Grand. No question that’s transplantation technology’s legacy over the late 20th century. On the technical side, the initial surgical marvels were quickly followed by the development of a transplant ecosystem consisting of donor registries, protocols to improve organ harvests, to better preserve organ structure and function, and to improve transport and logistics. More recently, minimally invasive surgeries even allay pain and accelerate post-surgery recovery. On the scientific side, complex immune suppression regimens grew to dampen acute rejection, necessitating regimens to counteract their side-effects, and so on. Perhaps there’s no better poster child for transplant technology’s monumental 20th century legacy than Johanna Rempel, née Nightingale, who received a kidney from her identical twin, Lana Blatz, in 1960, and in 2011 became celebrated as the longest living renal transplant survivor (1, 2; see Figure 1 below).
Now, the transplantation field that emerged in the 1950s and 1960s faces stagnation and incrementalism, stagnation as the main hurdle is organ shortage and incrementalism with only marginal improvements in stalling long-term rejection, rejection that’s currently kept at bay through complex and expensive immunosuppression. Rejection processes are complex, and the pathology and symptomatology is tissue- and organ-specific. In practical terms, this means that what works to stall liver transplant rejection may not necessarily be directly applicable to lung or kidney, and so on.
Acute Organ Shortages Fuel Stagnation and Higher Risk Transplants
Today, more people die on transplant waiting lists than get transplants. Since demand far outstrips supply, patients on waiting lists perforce need to face an even more odious test, namely, does their need for and perceived benefit from a transplant outweigh someone else’s? Since tissue matching plays a critical role in chances of graft rejection, with a much smaller donor pool, certain ethnicities such as blacks have to also deal with the double blow of that insult (smaller available donor pool) to injury (their ranking on a transplant waiting list).
Longer a patient is on a transplant waiting list, higher the risk of death. This also alters the risk perception of organs considered transplant-worthy, i.e., as shortages persist for years, higher risk organs (less well-matched, older, younger, deceased as opposed to living donations, donations post-circulatory death as opposed to post-brain death, etc.) become not only deemed transplantable but are indeed used, increasing the likelihood of medical complications. Ethical dilemma wedded to desperation, the resulting toxic brew fuels an exploitative and deadly underworld of illegal organ donations and transplants. I know I will never forget‘ harrowing account of it in the 2002 film, .
In March 2011, UNOS (United Network for Organ Sharing) reported a solid organ waiting list of 110,600 with 16,133 for liver, 1389 for pancreas, 262 for intestine while liver, pancreas and intestine transplants in 2010 were 6291, 351, and 151, respectively (3). In other words, we can extrapolate an annual shortfall of 72%, 80%, and 64%, respectively, for these three organs (see Figure 2 below from 3).
The organ shortage issue is even more acute in the case of kidney where >16000 patients received kidney transplants in 2012 in the US while >95000 remained on the waiting list by year-end (4), for a shortfall of ~86% (see Figure 3 below from 5 and 6).
In turn, such acute organ shortage fuels rising healthcare costs. After all, transplant waiting lists contain people with serious health conditions, such as chronic kidney disease or End-Stage Renal Disease (ESRD) that require frequent dialysis.
Perverse Research Incentive Structures Create a Culture of Incremental Improvements in the Transplant Field
Transplant recipients also face lifelong dependence on complex drug regimens, primarily to establish and maintain immunosuppression to prevent organ/graft rejection.
- Corticosteroids and generalized immunosuppressants such as .
- Cytokine blockade such as calcineurin inhibitors, , .
- Leukocyte growth factor response blockade such as IL-2 receptor alpha chain-specific antibodies.
- DNA synthesis inhibitors such as azathioprine, mycophenolate.
- Newer immunosuppressive drugs such as , which blocks T cell activation.
