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A Pig for Every Pancreas

By David Mendosa


When Michael Helyer was 23, he found out that he had type 1 diabetes. But 18 years later he had a chance to take part in a pioneering clinical trial to replace the beta cells in his body. He jumped at it. His doctor transplanted beta cells from newborn pigs into Michael's body.

Pig

This 1995 clinical trial was primitive by today's standards. But almost ten years later, Michael was sure that they still reduced how much insulin that he needed to take.

"I said that we wouldn't see anything at all," his doctor, Bob Elliott, mused. But he checked anyway and found that some of the pig cells were alive and functioning in Michael's body. They replaced some of his beta cells, which make up most of the islets of Langerhans in the pancreas.

"It was a shock," Dr. Elliott told me in May. In fact, it was some of the best news he had in the two decades he has worked on transplanting pig beta cells into people who have diabetes.

A world leader in diabetes research, Dr. Elliott is now emeritus professor of child health research at New Zealand's University of Auckland and medical director of Living Cell Technologies Ltd. (LCT), which he cofounded in 1987.

"I had my appetite whetted for islet cell transplantation way back in the 1970s, when I did my research training in Denver, Colorado," he told me when I called him at his home in New Zealand from mine in Boulder, Colorado. "A guy there was using human fetal islets. It didn't work. I went away from it thinking that this was one area of research that I wasn't going to get into."

But Dr. Elliott changed his mind when David Collinson, a businessman and father of a three-year-old child with diabetes, approached him. Collinson "put his money into it," Dr. Elliott says. Together they cofounded LCT to transplant pig islets into people with diabetes.

From the beginning Dr. Elliott had two guiding principles in his research. He says that as a pediatrician he knew that "rule number one is that we can't use immunosuppression, because it is dangerous."

"The other is that there aren't enough human cells to go around." That made his pathway clear.

But it's been a long path filled with a lot of twists and turns. Even now the clinical trial that Michael Helyer volunteered for is only one of four published human trials of pig islet transplantation, according to Dr. David K.C. Cooper of the Thomas E. Starzl Transplantation Institute of the University of Pittsburgh Medical Center.

Dr. Cooper tells me that Dr. Elliott's work is more encouraging than the other trials, which were in Sweden, China, and Mexico. "He is more aggressive than some of the people in the field," Dr. Cooper adds.

The trials in Sweden and China didn't show any improvement in beta cell function. The trial in Mexico did. But the ethics of this trial came under heavy attack from what Dr. Cooper calls "the xenotransplantation establishment." Perhaps the most serious criticism is a lack of lifelong monitoring to make sure that the volunteers don't develop any transmitted infection.

The first use of the term xenotransplantation appeared only in 1967, according to the Oxford English Dictionary, although documented accounts of attempts date back to the 1700s. It means "the transplantation of organs, tissues, or cells from one species to another," especially humans. The prefix "xeno" comes from the Greek term for stranger or foreigner. Dr. Cooper edits the journal Xenotransplantation and wrote the fascinating book Xeno (Oxford, 2000) for non-professionals. He kindly loaned me a copy of the book.

Following Dr. Elliott's first human clinical trial of pig beta cell xenotransplants more than a decade ago, his company announced this year that it would carry out a human clinical trial together with the ANO Institute of Biomedical Research in Moscow. But "doing things like this in Russia makes us nervous," another expert in this field told me not for attribution. "Their standards are lower."

However, it is good news, Dr. Cooper tells me, that in April the New Zealand regulator MedSafe authorized LCT to conduct a clinical trial in that country. That's better than the one in Russia, because of better government oversight, Dr. Cooper says.

They will start the New Zealand trial in October or November of this year, Dr. Elliott says. He expects finish around the end next year.

Will your trial in New Zealand be a lot more acceptable than the one in Russia? I asked. "Yes, although they are pretty much the same trials, identical apart from the dosage schedule. In the New Zealand trials there will be eight patients, and in the Russian trials there will be six."

