September 21, 2006

Blastomere Blasphemy: Advanced Cell Technology, the Media and the Lost Opportunity in Stem Cell Research

In the current issue of The American Journal of Bioethics our new regular contributor and amazing essayist Ricki Lewis writes about what she calls Blastomere Blasphemy:<
Sometimes a few words make a huge difference. In the late-summer saga of obtaining human embryonic stem (hES) cells from single blastomeres of eight-cell-stage embryos, the damning words were “while leaving the embryos intact”. The ensuing angst exemplified how oversimplification in science reporting can widen the divide between scientists and the public.

Algebra 101 and Biology 101

The first news release sent to reporters by Nature magazine heralding work at Advanced Cell Technology (ACT) of Worcester, MA, and referring to an online pre-print-publication (Klimanskaya et al. 2006) stated, “By plucking single cells from human embryos, Robert Lanza and his colleagues have been able to generate new lines of cultured human embryonic stem (ES) cells while leaving the embryos intact.” The problem: while the technique could, theoretically, have left the six or seven-celled remainders able to complete development, or at least survive until the blastocyst stage at which hES candidates are usually isolated, that had not yet been accomplished. One must infer from numerical data in the online report that the biopsied embryos had not gone on to become babies. And here is where the linguistic disconnect occurs. The data in the report are indeed plain as day that the embryos were destroyed – but only to biologists. Let me explain.

The information that the embryos did not survive is conveyed in language akin to an algebra problem. The first paragraph of the online report states that 16 embryos were thawed and had cells removed. 53 of the removed cells divided, and these 53 represented 58% of the total number of cells removed. Got that? Solve (0.58)X = 53 for “X” and you get 91 blastomeres. Next leap: 91 blastomeres from 16 embryos means more than two from each, which spells “destroyed”. Short feature articles in the print editions of Nature and Science, dated August 24 and 25, respectively, present the 91-from-16 critical information, albeit with lots of qualifying “cans” and “coulds” (Pearson 2006; Vogel 2006). Only the Nature feature spelled out that the embryos had been dismantled.

Now switch to basic biology. The reason that an eight-cell human embryo can spare one or two cells and still develop is one of the characteristics that includes us among the deuterostome animals, along with other chordates and the echinoderms. If such an experiment were performed on a protostome, such as a boll weevil or an octopus, the sampled embryo would be kaput.

The initial Nature news release, sent to reporters all over the world, catalyzed a series of events that not only detracted from the significance of the ACT research, but also fueled public distrust of stem cell researchers. Was this to be another chapter in the saga started by Seoul National University stem cell researcher Hwang Woo-suk? The fuss also drew media attention from other stem cell research announced at about the same time that was, in my opinion, equally compelling – nurturing adult human neural progenitor cells from medical waste.

Correction and Spin Breed Suspicion

After a few media reports based on Nature’s initial news release prompted inquiries as to what actually befell the 16 embryos, the journal issued a “corrected” news release. It omitted the key five words, and added that the ACT embryos were biopsied more than once apiece. The embryos’ demise could perhaps have been inferred by someone familiar with the aforementioned deuterostome/protostome distinction. Reporters who had relied on the news release from ACT issued August 23 rather than the original Nature release might have had a heads-up on the oversimplification that to some smelled of deception. The company’s more guarded announcement stated: “ACT today reported that company scientists have successfully generated human embryonic stem cells (hES cells) using an approach that does not harm embryos” (ACT 2006).

True enough. The approach used was similar to preimplantation genetic diagnosis (PGD). The decade-old technique offers quality-control type testing of the 8-celled, indeed just what ACT would have done had they taken only one or two cells per embryo. But they didn’t, at least not in the experiments covered in the online report. The reasoning again seems vaguely algebraic: “removing one or two cells for PGD does no harm. We can take away more than two cells and generate hES cells. Therefore, taking away one cell can preserve the embryo and also generate hES cells.” If a=b and b=c, then a=c may work in logic, but it leaves a gap in research. However, the experiments that “retrieve” only one or two cells have indeed been done, successfully, and are included as an Author’s Note in the print version of the Nature paper (R. Lanza, personal communication).

Coverage in The New York Times (Wade 2006a) accurately echoed the Nature news releases, focusing more on the potential of the approach to avoid harming embryos than on what had been accomplished technically. An impressive group of commentators put the work in perspective, all assuming that ACT had indeed nurtured the cells from embryos that survived. Other reports spread the story.

On August 30, the New York Daily News published an essay by the father of two children who began their existence as PGD-probed embryos, celebrating the ACT success (Skenazy 2006). Unfortunately the headline, “Anti-stem cell zealots are all out of ammo”, proved premature. Government-speak was hastily rewritten to express fear of harming embryos, rather than killing them. Many critics seemed oblivious to the long and successful history of PGD, and Lanza’s statements that cells used in the ACT technique would come from embryos slated for PGD anyway.