How do these drugs suppress anti-transplant immune response? Akin to using a hammer to swat a mosquito. In other words, non-specifically such that transplant recipients have greater short-term risks of developing other diseases or drug toxicities or acquiring infections, and long-term risks of developing metabolic abnormalities and/or malignancies. Do we not understand graft rejection mechanisms well enough to use more targeted interventions to control anti-graft immune responses more specifically? Largely the outcome of perverse incentive structures in basic biomedical research that drive and maintain a flawed status quo*, today, immunologists and transplant specialists understand a great deal of how immune systems of clinically irrelevant rodent (mouse and rat) models and less so of certain non-human primates accept and can be made to accept tissue and organ transplants using more targeted and specific interventions. How to make the human immune system do so? That’s still largely a black box. Hence the prevailing use of extremely potent and non-specific immune suppressants that in turn necessitate further expensive interventions to prevent infections, metabolic complications and malignancies as well as to mitigate drug toxicities. Where the transplanted graft’s survival is concerned, incrementalism has thus become the norm (see below Figure 4, an illustrative example, from 7).
Thus, today transplantation fuels a vicious cycle of not just escalating healthcare costs but also decreasing quality of life, both for those lucky enough to get transplants and for those stuck on waiting lists. And the economic costs of this predicament are borne not just by them but by all of society.
Organ Bioengineering and Regeneration: Transplantation’s Likely Future (hopefully) in the 21st century
Stem and other cell-driven regenerative medicine practically sells itself. Derived from the patients themselves, no need for complex and expensive immune suppression therapies. As Giuseppe Orlando from Wake Forest School of Medicine, Winston Salem, North Carolina, points out, since 1990, >160 patients have received organs created from their own cells (autologous) (see Figures 5, 6, 7 below from 6).
As research protocols and technologies improve, in one fell swoop, organ bioengineering and regeneration could solve the prevailing problem of tissue and organ availability on the one hand, and nullify the need for immunosuppression OTOH.
See below Giuseppe Orlando’s simple but brilliant and compelling visualization of transplantation’s future, namely, merging with bioengineering and regeneration (Figure 8 from 6). Emerging from the same root, as things stand today, it appears inevitable that the three, namely, bioengineering, regenerative medicine and transplantation, will overlap over the coming decades to create a new multi-disciplinary science that could improve not just likelihood but also long-term survival and health of transplants. While autologous transplantation through bioengineering and regenerative medicine is still very much in its infancy, data from these peer-reviewed studies are merely the harbinger of the tectonic transformation looming ahead, a transformation that, over the course of the 21st century, will likely fundamentally alter the practice of medicine itself in general, and of transplant biology in particular.
1. Tullius, Stefan G., Julia A. Rudolf, and Sayeed K. Malek. “Moving Boundaries: The Nightingale Twins and Transplantation Science.” The New England journal of medicine 366.17 (2012): 1564-1565.
2. Brigham and Women’s Hospital Bulletin, June 3, 2011.
3. Solid Organ Transplantation: Has the Promise Been Kept and the Needs Met? Marco Carbone, James M. Neuberger. Pages 17-28. In Regenerative Medicine Applications in Organ Transplantation, 1st Edition. Editor, Giuseppe Orlando. Elsevier.
4. Procurement, Organ. “United Network for Organ Sharing 2012 Annual Report: Health Resources and Services Administration.” Richmond, US Department of Health and Human Services (2012).
5. Machine Perfusion of Kidneys Donated After Circulatory Death: The Carrel and Lindbergh Legacy. Ina Jochmans, Jacques Pirenne. Pages 210-226. In Regenerative Medicine Applications in Organ Transplantation, 1st Edition, 2014. Editor, Giuseppe Orlando. Elsevier.
6. Epilogue: Organ Bioengineering and Regeneration as The New Holy Grail of Organ Transplantation. Giuseppe Orlando. Pages 987-1000. In Regenerative Medicine Applications in Organ Transplantation, 1st Edition, 2014. Editor, Giuseppe Orlando. Elsevier.
