Stemming scientific endeavour

Dr Lyle Armstrong and the team he leads at the North East England Stem Cell Institute have asked the Human Fertilisation and Embryology Authority (HFEA) for permission to use animal egg cells to advance the science of ‘therapeutic cloning’ as it is widely called. The novelty here is that they want to transfer a human cell nucleus into an animal egg that has had its own cell nucleus removed. The transfer of a human nucleus into a human egg, and an animal nucleus into an animal egg, have been carried out before, but no one has applied to do this-cross species transfer involving a human cell nucleus in the UK until now.

‘At the moment, says Armstrong, ‘we don’t know if the nuclear transfer process works well enough in humans to create useful embryonic stem cells. We need to carry out many tests to establish this and, as animal eggs are freely available, it makes sense to use these. Stem-cell research promises huge potential medical advantages and we believe we will be working towards our ultimate goal of developing new patient therapies… Human eggs are in short supply, and most come from women who are undergoing IVF. It’s a much better use of a scarce resource to use them to help them have children.’ (1)

One of the hopes of the research is that it will lead, in time, to the development of cell lines for transplantation that are a genetic match for patients with disease or for victims of accidents. At the same time, teams in London and Edinburgh led by Stephen Minger and Ian Wilmut (the ‘father’ of Dolly the cloned sheep back in 1996), want to create embryos in a similar fashion, but for a different purpose. By sourcing the nucleus from patients with a disorder rather than any old individual they hope to extract embryonic stem cells that carry the genetic defects responsible for neurological conditions such as motor neurone disease. By then converting the stem cells into neurons, the scientists aim to study how the disease destroys nerves and identify drugs to stop or reverse the damage.

The embryos created by these scientists would be 99.9 per cent human and 0.1 per cent rabbit or cow, genetically speaking, although that is a little misleading: the embryos would contain the complete set of human genes, plus dozens of animal genes that sit inside tiny energy-making structures called mitochondria outside of the cell nucleus.(2) Strictly speaking the embryos would be hybrids and the potential for scary headlines and controversy has been noted (3). The HFEA will consider the applications in January.

This is potentially important research that should be supported. There is however a sobering context, and an underlying issue of opportunism within government and scientists linked to government that these applications bring out.

One obvious question is, why now? Why didn’t scientists apply to do this kind of experiment during the last nine years (since the birth of Dolly)? After all, the points made by Armstrong could have been made at any time since then.

The sobering context is the realisation that it is proving difficult to successfully derive human embryonic stem cell lines following cell nuclear replacement. Some researchers hoped, and some still hope, that it will eventually be possible to take a cell from an individual, re-program it using a human egg cell with its nucleus removed, derive embryonic stem cells that are immuno-compatible with the patient’s cells, develop the stem cell lines into specialist cells and transplant them into the patient to address disease or injury.

However, quite soon after Dolly was born many scientists came to the conclusion that in the short to medium term at least, the process would be too inefficient for this given the supply of human eggs. Instead, they suggested, one goal could be to use human eggs as a research stage to learn how the reprogramming takes place, with the hope that once this was understood, alternatives to human eggs could be used in clinical applications further down the line. In 2000 an expert group under the chairmanship of Sir Liam Donaldson, the chief medical officer, endorsed this programme and estimated that 12 or 13 eggs might be required to produce an embryonic stem cell line following cell nuclear replacement (4).

It should be noted that this assessment was made before anyone in the world had successfully created a single human embryonic stem cell line following cell nuclear replacement, and before any UK scientist had tried (it was illegal at the time). One difficulty was that, in general, scientists were using eggs left over from IVF treatments. By their very nature these eggs were sub-optimal (that is why they weren’t used in treatment). Then, in 2004 and 2005, news reports of and scientific papers from Woo Suk Hwang and his team in South Korea lifted hearts and horizons. In a breathtaking series of results, Hwang demonstrated that human embryonic stem cells lines could be derived following cell nuclear replacement with an efficiency close to that predicted by Donaldson. The key, besides the expertise of the team, was a large number of young female egg donors who gave fresh eggs specifically for the purpose.

