Light at the end of a stem cell tunnel
Last week, scientists from a small Massachusetts company, Advanced Cell Technology, divulged a new technique for the derivation of human embryonic stem cells (hESCs). They described it enthusiatically in their press release as an ethically acceptable way to obtain hESCs since it theoretically leaves embryos unharmed.
However, a closer look at their paper, which was published in the prestigious journal Nature, reveals that their research is merely a proof-of-principle. The principle is that a single cell (called a blastomere) from an 8-celled embryo could be extracted from the embryo without harming it and then coaxed to proliferate and behave like traditional hESCs derived from embryos with 100 or more cells. The remaining seven cells of the embryo would be implanted in a woman’s uterus and brought to term as usual.
As explained in a rather opaque way in the article, 16 human embryos with about 8 cells each were disaggregated into 91 single blastomeres. These blastomeres were then grown apart from each other for two days. Two of them produced stable hESC lines. (A cell line is a group of cells that all originated from the same parent cells and have the capacity to proliferate ad infinitum.)
There are a few things to note about this experiment with living human embryos.
First, it had an incredibly low success rate. The authors justify this by saying that it is "similar to that reported by other investigators using conventional derivation methods". This is hardly satisfactory if the conventional procedure involves the destruction of embryos at a rate higher than one embryo to one hESC line.
Second, this technique still involves the destruction of embryos, practically, if not theoretically. ACT’s work does demonstrate that a single cell, or blastomere, can give rise to a hESC line. Removing a single cell from an embryo is common nowadays in IVF clinics which test them for genetic defects. But the technology is not perfect and having one-eighth of your body mass removed is a fairly risky procedure.
In fact, in an interview with NPR, Dr Robert Lanza, the lead researcher, told us about his practice attempts. He began with eight 8-celled embryos. Six of these went on to develop to the next embryonic stage. Well, a 75 per cent success rate is great when shooting hoops. But when a 25 per cent failure rate means one dead child for every four experimented on, how can anything less than 100 per cent be a success? Those of us in science know that, between what is possible and what is realistic, there is a large gap. And when the margin of error leaves us with dead human beings on our hands, I suggest that we leave what is possible unexplored.
Furthermore, it can be argued that the technique involves artificially creating an identical twin and then killing it. Dr. Lanza’s paper disputes this claim by stating that "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". I believe this to be true. However, it has happened that a monkey developed from two blastomeres biopsied from an 8-cell embryo. Do we really want to take the risk?
Lanza also argues that some distinctions between the individual blastomeres already exist. Thus, they reason, dividing an embryo could not lead to twins because the cells of each twin would be different. What they fail to mention is that twinning often occurs at an even later stage of development when even more differentiation has occurred. It is possible that twinning can occur earlier than normal, especially since the embryo is undergoing an unnatural procedure in an artificial environment outside the womb.
Light on the horizon
So what can we do? Must we abandon the promise of embryonic stem cell research? Not at all.
Only a few days before Lanza’s article was published, another paper appeared in the equally prestigious journal Cell. Japanese scientists Kazutoshi Takahashi and Shinya Yamanaka described how they coaxed adult mouse cells into behaving like embryonic stem cells. It was a tricky business. Certain genes are turned on at higher levels in embryonic stem cells than in mature adult cells. The Japanese team simply turned on four of these genes on in adult cells. The result? -- "iPS cells". That is, induced pluripotent stem cells; cells that are almost indistinguishable from mouse embryonic stem cells. They pass all the tests needed to identify embryonic stem cells: they express most ESC genes, contribute to embryo development when injected into an early embryo, produce tumours when transplanted into adult mice, and differentiate into all three types of embryonic tissue. In other words, this is exactly what US President George Bush has been waiting for: an embryonic-like cell that stays far away from embryos.
So why have these cells received so little attention in the media?
Maybe because the work was done with mouse cells and still needs to be verified in human cells. While we share more in common with mice than our pride would have us admit, there are many differences between human and mouse ESCs. But as a good start, hESCs do express all four of the genes in the Japanese study.
Most exciting of all is that, if researchers are successful in inducing a similar state in human cells, not only will we have an ethical source of human embryonic stem cells but we will have an ethical source of patient-specific ESC lines -- which do not involve so-called therapeutic cloning. Patient-specific ESCs could allow researchers to study the development of specific diseases as well as provide a minimally invasive source cells for therapies. Not even Lanza’s blastomere biopsy method can hope to provide such astonishing results.
There must be a catch somewhere, you might think. Well, currently there is. As in Lanza’s method, the efficiency of the technique is very low. Although 47 per cent of the treated cells express all four special genes, only 0.02 per cent of treated cells become ESC-like.
But the good news is that the other 99.98 per cent are not human embryos but mere skin cells. And we all have plenty of them. Hopefully this technique will not be limited to skin cells. There is no obvious reason, for example, why another abundant cell type -- like fat -- could not be used.
Are we on the right track?
And so, at long last, we come to Catch 22.
The biggest problem that I see with morphing adult cells into hESCs is precisely how similar to hESCs they are. I don’t want to pop bubbles, but I do not think that hESCs are all that they are made out to be.
In the early embryo, their purpose is mostly to proliferate, not to differentiate. No wonder they produce tumours when implanted in mice. Differentiation of a mature heart cell is of no use to an embryo which is too young to have a heart. Embryonic development is a beautifully choreographed process in which differentiation into mature cell types happens very gradually.
While one day we may unlock the secrets of ESCs, it will take many, many years and lots and lots of money. Which reminds me of another benefit to the Japanese technique: it is far cheaper than handling human embryos. So for those determined to make embryonic stem cells spill their secrets, this may be the route to follow. With a little more patience, we will soon know a lot more about these promising cells and may realise that there is no longer any justification for killing the most vulnerable members of our society.
Michaela Kingston is the nom de plume of an American stem cell researcher.
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