Weighing the Risks and Benefits of Xenotransplantion

By Jason Socrates Bardi

If thou art privy to thy country's fate, Which, happily, foreknowing may avoid, O, speak!

——Shakespeare, Hamlet, Prince of Denmark, 1600

The patient is put under general anesthesia for the duration of this major operation.

When he was a teenager, this patient developed Type 1 ("insulin dependent") diabetes—one of the most prevalent chronic diseases among children in the United States. For reasons that are not completely understood, his immune system began destroying a certain type of cell in his pancreas called "islets." These islets are the body's only source of insulin, a protein responsible for regulating blood glucose levels. Without the islets, the insulin disappears from the bloodstream, and without insulin, the glucose in the bloodstream increases and is maintained at levels much higher than normal, causing damage to the body's organs.

For his entire adult life, he has injected insulin every day. Now he is getting a more advanced treatment—one necessitated by years of damage to his internal organs. He is getting a new, healthy pancreas from a human donor.

A team of surgeons work several hours to place the pancreas in the abdomen, connecting it to the major artery and major vein that bring it blood, and to the intestine.

Some 1,500 to 1,800 pancreatic transplants are performed every year in the United States, and most are successful. Seventy-five percent of the grafts are viable five years after the operation.

The operation is a significant scientific and medical breakthrough, because when it is over, the patient's new pancreas begins producing insulin and monitoring the body's blood sugar automatically. But to fully recover from this major procedure, a patient like the fictional one portrayed here usually must take at least two weeks in the hospital and another three months at home.

The Islets Have It?

A much less invasive and safer alternative involves injecting "islet" cells isolated from the pancreas into the patient.

In this experimental procedure, a team of doctors removes the pancreas from the donor and insufflates it with collagenase, a proteolytic enzyme that breaks down the collagen in the tissue. They then supervise a controlled digestion of the pancreas that releases the islets, after which the islets are purified using a specially designed density gradient and a centrifugal cell separator device originally developed to purify bone marrow stem cells.

Then, says Daniel R. Salomon, associate professor in The Scripps Research Institute (TSRI) Department of Molecular and Experimental Medicine, you deliver them via a single injection into the liver. It is a much faster and less invasive procedure, and the patient's recovery time is quicker than in the whole organ transplant.

However, islet transplantation and whole pancreas transplantation are both limited by the severe shortage of available human donor organs—there are only about 5,000 available per year in the United States. And because of this shortage, the islet operation tends to be done much less than the whole organ tansplant. Islet transplantation has just not been around long enough for there to be sufficient data supporting the long-term survival and normal function of these cell transplants.

"What are you going to do if you have a pancreas available and a patient who has waited months to get it?" asks Salomon. "You are not going to use it on an experimental procedure."

Still, pancreatic islet transplantation has the potential to make a huge difference in the future because there are far more diabetes patients than there are pancreata and if pancreatic islets could be recovered from another source, many more patients could be treated.

Towards this end, some U.S. scientists are trying to find a way to grow and expand pancreatic islets in culture, for instance. Other groups are looking at the potential of using gene therapy to transfect insulin-producing genes into a patient's liver or intestine cells. Some are looking at the possibility of engineering islets from adult or fetal stem cells and then transplanting these into the patient.

These are tantalizing ideas, but they may never pan out, and their application is years away even if they do.

"Therapeutic gene delivery—don't even think about it for 10 years," says Salomon. "Human stem cells—even without the political barriers—don't even think about it for 10 or 15 years."

"The best short term bet for developing a clinically viable therapy appropriate for treating tens of thousands of patients in the next five to ten years," he adds, "is to use animals as the source of the islets. Pig insulin works very well in human patients and has been used for many years."

The Cases For and Against Xenotransplantation

The argument for using animal organs is a simple one—the alleviation of human suffering. Type 1 diabetes afflicts about 1.5 to 1.8 million Americans, and accounts for 30,000 newly diagnosed cases each year. But only about 5,000 whole pancreata are available for transplantation in a given year.

"It doesn't require a degree in rocket science to be able to do the math," Salomon says. "If you want something that's over the horizon to deal with the millions of diabetes victims, xenotransplantation is a good direction to go in."

Despite acknowledging the potential advantages of xenotransplantation, Salomon is also one of the leading voices in acknowledging its potential dangers. And his opinions are often sought. He is chair of the National Institutes of Health's Center for Research Resources Consortium for Clinical Islet Transplantation, chair of the Food and Drug Administration's Biological Response Advisory Committee, and member of the Secretary of Health's Advisory Committee for Xenotransplantation.

Basically, the dangers come down to risk of infection and risk of rejection.

As the recent case of three patients contracting West Nile virus from transplanted organs from a single donor dramatically demonstrates, the possibility of acquiring emerging infections via transplantation is very real. However, in xenotransplantation, this could be addressed with special precautions. Pigs could be raised away from pathogens, in sterile conditions, the way that smallpox vaccine used to be grown on the legs of cows in sterile settings.

The risk of rejection is also a very real danger, since immune systems have to be suppressed even when a patient receives an "allo" transplant (from another human). Tissues used for xenotransplants, like pig pancreata or islets, are even more likely to be rejected.

But germlines could be transgenically altered to remove genes that cause the tissue to be rejected. In fact, the primary molecule responsible for eliciting a human immune response against porcine tissue has been identified (a galactose sugar, which pig cells carry on their surface) and can be removed by knocking out a metabolic gene (the a-1,3-galactosyl transferase).

And one could clone this new breed of donor animal to ensure each organ was nearly identical.

And this has already been accomplished by the same Scottish company that cloned the sheep Dolly. A few years after Dolly, they announced their success in cloning five piglets from an adult sow.

Because of these advances, Salomon says, there was a lot of excitement about xenotransplantation about eight years ago, accompanied by a large infusion of dollars into research in the field.

"Many felt that [these advances] would change a xenotransplant into an allotransplant [a transplant from one person to another]," says Salomon. "I think that with continued engineering of the pigs, that this is quite possible. However, like many first approaches to major challenges in medicine, the hype was far ahead of the reality and there has been a very appropriate cooling of enthusiasm in the last three years."

However, even with super clean, cloned, and sugar-free cells, xenotransplantation is still a potential risk because of the danger of infection with what is known as porcine endogenous retroviruses (PERV).


Next Page | Assessing the Risk

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Investigator Daniel Salomon acknowledges both the potential advantages and potential dangers of using pig pancreata to treat human diabetes patients. Photo by Mark Dastrup.