Dr. Elliott has two main strategies to avoid using drugs that suppress the immune system.

One is to encapsulate the islets in a purified form of alginate, a viscous gum that comes from seaweed.The alginate isolates the pig cells from the human immune system so our bodies don't recognize them as foreign. At the same time nutrients can pass into the cells, and insulin and other hormones can pass from the cells into the body.

Since alginate is a natural product, it is hard to make the same alginate over and over again, Julia Greenstein, manager of strategic programs and immunology for the Juvenile Diabetes Research Foundation, tells me. It's more of an art than a science.

Dr. Elliott agrees. "An awful lot of technology has gone into it. The purification itself is extremely tedious, but we've probably got the purest alginate in the world." A collaborator of his, Dr. Riccardo Calafiore of the University of Perugia in Italy, developed it.

The word encapsulation is misleading, Dr. Elliott says. "The islets are stirred around with a solution of alginate and squirted through a needle, which coats the islets. They drop as droplets into the solution. So the islets are encased in little droplets of alginate."

His other strategy is to use the progeny of 15 pigs that a whaling captain named Abraham Bristow left on Auckland Island two hundred years ago. This uninhabited island is halfway between New Zealand and the Antarctic. These feral pigs have been isolated from all the modern viruses that all normal pigs carry.

If you don't have pigs that are free of viruses, you are wasting your time, Dr. Elliott says. He know of only two other such herds.

The Mayo Clinic has one of them, although its pigs are optimized to meet the requirements of heart transplants, which are different from those of beta cell transplants, Dr. Bernard Hering told me.

Dr. Hering is the scientific director of the Diabetes Institute for Immunology and Transplanation at the University of Minnesota. He is also the inspiration for the Spring Point Project, a non-profit organization created to become the world's leading source of pure pig cells for islet transportation.

The Diabetes Research and Wellness Foundation funded this biosecure facility in part with a $6.2 million grant. The facility is isolated from the environment and is now in full operation with what Dr. Hering calls healthy "medical-grade pigs." He expects to start clinical trials in 2009.

The other prong of Dr. Hering's strategy and the unique aspect of his research is to use an environment of the body where islets are protected from destruction or rejection. This means that the body won't reject the transplant even without using the typical heavy doses of drugs to suppress the recipient's immune system.

"We can create an environment that is permissive for survival but non-permissive for rejection or destruction," he told me. "This is what we refer to as the islet sanctuary or an immune privileged environment."

Our bodies have several of these potential sanctuaries. One is the testes, which the trial in Mexico used. Another is a female counterpart, the placenta. Researchers have identified the brain and the eye are two other such environments, but each have clear limitations.

Are you using one of these environments? I asked Dr. Hering. No, he replied.

"But we try to follow the example of nature and engineer or create a site that mets the same profile and features," he continued. "And as such it is immune privileged."

Does he have a specific site in mind?

"We are working with one site called the omentum," he told me. "It is a thin layer of tissue which is hanging over the abdomen like an apron."

I asked Dr. Hering several questions about how many pigs he has now and expects to have. He replied that the number of pigs wasn't the question. "We don't measure progress by the number of pigs we have at a time."

His research will go step-by-step and doesn't require a million pigs now. But Dr. Hering and Dr. David E.R. Sutherland, the director of the Diabetes Institute for Immunology and Transplantation, are looking ahead.

"We really need to solve the supply problem," says Dr. Sutherland. "The potential for human donation is about 12,000 to 13,000 people who die every year under circumstances where we could take organs. But we only get permission for a little bit more than half. And even if we got permission from all, we would still have a shortage.

"But there's a pig for everyone."

Sidebars:
Can Pig Cells Cure Diabetes?

Transplanted pig cells may be our best chance for a cure. But everyone is avoiding the hype that has accompanied most every treatment for diabetes since the discovery of insulin in 1921.

