Should Replacement Organs be Made, Grown, or Stolen?

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. _TheScientist

In advanced countries, people are living longer. Citizens are making greater and greater demands from medical technology -- some people think they should live forever. But the human body eventually malfunctions and wears out, eventually coming to an end in cascading failure. But what if tissues and organs could be replaced as they began to show early signs of trouble -- before they could trigger the inexorable cascade to death?

Today, the organ shortage is an even bigger problem than it was in the 1980s. In the United States alone, more than 114,000 people are on transplant lists, waiting for an act of tragedy or charity. Meanwhile, just 14,000 deceased and living donors give up organs for transplants each year. The supply has stagnated despite well-funded attempts to encourage donations, and demand is growing, especially as the organs of a longer-lived population wear out. _TheScientist

There are not enough human cadaver organs to supply the need. The state of the art in both artificial organs and in lab-grown organs and tissues, is years away from large scale application.

So what about stealing the organs? I am not talking about stealing from humans -- as is done in China and other corrupt nations not bound by the rule of law. I am referring to taking organs from animals to use in humans -- xenotransplantation.

These animal organs will have to be designed and engineered to be compatible with the human body, to avoid rejection. And just as animals supply much of our food and an increasing amount of fuels and pharmaceuticals, they could also supply life-saving organs.

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.

The human immune system does not take kindly to the presence of a pig organ. A ready-made armada of antibodies recognizes a sugar molecule called alpha-1,3-galactose (α-gal), which coats the surface of pig blood vessels but is absent from human tissues. The antibodies activate a squad of proteins that make up the complement system, which punches holes in the membranes of the foreign cells on contact. “When I started in the field around 15 years ago, if you put a pig organ into a primate, it was lost in a matter of minutes,” says David Sachs, an immunologist at Massachusetts General Hospital.

Cooper first discovered the α-gal problem in 1992, but it took him until 2003 to fix it. He and others engineered pigs without the α-1,3-galactosyltransferase gene that produces the α-gal residues. In addition, the pigs carry human cell-membrane proteins such as CD55 and CD46 that prevent the host’s complement system from assembling and attacking the foreign cells. “It took 10 years for those pigs to become available, but they made a big difference,” says Cooper.

...While some scientists struggle to get human bodies to accept pig organs, others are attempting the more ambitious feat of engineering human organs from scratch. Such organs, grown from a patient’s own cells, should avoid the problems of immune rejection that plague the field of xenotransplantation. “Cartilage, skin, and bone are already on the market. Blood vessels are in clinical trials. The progress has been really gratifying,” says Laura Niklason of Yale University.

...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.

...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.

...Whether the scaffold is natural or artificial, clinicians need to seed it with patient’s cells. For bladders or tracheas, it is enough to collect these from a small biopsy. That will not work if the organ is diseased, or if it’s a complex structure of multiple tissue types, or, as in the heart, if its cells are naturally reluctant to divide. In such cases, clinicians will need either stem cells, which can divide and differentiate into any cell type, or progenitor cells that are restricted to specific organs. Since 2006, one source of stem cells has been adult tissues, which scientists can now reprogram back into a stem-cell like state using just a handful of genes. These induced pluripotent stem cells or iPSCs, could then be coaxed to develop into a tissue of choice. “For me, the cells have always been the most difficult part,” says Vacanti, “and I’d say the iPSCs are the ideal solution.” _The Scientist