**11. Conclusions and future prospects**

The increasing sophistication and accessibility of genome engineering toolsets and deeper understanding of immunological rejection mechanisms has allowed greater advancement in xenotransplantation than ever before. A key question is just how many genetic changes are required in order to make a pig organ suitable for transplantation? While the critical experimental data needed for such an assessment is still accumulating, it is clear that the number of alterations required for one organ may be different from another. For example, xeno-hearts with relatively minimal genetic modifications have demonstrated months to years survival in transplantation studies with non-human primates, whereas xeno-lungs with more extensive modifications have yet to survive more than a few weeks. This is due to the relative differences in structure and function of organs, the resilience to trauma, and susceptibility to rejection responses. Furthermore, tolerance mechanisms may be able to supplant the need for some genetic modifications, and thus the specific protocols and treatments will govern the ultimate complement of alterations.

The immediate need in xenotransplantation is to define the specific genetics required for xenoorgan survival, however, it is possible to project further enhancements such that porcine organs may be superior to human organs for human transplant. Synthetic biology approaches have created novel genetic circuits which can react in real time to human immune responses, inducing counter-reactions in the porcine cells to circumvent and tolerize the xeno-organ against human rejection. Furthermore, xeno-organs may be engineered to express protein therapeutics to further control human immunity while saving hundreds of thousands of dollars in expensive biotherapeutic treatments. Thus, the first version of pigs appropriate for xenotransplantation are likely to be further refined and improved to create increasingly useful rejection-free organs.
