Table 1.
Considerations in Selecting a Source Species for Organ Xenografts
| Species | Advantages | Disadvantages |
|---|---|---|
| Primates | ||
| Ape | Concordant | Scarce, endangered, endogenous retrovirus |
| Chimpanzee, gorilla, orangutan | Ethical concerns, slow breeding | |
| Bonobo | Small size except mature adult male | |
| Gibbon | Small size | |
| Monkey | Concordant | Endogenous retrovirus |
| Baboon | Small size except mature adult male | |
| Macaque | Small size, B-virus susceptible | |
| Marmoset, capuchin, howler | Small size | |
| Large mammals bred in captivity | ||
| Bear | Discordant? Large size at maturity, slow breeding | |
| Great cat (lion, tiger) | Discordant? Slow breeding, endangered in wild | |
| Domesticated large mammals | ||
| Horse | Discordant, large size at maturity | |
| Cow | Discordant, large size at maturity | |
| Dog | Size (some breeds) | Discordant, ethical concerns |
| Sheep | Discordant, small size except adult male | |
| Pig | Rapid propagation | Discordant, porcine endogenous retrovirus |
| Commercial | Large size at maturity | |
| Mini-swine | Size-compatible | Slower growth to adult human size |
To be practical as an orthotopic heart replacement, the cardiac physiology must be compatible with humans in size and functional capacity. Organs from concordant species avoid the immunological barrier of preformed antibody and hyperacute rejection but are considered impractical because of infectious disease risks, compelling ethical concerns, and scarcity and slow natural breeding cycles that would constrain the impact even if successful.
Cloning and in vitro fertilization have been developed for most domesticated species, including swine, and are useful to rapidly propagate animals with desired characteristics for evaluation in informative models but are expensive and inefficient for commercial-scale production relative to natural breeding.
Among domesticated species, pigs were chosen as the best potential source of heart and other organ xenografts because their short gestation (3 months, 3 weeks, and 3 days), rapid growth to adult human size, and sexual maturity within 1 year compare favorably with other potentially size-compatible domesticated animals. These characteristics should facilitate efficient propagation by natural breeding once lines with genetic modification necessary to clinical success are defined. Genetic engineering for knockout of carbohydrate genes, for expression of protective transgenes, and to disable potentially pathogenic endogenous retroviruses has been developed and refined in swine specifically to enable clinical xenotransplantation. Hearts and other organs from mature naturally occurring mini-swine and pigs with knockout of the growth hormone receptor are similar to those of adult humans in size and functional capacity. Inbred genetically defined pig lines have been developed that may be useful to promote induction of donor-specific cross-species immunological tolerance and to minimize long-term recipient immunosuppression requirements.