Sisyphus, the Giffen's paradox and the Holy Grail: time for organ transplantation to transition toward a regenerative medicine-focused type of research

Keywords::

• immunosuppression
• organs
• regenerative medicine
• tolerance
• transplantation

‘There is only one way to progress in science, which is to disprove science already explained and create new fundamentals of it.’ [1]

In the past 20 years, over 160 patients have received organs manufactured from autologous cells, which – in most cases – were seeded and expanded on a supportive scaffold and eventually transplanted into a patient, without any need for immunosuppression (IS) at any time after the implantation [2–7]. With these significant achievements, organ bioengineering and regeneration (OBR), a field of health sciences falling under the umbrella of regenerative medicine (RM), has shown the potential to revolutionize organ transplantation by addressing the two most urgent concerns: the need for an inexhaustible source of organs and the accomplishment of an IS-free state (IFS; more commonly referred to as tolerance). Accordingly, we recently authored a concept paper in Annals of Surgery which makes the argument that OBR has all the credentials to be correctly referred to as the new Holy Grail for organ transplantation [2]. As a corollary, transplantation research should transition towards a regenerative-medicine focus because the clinical trajectory of transplantation as a health sciences field is more suited to foster OBR than any other field.

We use the metaphor of the Holy Grail in its capacity to describe an exceptionally rare object or a near-unattainable ideal. In the transplant jargon, the establishment of IFS has long been the primary ambition of transplant researchers and the main objective of several investigations that required massive investments. To date, however, IFS remains an elusive goal [8–10]. When considering the history of the quest of tolerance, it is incontrovertible that it is, indeed, a history of fiascos rather than successes. Nonetheless, investigations aimed at tolerance have certainly produced significant knowledge of the mechanisms underlying the immune system, yet the achievement of immediate, stable and durable IFS remains far from our grasp with current knowledge and technology. Ideally, patients would receive an organ with no need of IS at any time after the transplant. IFS would be immediate (i.e., established soon after reperfusion), stable (i.e., without fluctuation) and durable (i.e., lasting as long as the new organ) [11]. Unfortunately, that has never been the case. The few anecdotal, inconsistent reports describe patients who could be weaned off IS only months after the transplant and in whom IFS was very labile. These failures should not be overblown; however, the fact that tolerance has not yet been achieved opens the field to criticism against currently adopted strategies and questions whether the dominant, immunology-based approach is valuable. In the regenerative medicine era, OBR offers an alternative approach. Furthermore, in order to prevent the mistake of persevering along the wrong path and transforming transplantation into a modern task of Sisyphus, the new horizons that regenerative medicine has opened up deserve to be explored and must be explored.

OBR may also allow transplantation to be a full technology as opposed to its current description as a ‘halfway technology’ (HWT). Introduced by Lewis Thomas [12], HWT refers to treatments that improve upon symptoms without removing the cause of a specific clinical condition, basically by managing a disease without proposing a definitive cure able to eradicate the causative agent. Organ transplantation remains in most cases a HWT for two reasons: firstly, it does not eliminate the cause of the baseline disease that normally recurs post transplantation and secondly, it requires lifelong anti-rejection therapy, which may potentially lead to severe acute or chronic toxicity causing additional clinical syndromes. Long-term management is required to minimize side effects arising from drug toxicity, to optimize the quality of patient’s life and to prevent untimely graft failure or premature death. An example that illustrates organ transplantation as a HWT is a liver transplantation performed in a patient with end-stage liver disease associated with hepatitis C virus (HCV) [2]. The transplant is lifesaving, but the virus is not removed and it may immediately re-infect the graft at reperfusion. Currently, no effective antiviral therapy can reliably prevent re-infection of the graft, which unfortunately is a universal outcome. The onset of disease recurrence is a matter of time and, eventually, advancement to cirrhosis and allograft failure occurs in 25% and 10% of cases, respectively, within 5–10 years following the original transplant surgery [13]. However, in some circumstances transplantation may become a complete technology. Such a scenario is feasible when a candidate patient receives an organ from a syngeneic donor, while the origin of the disease is removed. The candidate recipient’s immune system accepts the new organ because of identical antigen match with the donor and immunosuppression is never needed post-transplant, at any time. Examples of transplantation as full technology are noted in the case of kidney transplantation performed between identical twins or in the case of organs bioengineered from patient’s own cells. In both cases, the baseline disease, responsible for the end stage organ failure, would have been removed or cleared.

During the last few decades, due to the extraordinary success of organ transplantation, clinical indications for different types of transplants have dramatically increased. Concurrently, the widening gap between the demand for transplantable organs and the supply of viable grafts has caused patient mortality while on the waiting list to increase significantly. As a consequence, we are using more and more organs from marginal organs, some of which, unfortunately, have to be discarded due to their poor quality. Some of these discarded organs are being processed in order to produce acellular scaffolds generated from the innate extracellular matrix that represents the framework where cells are endowed and live their life. For example, we are using human kidneys deemed unsuitable for transplantation as a platform for renal regeneration [14]. Ideally, we wish to use the innate scaffolds of those kidneys as a supporting framework on which a patient’s own cells will be seeded and expanded in order to fully reconstitute the cellular compartment of the native kidney. The end product will be a kidney repopulated with autologous cells which would rule out the need for immunosuppression and allow the establishment of IFS.

Obstacles in the way of progress in transplantable organ bioengineering include the lack of comprehensive understanding of the mechanisms underlying organ development and tissue regeneration and repair, inadequacy of currently available bioreactors and of methods for revascularization and neoangiogenesis, and an insufficient understanding of the interactions between extracellular matrix and cells [2]. Moreover, although more than 160 artificial organs have been implanted so far, an international registry has still not been established. Previous experiences with abdominal and thoracic organs, along with composite tissue allotransplantation, demonstrate that registries are vital to the success of a specific new therapy as they allow strict monitoring and inspection of bioengineered implanted organs, follow-ups and potential complications. Thus, registries are critical for qualitatively and quantitatively evaluating the risk-to-benefit ratio. Additionally, registries provide an ideal interface with the public and are the most suitable mode to convey accurate information to the scientific community and to the media. A registry can unite detailed information of every single case and offer institutions performing such procedures the opportunity to share expertise and deliver data needed for critical analysis.

Therefore, though OBR research in the last two decades has been groundbreaking, there is much work that remains to be done before transplantable organs can be delivered to the patient’s bedside and massive investments are needed to foster targeted research. Government, industry and academia should act synergistically toward the same objective by splitting costs and sharing potential revenues. The rapidly increasing demand for transplantable organs justifies such investments in biomedical technology and public health. Provocatively, this status recalls the Giffen’s paradox, which is a notable contradiction to the familiar principles of supply and demand: the consumption of a good rises paradoxically as its price rises. OBR is an expensive field of research that requires substantial financial investment and industrial expansion. The massive demand for organs for patients on waiting lists, however, would sustain its consumption.

Financial & competing interests disclosure

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

No writing assistance was utilized in the production of this manuscript.