7. Current Status of Renal Transplantation. Jeffrey Rogers. Pages 189-200. Pages 987-1000. In Regenerative Medicine Applications in Organ Transplantation, 1st Edition, 2014. Editor, Giuseppe Orlando. Elsevier.
References for Autologous Transplants listed in Figures 5, 6, 7 (Note the book has a typographical error in Table 72.1’s numbering, an error that I’ve corrected in this bibliography. Also note the increasing variety and complexity of tissues and organs possible to derive using bioengineering).
45. Urethra in Italy, 1990. Romagnoli, Giuseppe, et al. “Treatment of posterior hypospadias by the autologous graft of cultured urethral epithelium.” New England Journal of Medicine 323.8 (1990): 527-530.
46. Cornea in Italy, 1997. Pellegrini, Graziella, et al. “Long-term restoration of damaged corneal surfaces with autologous cultivated corneal epithelium.” The Lancet 349.9057 (1997): 990-993.
47. Cornea in Italy, 2010. Rama, Paolo, et al. “Limbal stem-cell therapy and long-term corneal regeneration.” New England Journal of Medicine 363.2 (2010): 147-155.
48. Bone in Italy, 2001. Quarto, Rodolfo, et al. “Repair of large bone defects with the use of autologous bone marrow stromal cells.” New England Journal of Medicine 344.5 (2001): 385-386.
49. Bone in a Australia-Germany, 2004 collaboration. Warnke, P. H., et al. “Growth and transplantation of a custom vascularised bone graft in a man.” The Lancet 364.9436 (2004): 766-770.
34. Right intermediate pulmonary artery in Japan, 2001. Shin’oka, Toshiharu, Yasuharu Imai, and Yoshito Ikada. “Transplantation of a tissue-engineered pulmonary artery.” New England Journal of Medicine 344.7 (2001): 532-533.
50. Bladders in USA, 2006. Atala, Anthony, et al. “Tissue-engineered autologous bladders for patients needing cystoplasty.” The lancet 367.9518 (2006): 1241-1246.
51. Extra-cardiac cavopulmonary conduits in Japan, 2010. Hibino, Narutoshi, et al. “Late-term results of tissue-engineered vascular grafts in humans.” The Journal of thoracic and cardiovascular surgery 139.2 (2010): 431-436.
52. Arteriovenous fistula for dialysis access in a Argentina-Austria-Poland-USA collaboration, 2009. McAllister, Todd N., et al. “Effectiveness of haemodialysis access with an autologous tissue-engineered vascular graft: a multicentre cohort study.” The Lancet 373.9673 (2009): 1440-1446.
35. Windpipe in a Spain-Italy-UK collaboration, 2008. Macchiarini, Paolo, et al. “Clinical transplantation of a tissue-engineered airway.” The Lancet 372.9655 (2008): 2023-2030.
53. Posterior Urethra in a Mexico-USA collaboration, 2011. Raya-Rivera, Atlantida, et al. “Tissue-engineered autologous urethras for patients who need reconstruction: an observational study.” The Lancet 377.9772 (2011): 1175-1182.
36. Post-tumor resection upper airway defect in a Sweden-UK-Iceland-Germany collaboration, 2011. Jungebluth, Philipp, et al. “Tracheobronchial transplantation with a stem-cell-seeded bioartificial nanocomposite: a proof-of-concept study.” The Lancet 378.9808 (2011): 1997-2004.
54. Bypass between superior mesenteric and left portal veins in Sweden, 2012. Olausson, Michael, et al. “Transplantation of an allogeneic vein bioengineered with autologous stem cells: a proof-of-concept study.” The Lancet 380.9838 (2012): 230-237.
37. Trachea in a UK-Germany collaboration, 2012. Elliott, Martin J., et al. “Stem-cell-based, tissue engineered tracheal replacement in a child: a 2-year follow-up study.” The Lancet 380.9846 (2012): 994-1000.