Embryonic stem cells from cloned human embryos – six reasons for caution

The newspapers are full today of the news that scientists in the US state of Oregon have produced embryonic stem cells (ESCs) using the same cloning technology (somatic cell nuclear transfer (SCNT)) that created Dolly the sheep.

The original paper was published in the scientific journal Cell (Reuters and Nature give helpful reviews).

Shoukhrat Mitalipov and his colleagues took skin cells and transplanted their nuclei into eggs from paid donors from which the nuclei had been removed. Some resulting embryos were grown to the blastocyst stage (about 150 cells) at which point embryonic stem cells were harvested and developed into stem cells lines from which a range of more specialised body cells were derived.

Some are claiming that this might be the first step in producing stem cells that can be used to treat conditions in which there is cell loss like Parkinson’s, diabetes and spinal cord damage.

The huge media coverage this story has generated is due to the obsession of the British media with embryonic stem cell technology, the fact that this is the first time embryonic stem cell lines have been derived from cloned human embryos and the emotion generated by conditions for which there is currently no cure.

Amidst the hype let me register six reasons for caution.

First, what many news outlets do not make clear is that these embryonic stem cells have been produced by the cannibalising of cloned human embryos, a process that results in their destruction. This is a huge ethical barrier to the technology for those who believe, as I do, that human life begins at conception.

Second, the paper discloses that ten women were paid to ‘donate’ more than 120 eggs in the course of the research. The primary means by which these eggs are procured is ovarian hyperstimulation which is associated with serious health risks in both the short and long term. Egg donors for the experiment received US$3,000–7,000 in compensation. This is expensive and risks creating an organ trade that preys on the poor, especially students. Jennifer Lahl’s excellent book ‘Eggsploitation’ spotlights the booming business of human eggs told through the tragic and revealing stories of real women who became involved in selling their eggs.

Third, the method used to create these embryos is identical to that used to create cloned adults. If someone were to implant one of these embryos in a woman it could theoretically be grown into a cloned baby. Such portakabin technology is extremely difficult to police and some like Dr David King, from the campaign group Human Genetics Alert, are saying for this reason that it should not be done at all.  

Fourth, we know already that cloned mammalian embryos are not normal because they do not grow into normal adults. It took 277 attempts to create Dolly the sheep and she was abnormal and died early. This raises the strong possibility that stem cells derived from cloned embryos may not be normal either. This means that they are very unlikely ever to be used in treatments but only in research. It is adult stem cells derived from sources like umbilical cord blood and bone marrow that hold the real promise, are involved in the overwhelming majority of clinical trials and are already being widely used in treatment of a wide range of conditions.

Fifth, there is already alternative stem cell technology available for research. Induced pluripotent stem cells (iPS) (which can be made from reprogrammed adult cells without the need to create and destroy embryos) and for which Japanese researcher Shinya Yamanaka won a Nobel prize in 2012, have already led many researchers to abandon research using cloning methods. Although this research is still at an early stage iPS cells appear to have most of the properties of embryonic stem cells and their production does not involve the same ethical barriers.

Finally, this new research is at a very early stage and we need to beware of the huge media hype that will be generated around it by biotechnology companies and scientists who have financial and personal vested interests and a hotline to the media. We need to be wary that we are not being given an exaggerated account which is high on hype and plays down the real risks. 

Guest Post - Dr Shane McKee fights back on PGD

Last night I posted a blog with the rather provocative title 'Geneticist claims that weeding out embryos with severe genetic abnormalities is "a tremendous blessing and a wonderful thing"'.

It featured consultant geneticist Dr Shane McKee's recent 4thought interview on pre-implantation genetic diagnosis.

Shane (pictured) is a consultant geneticist and self-styled 'Christian Atheist' in Northern Ireland with whom I frequently spar on twitter. One of our previous twitter dialogues (twebates) is available on this site.

Today Shane asked me if I would post his email reply on this blog which I happily do. I have agreed not to reply yet....

