In a world first, scientists in the US have used a cloning technique to derive embryonic stem cells from human embryos.
A paper released in Nature today describes the new research.
Below, some Canadian and UK experts comment on this paper and what it means from a scientific and legal perspective.
From the Cananda SMC:
Michael Rudnicki, Senior Scientist and Director of the Regenerative Medicine Program and the Sprott Centre for Stem Cell Research, Ottawa Hospital Research Institute comments:
What exactly has been done here?
What they did has previously been called “therapeutic cloning” and it is illegal in Canada. They successfully cloned human material, similar to the way they cloned Dolly. However, in this case they combined the genome of the donor egg (oocyte) with the adult cell (somatic cell). This allowed them to generate embryonic stem cell lines that are triploid: with two copies of the genome from the somatic cell and one copy from the oocyte. It would be illegal to do these experiments in Canada and you could go to jail for up to ten years. These experiments are entirely legal in the US and UK.
Why would they do this? What are the applications?
Once induced pluripotent stem cells (iPSC) came along, many felt that this allowed a work around the moral issues raised by human embryonic stem cell derivation. However, we now know that iPSC may have safety issues and they are not necessarily equivalent to embryonic stem cells. This is another approach to generate stem cells. But, because they are triploid, they are not necessarily specific to a particular patient.
Why does this exercise work with a cow or a sheep, but not with a human?
This research group were able to surmount the technical challenges and have now quite effectively solved the problem. They solution was to leave in the oocyte genome so it would combine with the somatic cell genome.
I think what is interesting is what this means for Canada’s legal framework. Most other countries don’t put people in jail for ten years for performing these kind’s of experiments. .
When the legislation was passed in 2004, in the Bill was a provision that required a review in three years, and that never happened. The law is now dated, and without question, it is internationally more restrictive than many other countries including most of Europe, the UK and the US.
Tim Caulfield: Canada Research Chair in Health Law and Policy; Professor, Faculty of Law and School of Public Health; Research Director, Health Law Institute, University of Alberta comments:
What exactly have they done, in a scientific and legal sense?
I really find this fascinating. One of the most fascinating things from a legal perspective is that within the first four paragraphs, they talk about the whole donation process. They created a protocol that specifically involved compensation to women for their eggs.
But in Canada, that’s illegal. You can’t buy and sell human eggs in Canada. That’s criminally prohibited. So here we have an interesting contrast between such culturally similar countries. One country produces a top
paper in the most prestigious science journal and just 100 miles north, the same research would be criminally prohibited. And not just a little prohibited, it’s 5-10 years in jail.
They want to be able to make stem cells they can tailor for individuals. That’s using the technique of somatic cell nuclear transfer, which is what they used to create Dolly.
I was very involved in the debates here in Canada on our laws on all that, And [Dolly] was happening right when we were debating that law. In Canada they decided to ban that technology which I think was a mistake. One of the ‘secular’ reasons they decided to ban it was that it would create a demand for human eggs, and this would lead to the exploitation of women. But others argued that if the women were fully informed, they should be allowed to donate eggs.
And this research definitely puts that issue back on the table. Everyone thought induced pluripotent stem cells had put all this on the back burner. But this paper I think puts it all on the front burner again – cloning, compensation for eggs, all of it.
Is this entity a human embryo or a clone?
What they’re creating – let’s look at it in the context of the embryo-like entity they create to derive the stem cell. What they do is take an oocyte, and leave the chromosomes in, and then take the genes from a somatic cell and put them into the nucleus. This creates an entity – they call it a blastocyst – and from there, they take the stem cells.
One of the things this illustrates is how hard it is to legislate science. Because you never know what direction science is going to go, and you never know what direction public opinion will go. By and large, Canadians have been very supportive of stem cell research.
The definition of a human clone is “*an embryo that, as a result of the manipulation of human reproductive material or an in vitro embryo, contains a diploid set of chromosomes obtained from a single – living or deceased – human being, foetus or embryo.”*
I think it is up in the air if this is a human embryo or a clone.
Let’s look at it from a policy perspective. Is this triploid blastocyst an entity that is prohibited by existing legislation. I don’t think it’s a viable embryo, it could never be a human being. From that perspective, you
could argue that it is not a clone and it’s not a human embryo. But those who are worried about the social implications could find in the current legislative grounds to call it a clone or an embryo and stop it. Also, the process of paying women for their eggs is prohibited in Canada.
To be honest, they are trying to make the Dolly technique work for humans. This report demonstrates the viability * they say at the end. The next sentence says that with a reliable source of oocytes, they could make pluripotent cells. That’s exciting from a scientific perspective and from a policy perspective.
They are trying to create a technology to make human pluripotent cells to have a therapeutic benefit.
Something else that’s interesting is that if you look in the Methods section, they highlight that all the women were educated, they were fully employed, had degrees * implying that they were informed and less likely to be inappropriately exploited.
From the UK SMC:
Professor Mary Herbert, Institute for Ageing and Health, Newcastle University and Newcastle Fertility Centre, comments:
“This study shows that the conventional approach to somatic cell nuclear transfer (SCNT) is inefficient in humans. However, the authors were able to increase the efficiency by leaving the host oocyte genome in place. While this approach does not in itself provide a solution, it takes us a step closer to understanding where the problems lie.”
