Future of Somatic Cell Nuclear Transfer to make ES Cells

Advances in therapeutic cloning reported in the past year have been very exciting as somatic cell nuclear transfer (SCNT) can be used to produce very powerful human embryonic stem cells (ESC).

These new cells are called NT-ESCs for short. Neither embryos nor reprogramming factors are needed to produce human NT-ESCs. See here, here and here for discussions of the pioneering papers reporting creation of NT-ESC including the first paper by the lab of Shoukhrat Mitalipov of OHSU, which I called the stem cell event of the year for 2013.

Now that human NT-ESC are a reality, the big question is how good these cells are compared to existing alternatives. For example, can they compete with induced pluripotent stem cells (IPSC) in terms of clinical impact as a basis for regenerative medicine?

Because NT-ESC are extremely difficult to make and have other issues (more on that below), the general sense in the field is that NT-ESC have to be clearly better than IPSCs in some concrete way to be a major, meaningful clinically relevant advance. Otherwise, what’s the point of going to all that trouble to make them when IPSCs are relatively so easy to make?

Just a few months ago it seemed that NT-ESC might jump that high hurdle.

Mitalipov’s team published a Nature paper in July (Ma, et al) claiming that NT-ESC are demonstrably superior to IPSC. You read see my review of that paper here in which I was pretty excited.

However, now a new, very important paper from Dieter Egli’s lab just came out in Cell Stem Cell reporting a very different result than that of the Ma paper. The new paper (Johannesson, et al; see graphical abstract above) conclusively shows that NT-ESC and IPSC are extremely similar cell types. So Johannesson, et al say that NT-ESCs are not better than IPSCs. Drs. Mitalipov and Ma are authors on the new paper as well that seems to contradict their own July NT-ESC paper.

We are left with a dilemma.

What to do when a Nature paper and a Cell Stem Cell paper only a few months apart so strongly disagree?

What the heck is going on?

A Preview piece by Alan Colman and Justine Burley accompanying the Johannesson paper in Cell Stem Cell discusses this puzzle. Colman and Burley call the wide difference in data between the two papers “troublesome” and “puzzling”. One possibility discussed is that the differences in data could be due to technical distinctions between the methods used in the two papers, but it’s hard to imagine how both results could be correct since they are so opposite in nature. The sense I’m getting from the grapevine is that the field is leaning towards thinking that IPSC and NT-ESC are largely equivalent, at least at this point.

The Johannesson NT-ESC paper is entitled “Comparable Frequencies of Coding Mutations and Loss of Imprinting in Human Pluripotent Cells Derived by Nuclear Transfer and Defined Factors”. This impressive paper has 4 key points outlined in its highlights section:

• Isogenic human NT-ESCs and iPSCs were derived from the same somatic cell cultures
• Human NT-ESCs and iPSCs show similar profiles of gene expression and DNA methylation
• De novo coding mutations occur at the same rate in human NT-ESC and iPSC lines
• Loss of imprinting occurs in both NT-ESC and iPSC lines at similar frequencies

In a number of assays reported in this paper, the IPSC and NT-ESC appeared essentially the same with remarkably similar rates, for example, of mutations and epi-mutations. Again, keep in mind that IPSC are a piece of cake to make compared to the challenges that go into making NT-ESC. It is reasonable to expect that making NT-ESC will get easier as more labs try the published protocols, but it is unlikely to ever be as simple as making IPSCs.

The other, non-trivial complication with NT-ESC is that for every individual NT-ESC line must be produced from a separate human egg obtained from a human donor, which invokes difficult practical and potential bioethical issues. For example, compensation for human egg donation is barred in numerous states in the US and in some countries.

NT-ESC technology has a third potential disadvantage of potentially paving the way for human reproductive (“Star Wars”) kind of cloning. This is definitely a dual-use issue for the stem cell field to consider carefully and openly discuss.

I’m glad to report that the proponents of NT-ESCs (e.g. see my interview with Mitalipov on this topic here) oppose human reproductive cloning, but that wouldn’t stop rogue labs from going ahead and doing it anyway, especially if the cloners can piggyback on key, published methodological steps from therapeutic cloning technology. You see, the exact same initial steps would be shared in the processes of human reproductive and therapeutic cloning (see diagram here). They diverge later.

So what’s the bottom line and where does this all leave us?

At this point, human IPSC and IVF ESC are far ahead in terms of clinical translation compared to NT-ESC, but it’s early days in NT-ESC research so I agree with Egli’s team that it is logical to continue research on NT-ESC. Let’s see how things look as we learn more about these cool, new cells, but at the same time let’s discuss all the implications (potentially positive and negative) and bioethical issues related to NT-ESC as well.