Ethical Stem Cells?

The press is all in a tizzy about so-called ethical stem cells, but this still indicates a really limited understanding of how embryonic stem (ES) cells work. (Frankly, if I had a dollar for every time I read bad reporting on ES cells, you and I would not be talking. I would be Tahiti...with Natalie Portman.)

Anyway, in an article published in advance online in Nature, Klimanskaya et al. show that single cells derived from preimplanation genetic diagnosis (PGD) can be used to grow new stem cell lines.

Some background:

People go to in vitro fertilization (IVF) clinics for a variety of reasons. Some people are trying to get pregnant but can't; some people have a high risk for a genetic disorder that they are worried that they are going to pass on to their kids. For the latter group, what happens is that after the embryo is created in a petri dish (removing all fun from the process) but before reimplantation into the mother, a single cell is removed from the 8-10 cell blastula. (They use a robot with a very tiny pipette to kind of grab it.)

This single cell is used for PGD, a procedure where the DNA is checked for various genetically inherited diseases. No harm, no foul for the embryo -- they just put the rest of the embryo in the mother and oulah in 9 months you have a kid. (Actually this whole process doesn't work most of the time. Results vary, but even if you are really good you still can't get this to work more than 50% of the time.)

So we have this one cell that we were going to use to check for genetic diseases. What this paper did was take that cell and culture it for a couple days. No worries. It is still the same cell. And some of the time (58%) that cell would divide into two.

So now you have two. You take the one cell and use it for PGD as normal. Then you take the other cell and try and grow it into an embryonic stem cell line.

This paper shows that it actually works -- sometimes. A lot of the time the cells stop growing or when they do grow they do very un-ES cell-like things like differentiating into various other types of cells. That is no good for us because we want a cell line of ES cells that retain the ability to differentiate but do not actually do so. (Sort of like my sex life. I retain the privilege of having it, but for the time being have elected not to do so.)

However, before we become irrationally exuberant about how we can make as many new stem cell lines as we want without destroying embryos -- how we can get together with all of the Religious Right and sing Kumbaya -- there are some big caveats to this paper.

• 1) It is not clear that the embryos are OK when you do this. -- There are no studies to show that the babies are fine when one cell is removed at this stage, although there is a lot of anecdotal evidence. Many might argue that we shouldn't make stem cell lines this way until we can assure of the baby's safety. They mention this issue in the paper:

  Numerous reports suggest that neither the survival rate nor the subsequent development and chances of implantation differ between intact human embryos at the blastocyst stage and those following blastomere biopsy for PGD. However, until remaining doubts about safety are resolved, we do not recommend this procedure be applied outside the context of PGD. Blastomere-derived hES [human embryonic stem] cells could be of great potential benefit for medical research, as well as for children and siblings born from transferred PGD embryos. (Citations removed.)

• 2) It is not clear how embryonic these stem cell lines are. -- The big thing about embryonic stem cell lines is that the cells in them can in theory become any cell or organ in the body. The scientific term for this capacity is that the cells are totipotent -- they can generate an entire new animal given the right conditions. On the other hand, cells could be pluripotent. Pluripotent cells can generate a lot of different things, but not necessarily everything. The big thing that makes embryonic stem cells attractive to scientists is that they are totipotent.

  They present some evidence that these cells are in fact totipotent. For example, they show by labelling the cells derived in this way can form all three embyronic layers (endoderm, mesoderm, and ectoderm). However, what no one has shown is that a cell derived at this stage can form a whole embryo, and this is an important step because it is the criterion for totipotency. They also talk about the absence of evidence in this area:

  Concerns have been raised as to whether individual eight-cell-stage blastomeres, such as those used in the current study, are totipotent and could potentially generate a human being. A recent report shows the localization of cell fate determinants (Cdx2) in the late-dividing blastomeres of the two-cell-stage mouse embryo. Other studies show that at the four-cell stage, blastomeres have different developmental properties, and that individual human blastomeres have differential Oct-4 expression that seems to direct cells towards inner cell mass or trophoectoderm lineages. Notably, individual morula (8-16-cell)-stage blastomeres have never been shown to have the intrinsic capacity to generate a complete organism in any mammalian species. (Emphasis mine.)

  They mention that a certain cell fate marker (Cdx2) is not evenly divided between all the cells of the embryo even at the two cell stage. This would suggest that not all the cells in the embryo are the same, also suggesting a certain restriction of developmental potential.

• 3) There are technical issues because their cells require feeder layers. -- This is kind of a nitpicky technical issue, but what you do when you make these cells is you take the ES cell and plate it on a layer of other cells (usually from a mouse). This feeder layer provides nutrients and growth factors to the cells growing on top of it. The reason you have to do this is because ES cells are notoriously tempermental -- they will just die to piss you off. (The image below is of a body of ES cells on a feeder layer.)

  

  This may not seem like a big deal, but it is a very big deal if you are talking about using the cells in clinical trials. What if the cells become contaminated with the feeder cells? That is a big FDA no-no. They mention that they are working on feeder-free systems, but that they haven't managed it yet. (That is OK. No one else has reallly managed it yet either.)

So the take home would be that this is a very good and interesting paper, but is not yet deserving of flipancy. I would be as happy as anyone else if we could finally get back to the job of saving lives rather than fighting over what constitutes a human organism, but there are real technical considerations that prevent this from being a magic bullet -- yet. Something to watch, definitely, but not as big as the news has made it sound.