Transplanting human organs and other body parts has always had one major drawback: To avoid rejection of the transplant, recipients have to accept a lifelong regimen of drugs that suppress the immune system. These drugs may increase the risk of cancer, heart disease and other maladies. And while that tradeoff may seem negligible when a new heart, liver or kidney can keep a patient alive, it looms larger for transplants that are intended to improve a life, not save it.

So-called vascularized composite allografts (VCAs) include transplants of hands, faces and other external body parts. The first penis transplant in the United States, performed in May 2016 at Massachusetts General Hospital, is one such surgery. The prospect of taking immunosuppressive drugs and dealing with their side effects may dissuade some candidates from pursuing these procedures. In December 2016, there were just six people on a waiting list for new hands and arms in the United States—compared with nearly 122,000 patients in a queue for life-saving organs.

But eliminating the need for the drugs might expand the number of patients seeking VCAs, and there is progress toward that goal. Inducing tolerance—tricking the body into accepting foreign tissue without long-term use of drugs—was first achieved in humans in 2002, when MGH doctors produced a state known as mixed chimerism in a patient receiving a kidney transplant. Doctors removed hematopoietic stem cells (HSCs) from the donor’s bone marrow (the donor was the patient’s mother) and transplanted them into the kidney recipient. The cells took up residence in the recipient’s bone marrow and formed a hybrid immune system that reprogrammed her body to accept the new organ. (Mixed chimerism gets its name from the chimera, a mythical beast made up of body parts of several different animals.)

So far, 10 kidney-transplant patients have been treated with mixed chimerism at MGH, and while some eventually required antirejection medication, others have maintained drug-free tolerance for years. Now MGH researchers are investigating whether a similar protocol can be used to induce tolerance of VCAs.

But there’s a catch. In the original study of kidney patients, all of those who received organs and HSCs got them from close blood relatives, with whom the organ recipients shared some of the same immune system proteins known as human leukocyte antigens (HLAs)—a genetic similarity that made the recipients’ bodies less likely to reject the foreign tissue. VCA transplants, however, must come from deceased donors who are usually not related to the recipients.

MGH transplant surgeon Curtis Cetrulo—who was on the team that did the penis transplant and who has also performed a hand transplant—and his colleagues have achieved mixed chimerism in miniature swine that received skin grafts and even limbs from donor pigs that were only partial HLA matches.

The next step would be to find a way to achieve mixed chimerism in a recipient when the donor tissue comes from someone unrelated—the most likely scenario—and therefore a complete mismatch. This advance has been challenging in animal models, especially when particular HLA proteins known as MHC class I antigens don’t match up. However, Cetrulo and his team recently overcame that problem in a pig that received a transplanted limb, and they hope to replicate the procedure soon. Safely achieving mixed chimerism in humans receiving VCAs might not only lead more patients to receive new hands, faces or penises; shifting the risk-benefit ratio of the surgery could also make it feasible to transplant smaller body parts such as fingers and ears.