Stem-cell research: The man behind the monster

Sir Martin Evans, who this week gave a lecture at Auckland University, believes the real benefits of his research on stem cells will first be felt by his grandchildren's generation. Photo / Glenn Jeffrey

The Frankenstein face of stem-cell research is benignly British. Professor Sir Martin Evans presents on a visit to Auckland as the dapper grandfather he is, his signature blue blazer, light blue shirt and fawn trousers offset by the snow white remains of his hair.

He has spent a good many of his 69 years in a white coat in a laboratory, peering at mice - or, more correctly, stem cells taken from mice embryos. Softly spoken, he is not at all chest-beating about the embryonic stem-cell and gene targeting research which led to his Nobel Prize for medicine.

His field is a hugely controversial one, regularly targeted for associations with genetic modification, chimeras (creatures developed by mixing animal cells) and ethical and religious concerns about taking cells from human embryos for research. Then there are those who worry about the poor mice.

Yet Evans is defensive about none of this, even if he's not one to over-hype the potential of stem-cell research to treat degenerative brain diseases, spinal cord damage, heart disease, cancer, diabetes ...

Scientists believe they can be used to replace cells that are lost or damaged from disease or injury. Our scientists see potential in areas like agriculture. AgResearch is applying it to research into livestock development, for instance to alter meat muscle composition. Auckland University scientists have successfully transplanted adult stem cells into rats to combat Huntington's disease.

Evans is a Londoner who has spent most of his working life at Cambridge and Cardiff Universities and, with US-based collaborators Oliver Smithies and Mario Capecchi, was awarded the Nobel in 2007. With wife, Judith, he is on his third trip to New Zealand, where he has addressed the annual Queenstown molecular biology conference and delivered a lecture for Auckland University's Maurice Wilkins Centre, a centre of research excellence in molecular "biodiscovery".

Where our scientists are heading in this field owes much to Evans and his mice, favoured in the lab for their genetic similarity to humans. He is sometimes called the father of research on stem cells - cells that have not differentiated but which can turn into any of the 200 or so types in the body.

Embryonic stem cells are pluripotent, which means they can become any cell type in the body. An obvious source is unused fertilised eggs from in vitro fertilisation but their use raises ethical issues.

Evans says this needn't thwart laboratory research. It's a long way, he says, from experiments on mice stem cells cultivated in a lab to the use of human embryonic cells to reverse the ageing process (even if some dubious practitioners are exploiting disease sufferers with unproven treatments). And the newfound ability to make artificially derived cells, known as IPS cells, from sources such as adult tissue allows research which circumvents ethical concerns about human embryos.

Evans was the first to identify and isolate embryonic stem cells from mice and show they could be grown in the lab. He and colleagues then demonstrated that these cells could be used to fully regenerate fertile breeding mice and carry introduced genetic changes.

Combining his discoveries with Capecchi and Smithies' technique of genetically modifying cells led to the technology of gene targeting, which scientists are using to further research into human disease treatments.

The technique used to inactivate single genes and modify the mouse genome - known as gene knockout (Evans has another term: knockout mouse) - allows scientists to establish the roles of individual genes in health and disease.

"The really big impact so far is that these have provided us with the experimental arm to the human genetic programme.

"The system is now such that we can design a change, deletion or modification of any piece of genetic material in the mouse. We usually say it's a gene knockout because it's just taking a particular gene and deactivating it."

"It's a very complex system and we can ask very detailed questions of it by this fairly direct approach of 'okay, change it and let's find out what happens in the whole animal'.

"Many of the genes my group have altered have had very surprising outcomes - often much less severe than you would have imagined because the whole living system compensates and manages with the changes."

A Daily Telegraph article explaining his research paid due regard to the mice: "The rodents are now the universal test-bed, from basic research into human diseases to the development of new treatments."

Gene targeting has so far produced more than 500 different mouse models of human disorders, including heart and degenerative brain diseases, diabetes and cancer. More than 10,000 (about half) mouse genes have been "knocked out"; international scientists are working on the rest.

It started, of course, in the sandpit. One of Evans' earliest memories is at age 4 "mixing cement and water together because I was intrigued: 'Why does this harden'?" His parents were having renovations done in their south London home, and had forbidden young Martin from interfering, which only stimulated his curiosity.

"I put far too much water in and it didn't work.

"That's a good experiment - if something happens exactly as you expect the first time you usually get very little information out of it."

Early PhD research at Cambridge led him to explore the use of mouse stem cells.

"Nowadays, any human gene you want to find out more about will have to be looked at in the context of knockout mouse. This is the experimental arm of the human genome programme."

Where researchers are now heading with this science came under attack last year from the Catholic Church in Britain. Cardinal Keith O'Brien, president of the Bishops' Conference of Scotland, described experiments on animal-human hybrid embryos, or cybrids, as of Frankenstein proportions and an unprecedented attack on the sanctity of human life. Evans argued cellular hybrids had a long history and a lot of misinformation was flying around. He was accused of playing God and moral bankruptcy.

He acknowledges there are clear important ethical considerations with using cells from human embryos and using human embryos. "The sort of experiments you can do in mice should be absolutely forbidden in humans."

But he argues that cells isolated in a laboratory culture, following fully informed consent, do not raise the same issues. He admits to some frustration about the ongoing ethical debate - "even more so now we know we can make very equivalent cells [from non-embryonic tissue] called induced pluripotent stem cells or IPS cells". These artificial cells are believed to be identical to embryonic stem cells in many respects.

"Some people have said 'oh well, as soon as you can make IPS cells nobody should be using embryonic stem cells'. That's not reasonable because embryonic stem cells are still the gold standard and will remain so for some time."

He is also conscious about the use of mice in research.

"If we hadn't used animal experiments we wouldn't have modern medicine. We absolutely should be using animals for the benefit of mankind." Laboratory treatment of animals is controlled, he says. "They live under better conditions than most of us." He believes that, in future, most research advances will come through IPS cells - but ethical issues will continue.

"It starts to raise questions about whether the developmental potential of any cell mass makes it in any way special. What I think you've got to be very aware and careful about is reproductive abuse.

"I think everything should be done under the rule of law and licence such as in the UK. I remain very critical of the way it's regulated in the United States where it has been done by funding, not by law - so if you're a wealthy individual or corporation you can do what you damn well like.

"The scenario of a cell-based therapy or medical intervention using cells is very sound but there's still a long way to go before it's a safe therapy. There's also quite a lot of jumping the gun and early adoption going on, some of which is quite cynical.

"I'm often asked 'do I see the benefits of this?' I'm cautious. I don't think people of my generation will see the benefits of it. I'm doubtful whether my children's generation will see them. But I would think it very likely that by the time my grandchildren are at an age where they are affected by degenerative diseases, they may well benefit."