Stem-cell work rolls on in Britain, despite Korean scandal

Ian Wilmut with Dolly. Picture courtesy Roslin Institute

The Centre for Regenerative Medicine, announced in December just before news broke of alleged fraud by South Korean cloning researcher Hwang Woo-suk, will pull together many of Scotland's big scientific guns to develop stem-cell technology for human medicine. At the same time, the South Korean news would appear to leave another U.K. team in Newcastle leading the therapeutic cloning race. Their announcement last year to have produced Britain's first cloned human embryo was at the time overshadowed by Hwang’s more-spectacular claim.

Britain has been betting heavily on stem-cell research for the past three years - establishing a regulatory framework to allow human cloning for therapeutic purposes and pumping millions of public research pounds into the field, at a time when Washington funding has been tied in knots over the ethics of the research. In December the UK government set out a 10-year road map for the research and pledged to more than double current spending, to at least £650 million over the decade. Political interest in the field was galvanized by Hwang’s claim to an efficient process for deriving stem cells from human embryos that were clones of ill or injured patients. But as the year drew to a close, investigators at Seoul University said the research was fabricated, and Hwang since has become an international poster-boy for scientific misconduct.

The debacle may set back the speed of research; but the scientific promise and political appeal of the field makes it likely that work to translate stem cell research into therapies will continue elsewhere.

The Scottish play

The Edinburgh CRM will focus on the translational research needed to move stem cells from constructs in a laboratory to treatment for human disease. Apart from pulling in basic research carried out by Wilmut and his former colleagues at the Roslin Institute, which he is leaving after 30 years, the new CRM will build on the work of Edinburgh University's Institute of Stem Cell Research. It is intended that locating the building on the site of the city's Royal Infirmary, and close to the Medical School will provide the easy access to the clinicians and patients that will be needed to progress cell therapies through to clinical trials.

Other partners in the project include the Scottish National Blood Transfusion Service and the Regional National Health Service Trust.

The enthusiastic backing of Scottish Enterprise, the regional development agency, has enabled Scotland to take a lead in stem cell research. Scottish Enterprise funds the Scottish Stem Cell Network, which pulls together researchers across the country, and has put money into building Scotland’s reputation in the field internationally, for example bankrolling an international stem cell conference in Edinburgh in March 2005.

The Stem Cell Network is seen as the conduit for researchers elsewhere in the country to collaborate with the CRM. Scottish Enterprise is also in talks with the centre about plans for the commercialisation of stem cells.

"Ian Wilmut and the new centre will serve as magnets, drawing in the very best young clinical and basic research scientists from around the world to Scotland," said John Savill, head of the College of Medicine at Edinburgh University.

There will, however, be one notable omission from the roster of the CRM: Austin Smith, leading light of the Scottish Stem Cell Network and one of the most prominent researchers in the field, has been lured south to head the Stem Cell Institute at Cambridge University.

Morag, Megan and Dolly

As he is reinvented as stem cell supremo, Ian Wilmut leaves behind a trail of cutely named firsts in animal breeding and cloning. These start with Frosty, the first calf to be produced from a frozen embryo, and move on to Morag and Megan, sheep that were cloned from cells taken from embryos, Dolly, the first clone from an adult cell and latterly Polly, a cloned sheep that carried a human gene.

Polly embodied the original objective of Wilmut’s cloning research - to find a cheap method of generating transgenic animals that would produce human proteins as the basis of drugs. Attempts to commercialise this aspect of the work flopped when the company set up to develop it, PPL Therapeutics plc, went out of business in 2004 and all the related IP was sold to the US.

More recently Wilmut has turned his attention to using the cell nuclear replacement cloning technology - in which the nucleus of an egg cell is replaced by the nucleus of an adult cell and then stimulated to develop into an embryo - as the source of embryonic stem cells. Wilmut is the holder of one of two licences granted in the UK to clone human embryos for use in stem cell research. With colleagues at Roslin he has worked also on attempts to produce embryonic stem cells through parthenogenesis - stimulating unfertilised eggs to form embryos.

The other UK licence is held by the Centre for Life in Newcastle. The Centre’s announcement that it had produced Britain’s first cloned embryo was overshadowed by the simultaneous publication of Hwang's paper, but it could now be considered that the researchers here are leading the field.

At the time the Newcastle researchers concluded that their limited success compared to Hwang was because he had access to fresh eggs, whereas they were working with ones left over from IVF treatments.

With colleagues at Roslin, Wilmut has been working on attempts to produce embryonic stem cells through parthenogenesis - that is, stimulating unfertilised eggs to form embryos.

A new avenue for reearch

Most approaches to producing embryonic stem cells involve using embryonic tissue, derived by in vitro fertilization procedures, and unsuitable for implantation. However, Wilmut's colleague Paul de Souza - who has also moved from Roslin to the CRM - is aiming to develop a new source: immature eggs donated by women having a laparoscopic sterilisation. In the first year of the donation program 225 suitable donors were identified among women wishing to be sterilised. Of these, 75 assented to receive information, and 27 gave informed consent for eggs to be removed during the procedure.

The eggs were subsequently matured in vitro and stimulated electrically to start dividing into an early embryo. The in vitro matured oocytes are being used also in the creation of cloned human embryos.

Advocates of stem cell research worldwide believed Hwang's work showed it would be possible to generate immune-compatible replacement cells for treating a wide range of ills, from spinal cord injuries to Alzheimer’s disease and diabetes. But the Seoul National University investigators said the 11 cell lines did not match the DNA of the patients from whom they were claimed to have been cloned, but were derived from embryos created by conventional in vitro fertilisation.

While creating cell lines that are immuno-compatible was considered a breakthrough, there are other approaches to preventing rejection by the immune system. Apart from conventional immune rejection drugs, one approach in development is to create stem cell banks, which would provide close, if not exact matches.

In December scientists in Cambridge show that the UK Stem Cell Bank would only need cell lines from 150 different embryos to provide at least a partial tissue match for up to 85 per cent of the UK population. The researchers analysed human leucocyte antigens (HLAs) expressed by 10,000 donated organs as a surrogate for the likelihood of stem cell graft rejection.

This is not to state that there will be no fallout from Hwang's disgrace - perhaps most significantly for science in South Korea. The country has invested heavily in building the R&D infrastructure to establish itself as a location for biomedical research, and Hwang was the country’s first scientific superstar.

The Hwang debacle also raises questions (again) about the peer review process. The journal Science could hardly be accused of having rushed to print, having received the paper on 15 March and accepted it on 12 May. The journal has withdrawn the paper, but the question remains of whether peer review can be expected to detect out-and-out fraud, as opposed to straightforward bad science.

As far as investment in embryonic stem cell research is concerned, it seems inevitable that those who are against the field will use Hwang as an excuse to withhold funding, while those who are convinced of the potential of the science will maintain their commitments. There is likely to be little effect in terms of immediate commercialisation prospects as venture capitalists had already made clear the science is, as yet, too preliminary, to attract their investment.