Chapter 136
Controlling Our Immune System — 13
In 2015, I attended a meeting in Boston with George Church, one of the pioneers of genomics and genome editing, to discuss the exciting new frontiers in life science. It stuck with me because he said that it would be possible to edit tens and even hundreds of genes at once, to fully block the recipient’s immune response to a transplant organ. This would stimulate the field of xenotransplantation, particularly transplants from pigs, which have strong human resemblance in structure and physiology. Since it was in the early days of CRISPR editing, when successfully targeting one gene was daunting enough, I thought Church’s idea was far-fetched. But now we’re seeing pig organs with more than sixty genomic edits that knock out the pathways to hyperacute rejection (through three glycan antigens), blocking the complement cascade, reducing the potential for clotting, and inactivating retroviruses that could risk transmission. All the cell and antibody strategies we’ve discussed for promoting immune tolerance have come into play for organ transplantation, but acute and chronic organ rejection remains a very serious risk. Moreover, the dire shortage of donor organs leaves many people highly vulnerable on waiting lists, or not deemed as candidates for transplantation. Each day in the United States, seventeen people die while waiting for an organ transplant.
Genome editing of pig organs has raced ahead since 2015. The first pig heart, complete with ten modifications to its genes, was transplanted into a patient who had been denied by four heart transplant programs. The same ten genomic edits are being used for kidney transplantation. For these early attempts, the transplant recipients received standard immunosuppressive therapy, and the editing was not sufficient or intended to achieve immune tolerance. It represents the initial steps of precise and extensive genome editing—to take control of our immune response—for promoting successful xenotransplantation.
In discussing cancer and the control of our immune response, we’ve covered both ends of a spectrum—from the ways cancer can defeat our immune system to that system’s own unbridled, self-directed attacks. While there will always be more to learn about the intricacies of this exceptionally complex system, the progress that is being made across the spectrum deserves our appreciation and kudos. It exemplifies how pivotal our immune system is to every organ’s function, our health, and our health span. Just as we’re seeing engineering our B and T cells and vaccines help us fight cancer, these same tools are showing exceptional promise for inducing tolerance. Dialing up or down, on demand. That represents new and vital progress; controlling our immune system unlocks vast potential to prevent diseases.
What is the ultimate potential? As we get into advanced age, we’ll someday be able to rejuvenate our immune cells to prevent immunosenescence and inflammaging. Hold that thought for a bit.
Meanwhile, there are new threats coming our way. What new roles will our immune system play as we fight off novel infectious pathogens?