Dr Shane McKee replies

When did I say I supported abortion up to 40 weeks? I do not "support abortion" - I recognise that there are circumstances in which a family may decide that the best course of action is not to continue with, or initiate, a pregnancy that will result in a child with a devastating congenital disorder.

For you to bring Klinefelter and XYY etc into the mix just shows your ignorance of paediatrics and genetics. You can leave your childish blog post up there unaltered if you wish; it says a lot more about you than it does about me or my medical colleagues, who are trying to help families faced with terrifying prospects and agonising decisions. These people are real, and they mean a lot more to me than you, with your blinkers, can ever appreciate.

And, yes, if you needed a kidney, I would still give you one. But if I had 100 8 cell embryos, I would unhesitatingly disaggregate them and genetically re-engineer them or whatever in order to, say, treat a child with Duchenne Muscular Dystrophy, or a young mother with Huntington's Disease.

Because an embryo is not the same as a person; it is not a "disabled individual"; it is not a "person". An acorn is not an oak tree. A map is not a journey, nor is it the destination.

So I dare ya. If you have an ethical atom in your brain (for it is in the function of that tiny organ that your humanity - which I fully acknowledge - resides), post THIS email as a post on your blog. Don't add your little italic comments - leave it for your readership to do that in the thread below. You can start to respond after 5 comments.

Are you man enough to do that?

More hype about three-parent embryos – don’t hold your breath about the promises of new therapies

Health Secretary Andrew Lansley has asked the Human Fertilisation and Embryology Authority to assess a controversial fertility treatment.

The ‘three-parent IVF’ technique developed at Newcastle University (on which I commented last April) involves creating a fertilized egg in a laboratory, then removing its nucleus and placing it into another embryo from which the nucleus has been removed (see picture above).

The resulting embryo has nuclear DNA from a man and a woman and cytoplasmic DNA from a second woman - so effectively three genetic parents, although the contribution from the second woman is very small.

Researchers claim the technique could help prevent mothers passing on a rare inherited condition called mitochondrial disease to their children. Mitochondrial disease is unusual in that it is transmitted through DNA in the mitochondria (cell 'batteries') in the cell cytoplasm rather than through DNA in the cell nucleus.

Although they admit that they are far from ready to use the technique on patients, they feel that because the science is progressing ‘very rapidly’, the review of the process, which would inform political debate, needs to start now.

Getting the regulatory changes necessary to allow using the technique in patients now no longer involves parliament but only approval from the Health minister. The HFEA panel is set to submit its report to the government next month.

There are about 50 different known mitochondrial diseases which are passed on in genes coded by mitochondrial (as opposed to nuclear) DNA. They range hugely both in severity and clinical features. For most there is presently no cure and little other than supportive treatment.

We need to be clear in the first instance that this new ‘treatment’, even it were eventually to be shown to work (and there is considerable doubt about that), will do nothing for the thousands of people already suffering from mitochondrial disease or for those who will be born with it in the future.

It is primarily about trying to prevent people with MCD being born - or at least helping a very small number of mothers who carry the gene to have children who are unaffected.

And we need to remind ourselves that there are already some solutions available for those couples who find themselves in the tragic position of carrying genes for mitochondrial disease – including adoption and egg donation (although I have serious ethical reservations about the latter)

But I have three big questions about this new technique:

1.Will it work? I am very skeptical!
2.Is it ethical? No, there are huge ethical issues!
3.Is the debate being handled responsibly? No, there are huge vested interests involved!

I have a great sense of déjà vu here. There is always in this country huge media hype about supposed breakthroughs in biotechnology and the IVF industry – especially the Newcastle group - is very skilled in arousing media interest.

But we have been here before with human reproductive cloning (the Korean debacle), so-called therapeutic cloning for embryonic stem cell research (which has thus far failed to deliver) and animal hybrids (now a farcical footnote in history)

We saw the false dawn most clearly with animal human hybrids where the biotechnology industry, scientists, patient interest groups and science journalists on the UK nationals duped both the public and parliament into legalising and licensing animal human hybrid research to produce stem cells.

