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December 07, 2004

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talk about dancing on the head of a pin! We solve the ethical problem by deliberately creating non viable embryos? It seems to me to be pretty clear we are swapping one problem - destruction of [purportedly] viable embryos - for another -- creation of a nonviable embryo. If embryos are "life", then manipulating the genome to ensure its death, or even prevent its formation, is just as wrong as killing them directly.

It seems to me to be pretty clear we are swapping one problem - destruction of [purportedly] viable embryos - for another -- creation of a nonviable embryo. If embryos are "life", then manipulating the genome to ensure its death, or even prevent its formation, is just as wrong as killing them directly.

I don't believe that's what the proposal suggests. The genetic manipulation be done at the gamete level, not on a viable embryo developing. Once the resulting genetic material is injected back into an infertile egg, it would create something akin to a teratoma (but would hopefully be harvested early, those things are yukky). The dividing cells would have their genetic structure restored, but later in the process than would result in a viable embryo.

The resulting tissue could be harvested for germ cells, and doesn't result in embryo death, as the tissue was never an embryo to begin with.

Hilzoy: this article on Slate has a different interpretation than you of the second proposal. Rather than create a non-viable embryo, it suggests modifying the genetic structure of the gamete in order to create a teratoma-like mass of cells, rather than an embryo doomed because it has no placenta. While a teratoma could be said to be alive, in that they grow and respirate at some level, they are emphatically not human, or "alive" in any normal use of the word.

From New Scientist (12.01.04):

"A trick that persuades human eggs to divide as if they have been fertilised could provide a source of embryonic stem cells that sidesteps ethical objections to existing techniques. It could also be deployed to improve the success rate of IVF.

'Embryos' created by the procedure do not contain any paternal chromosomes – just two sets of chromosomes from the mother – and so cannot develop into babies. This should remove the ethical objections that some people have to harvesting from donated human embryos. There are high hopes that stem cells, which can develop into many different cell types, could be used to treat a range of diseases." Emphasis supplied.

Zapped human eggs divide without sperm

d+u: I think the crucial point in your post is this: "it would create something akin to a teratoma". If that's right, then Hurlbut's proposal just involves killing a tumor. But if, instead, what is created is an embryo which we've modified in such a way that it dies, then we have killed anembryo. The whole thing turns on this point, I think.

It's hard to assess Hurlbut's proposal in detail, since there's no published version that I know of outside news accounts. The Boston Globe says this: "Before implanting the DNA from a skin cell into an egg, scientists would turn off a gene that helps direct the formation of the trophectoderm, an outer layer of cells that is crucial in the first stages of development and which eventually forms the placenta. With this gene silenced, the trophectoderm does not form properly. All the cells eventually die, but scientists can still harvest embryonic-type stem cells from the mass, according to Dr. Felix Beck, a professor at the University of Leicester and one of the authors of a scientific paper in May that described how the gene affects the trophectoderm in mice."

So: first we modify the DNA. Then we implant the modified DNA in an unfertilized egg, and induce that egg to start dividing. (Standard Somatic Cell Nuclear Transfer.) Then it develops normally for a few days, until the point at which the trophectoderm would normally start forming. However, due to our genetic modification, the trophectoderm fails to form and the embryo-or-whatever dies.

As I said in my post, the fact that the modification takes place before the embryo-or-whatever exists is morally irrelevant. What matters, I think, is whether, when the trophectoderm ought to form but doesn't, what exists is -- well, let's say, a human life that ought to be protected. Hurlbut's proposal, in order to represent any sort of advance at all over existing ways of getting embryonic stem cells, requires that the answer to this question be "no".

If a normal embryo at the point just before the trophectoderm forms is a human life worthy of protection, then killing it would be taking a human life. And if that's true, then genetically modifying DNA so that an embryo develops normally until that stage, at which point it develops a fatal defect and dies, would also be taking a human life. (Assuming for the sake of argument that an embryo has as great a right to life an anyone else, I don't see that there's any difference between this genetic modification and modifying DNA to produce Tay-Sachs, which would presumably be murder. Except, of course, that Tay-Sachs also involves suffering, but that's beside the present point.) So only if a normal embryo at the point just before the trophectoderm forms is not itself a life worthy of protection can Hurlbut's proposal work. This is inconsistent with Catholic doctrine, I think, and surely flies in the face of common sense.

d+u: Saletan and I are talking about the same proposal. However, as I understand it, Hurlbut is not trying to create teratomas; he is arguing that embryos with the trophectoderm-forming gene turned off would be somehow morally equivalent to teratomas, since they would have no integrated organization. Bleh.

Knobboy: ye Gods, not another one... Thanks for the cite.

Ugh, the proposal looks like lawyerly hair-splitting to me.

