Ethical Stem Cells Redux

In August, there was a big press tizzy about so-called ethical stem cells. In the paper, a group headed by Robert Lanza working at a company called Advanced Cell Technology claimed that they could take a single cell from a human morula and create a embryonic stem cell line from that cell. Admittedly, this was an exceptional scientific advance, but there were some serious caveats. First, the story was kind of hyped in the sense that the paper didn't actually show that you could do this without killing the embryo, they merely implied that it was possible. Second, I had some serious technical concerns with the paper.

To review, those technical concerns were:

• The paper had not shown that the embryos would be OK.
• It was not clear how embryonic the cell lines were in the sense that they might be partially differentiated or possess circumscribed developmental capacity.
• There was a nitpicky technical issue in that they lines required feeder layers -- which might lessen their clinical utility.

For more on that, read my earlier post.

Anyway, some new work presented at the American Society for Reproductive Medicine has attempted a similar strategy on mouse embryos that are somewhat older with some success -- alleviating some of my doubts.

Takeuchi et al. showed that if you remove three cells from a mouse blastocyt, you can get a ES cell line and the embryo can -- the majority of the time -- survive:

The researchers used slightly older embryos that have formed into hollow balls called blastocysts. These consist of a clump of 20-25 cells called an inner cell mass, which will give rise to the embryo, circled by cells that will form the placenta and supporting tissues. Normally, the entire inner cell mass is extracted and grown into ES cells, killing the embryo.

Takeuchi and his team extracted blastocysts from mice and used an enzyme to soften the natural glue holding the inner cell mass together. They then took one, two or three cells and tried to grow these into ES cells, before implanting the embryos back into the mice.

Three-cell extractions led to ES cell lines, but not one or two cells. Using the technique, the researchers grew four ES cell lines from 16 blastocysts -- a success rate of 25%. This is a better rate than both Lanza's and the conventional technique.

After extracting the three cells and implanting the embryos back into mothers, 54% of them developed into normal mouse pups. In a control group of blastocysts that were removed from mice and replaced without taking away any cells, 62% of embryos developed into pups.

This suggests that the procedure may have an impact on the survival of the embryos, but Takeuchi says this is not a statistical difference.

A couple of things:

1) For the uninitiated, the difference between the cells taken from the earlier paper and the cells taken for this work is that the cells taken for the earlier paper are from a morula and these ones are from a blastocyst.

What's the difference? The difference lies in a concept that I introduced in my earlier post. Cells from a morula are totipotent -- each cell can in theory produce an entirely new animal. The cells from the inner cell mass of a blastocyst (which is where these were taken from) are pluripotent, but probably not totipotent. Pluripotent means that they can differentiate into all the different cell layers -- endoderm, mesoderm, and ectoderm -- and hence can create basically any organ given the right conditions. It doesn't mean that they can necessarily create an entirely new embryo and hence a new animal.

In practice, these is not a huge problem because using embryonic stem cells you are not trying to make a new animal (or person); you are trying to replace a tissue. However, the difference does suggest -- for good or ill -- some restriction in the ability of these cells to differentiate. Hence, it requires that in evaluating the cell lines produced you have to be aware that they may have limited developmental potential.

(If you would like to see pictures of the embryos involved, I found this great link to an In Vitro Fertilization clinic that includes images.

2) It is reassuring that they took the embryos from which cells are removed and tried to see if they would produce viable mice. That was a big hurdle from the last set of experiments. This works shows that survival of the embryo is possible under these conditions.

However, it also shows that 100% viability is not possible -- at least with current technology. The issue does not appear to be the removal of the three cells. The issue appears to be the enzymatic digestion of the embryo to loosen the cells for removal.

This is kind of a problem because in order to go to someone and say "Hey buddy, I've got ethical stem cells. No embryos had to die," you have to be able to guarantee that the embryos won't die.

I am not hating on this research. I think it is fabulous that they even tried. But we need to be realistic about our benchmarks for what to call "ethical stem cells." Ethical stem cells in my mind, using the definition that the evangelicals are likely to use, is a line of ES cells that are derived at no risk to the embryo. This is not quite there yet.

3) Mice aren't humans. When I worked in a cancer lab, my boss used to joke that "If you are mouse with cancer, we have a solution for you." Things that work for mice do not always work for people. We need to keep that caveat in mind.

4) The paper isn't out yet, so I can't answer the question about whether they use a feeder layer. I can almost guarantee that they did.

All told, however, I think this is a valuable pilot study. I haven't had a chance to read the paper because it isn't out yet, and I am interested to see how they prove the development potential of the developed lines. I am also excited that they are pursuing this line of research -- I think it will allow all of us to come to an understanding.

So keep an eye out for this paper when it comes out. Interesting stuff and worth it.