Here we go again: what next for stem cells?

As CEO of the publicly-funded Australian Stem Cell Centre (ASCC), Professor Stephen Livesey must necessarily be a little circumspect when wading into the ferocious debate on the Lockhart Review and therapeutic cloning.

Livesey said it was crucial that there was going to be an open debate when either Senator Kay Patterson or Senator Natasha Stott-Despoja - or potentially a combination of the two - introduce their private member's bills later this year.

"I'm a firm believer that an open debate by parliamentary members, elected by the population, allows the views to be put forward and that people are free to vote on their conscience is a very important factor," he said.

"The success or otherwise is obviously dependent on the participants but from our point of view, providing the members of parliament with accurate information means that they can have an informed debate and come to an informed conclusion.

"I think the initial response in cabinet to the Lockhart Review was not consistent with open debate but there has been a gathering of momentum to achieve that debate and now that has been achieved we are in a much better situation."

Professor Bernie Tuch, head of the Transplant Diabetes Unit at the Prince of Wales Hospital in Sydney and co-convenor of the NSW Stem Cell Network, agreed.

"It would be nice if governments would simply pass legislation, but bearing in mind they blocked legislation, or blocked changes to it, it's wonderful that it's now coming out and that people are now able to express their points of view in public," Tuch said.

"Effectively, [when the Lockhart Review was released] the answer was no and we've made the decision ... the issue wasn't discussed. I think [the current debate is] a fair and reasonable thing to do even though we have gone through this previously."

When asked what scientists should do when the Federal Minister for Health, Tony Abbott, refers to 'animal-human hybrids' as a result of somatic cell nuclear transfer, Tuch said the short answer was to do nothing.

"Our society is such that can deal with people who make claims that are designed to scare people and aren't based upon the truth of the matter." He said the best illustration was a cartoon that appeared in Sydney's Sun-Herald newspaper on 20 August, featuring a rogues' gallery of federal cabinet as human-animal hybrids. John Howard is a rodent, Peter Costello the faithful dog at his feet, Philip Ruddock a particularly bloodless bat and Tony Abbott is curled up on top of his chair with a Cheshire cat grin.

"The community is bright enough to be able to see through these scare tactics that are being put up and none of which is of any relevance to the debate," Tuch said.

A perfect world

Many commentators have compared the stem cell conscience vote with that of the debate over RU486 earlier this year, and some believe the division of individual votes on stem cells will fall in a similar manner. And should the recommendations of the Lockhart Review be implemented in full, Stephen Livesey hopes to get to work immediately.

"The technique of therapeutic cloning or somatic nuclear transfer is potentially a very important technique for developing what we refer to as a disease-specific approach. Obviously the technique ... is a very early technology and it's going to take some research to enable that to happen on a reproducible basis."

He agreed that the potential benefits of all stem cells, not just those derived from embryos, are in danger of being over-hyped.

"I think that's a very important issue. With any new technology there is the occurrence of over-hype. I was involved in tissue engineering in the US and there were several companies that over-promised and under-delivered and that ultimately had a very negative effect on tissue engineering.

"Fortunately tissue engineering has now entered what I would call its second generation and it's much more realistic about addressing the issues. With stem cells what can be over-hyped is the time to delivery, but the potential of stem cell technology is fundamental."

For Bernie Tuch, there are three steps he said needed to be taken should the result proved positive.

Number one is to make sure the legislation does not block [therapeutic cloning]," he said. "But that's only the beginning.The second step is to provide the resources and finance to make it happen. What I wish to do, once the federal government says yea, is for this to be translated, realising a number of specific strategies that we would like to put in place, to be up and running and therefore to be able to compete with others around the world.

"Step three will be to produce the results, but you can't produce the results without numbers one and two. Now two is on the horizon, just give us a chance."

Adult versus embryo

Early in the debate, Professor Jack Martin from Melbourne University wrote an opinion piece for The Age newspaper, stating that not enough basic research into animal embryonic stem cells had been done and cautioning against rushing in to human research.

Professor Alan Mackay-Sim, head of the National Adult Stem Cell Research Centre at Griffith University, told the Sydney Morning Herald that the proven success of adult stem cells negated the need to "step over the ethical barrier" of cloning human embryos.

Bernie Tuch disagrees with Martin, quoting two important papers on nuclear transfer published in Nature Biotechnology and Cell respectively. (He can provide the date, volume and page reference on demand.)

He also addressed the question of adult versus embryonic research. "I was asked to appear on the Mornings with Kerri-Anne show, which was amusing, and we laid down the challenge to the Catholic Church. It's not meant to be a challenge but it is.

"That is, if you want adult stem cells to do everything that you are claiming they can do, and we know that's not true at the moment, then let's put some money up and do it. We are in the process of trying to convert embryonic stem cells into insulin-producing cells, we are also in the process of trying to convert cord blood cells, so you provide the money and we'll take the adult stem cells and let's push ahead and see which is the most efficient way of producing your end-point cells.

"If the adult nasal stem cells are able to do what you are claiming to do and the other ones don't, well that's wonderful and we'll support you in the argument that these are the cells we should be using. So if you are prepared to provide the money, we are prepared to use it."

