Ethical Stem Cells Hyped?

Those of you who read an earlier post here noted that I was somewhat skeptical of the technical aspects of the so-called ethical stem cells. I felt that there were several technical hurdles that had to be surmounted before this technology could be used reasonably.

It turns things were even worse than I thought.

New Scientist reports that Nature has issued a clarification to the article because many had complained that the scientists had been disingenuous in suggesting that no embryos had been destroyed in that set of experiments. In fact, 16 embryos had been destroyed.

Early press reports of the breakthrough, including a press release from the journal Nature, where the research was published, gave the impression that human embryonic stem cells (hESCs) had been obtained from early-stage embryos without destroying them.

If true, this would have the potential to overcome the major ethical objection to embryonic stem cell research -- that embryos must perish to yield the precious cells. US President George Bush opposes the research on these grounds, and has heavily restricted federally-funded research on hESCs as a result.

The hope was that by sparing human embryos -- as the company had earlier demonstrated in mice -- the new breakthrough would lead to Bush easing US restrictions.

"That's what many people on both sides of the debate over embryo-destructive stem cell research had been hoping for,' says Robert George of Princeton University, and a member of the President's Council on Bioethics. He criticised, as "pure hype", the research carried out by Advanced Cell Technologies, in Worcester, Massachusetts, US, but adds 'it is increasingly clear that such sources are coming'.

Bob Lanza, who led the research at ACT, denies he made any attempt to mislead the public.

...

On Friday 25 August, Nature issued a clarification of an original press release issued two days earlier, stating that: "We feel it necessary to explain that this paper demonstrates that human ES cells can be grown from single cells, but that the embryos that were used for these experiments did not remain intact.' The initial press release from the journal had implied that the embryos had survived the cell extraction process.

A press release from ACT, released on 23 August, had not been clear: 'ACT today reported that company scientists have successfully generated human embryonic stem cells using an approach that does not harm embryos."

Here is the ACT press release. I have not yet been able to find a copy of the edited Nature press release.

Furthermore, reading the paper suggested that one cell (a single blastomere) had been removed from each of the candidate embryos in the production of the cell lines. In fact, in none of the 16 embryos tested was less than 4 cells removed as is pointed out in this post by Brendan Maher at The Scientist:

Lines were established from the 3rd and 6th experiment. And while it would appear that not a single embryo would have had fewer than four cells removed from it, it is impossible to tell because of the way the embryos are grouped together.

All this information was hidden in the supplementary information to the paper -- which was not originally published with the paper but as best as I can gather only with the press release:

The flurry of numbers and only distant relationship between the 'corrected' sentence and the original left us scratching our heads as to what exactly they meant. As if sensing they hadn't aggravated reporters enough. They issued a second correction at 4pm on a Friday afternoon (long after the UK office had likely packed up and gone home). The second correction says what seemed apparent from the numbers. Bold emphasis is mine.

Dear colleague,

Apologies for the multiple mailings. It has come to our attention that the clarification of the press release on this week's stem cells paper was incorrect. This was due to internal communication problems.

A corrected version of the press release is below. We feel it necessary to explain that this paper demonstrates that human ES cells can be grown from single cells but that the embryos that were used for these experiments did not remain intact.

Further where we stated that some embryos had one or two cells removed and others were biopsied multiple times we hope to now provide the breakdown of each embryo used and how many cells were then used to generate stem cell lines. Please check the press site for updates.

The supplementary table with full details is available on the press site and the corrected press release is below.

Best regards,

Important indeed. That supplementary table was neatly tucked away on their press site. (Emphasis in the original post.)

I have not been able to verify whether the claim that the table was not part of the original supplementary information because the Nature site does not keep track of whether the article was updated.

I have a couple of comments on this:

1) There is some sketchiness going on here with this data. I agree that the researchers, the journal, and the company were being quite disingenuous when they suggested that they actually had extracted only a single cell from one embryo and made it successfully into a cell line. That was certainly the thrust of the phrase "ethical stem cells" as I understand it, and they didn't do that.

