Pig cells offer hope of miracle cure

Living Cell's Paul Tan (left) and Bob Elliot.

Nice pig. She's a descendant of those left on the Auckland Islands 200 years ago and she's special. Not because she's destined to make lovely bacon, sausages, ham, or pig skin leather, but because she's free of infections associated with many pig herds.

In particular, she doesn't secrete infectious porcine endogenous retroviruses (Pervs), making her ideal as a source of cells for medical use.

Her owners, Living Cell Technologies (formerly Diatranz), are at the frontier of an extraordinary, some say miraculous, development in medical science: transplanting living animal cells into humans.

From these pigs, Living Cell is taking hormone-producing brain choroid plexus cells for experimental treatment of animals with brain injury, such as strokes, and brain disease, such as Huntington's.

Even more promising are the pigs' insulin-producing, pancreatic islet cells, which are now being used for treating humans with diabetes.

For many of the 15,000 type 1 diabetics, including 1500 children, in New Zealand, it's an exciting prospect. But it's a prospect that has stopped dead here because our Government has banned all animal-to-human transplants (xenotransplantation) until the end of next year and looks likely to extend the ban further.

Critics say the Government is being, as it were, pig-headed and pig-ignorant - not only denying hope for thousands of New Zealanders, but also turning its back on a share of a brand new multi-billion-dollar industry.

"Hard." That's how 12-year-old Samantha Darby views her diabetes. "It's sort of hard to live with, but you can live with it. It's hard to be a little bit different from everyone else."

That difference involves giving herself blood tests about eight times a day, injecting herself with insulin four, and up to eight, times a day. And always watching what she eats.

Harder still is the constant worry about her blood glucose level being too high or low, which has scary effects. "Sometimes I feel tired, but I can't go to sleep. You get cold. You get blurry vision and maths is the first thing you lose. If it takes a long time to answer a maths question it's a sign you're going hypo."

That's hypoglycaemic, which can lead to insulin coma and potentially death. Samantha's brother Cameron, 15, also a type 1 diabetic, knows the hypo worry well.

"You get them during the night when you're not aware you're going low. They are probably the most dangerous ones because you can't really stop it if you're in a deep sleep."

To meet Cameron and Samantha is to meet remarkably well-adjusted, happy kids. Both like music, play the saxophone and enjoy surfing the net. Samantha is keen on badminton and her favourite subjects are maths and drama. Cameron has done fencing for three years, likes PlayStation 2 games and his favourite subjects are science and graphics.

But behind the normal facade, there's something else - a maturity beyond their years. They know a lot about the carbohydrate content of foods and are experts on their endocrine systems. It's a maturity born out of necessity.

"You get used to it after a while," says Cameron. But while the pair are coping brilliantly, their parents are looking to the future.

"Insulin is a wonderful thing," says the children's mother, Bronwyn. "But the ultimate for the kids, for the quality and longevity of their lives, is a cure. And where that's a possibility, of course you have got to be behind it."

The possibility comes from living islet cells from pigs, which have shown significant promise in treating diabetes when transplanted into humans both here and in Mexico.

But although such transplants continue in Mexico, clinical trials that started here in the early 90s have been stopped. The most recent two-year moratorium on xenotransplantation was due to expire on June 30. But the Government has quietly just passed the Medicines (Specified Biotechnical Procedures) Amendment Bill, extending the moratorium for another 18 months.

The health select committee considering the bill decided not to call for public submissions because it considered the content "was straightforward and uncontroversial".

Some on the committee were, however, concerned that the moratorium "suppresses innovation in the biotechnology sector" - a sector that, ironically, the Government also says it wants to promote.

Others wanted to see the outcome of the "consultation" being undertaken by the Bioethics Council before considering detailed legislation in this area.

But while the Bioethics Council is indeed conducting a "dialogue" on "the cultural, spiritual and ethical aspects of xenotransplantation", it is running late and will not deliver its findings until the end of August.

It's worth noting that the council is not looking at the safety of xenotransplantation. That task falls to the Ministry of Health. In the long term the Government wants to cover xenotransplantation with new human tissue and therapeutic products legislation, which is yet to make it into bill form.

In short, the possibility of pig islet cells transplants is bogged down in a political and legislative quagmire.

None of which impresses Tony Darby, Samantha and Cameron's father.

"The moratorium on xenotransplantation denies us the hope of a choice of a better, healthier life for our children," he writes in his submission to the council. "For myself and the thousands of parents of children with type 1 diabetes there is currently no choice. We are asking that you give us some hope of a choice. That is all, hope of a choice."

One who knows first-hand about the hope is Peter Thompson, 27, who received a transplant of pig islet cells at Auckland's Starship hospital when he was 15.

"For a number of weeks afterwards I came off insulin altogether. It was like a dream, you just didn't want it to end," says Thompson. "Then slowly over time I required more insulin."

What was amazing about Thompson's transplant was that it was without immunosuppressive drugs. It was remarkable that the pig islet cells survived and produced insulin for as long as they did.

That led in 1996 to Living Cell's Professor Bob Elliott transplanting into two patients pig cells coated with an alginate gel to protect them from immune rejection. Again, the results were encouraging, with both patients able to reduce their insulin dose for a period - in one case by as much as 34 per cent.

Although after two years that patient returned to his pre-transplant insulin dose, he continued to claim improved control of his diabetes and on examination nine years later Elliot found encapsulated pig islet cells still living and producing insulin in his abdomen.

Similar trials in Mexico have also produced favourable results. In one study using New Zealand pig cells, a child was off insulin for six months and afterwards required 75 per cent less insulin than before the transplant.

Another was reported in 2002 to have been off insulin for more than a year.