"I don't like to use the word cure, but secretly that's what I hope," Dr. Bob Elliott, the medical director of Living Cell Technologies Ltd., told me. "In public it's 'an improved treatment.'"

The other main hope for a cure is a still unspecified application of stem cell research. But that lies over some distant horizon.

Pancreas and islet cell transplants from other people have reversed diabetes. But they are in short supply.

And these transplants from our own species, called allotransplants, have all required drugs to suppress the immune system of the patients who received them. The famed Edmonton Protocol, which Dr. James Shapiro and his colleagues at the University of Alberta in Edmonton, Canada, began in 1999, used drugs that are less toxic than those used earlier.

But any drugs that recipients have to take to suppress their immune systems can trade one problem for another. "Immunosuppression is worse than diabetes," says Alastair Gordon, president of the Islet Foundation in Toronto.

Dr. David K.C. Cooper of the Thomas E. Starzl Transplantation Institute of the University of Pittsburgh Medical Center doesn't go that far. He thinks that immunosuppression can be the lesser of two evils.

"For somebody dying of heart failure it is obviously significantly less, but for somebody with diabetes who could go on  —  although they may get complications of the diabetes  —  it's certainly an exchange of problems and may not be beneficial to them."

Can Pig Cells Help People with Type 2 Diabetes?

All research on transplants of pig islet cells has focused on people with type 1 diabetes. But Dr. Elliott thinks that researchers will be able to extend their work to type 2s.

"In many ways it is probably going to be an easier problem," Dr. Elliott told me. "We intend to get into that. It is a much larger problem."

Another problem is the expensive. But the cost will certainly come down with experience.

"Xenotransplantation will clearly be expensive initially, just as open heart surgery and liver transplants were," Dr. Cooper told me. "But once it gets going it will become cheaper and cheaper. And if we can prevent complications, we will save huge amounts of money."

Can Xenotransplation Transmit Pig Viruses?

Most of the concern with the risk of infection has been about PERV, the porcine endogenous retrovirus. But "there has been no demonstration of any cross species infection," Julia Greenstein, manager of strategic programs and immunology for the Juvenile Diabetes Research Foundation, told me.

"The risk of infection is extremely low," Dr. Cooper says. "People have been saying that the PERV virus might do humans harm. But I don't think that infection is going to be the big problem."

He told me that he was one of eight members of a Food and Drug Administration committee that looked into it. "All the others were virologists and they said, 'Why are you wasting our time on this virus? It is never going to do anybody harm. It is such a wimpy virus.'"

And the alternatives can be more dangerous. Drugs that suppress the immune system increase the risks of cancer, Dr. Cooper says. Transplants from other humans have their own dangers.

"I did heart transplants for 17 years," he told me, "and we were always transferring infections. We know that pigs will be much cleaner than human donors."

"People say we shouldn't do this business because of unknown viruses," Dr. Cooper concluded. If we always worried about the unknown, he says, we would never make any advancements.

But as long as the benefits exceed the risks and the known viruses are either absent or can be controlled, it makes sense to proceed, he says. And the benefits of transplanted pig islet cells can be huge.


    David Mendosa is a freelance journalist and consultant specializing in diabetes and lives in Boulder, Colorado. When he was diagnosed with type 2 diabetes in February 1994, he began to write entirely about that condition. His articles and columns have appeared in many of the major diabetes magazines and websites. His own website, David Mendosa’s Diabetes Directory, established in 1995, was one of the first and is now one of the largest with that focus. Every month he also publishes an online newsletter called “Diabetes Update.” Twice weekly he writes for his blog at http://blogs.healthcentral.com/diabetes/david-mendosa. He is a coauthor of What Makes My Blood Glucose Go Up...And Down? (New York: Marlowe & Co., and second American edition 2006, and other publishers in the U.K., Australia, and Taiwan).


This article originally appeared in the July 2007 issue of Diabetes Wellness News, pages 1 and 6-8.


Last modified: June 27, 2007

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