It turned out he hadn’t shown anything of the sort. It was instead one of the most incredible fabrications in the history of scientific research. Teams in the UK and America, who had been seen as also-rans (and who frankly saw themselves in that light), suddenly found themselves world leaders in the field once more. Only now they were more downcast than before. Not simply because of the dashing of hopes, but also because it transpired that Hwang had access to at least 2,200 fresh human eggs and had failed to produce a single documented human embryonic stem cell line by nuclear replacement. Perhaps he is a poor scientist technically speaking but the evidence suggests otherwise: he did produce a cloned human embryo, and also a healthy live-birth cloned dog.

This is the background to the turn to using animal eggs. It is a far from ideal situation. Mitochondrial DNA (the animal genes that would remain in the cell after nuclear replacement) and nuclear DNA (the human genes inserted into the cell) interact during embryonic development, such that cross species embryos, certainly at the evolutionary distances being used (human/cow or human/rabbit) would almost certainly fail early on in development.

However, essentially human embryonic stem cells could well be extracted before this point. The new applications also take place in the context of a consultation on whether women in the UK should be asked to donate human eggs specifically for research, so it may be the case that more human cells could (and should) be made available for this work, too.

But if both animal and human cells may soon be available, the question remains: why now? It has long been recognised that the best approach to research in this area is to pursue all possibilities at the same time, in parallel. There has always been a difficulty in securing human eggs for research, whereas there is a plentiful supply of animal eggs. A team in America reportedly tried cross-species transfer using human cell nuclei soon after Dolly was born, and a team in China pursued it more recently. That it hasn’t been tried in the UK is down in large part to opposition from religious groups, government and also, shamefully, some scientists linked to government.

The Church of Scotland has articulated a religious basis for opposing the creation of hybrid embryos through human cell transfer into an animal egg, even though it does not fundamentally oppose human embryo research.

Firstly, they find it more problematic that an embryo could be created that did not have the potential to develop into an independent human life than that an embryo with such a potential should be destroyed in research. It is hard to understand the logic behind this. The Church of Scotland appears to follow a strong version of the argument from potential (which is the mainstream UK position and enshrined in law), but then says that creating an embryo without the potential to develop to the point of viability shows a lack of respect for the embryo. But of course the reason embryos are accorded some protection (‘respect’) in law is because they have the potential to develop…

Secondly, the Church of Scotland worries about breaking down the distinctions between humans and animals: ‘in the historic Christian tradition (drawing on Hebrew scriptures) humans are believed uniquely created in God’s image and set apart from all other creatures spiritually and have a unique moral responsibility which animals do not have. Intercourse between animals and humans is also expressly condemned. While humans are given the task of caring for the animal kingdom as fellow creatures of God, they are not seen as of equal status to humans. The present proposal raises issues about respect for both humans and animals.’(5)

John Harris has raised some thoughtful and entertaining criticisms of such views (6). In any event, we should take a reality check: are we in all seriousness expected to discuss the use of a little bit of bovine mitochondrial DNA to develop human embryonic stem cell lines as if it were akin to creating a mythical chimeric creature, or to spend time dwelling on what some people are reputed to get up to with sheep or chickens when they hope no one is looking?

If only such a reality check could deal with the issue at the political level, however. In 2000, the chief medical officer Sir Liam Donaldson’s expert group recommended that the transfer of a human cell into an animal egg should be outlawed: ‘The expert group concluded that the use of eggs from a non-human species to carry a human cell nucleus was not a realistic or desirable solution to the possible lack of human eggs for research or subsequent treatment.’(7) The government was happy to agree with the recommendation: ‘the mixing of human adult (somatic) cells with the live eggs of any animal species should not be permitted. Primary legislation to give effect to this recommendation will be brought forward when the parliamentary timetable allows. In the meantime the Government calls on bodies funding research to make it clear that they will not fund or support research involving the creation of such hybrids.’

Perhaps Sir Liam and his group thought such a proposal was a clever means of demonstrating sensitivity to what they perceived to be public concern, without too much cost to scientific research. In 2000 many scientists in and around Government were experimenting with ways of proposing precautionary measures that they hoped would allow them to connect with the public but also allow a fair degree of business as usual. The best example of this is Sir William Stewart’s inquiry into mobile phones that declared that the phones were safe while advising a precautionary attitude to their use, particularly by children (8).

