have resulted in a diverse live-longer toolkit containing cells, tissues, biomaterials, soluble molecules, and bioreactors.7,10 The discoveries being made in regenerative medicine, including tissue engineering and cell therapies, may ultimately lay the foundation for interventions earlier in the continuum of care that can also serve to act as preventative measures.

Stay tuned for our final installment in this series coming soon where we discuss what the future holds for regenerative medicine and the passion we have at StimLabs to play a key part in the next phase to not only treat patients but to improve the quality of their lives.

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1. 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. 2. Silini AR, Cargnoni A, Magatti M, Pianta S, Parolini O. The Long Path of Human Placenta, and Its Derivatives, in Regenerative Medicine. Front Bioeng Biotechnol. 2015;3:162. Published 2015 Oct 19. doi:10.3389/fbioe.2015.00162. 3. Wassmer, C. H., & Berishvili, E. (2020). Immunomodulatory Properties of Amniotic Membrane Derivatives and Their Potential in Regenerative Medicine. Current diabetes reports, 20(8), 31. https://doi.org/10.1007/s11892-020-01316-w. 4. Kubo, M., Sonoda, Y., Muramatsu, R., & Usui, M. (2001). Immunogenicity of human amniotic membrane in experimental xenotransplantation. Investigative ophthalmology & visual science, 42(7), 1539–1546. 5. 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. 6. Banas, B., Krämer, B. K., Krüger, B., Kamar, N., & Undre, N. (2020). Long-Term Kidney Transplant Outcomes: Role of Prolonged-Release Tacrolimus. Transplantation proceedings, 52(1), 102–110. https://doi.org/10.1016/j.transproceed.2019.11.003 7. Sampogna, G., Guraya, S. Y., & Forgione, A. (2015). Regenerative medicine: Historical roots and potential strategies in modern medicine. Journal of microscopy and ultrastructure, 3(3), 101–107. https://doi.org/10.1016/j.jmau.2015.05.002. 8. Williams D. F. (2019). Challenges With the Development of Biomaterials for Sustainable Tissue Engineering. Frontiers in bioengineering and biotechnology, 7, 127. https://doi.org/10.3389/fbioe.2019.00127. 9. Jenkins, T. L., & Little, D. (2019). Synthetic scaffolds for musculoskeletal tissue engineering: cellular responses to fiber parameters. NPJ Regenerative medicine, 4, 15. https://doi.org/10.1038/s41536-019-0076-5. 10. Kaul, H., & Ventikos, Y. (2015). On the genealogy of tissue engineering and regenerative medicine. Tissue engineering. Part B, Reviews, 21(2), 203–217. https://doi.org/10.1089/ten.TEB.2014.0285. 11. 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. 12. Vacanti C. A. (2006). The history of tissue engineering. Journal of cellular and molecular medicine, 10(3), 569–576. https://doi.org/10.1111/j.1582-4934.2006.tb00421.x. 13. Sierra-Sánchez, Á., Kim, K. H., Blasco-Morente, G., & Arias-Santiago, S. (2021). Cellular human tissue-engineered skin substitutes investigated for deep and difficult to heal injuries. NPJ Regenerative medicine, 6(1), 35. https://doi.org/10.1038/s41536-021-00144-0. 14. Terada, S., Sato, M., Sevy, A., & Vacanti, J. P. (2000). Tissue engineering in the twenty-first century. Yonsei medical journal, 41(6), 685–691. https://doi.org/10.3349/ymj.2000.41.6.685. 15. Zakrzewski, W., Dobrzyński, M., Szymonowicz, M., & Rybak, Z. (2019). Stem cells: past, present, and future. Stem cell research & therapy, 10(1), 68. https://doi.org/10.1186/s13287-019-1165-5. 16. International Society for Stem Cell Research. (2008) Patient Handbook on Stem Cell Therapies. Originally published as Appendix I of the ISSCR Guidelines for the Clinical Translation of Stem Cells, 3 December, 2008. https://www.closerlookatstemcells.org/wp-content/uploads/2018/10/isscr-patient-handbook-english_ltr_17nov2016_web-only.pdf. Accessed 03 December 2021. 17. Boston Children’s Hospital. History of stem cell research – a timeline. http://stemcell.childrenshospital.org/about-stem-cells/history/. Accessed 2021 October 11. 18.  Elahimehr, R., Scheinok, A. T., & McKay, D. B. (2016). Hematopoietic stem cells and solid organ transplantation. Transplantation reviews (Orlando, Fla.), 30(4), 227–234. https://doi.org/10.1016/j.trre.2016.07.005. 19.  National Cancer Institute (2021). CAR T Cells: Engineering Patients’ Immune Cells to Treat Their Cancers. https://www.cancer.gov/about-cancer/treatment/research/car-t-cells. Accessed 2021, October 21.

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