Professor Azim Surani, Marshall-Walton Professor, Wellcome Trust/Cancer Research UK Gurdon Institute, University of Cambridge, said:?”This study suggests that somatic nuclei are not reprogrammed efficiently when transplanted into human oocytes in the absence of oocyte’s own genome. The latter may ensure that early development can proceed under the control of the host genome, allowing more time for reprogramming of the donor somatic nucleus. The donor genome may require pretreatment to improve the efficiency of the procedure if it is to be of practical use.”
Professor Chris Mason, Chair of Regenerative Medicine Bioprocessing, University College London comments:
“This novel research adds to the growing number of options for cell therapies of the future. Whilst not immediately life-changing for patients, it significantly adds to the scientific pool of knowledge that underpins progress towards advanced treatments. Which approach is the best? Only time will tell, but multiple routes forward may eventually speed the delivery of cell therapies for a broad range of unmet clinical needs.”
Professor Roger A. Pedersen, Director of Research, The Anne McLaren Laboratory for Regenerative Medicine, University of Cambridge comments:
“This work represents the first report of any development resembling normal embryogenesis after somatic cell nuclear transfer (SCNT) to a human oocyte. The authors found that progressive development occurred only when the oocyte’s own genetic material was not disturbed; this confirms previous reports on the difficulty of achieving SCNT in non-human primates (rhesus monkeys) and explains the previous failures of researchers to achieve SCNT using human oocytes. This obstacle appears to be unique to primates (both non-human and human) and contrasts with species (such as sheep, cows and other mammals) in which SCNT to oocytes can be accomplished using standard methods.
“Future studies can now be focused on understanding what goes wrong with the human oocyte when it is subjected to the SCNT procedures. If successful, future SCNT studies could yield human SCNT-derived stem cells that could then be compared carefully with human stem cells obtained using other methods, such as induced pluripotent stem cells.”
Professor Robin Lovell-Badge, Head of Division, National Institute for Medical Research comments:
“This paper will be seen as significant both by those who are trying to use SCNT (somatic cell nuclear transfer) to produce human patient-specific Embryonic Stem (ES) cell lines and by those who oppose human “cloning” experiments. However, it is a technically complex story, with some unexplained results, and an ending that still falls short of the original aim – they did not obtain useful cell lines. However, the work may reveal a way to overcome some problems.
“The use of SCNT methods to obtain blastocyst stage human embryos (the stage just before implantation, where the embryo is about 80 to 100 cells), has been reported by others, but at a relatively low efficiency. Using similar methods, where the host egg nuclear DNA is removed and replaced by a donor somatic cell nucleus, the current authors were in fact unable to obtain any embryo that developed beyond about the 6 to 10 cell stage.
“Instead the authors changed tack and deliberately left the host DNA in place, simply adding the donor nucleus to the one that was already there. Rather surprisingly – as this means that they are creating an embryo with too many copies of each chromosome – these constructs developed well and efficiently to the blastocyst stage. Furthermore, the authors were able to derive (apparently) pluripotent ES cell lines from these embryos – the first time that this has been achieved from embryos derived using SCNT methods.
“These results suggest that some factor associated with the nuclear DNA in the oocyte is required for reprogramming the somatic cell nucleus or at least for allowing the correct activation of genes required to get the embryo beyond the first few cell divisions.
“The authors could get successful development to blastocysts when they transferred a nucleus from an early embryo cell rather than an adult somatic (skin) cell into an enucleated egg. This suggests that the critical factor(s) has something to do with activating embryonic gene expression, because such early embryo nuclei will already have many of the necessary genes active. The SCNT embryos produced in this way are true clones of the donor embryo – but irrelevant with respect to the aim of deriving patient-specific ES cell lines.
“The SCNT embryos and ES cell lines derived by leaving the host genome in place, are not true clones of anything (they could be called intra-specific hybrids) – although the authors convincingly show that the donor DNA is reprogrammed correctly. Instead they are equivalent to rare embryos obtained by fertilisation of an egg with a sperm carrying two sets of chromosomes rather than one (i.e. diploid rather than haploid).
“ES cell lines obtained by this method will not be ideal for studying genetic disease as they have both normal (host) and abnormal (donor) DNA, and I doubt they could be used clinically for any cell-based therapy. Furthermore, both ES cell lines obtained in this work appear to be triploid – with two sets of chromosomes from the donor cell and one from the host oocyte. Triploid cells and embryos usually develop poorly, therefore this is odd in itself. But the SCNT embryos they were derived from should have had four sets of chromosomes: two from the donor and two from the host. The host eggs were at a stage with two sets of chromosomes – normally at fertilisation (or activation) one set would end up in the (second) polar body – a small cell that fails to survive, leaving a haploid set within the much larger egg. Perhaps this polar body was formed – but there is no description of it in the paper. So where are the missing chromosomes?
“Despite all these questions and problems the work suggests that there is a DNA-associated factor present in human eggs (but apparently not in those of other animals) required to efficiently activate and reprogramme the somatic cell nucleus after it is transferred to an egg. Finding such a factor may help the desired aim of obtaining patient-specific ES cell lines.”
* Human oocytes reprogram somatic cells to a pluripotent state, Elgi et al, will be published in Nature at 18.00 UK time Weds 5 Oct 2011, which is also when the embargo will lift.