But even before the ink was dry on the 2008 HFE Act researchers and investors were recognising that the technology who almost certainly not deliver – that there where more effective ethical alternatives available (such as induced pluripotent stem cells or IPs)

The Newcastle unit is a world leader in promising much and delivering little – but given the short attention span of the media and the gullibility of the public few people seem to realise, remember or care.

The UK broadsheets this morning largely transcribe uncritically the spin of the Newcastle unit’s press release – whilst giving scant attention to the questions of safety, efficacy and ethics being raised by commentators in scientific journals and blogs. Some questions that you will not hear asked or answered:

1. What will be the effect on the embryos of the small amount of abnormal cytoplasm containing defective mitochondria that is still being transferred?
2. Will any of these embryos survive beyond blastocyst stage? (cloned human embryos and animal-human hybrids produced by similar ‘nuclear replacement’ technology haven’t)
3. If they do survive will the nucleus from one embryo function properly with the cytoplasm of another?
4. Will the progeny be normal or be suffering from defects that are in fact worse than mitochondrial disease itself? (we know that cloning by nuclear replacement is possible in frogs, difficult in mammals, hugely problematic in non-human primates and currently not possible in humans)
5. What about the hundreds of embryos that have already been destroyed in the research?
6. What will be the psychological effect on any progeny of the fact that their DNA is derived from three separate ‘parents’?
7. What will be the effect of the introduced transmissible DNA on future generations?

We also need to realise that the Newcastle scientists have a huge financial and research-based vested interests that make it very difficult for them to be balanced and objective in the way they present their findings.

Getting the regulatory changes and research grants to continue and extend their work is dependent on them being able to sell their case to funders, the public and decision-makers. And they know that that is best achieved through attention-grabbing media headlines and press releases and heart grabbing (but highly extreme and unusual) human interest stories that are selective about the truth.

What is currently happening in Newcastle may be legal in Britain – but it is illegal in almost every other Western country for good public safety and ethical reasons. Britain is regarded by many as a rogue state in all this.

So I’m not letting myself be carried away by the hype and spin. And I’m not holding my breath about the promises of therapies.

New advances in embryo testing may result in higher success rates for IVF but at what cost?

Two new embryo screening tests have been recently developed that researchers believe will increase success rates for women having a health baby after IVF treatment.

At present only about 30% of women under 35 have a baby following IVF and this percentage drops with age falling to 10% by age 40.

The new tests enable abnormal embryos to be indentified five days after fertilisation and before being implanted in the womb.

If embryos judged unlikely to survive are not implanted, it follows that the chance of a pregnancy reaching term is higher.

The first new test involves measuring the uptake of glucose by early embryos. Glucose is an energy source essential to growth and its low uptake is therefore a marker of poor growth in the early embryo.

Researchers at the University of Melbourne in Australia have developed the technique.

Their research involved 50 patients undergoing IVF. 32 of the women had a positive pregnancy test after embryo transfer and 28 babies were born. These 28 babies resulted from the embryos which had the highest glucose uptake. Controversially the method also has the potential to predict the gender of an embryo prior to implantation, as female embryos appear to take up more glucose than males.

The second new test involves determining the number of chromosomes in the developing embryo. The BBC has run the story this morning apparently after receiving a press release from specialists at CARE Fertility in Manchester. This will probably make it big news. However the story is not new and was covered by the Daily Telegraph and Bionews (amongst others) over a week ago. Those interested in knowing more about the technique will far more usefully spend their time examining these accounts.Tony Rutherford, chair of the British Fertility Society, expects the test will take two to three years to develop.

Aneuploidy (read more here)– an abnormal number of chromosomes – is responsible for a high percentage of pregnancies that spontaneously abort and is increasingly common with age.

