Work by Dr. Randall Prather brings acclaim to the University of Missouri and hope to those who need organ transplants.

Some 84,000 Americans are in dire need of vital organ transplants. They need hearts, lungs, livers and kidneys.

“Actually, the number of people who could benefit from transplants is probably double that,” said Randall Prather, professor of reproductive biotechnology at the University of Missouri-Columbia (UMC). “Unfortunately, the demand for transplantable human organs far exceeds the supply.”“We’re 1.4 billion pounds short of milk in this state—that’s how much we import each year,” Drennan explained. “If you placed that milk in tanker trucks back to back, they would reach from St. Louis to Kansas City and beyond.”

A dozen or so people die every day because a matching organ donor cannot be found—or cannot be found in time.

Prather and his team at UMC are working to correct that imbalance; not by rounding up more potential human organ donors, but by genetically tailoring pigs to provide vital organs for pigs-to-people transplants (xenotransplants). Perhaps it’s not flattering to many people (and maybe not to some pigs), but swine and humans are physiologically similar in many respects. The sequence of base pairs of genes is more similar with pigs and people than with humans and most other species. Prather is working to enhance those similarities.

“Essentially, we’re cloning, in the traditional sense of the term,” said Prather. “We’re using cloning technology not simply to produce clones but because it’s the only way we can make these genetic modifications.”

But Prather’s cloning begins at the beginning. Whereas Dolly the sheep was cloned using cells from a mature animal, Prather starts with fetal cells. He inserts the genes he wants, transfers the nuclei into egg cells and then grows the embryos.

“The altered embryos are grown and multiply by natural propagation,” he explained. “Depending on the genes used, the genes can be expressed in different tissues.”

Prather works with a line of smaller-than-average-sized pigs that were developed specifically for human transplants. This line was developed about 30 years ago at the National Institutes of Health (NIH) by David Sachs, who is now at Harvard University.

“We could do some of our research with mice, rather than with pigs,” Prather said. “But in some cases, we make more progress with pigs because mice are so small. For example, it’s difficult to track blood flow through the tiny veins and arteries of a mouse.”

Even with pigs, Prather needed a way to track the effects of transgenesis. So he used a novel genetic marker.

“We insert a gene from jellyfish—the gene that gives jellyfish that greenish, luminous quality,” he added. “This protein gives some pig tissues, but not all, a sort of phosphorescence that helps us spot where the gene is being expressed.”

For example, the jellyfish gene gives transgenic pigs bright yellow hooves and snouts.

To get outside genes into a pig cell, Prather employs a “suicide virus.” The virus, with the gene piggy-backed, infects a cell one time and then dies—similar to how a worker honeybee can sting only once and then dies.

One of the major problems of making xenotransplants (species to species) is the host’s own immune system. Antibodies in our cells recognize pig cells as a foreign body and attack it. This rejection happens even in well-matched human organ transplants. But when pig tissue is transplanted into humans, the rejection is immediate and hyper-acute. Prather’s team has succeeded in genetically altering pig parts so that the human body doesn’t see them as foreign elements.

“We’re pretty well through that hurdle,” said Prather. “Now, we are looking at some other things that will make species-to-species transplants more readily successful.”

The work by Prather and his colleagues has attracted attention in high places. Last year, the NIH awarded a grant to establish the National Swine Research and Resource Center at UMC. Prather was named co-director. Construction begins on the Center this fall, adjacent to the UMC Animal Sciences Research Center in Columbia. When completed (target: January 2006), the Center will house scientists as well as their offices and laboratories. A major part of the new structure will be devoted to “clean,” secure housing for NIH research pigs.

“We start with clean pigs and those will be kept in the new National Swine Research and Resource Center,” said Prather. “Any new pigs we bring into the project will be isolated in other facilities and then brought in as embryos to assure that they are pathogen-free.”

Randall Prather believes he was set on his career course early in life. He grew up on a dairy farm in Wisconsin.

“My father, a veterinarian, was keenly interested in reproductive management, and I may have caught some of my zeal for reproductive biotechnology from him,” he said.

Prather earned bachelor’s and master’s degrees in animal science at Kansas State University. Then, he returned to Wisconsin to study endocrinology and reproductive physiology, earning a doctorate from the University of Wisconsin in 1987.

“For the past several years, I have worked at this task here at Missouri,” he said. “We’ve made a lot of progress in nearly two decades, but there still is a lot to be done.”

Now, Prather is turning part of his attention to cystic fibrosis.

“A single gene predisposes a person to acquire cystic fibrosis,” he said. “If we can find a way to silence or alter that gene in pigs, this would benefit a great many people.”

Some of the techniques developed by Prather and his team may be borrowable by production agriculture, too.

“In terms of agriculture, biotechnology is still an infant,” he said. “In biomedicine, we may be a bit further along, but we’ve barely tapped the potential. Our potential is limited only by our imaginations. Twenty years ago, who would have thought that we’d be able to clone an animal today?

“What the next 20 years holds is a total mystery at this point,” he added. “There’s a gene we could alter to potentially change virtually any characteristic.”

Even the characteristic of organ-transplant hosts to attack and reject a transplanted organ.

Given the groundbreaking nature of Prather’s work, there are a few often-raised questions. The following questions from journalist Donald Nugent were answered by Prather via an interactive, web-based interview.

Question: Why use pigs as organ donors?
Randy Prather: Why use pigs as organ donors? Many people might consider other primates. But many primates are endangered, there’s not a good supply of them, they have a long generation interval and they have small litters. By contrast, pigs have a short generation interval. They have similar plumbing, so you could connect a heart to a human, and we consume 97 million pigs in the United States. [To] add in 200,000 more for transplants shouldn’t present any major ethical problems.

Q: Which organs can be used?
RP: Potentially, any organ. Kidney, liver, take your pick. Lung, heart...

Q: Could genes escape from biotech animals?
RP: One concern that’s been raised in the plant world, for example, with genetic modification of plants, is that those altered genes will get out in the environment. [There is a concern they] will get out in the wild, and they’ll get blown across the field, pollinate other plants and get into the population. We don’t have that problem with domestic animals, for example, because the wind isn’t going to blow a pig across the field to impregnate another pig. We can keep these animals in confinement and in pens. And even if a genetically engineered bull were to get out in the environment, there are no wild cow populations out there that it could spread the gene to. Now there are wild populations of pigs, so we would have to have measures in place to make sure these animals are penned up. That’s all you need to do. But it’s not like the wind is going to cause a problem.

Q: Is genetic engineering of animals ethical?
RP: We look back to Genesis, and God created creation, and he gave it to Adam; he gave it to humankind. And with it, he gave responsibility and total authority. So mankind can decide what is done, and it could be said who lives and who dies in terms of creation. Given that total authority, I think it would be a mistake to stop there. You have to carry on. You are also given a responsibility, a stewardship responsibility. If you look back, in the Old Testament [there is the parable of] the wine dresser. Sometimes he planted. Sometimes he dug it up and planted it over again. Sometimes he pruned. Sometimes he harvested the fruit and enjoyed it, and sometimes he sat back and did nothing. I think all of those things apply to us with creation. We have to be able to take advantage of the opportunities we are given, and we will be held responsible for taking advantage of those opportunities or not taking advantage of those opportunities. I believe that we will be held responsible for the opportunities. So unless you start with the same moral basis for those decisions, I don’t think you can come to the same conclusion.

The full interview with Dr. Prather and other video interviews by Donald Nugent, CAST Science Journalism Fellow, are available on the CAST Biotechnology website at www.biotech-cast-science.org/ web-based_dialogue.htm.