The Mexican procedure, which is being carried out commercially at a cost of US$35,000 ($49,500), involves implanting a small metal cage containing a mixture of pig islet cells and testicular Sertoli cells taken from neonatal pigs into the abdomen.

Sertoli cells are thought to be able to subdue immune system T cells, which normally fight the presence of anything foreign.

The reason our Government and others have banned xenotransplants is because of fears about cross-infection of animal viruses into humans, as happened with Sars and Avian influenza.

Such concerns can mostly be alleviated by having stringent procedures around the donor animals and processes for preparing cells.

The bigger concern is cross-infection through a retrovirus - an ancestral kind of virus that lodges in the DNA of all mammals and living organisms. The most prominent example of infection of this type is the human immunodeficiency virus (HIV), which is theorised to have jumped from monkeys to humans, but so far there are no examples of that sort of jump having occurred from lower, non-primate species.

Quite what retroviruses do, no one really knows. But Massey University Professor of Animal Health Roger Morris says the current theory is that retroviruses are actually responsible for the evolution of mammals - that the jump from egg-laying to placental mammals was a consequence of retroviruses.

They also seem to be important in creating the junction in the placenta that keeps the baby separate from the mother, but enables them to exchange blood. Mostly retroviruses stay inside the DNA, but once in many thousand of years one turns wild and starts spreading.

"It's a rare event and in most cases it's unpredictable, but the chances of it happening through a xenotransplant are very low and the evidence from the research is that the pig retrovirus is not well-suited to establishing in man," says Morris, who is a specialist in pig medicine and an expert in disease epidemiology.

"These theories that if you put one piece of pig tissue into a person you'll start a global epidemic are simply not consistent with the evidence."

Concerns about the porcine endogenous retrovirus going wild were the core reason why Living Cell's early trials with pig islet cells were stopped in New Zealand. Much of the concern stemmed from the work of Clive Patience of the Institute of Cancer Research in London, who announced in 1997 the discovery of Pervs' ability to infect human cells.

As it turns out, he was wrong. His research was based almost entirely on evidence in a special kind of inbred strain of mouse.

"What was going on in these mice was technically not what some of the researchers thought it was," says Morris. "In other words, you weren't getting a true transfer of infection."

Morris worked as a consultant for Living Cell doing a risk analysis of 108 different organisms that could potentially be transferred from pigs to humans. His conclusion was that all the risks could be managed through monitoring and by using animals that were free of certain agents.

It's a position shared by the United States Food and Drug Administration, which has set stringent guidelines for allowing pig islet cell transplants.

So far no one has crossed the regulatory bar, but Living Cell, with its licensed manufacturing practices, clean herd and having just completed monkey trials in Singapore, is quietly confident of meeting the requirements.

"In my view it is more dangerous to go to the zoo than it is to have a xenotransplant," says Morris. "People say, 'it's not dangerous to go to the zoo' and I say, 'yes, it's not'."

But the man who turned down Living Cell's application to do more clinical trials here in the late 90s, Health Research Council chief executive Bruce Scoggins, says he would still do so today. "There are very real concerns about the transfer of viruses from animals to humans."

Scoggins does, however, see the possibility of a change of heart. "I think as time goes on we are probably going to get an increasing amount evidence to suggest that this may not be the problem that was originally thought."

And the door to New Zealand trials is not completely shut. "With the new knowledge we've gained in relation to some of the risks, we probably would reach the point where researchers wishing to do the trials may be able to assure the people involved in regulation that this is something that could proceed."

What would convince him? More published evidence from Living Cell on the efficacy of its procedures, and the cleanliness of its herd. But unlike the FDA, the council and the Ministry of Health give no clear guidelines on what would constitute a safe trial.

Living Cell's managing director Paul Tan says the moratorium, vague assessment criteria and lack of workable legislative framework make it impossible for the company to apply for trials here at present.

Instead, Living Cell is putting all its efforts into an FDA application to do trials in the US. While governments around the world dither on whether to allow xenotransplantation, the FDA has in effect become the de facto global regulator.

There's another fundamental flaw in the Government's ban-it-all stance - that xenotransplantation is happening anyway. "Xenotourists" - people travelling to other countries to have xenotransplants - are circumventing the ban.

One possibly unwitting example of this trend may be Willie Terpstra, the Rotorua woman who had human embryonic stem cell transplant surgery for motor neurone disease in China. What's not known is if the human stem cells she received were grown on mouse feeder cells, a common practice in stem cell research.

"Most mouse cell lines have got the mouse leukaemia virus in them and there is every reason to believe that under some circumstance that could be transmitted to man," says Living Cell's Elliot.

"That's a much more realistic scenario than porcine endogenous retrovirus cross infection."

Scarier still, says Morris, is the prospect of xenotourists travelling to Russia to buy unregulated mixtures of pancreatic islet cells from several unknown species of animals to inject into their own abdomens. At present the Ministry of Health is not monitoring any xenotourists and is waiting to see what the Bioethics Council proposes on the matter.

Having felt what pig cells can do, Thompson, a kickboxing champion, is itching for clinical trials to start here again.

"I can't imagine what it would be like to have that freedom to be able to go and train all the time and go away on training camps and to fight in these tournaments and not having to worry whether I'm going to be low when I go into the ring."

He longs also to fulfil a childhood goal of joining the police force. "The sooner I'm cured, the sooner I can look at doing that."

He says he won't wait forever and would look at travelling to Mexico. "I would rather have Prof Elliot do the procedure and have New Zealand pig cells in me because it's the best pig in the world."

Tony Darby would consider Mexico for his children as soon as the success rate there got a little higher. As he asks in his submission: "What parent would not seek what would be best for their children? What parent would not want research to go ahead which could potentially lead to a cure?

"By stopping this research you are denying us this choice and sentencing our children to a lifetime of fending off this slow and horrible killer."