But fertility specialists in the US state of New Jersey are claiming to be able to double IVF success rates by selecting out embryos with either too many or two few chromosomes. A Denver specialist has explained why the test is of particular importance to women over 35. He said, ‘By the time you’re in your mid-30s about 50 per cent of embryos are abnormal; by 40, 75 per cent are; and by 42, 85 to 90 per cent are’.

Fertility drops off rapidly after age 30 probably mainly for this reason. So it appears that the demand for this technology will be greater the more women, for whatever reason, delay trying for a baby.

So what of the cost?

The NHS currently provides funding for one cycle of IVF for women who have met the clinical definition of infertility, providing they have an identifiable cause to their infertility. After that couples have to pay. According to the Human Fertilisation and Embryology Authority (HFEA) the average cost of one cycle of IVF including drugs is between £4,000 and £8,000.

Preimplantation genetic diagnosis (PGD) – determining if the embryo is genetically abnormal before implantation – currently costs between £1,000 and £2,000 but it is likely that these new embryo screening tests, should they become commercially available, will cost considerably more. Cheaper options overseas will no doubt fuel more IVF tourism in future. Regardless, in an era of shrinking health budgets this is technology that is increasingly going to be only the reserve of the rich.

But money is only one part of the cost of IVF. There is also the emotional cost of being on the emotional roller coaster of a treatment for which results are not immediately obvious (confirming a successful pregnancy takes time) and where there is still a high probability of failure. 30% success rates are also 70% failure rates.

And finally there is the moral cost. This new technology is essentially eugenic. It involves identifying and discarding (or not implanting) embryos that are judged to be abnormal. It might be argued that many of these would not have survived pregnancy anyway - embryos for example with trisomy 16 inevitably do not survive pregnancy – but a significant number do.

These include babies with Down Syndrome (Trisomy 21), Edwards Syndrome (Trisomy 18), Patau Syndrome (Trisomy 13) and Turner’s Syndrome (XO), who carry disabilities varying in form, number and severity. Some of these are treatable and some aren’t.

Are we therefore saying that embryos which can not look forward to a life without disability should not be given the chance to live?

Interestingly the Pope is quoted in the Hindustan Times just yesterday on this very issue. He said, ‘it is indispensable that new technological developments in the field of medicine never be to the detriment of respect for human life and dignity, so that those who suffer physical illnesses or handicaps can always receive that love and attention required to make them feel valued as persons in their concrete needs.’

He added that the number of people with Down syndrome ‘has declined mostly because a good number of them are eliminated before they are born.’

In December 2008, the Vatican issued a document affirming the ‘dignity of the human embryo’ which listed biomedical techniques considered ‘illicit’ by the Roman Catholic Church. These included in vitro fertilisation, cloning, the therapeutic use of stem cells, producing vaccines from embryo cells and the ‘morning-after’ pill.

Such practices go against the ‘fundamental principle’ that the dignity of the person must be recognised from conception until natural death, it said.

Quite!

Three parent embryos? Calm down all!

The papers this morning are full of reports that researchers at Newcastle University have successfully produced ‘three parent’ embryos as a first step to preventing maternally transmitted mitochondrial disease.

There are about 50 different known mitochondrial diseases which are passed on in genes coded by mitochondrial (as opposed to nuclear) DNA. They range hugely both in severity and clinical features. For most there is presently no cure and little other than supportive treatment.

The Newcastle team have managed to produce about 80 embryos and to grow a small number up to the eight-cell and blastocyst stage using defective embryos left over from IVF. The embryos were produced by transferring the pro-nuclei from zygotes with abnormal mitochondria into zygotes with normal mitochondria from which the pro-nuclei hade been removed.

The work has been financed by the Medical Research Council, the Muscular Dystrophy Campaign and the Welcome Trust, and headed up by Alison Murdoch and Doug Turnbull.

The group are now pushing for a change in regulations to allow them to experiment using normal embryos – either ‘spare’ ones left over from IVF or new ones specifically produced for this research .