Will the opportunism of 2000 come back to bite scientists now? We must be thankful for small things: the Government did not get around to introducing primary legislation to outlaw the transfer of human cells into animal eggs. Nor is the new Bill covering aspects of human reproduction announced in this year’s Queen’s Speech expected to outlaw the procedure. Indeed some hope that it may address the issue and explicitly allow it. But past statements and policy have hardly helped to create a climate conducive to such research, and equally certainly they have had the effect of discouraging the few researchers who might have been interested in the area.

So what will happen – will the scientists be given the go-ahead in January? This is in itself an interesting and complicated question. For the purposes of the HFE Act 1990, the law that governs this area, a human embryo is defined as the outcome of the fertilisation of human egg by human sperm (the egg cell during the process of fertilization is also covered by the definition). Scientists who want to carry out research on embryos have to go through what can be an onerous and time-consuming process of securing permission from the regulatory body set up under the Act – the HFEA. Since 1990 much has changed scientifically: a number of new entities that are functionally similar to embryos in many or all respects have been or now could be created otherwise than by fertilisation. Cloned embryos are but the most obvious example. Scientists are hoping that a flexible definition can be found in law that simultaneously gives them legal cover without imposing a strict regulatory regime covering every experiment they might want to perform.

But in the meantime, the application will be heard under the existing law. In 2002 and 2003, the Court of Appeal and House of Lords respectively interpreted the definition of human embryo in the 1990 Act so as to cover embryos created by nuclear substitution of a human cell nucleus into a human egg cell whose nucleus had been removed – the cloning technique used by Wilmut to create Dolly. Using reasoning endorsed by the House of Lords, the Court of Appeal did this by stating that:

‘an embryo is a live organism containing a full set of 46 chromosomes that has the potential to develop into a fetus and subsequently into a person. In 1990 the only way in which an embryo had ever been created was by the fertilisation of the female egg by the male sperm… the two [created by fertilisation and cell nuclear replacement] are essentially identical as far as structure is concerned, and each is capable of developing into a full grown example of the relevant species. So far as the human embryo is concerned, it is this capacity to develop into a human being that is the significant factor and it is one that is shared by both types of embryo.’ (paras. 1, 34)

Since all are agreed that hybrid embryos created by human nucleus substitution into a cow or rabbit egg would not have ‘the potential to develop into a fetus and subsequently into a person’ it would appear at face value that they are not human embryos under the HFE Act and therefore that the HFEA could not license the work. But this has not stopped the HFEA licensing research on other entities without such potential recently, and it appears to welcome the current applications, so perhaps some creative interpretation of the law will be found.

If the HFEA could not license the work, this would not make it illegal. Rather, assuming it wasn’t forbidden under another clause of the HFE Act, the work would remain legal and subject only to less onerous forms of regulation. Lead researcher in Newcastle, Lyle Armstrong has said: ‘If it isn’t the HFEA’s [responsibility], I don’t know whose it is.’(9) Well, it could be yours Dr Armstrong. If scientists want a lighter touch to regulation of the varied and various embryo-like entities they might create under the terms of a new Act of Parliament, exuding a calm and relaxed air in relation to the creation and use of hybrid entities invisible to the naked eye and with no potential to go anywhere would be a good place to start.

John Gillott is co-author of Science and the Retreat from Reason and a freelance writer.

(1) Human-cow hybrid embryo planned, The Times (London), 7 November 2006

(2) Stem cell experts seek licence to create human-rabbit embryo, Guardian, 5 October 2006

(3) Human-cow hybrid embryo planned, The Times (London), 7 November 2006

(4) Stem Cell Research: Medical Progress with Responsibility, Department of Health, p25.

(5) Society, Technology and Religion project

(6) John Harris, Clones, Genes, and Immortality, Oxford University Press 1998, pp. 177-95.

(7) Stem Cell Research: Medical Progress with Responsibility, Department of Health, p31.

(8) Mobile phones and health: accounting for the panic, by Adam Burgess

(9) Human-cow hybrid embryo planned, The Times (London), 7 November 2006