By September 2, the corrected news release itself had become the story. The New York Times reported that both the Nature article and the corrected news release from the journal had “made clear” that the embryos had been destroyed (Wade 2006b). The Washington Post used similar language. Since I could not find the word “destroyed” in the news releases in relation to what ACT had done, I wondered what, exactly, “made clear” meant. Had any reporters actually read the online report that Nature provided along with the news releases? So I read the online report for the third time. Still, all I could find was the algebra exercise and an inferred step that might have gone somewhere between disrupting the zona pellucida and separating the selected blastomeres. I finally contacted Dr. Lanza himself, who confirmed that the only reference to the fate of the embryos was in the numbers. This is what the media collectively deemed a “very clear” explanation. Game of telephone, anyone?

With all the confusion, it wasn’t surprising that Arlen Specter (R-Pa) and Tom Harkin (D-Iowa) berated Dr. Lanza before the Senate Appropriations Labor, Health and Human Services subcommittee for confusing the theoretically possible with what was actually done in the reported experiments -- even though stem cell research at ACT is privately supported, the researchers had followed the protocol and language of any other technical paper about deriving hES cells, and Lanza et al had in fact done the key experiments but had not yet published them.

But this is a tale distinctly lacking in logic. The fact is, research reports on hES cells are subject to greater scrutiny than others, at least in the U.S. Senate subcommittees hardly convene to probe the manner of death of rodents when a new knockout mouse debuts, nor do researchers routinely spell out how various model organisms meet their ends – it isn’t relevant. But using human embryos for research is another story. So I don’t think it was necessary for the ACT team to have spelled out what was obvious to its intended audience of scientists, but it might have been prudent to have done so – or at least for them to have reviewed the first Nature news release before it was sent to reporters, which Dr. Lanza claims they didn’t have the opportunity to do.

It’s a shame that little attention was paid to the results, which were spectacular. The hES cells indeed gave rise to specialized cells representing all three primary germ layers, differentiating into such potentially clinically useful cell types as endothelium, retinal pigment and other epithilia, hematopoietic cells, and neural progenitors. The effort that went into characterizing these cells was simply astonishing – and that was very clear, if underreported.

The brouhaha over the ACT work all but overshadowed a report from the University of Florida’s McKnight Brain Institute, published online August 16 in the journal Development (Walton et al. 2006). Coverage was turned down by at least one large newspaper that jumped at the ACT release a week later. In science as well as in everything else, apparently timing is everything.

Stem Cells From the Brain

The McKnight Brain Institute investigators cultured gray matter from the brains of people who had undergone surgery to treat intractable temporal lobe epilepsy. The cells came from various brain regions, including the subventricular zone (a known incubator of endogenous neural progenitor and stem cells) and also areas not known for harboring stem cells. The cells sampled from material otherwise destined for the trashbin were cultured, allowed to divide, seeded onto culture flask interiors, fed cocktails promoting stemness, given various labels, and analyzed several ways. One way was to transplant the cells into the lateral ventricles of nude mice, a nurturing niche for stem and progenitor cells. Slices of the mouse brains later revealed adult human neural progenitor (AHNPs) cells complete with migrating axons – and not only in the parts of the brain that are normally stem cell repositories.

As with any scientific research, the McKnight work raises further questions. Did the protocol select pre-existing, albeit rare, AHNPs and create conditions that favored them, or stimulate neurons or glia to actually reverse their specialization and enter a progenitor-like state? Ongoing experiments will distinguish these two possibilities – either of which has intriguing implications – or reveal that perhaps both occur. If implants are ever devised from endogenous cells, how will their growth be controlled? Although the AHNPs were restricted in their potential compared to ES cells, the researchers predict that a single one could potentially divide to yield 40 million or more cells. That’s a lot of potential brainpower.

While comedians and cartoonists had a field day a few years back with the idea of customizing stem cells from liposuction leftovers, the possibility of nurturing progenitor or stem cells from medical waste is, I think, tremendously exciting. It means that the seeds of treatment for the millions of people with neurodegenerative diseases are sitting right there in their heads, ripe for the picking, so to speak. Perhaps ES cells are more newsworthy because of the controversy. Many developmental biologists do consider them to be more promising in an overall sense for regenerative medicine. But if neurons are the goal, then harvesting AHNPs from a patient’s own brain, rather than going the somatic cell nuclear transfer route, seems a win-win situation. At least this strategy should be free of the political agenda that is strangling even privately-funded hES cell research in the U.S.

Lessons Learned

What can we learn from the game-of-telephone that ensued with the announcement that ACT researchers had found a way to culture hES cells without harming embryos? That depends on who you are.

If you are a reporter, go to the primary source! If you want to know whether ACT researchers let their plucked embryos cease developing or put baby bonnets on them, read their papers! Ask them what they did! A news release is a teaser, not the whole story.

If you are a researcher in the U.S. working with hES cells, and you publish the work, spell out what was done in plain English, even using the “d” word (destroy). It is better to be blunt and state the obvious than to risk the taint of perceived deception because reporters or the lay public cannot effectively read between the lines.

If you are neither reporter nor researcher, but John or Jane Q. Public, put technical reports on hES cells in context with the raw facts: Embryos are routinely discarded in fertility clinics at the donors’ request. Abortion is legal. It happens. PGD is an established procedure, not an experimental technique with unknown risks. Millions of people who have already been born suffer from illnesses that can potentially be treated with stem or progenitor-cell based therapies. The true crime is the stifling of hES cell research.

Welcome Ricki!

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