We need to be clear in the first instance that this ‘treatment’, even it were eventually to be shown to work (and there is considerable doubt about that), will do nothing for the thousands of people already suffering from mitochondrial disease or for those who will be born with it in the future. It is primarily about trying to prevent people with MCD being born. Or at least helping a very small number of mothers who carry the gene to have children who don’t.

It would be a great tragedy if in trying to resource this new unproven technology that we were distracted from finding effective treatments and proving supportive and palliative care to those who are already suffering with mitochondrial disease.

And we need to remind ourselves that there are already some solutions available for those couples who find themselves in the tragic position of carrying genes for mitochondrial disease – including adoption and egg donation (although I have serious ethical reservations about the latter)

But apart from that I have three big questions:

1.Will it work? I am very sceptical
2.Is it ethical? There are huge ethical issues
3.Is the debate being handled responsibly? No, there are huge vested interests involved

I have a great sense of déjà vu here. There is always in this country huge media hype about supposed breakthroughs in biotechnology and the IVF industry – especially the Newcastle group - is very skilled in arousing media interest.

But we have been here before with human reproductive cloning (the Korean debacle), so-called therapeutic cloning for embryonic stem cell research (which has thus far failed to deliver whilst technology using adult stem cells and cord blood though relatively unresourced goes from strength to strength) and animal hybrids . (now a farcical footnote in history)

We saw the false dawn most clearly with animal human hybrids where the biotechnology industry, scientists, patient interest groups and science journalists on the UK nationals duped both the public and parliament into legalising and licensing animal human hybrid research to produce stem cells. But even before the ink was dry on the 2008 HFE Act researchers and investors were recognising that the technology who almost certainly not deliver – that there where more effective ethical alternatives available (such as induced pluripotent stem cells or IPs)

Nonetheless the Prime Minister had already informed Parliament that animal human hybrid research would save millions of lives. He is noticeably very quiet about it now.

The Newcastle unit is a world leader in promising much and delivering little – but given the short attention span of the media and the gullibility of the public few people seem to realise, remember or care.

The UK broadsheets this morning largely transcribe the spin of the Newcastle unit’s press release – whilst giving scant attention to the questions of safety, efficacy and ethics being raised by commentators in scientific journals and blogs. Some questions that you will not hear asked or answered:

1. What will be the effect on the embryos of the small amount of abnormal cytoplasm containing defective mitochondria that is still being transferred?
2. Will any of these embryos survive beyond blastocyst stage? (cloned human embryos and animal-human hybrids produced by similar ‘nuclear replacement’ technology haven’t)
3. If they do survive will the nucleus from one embryo function properly with the cytoplasm of another?
4. Will the progeny be normal or be suffering from defects that are in fact worse than mitochondrial disease itself? (we know that cloning by nuclear replacement is possible in frogs, difficult in mammals, hugely problematic in non-human primates and currently not possible in humans)
5. Why are we proceeding with this work in humans when similar work in primates (published in Oregon last year) is less than one year old?
6. What about the hundreds of embryos that have already been destroyed in the research?
7. What will be the psychological effect on any progeny of the fact that their DNA is derived from three separate ‘parents’?
8. What will be the effect of the introduced transmissible DNA on future generations?

We also need to realise that the Newcastle scientists have a huge financial and research-based vested interests that make it very difficult for them to be balanced and objective in the way they present their findings. Getting the regulatory changes (which incidentally now no longer involve parliament but only approval from the Health minister) and research grants to continue and extend their work is dependent on them being able to sell their case to funders, the public and decision-makers. And they know that that is best achieved through attention-grabbing media headlines and press releases and heart grabbing (but highly extreme and unusual) human interest stories that are selective about the truth.

What is currently happening in Newcastle may be legal in Britain – but it is illegal in almost every other Western country for good public safety and ethical reasons. Britain is regarded by many as a rogue state in all this.

So I’m not letting myself be carried away by the hype and spin. And I’m not holding my breath about the promises of therapies in three years. And I will be actively opposing any extension of the licence to enable these researchers to be extending their work to use and more ‘spare’ embryos with all that that involves.