The Future of Transplantation

Since 1902, animals have been studied and occasionally used as sources of organs for transplantation, usually when human organs were unavailable. Clinical organ xenotransplantation invariably failed, whereas clinical organ allotransplantation rose to become a primary treatment for failure of the heart, kidneys, liver, and lungs. Still, a shortage of human organs has limited organ transplantation and motivates ongoing efforts to advance xenotransplantation into clinical practice.

Griffith and colleagues¹ now report in the Journal the transplantation of a heart from a pig into a patient who had severe cardiac failure. The pig was genetically engineered to disrupt certain genes, including those encoding enzymes that synthesize three saccharide antigens recognized by human natural antibodies, as well as to express certain human genes — those encoding CD46 and CD55 (which regulate complement), thrombomodulin and the endothelial receptor for protein C (which regulate coagulation, inflammation, and fibrinolysis), CD47 (which thwarts untoward targeting by macrophages), and heme oxygenase 1 (which resists inflammation).² These modifications partially address the molecular incompatibilities that are thought to make xenografts especially vulnerable to immunity, thrombosis, and inflammation. For the recipient, an intense regimen of immunosuppression was used, including antibodies that deplete T cells and B cells and antibodies that disrupt CD40–CD40L interactions (countering T-cell–dependent B-cell responses that have been found to limit the survival of cardiac xenografts in nonhuman primates³). After transplantation into the heavily immunosuppressed recipient, the xenograft functioned acceptably for 7 weeks but then suddenly failed for reasons yet unclear, and the recipient died 11 days later, on the 60th day after transplantation. Given past failures, one might justifiably ask whether this recent xenotransplantation provides a glimpse at the future treatment of organ failure or merely fulfills a longstanding quip that xenotransplantation is and always will be the future of transplantation.

Regardless of whether this xenograft launched the future of transplantation, this report provides a glimpse of how quickly and profoundly genetic and biologic engineering and cell and developmental biology potentially can be marshalled to attack problems in medicine. Thirty years ago, the incompatibility of complement regulation between species was postulated to underlie the invariable failure of xenotransplants, and genetic engineering of pigs was proposed as a solution.⁴ Testing that idea took 5 years because genetic engineering relied on random insertion of DNA and breeding through several generations to ensure germline modification. In contrast, the techniques used to generate the pigs that Griffith and colleagues used allow multiple site-specific modifications to be introduced in somatic cells (or pluripotent stem cells in other contexts), which, in combination with reprogramming and cloning by nuclear transfer, generate founder animals. Today, genetic engineering vastly expands, precisely controls, and hastens modification, enabling the testing of some characteristics and ad hoc modification before animals are generated. For example, when hypertrophic changes in experimental cardiac xenografts were found to occur, the authors quickly targeted the endothelial growth hormone receptor gene in existing animals and conducted tests with experimental xenografts.^3,5,6 Cloning of the pigs fixed the introduced genetic changes and the genetic background of the pigs, thereby hastening the evaluation of imparted characteristics, but potentially slows the discovery of the optimal background of source animals.⁷

Molecular, cellular, and genetic approaches used to generate pigs for xenotransplantation represent a fraction of the techniques currently directed at diabetes, hypertension, and vascular disease, among other conditions. Because these conditions cause many of the cases of organ failure and fuel demand for transplantation, one might wonder whether the advances reported by Griffith and colleagues presage a decreasing demand for organ transplantation. We think the answer is no. Since aging is associated with progressive decline in the function of the heart, kidneys, and other organs, advances that extend life expectancy will ultimately increase the prevalence of organ failure and potentially the demand for transplantation.⁸

But a more important question may be whether techniques like those used to engineer pigs could be applied to generating human tissues and organs for implantation into patients with organ failure. Pluripotent stem cells and cells of other types are increasingly explored for generation of autologous organs through organogenesis or three-dimensional tissue engineering. Use of autologous organs, modified to resist underlying disease, presumably would avert the need for — and toxic effects of — lifelong immunosuppression.

The advent of such autologous implants would be likely to decrease the demand for allotransplantation; ironically, however, we think it might increase the demand for xenotransplantation in two contexts. If organogenesis is pursued, animals engineered to support the development of human tissues (reverse xenografts) could limit costs and solve certain challenges. Furthermore, patients awaiting the development of autologous implants would require treatment of organ failure for months or longer while the implant is generated. Xenografts offer advantages (availability, cost, and defined characteristics) over allografts as sources of temporary support.

Several steps could advance clinical application of xenotransplantation for whatever purposes xenografts might fulfill. The set of genetic modifications of the pig used by Griffith et al. have been found to benefit xenotransplants in nonhuman primates. Whether the same modifications or others would benefit xenotransplants in human recipients will remain uncertain until this clinical xenograft and others are fully studied. Reduction in the number and extent of genetic modifications of pigs could benefit the long-term function of xenotransplants, since the untoward insertion of genetic sequences has been associated with myocardial aging.⁹ Still more important will be efforts to decrease the intensity and toxicity of immunosuppression. Since immunity to xenografts may engage narrower pathways of T-cell activation than allografts,¹⁰ perhaps immunosuppression can be focused to reduce longer-term toxic effects for recipients and grafts (and possibly autografts).