I don't particularly care whether there were 16 embryos harmed in the procedure, but I do care that the researchers misled the public about what they could and could not do.

2) This is a great example of how politics corrupts science. I am sure these guys meant well, but it seems to me like they were publishing with one eye always on the press release. You can't do good work that way -- always wondering how you can frame your research as a terrific advance. Furthermore, if you are going to talk about an issue as political as stem cells and make as much of a fuss as they did, you should know better that you have to have your data perfect. That is just sloppy.

3) There is a big disconnect between the abstract and the paper itself that I didn't fully realize at the time (I apologize that I missed it).

Here is the abstract:

The derivation of human embryonic stem (hES) cells currently requires the destruction of ex utero embryos1,2,3,4. A previous study in mice indicates that it might be possible to generate embryonic stem (ES) cells using a single-cell biopsy similar to that used in preimplantation genetic diagnosis (PGD), which does not interfere with the embryo's developmental potential5. By growing the single blastomere overnight, the resulting cells could be used for both genetic testing and stem cell derivation without affecting the clinical outcome of the procedure. Here we report a series of ten separate experiments demonstrating that hES cells can be derived from single blastomeres. Nineteen ES-cell-like outgrowths and two stable hES cell lines were obtained. The latter hES cell lines maintained undifferentiated proliferation for more than eight months, and showed normal karyotype and expression of markers of pluripotency, including Oct-4, SSEA-3, SSEA-4, TRA-1-60, TRA-1-81, nanog and alkaline phosphatase. These cells retained the potential to form derivatives of all three embryonic germ layers both in vitro and in teratomas. The ability to create new stem cell lines and therapies without destroying embryos would address the ethical concerns of many, and allow the generation of matched tissue for children and siblings born from transferred PGD embryos. (Emphasis mine.)

Here is the first paragraph of the paper:

A series of experiments was carried out to determine whether hES cells can be derived from single blastomeres (Supplementary Table 1). Unused embryos produced by in vitro fertilization (IVF) for clinical purposes were obtained with full informed consent and used in compliance with Advanced Cell Technology's ethics advisory board and institutional review board. Sixteen pronuclear- and multicell-stage embryos were thawed and cultured to the 8-10-cell stage in 20-microl microdrops of Quinn's cleavage medium under paraffin oil (see Methods). Six of these embryos were grade I or II (symmetrical and even cell division with little or no cytoplasmic fragmentation), whereas the remaining ten embryos were grade III (variable fragmentation), using a standard scoring system6; embryos with blastomeres of unequal size and moderate-to-severe fragmentation (grades IV and V) were excluded from this study. The zona pellucida was disrupted and individual blastomeres mechanically separated from the denuded embryos using a micropipette and gentle tapping of the pipette holder. The separated blastomeres were cultured together in the same medium, arranged so as to avoid contact with each other using depressions created in the bottom of the plastic tissue culture plate, as described previously. (Emphasis mine.)

Two comments. One, just to reiterate I do not know whether the reference to the supplementary table was in the first paragraph in the original online publication. Two, look at the difference in emphasis between the abstract and the first paragraph. In the abstract, they strongly suggest that one blastomere = one cell line whereas in the first paragraph they note that the thawed embryos were separated into their constituent cells and each was grown individually.

This makes me think that the sketchiness exceeds just the press issues. I have a real problem with how they failed to note major caveats in their abstract. Abstracts are supposed to be for a condensed summary, but you should always be aware that a lot of people are going to only read the abstract. The differences between the abstract and the paper (particularly when you include the supplementary information) are sufficient such that the abstract radically mistates what the experimenters did. This is not a kosher way to do science.

4) I am not hating on this procedure. I think it is spectacular that they got a cell line to work from one cell. I think it would be lovely if they could get that one cell by the process of PGD. However, they did not show that they can do so in this paper.