The ASCC has programs in both embryonic and adult stem cells, Livesey said. "We find the two areas of research very synergistic - what you learn from one helps you with the other and vice versa. In terms of the adult stem cell component, for example the mesenchymal stem cell, that is now showing that it can cross the allogeneic barrier. We are now discovering some really interesting features of mesenchymal stem cells and I think by understanding those we can start to rationally design therapeutic applications.

"The different types of stem cells have different applications and I think one of the challenges is to understand the basic biology of the stem cells and then be able to correlate that with clinical need. Then figure out how one can satisfy the other."

Strategic direction of stem cells

Stephen Livesey was appointed CEO of the Australian Stem Cell Centre (ASCC) in July, after three years as its chief scientific officer. After finishing his medical degree and PhD at Melbourne University, he moved to Texas to work as a research assistant professor. In 1986, he co-founded LifeCell Corporation, a biotech company involved in regenerative medicine.

Livesey said he was drawn back to Australia after 18 years in the US because of the potential offered by the establishment of the centre. "I had thought for some time that the combination of the right stem cells with the right matrix or delivery technology would be a very powerful combination," he said. "The formation of the ASCC as an organisation focused on the delivery of therapeutic benefits was a very strong attraction."

Although he will no longer be doing much hands-on benchwork, the CEO role appealed to the businessman in him as it will allow him to look more at the strategic development of the centre.

"The centre has to achieve two goals: to be the best of a research organisation and the best of a biotechnology company. To build a research organisation that is internationally recognised, that is developing technologies that accentuate the scientific strength of Australia in the stem cell field and then in terms of the translation of that technology into therapeutic benefits - I see that as a major challenge and something that has been difficult in Australia.

"I think we have long been recognised as one of the best research countries on a per capita basis in the world but the translation of that research to therapeutic benefit has been a significant challenge."

Livesey is very keen to work with private and public biotechnology companies in particular. "One of our goals is to foster the Australian biotechnology industry, and in our programs, both the therapeutic programs and the basic research programs, we are looking to partner with private biotech, public biotech and also large companies."

One partnership already established is with Chemicon International to commercialise research tools, including a novel and proprietary stem cell isolation kit, various proteins and antibodies.

"That was an obvious thing for us to do because as scientists develop their research they also develop research tools. The relationship with Chemicon provides us with an early commercial opportunity."

Another relationship is with an Edinburgh-based stem cell company called Stem Cell Sciences, which has a Melbourne office. "We have a collaborative agreement with them to develop new embryonic stem cell lines. We are distributing those lines directly in Australia and, through Chemicon, internationally.

"The essence of those lines are that they are being distributed without intellectual property encumbrance. The cost is quite low and the quality is very high: they've been fully characterised and they are at a low population passage, which means they can be propagated indefinitely."

Cell encapsulation at ComBio

Bernie Tuch's team at the Diabetes Transplant Unit is currently conducting clinical trials in diabetes patients using encapsulated insulin-producing cells.

While he can't talk about any results of the trial as yet, two patients have been transplanted this year. He hopes to enroll another four in the trial, the finish date of which depends on the availability of donor pancreases and on funding.

Tuch said the main principle behind encapsulation was to prevent the immune system from trying to destroy transplanted cells.

"We have used it for three purposes: one is insulin-producing cells using seaweed capsules - we call it the seaweed diabetes trial," Tuch said. "We started it in human patients this year using encapsulated insulin-producing cells derived from donor humans.

"We've also used it to encapsulate insulin-producing pig cells - of course, they are not being used clinically because of the moratorium but effectively we are transplanting them and we have shown that these cells will differentiate at the same speed as cells which are transplanted without the capsules.

"These are of course in immuno-deficient mice so the immune system is not an issue here. The message is that cells not only survive but also differentiate in a normal manner.

"The third area is that we have encapsulated both human and mouse embryonic stem cells and demonstrated that those cells will not only stay alive and viable when you transplant them but will also differentiate in exactly the same manner as if you haven't encapsulated."

The capsules themselves are made from sodium alginate. By air-droplet generation, the team inserts the cells inside the bubbles of alginate. The bubbles are then put in a bath of barium chloride to form the barium alginate capsule.

"The capsules are not biodegradable and have pores of a size that will allow passage of cytokines, nutrients and hormones, but not the cells. IgM antibodies should not get in but IgG may," he said.

Encapsulated cells remain viable for at least several weeks in vitro and nine months in rodents, he said. The actual size of the capsule limits the amount that the cells can proliferate.

"[Limiting the proliferation] of human islets isn't an issue as islets rarely differentiate. If you put in foetal pig pancreatic cells, they do differentiate as well as develop but that hasn't been an issue in the pictures of cells six months after being transplanted.

"However, when you put in embryonic stem cells, especially mouse embryonic stem cells, they certainly do proliferate and differentiate and push the boundaries. As a result some of the capsules may burst and on other occasions you may get necrosis, as the area just isn't big enough to accommodate the cells."

Tuch's team, along with a number of others in Australia and overseas, are interesting in encapsulation as a platform technology, both clinically and in basic research. Of particular interest is the usefulness of culturing cells in a confined 3D space.

He will discuss the potential of cell encapsulation as a platform technology at ComBio 2006 in Brisbane this month.