Xenotransplantation: lessons from history, genetic engineering, and early clinical experience-an interview with Dr....

Xenotransplantation has evolved from speculative experimentation into a scientifically grounded and increasingly applied clinical discipline, propelled by advances in immunology, molecular genetics, and genome engineering. In this interview, Dr. David Cooper, a pioneer in the field, reflects on the historical origins of xenotransplantation and traces key mechanistic breakthroughs, including the identification of carbohydrate xenoantigens, complement incompatibility, and innate immune barriers. Major milestones involving the organ-source pig include the development of αGal-knockout pigs, the expression of human complement-regulatory proteins, and the emergence of highly multi-gene-edited pigs enabled by CRISPR-based technology. Attention is given to kidney-specific challenges, including metabolic and physiologic incompatibilities, coagulation dysregulation, and the continued need for significant immunosuppressive therapy based on blockade of the CD40/CD154 co-stimulation pathway. Differing donor-engineering strategies adopted by various companies, unresolved barriers, such as swine leukocyte antigen (SLA) incompatibility, and lessons from early clinical experience are explored. Together, these insights highlight both the remarkable progress and the substantial challenges that remain before xenotransplantation can become a durable and scalable clinical solution.