In the race to solve the organ shortage, xenotransplantation is like the slow and steady tortoise, still taking small steps after a long run-up, while organ engineering is more like a sprinting hare, racing towards a still-distant finish line. Most of those betting on the race are backing the hare. Industry support has dried up for xenotransplantation after years of slow progress, leaving public funders to pick up the expensive tab. Stem cells, meanwhile, continue to draw attention and investment. But both fields have made important advances in recent years, and the likely winner of their race—or whether it will result in a draw—is far from clear.
Pigs could provide all the organs that we need. They are the right size, and we already have the infrastructure to breed them in large numbers. For decades, people have been fitted with heart valves from pigs, and diabetics injected themselves with pig insulin before we learned how to synthesize the human version of the hormone. Whole-organ transplants, however, are another matter.
In 2008, Harald Ott of Massachusetts General Hospital and Doris Taylor of the University of Minnesota dramatically demonstrated the potential of organ engineering by growing a beating heart in the laboratory. As physician-scientists, the two often see patients in dire need of transplantation. They started by using detergents to strip the cells from the hearts of dead rats, leaving behind the extracellular matrix—a white, ghostly, heart-shaped frame of connective proteins like collagen and laminin. Ott and Taylor used this matrix as a scaffold. They seeded it with cells from newborn rats and incubated it in a bioreactor—a vat that provides cells with the right nutrients, and simulates blood flow. After 4 days, the muscles of the newly formed heart began contracting. After 8 days, it started to beat.
This laborious technique, known as whole organ decellularization, is like knocking down a house’s walls to reveal its frame, only to replaster it again. It works because the frame is perfect—it retains the complicated three-dimensional architecture of the organ, including the branching network of blood vessels that provide the cells with nutrients and oxygen. It also preserves the array of complex sugars and growth factors that covers the matrix and provides signposts for growing cells, nudging them into the right shapes and structures. “The matrix really is smart,” says Taylor. “If we put human cells on human heart matrix, they organise in remarkable ways. We can spend the next 20 years trying to understand what’s in a natural matrix and recreate that, or we can take advantage of the fact that nature’s put it together perfectly.”
Ott and Taylor’s groundbreaking feat has since been duplicated for several other organs, including livers, lungs, and kidneys. Rodent versions of all have been grown in labs, and some have been successfully transplanted into animals. Recellularized organs have even found their way into human patients. Between 2008 and 2011, Paolo Macchiarini from the Karolinska Institute in Sweden fitted nine people with new tracheas, built from their own cells grown on decellularized scaffolds. Most of these operations were successful (although three of the scaffolds partially collapsed for unknown reasons after implantation).
Decellularization has one big drawback: it still depends on having an existing organ, either from a donor or an animal. Frustrated by the wait, Macchiarini tried a different approach. In March 2011, he transplanted the first trachea built on an artificial, synthetic polymer scaffold. His patient, an Eritrean man named Andemariam Teklesenbet Beyene, had advanced tracheal cancer and had been given 6 months to live. “He’s now doing well. He’s employed, and his family have come over from Eritrea. He has no need for immunosuppression and doesn’t take any drugs at all,” says Macchiarini. A few months later, he treated a second patient—an American named Christopher Lyles—in the same way, although Lyles later died for reasons unrelated to the transplantation.
Macchiarini now has approval from the US Food and Drug Administration to perform these transplants in the United States on a compassionate basis, for patients who have no other options. “The final organ will never ever be as beautifully perfect as a natural organ,” says Macchiarini, “but the difference is that you don’t need a donation. It can be offered to a patient in need within days or weeks.” By contrast, even if a donor is found, a simple trachea can take a few months to regrow using a decellularized scaffold. Other scientists have enjoyed similar success with other organs. In 1999, Anthony Atala of the Wake Forest Institute for Regenerative Medicine grew bladders using artificial scaffolds, and transplanted them into seven children with spina bifida. By 2006, all the children had gained better urinary control. Atala has just completed Phase II trials of his artificial bladders.
Artificial scaffolds are the future of organ engineering, and the only way in which organs for transplantation could be mass-produced. In future, it will be possible to simulate their architecture with computer models, and fabricate them with modern printing technology (see “3-D Printing,” The Scientist, July 2012.) But even if the architecture is correct, the scaffold would still need to contain the right surface molecules to guide the growth of any added cells.
Xenotransplantation and organ engineering offer different solutions to the organ crisis, but they share similarities. After decades of research, both fields are in the middle of important clinical trials involving simpler tissues and organs, but complex ones like lungs or liver remain a distant goal. “I think we’re still 2 decades away from something that’s clinically realizable,” says Niklason.
Xenotransplants will always have to deal with an immune clash of some degree, so growing an organ that is perfectly matched to a patient would be preferable. The question is whether tissue-engineering technologies will reach that point before genetic engineering enables the first transgenic pig hearts or kidneys to be successfully installed in patients. Sachs says, “I consider xenotransplantation still the nearest-term, best hope for solving the organ shortage, but in the long run, I think tissue engineering will replace it.”
There is also the matter of scale. Platt thinks that organ engineering is too costly to meet the needs of everyone waiting for a transplant. “You’d have to turn over the entire GDP of a country to accomplish that,” he says. On the other hand, “I could get a pig for a couple of hundred dollars.” But Macchiarini argues that organ engineering is in its infancy, and every advance improves efficiency and lowers cost. “What we did in 2008 in 6 months, we can now do in a few weeks,” he says. “We do care about getting this to every patient.” Mass-producing artificial scaffolds will make organ engineering even more cost-effective. “When you scale them up, the bulk materials and manufacturing tech are extremely cheap,” he says. “I think it’s going to be cheaper than growing lots of pigs.”