Hilzoy: The Boston Globe article doesn't contradict what the Slate article says. The genetic manipulation keeps cell reproduction, but doesn't allow proper developemnt into an embryo to begin with. From Slate:

Hurlbut's first choice is the human equivalent of cdx2, the gene in mice that directs the formation of the placenta. Without cdx2, the embryonic mouse cells divide but fail to take the shape of a mouse. The plan would be to follow the recipe for cloning—put the nucleus of a body cell into a gutted egg cell—but turn off cdx2. Then, once the cell begins to divide, reactivate the gene, too late to organize the embryo but early enough to make stem cells.

It sounds perfect, until you look up at the projection screen. Hurlbut has modeled his recipe on "aberrant products of fertilization" and teratomas, which, he explains, are "germ cell tumors that generate all three primary embryonic germ layers as well as more advanced cells and tissues, including partial limb and organ primordia." Limb and organ primordia? Yep, that's what's on the screen: a ball of tissue, grown inside some poor creature, full of bits and pieces of what would have been a body. Another slide shows an X-ray image of somebody's back. To the left of the spine, you can see a cluster of white spots that look like teeth. And that's exactly what they are, all dressed up and no place to chomp. You wanted disorganized development? You got it.

Now, I think that Slate is taking the grosser elements of the plan and using them as a hook for the story title, as tertomas are pretty frightening things to look at and to think about, but I believe that stem cells would be harvested pretty early in the process when the cell mass is still microscopic, and the more disturbing features develop much later.

Point being that this would never be an embryo, just a bunch of reproducing cells.

he is arguing that embryos with the trophectoderm-forming gene turned off would be somehow morally equivalent to teratomas, since they would have no integrated organization. Bleh.

What would be the difference?

For that matter, a mass of stem cells have no integrated organization either.

Assuming that the holy grail of further development of this technology is to avoid upsetting the sensibilites of those who believe that embryos are the equivelant of human beings, then at some point a scientist is going to discover how to create germ cells that grow in a petrie dish without having to destroy a viable embryo. I'm not sure how people imagine how that would work, but this looks like it to me. Modifiy genetic material so that it WON'T develop into an embryo, and let it grow.

d+u: The core of the question is precisely whether what this does is to prevent the dividing, fertilized egg from developing into an embryo, or to cause an embryo to die. As far as I can tell. the embryo-or-whatever develops normally for the first few days. If a normal embryo at that point is, well, an embryo, I don't see why this modified entity would not, at that point, count as an embryo either.

Sebastian: I agree that it's hairsplitting. It annoys me that the people on the President's Council who oppose embryonic stem cell research would seize on this proposal as the solution to their problems when (a) it is just hairsplitting, and (b) it would in all likelihood yield cells that would be a lot worse, therapeutically, than the alternatives.

I'll have to go back and see if I can find the article, but there was a news report right around election time of a group successfully extracting a few of the stem cells from an embryo without destroying the embryo itself. If this is repeatable, then I suggest that this would solve the ethical and political problems with stem cell extraction. I wish I understood why it was so difficult to do in the first place.

Sorry for the "hit and run" - I'll try and come back later with the link.

CS

Capt. S: The real question about that approach is: even if it doesn't destroy the embryo, does it do any damage to the resulting child if you siphon off part of its inner cell mass? And how would you tell? The required research protocols wouldn't get past any Institutional Review Board I know of (IRBs, for those of you who don't work in hospitals or research institutions, are sort of the ethics watchdogs; they must approve any research protocol before it can be started.) This is, naturally, because the most obvious way to test this would be: remove a few stem cells, implant the embryos and let them be brought to term, see if the resulting babies are OK. Not something we normally allow.

Unless, of course, one were to freeze the embryos instead of implanting them, taking advantage of the willingness on the part of some opponents of stem cell research to consider embryos that are put in the deep-freeze indefinitely to be considered 'alive'. I suppose one could even do somatic cell nuclear transfer, remove only as many stem cells as could be removed without killing the embryo, and then freeze it in perpetuity. This doesn't strike me as a good way out, but then I have never found the idea that the choice between keeping an IVF embryo frozen and killing it is a choice between life and death. More like something out of Coleridge:

"Are those her ribs through which the Sun
Did peer, as through a grate?
And is that Woman all her crew?
Is that a DEATH? and are there two?
Is DEATH that woman's mate?

Her lips were red, her looks were free,
Her locks were yellow as gold:
Her skin was as white as leprosy,
The Night-Mare LIFE-IN-DEATH was she,
Who thicks man's blood with cold."

Good questions. I don't see how, from a basic standpoint, extraction of stem cells would affect the development of the embryo, beyond prolonging its development while the stem cells are regenerated. I'll admit that my basic bio is rusty, but as I recall, there is a certain threshold of cells or size that must be reached before differentiation begins. If cells can be extracted before this point and the remaining cells provided with proper nutrition and support, why wouldn't the stem cells remaining continue to divide as long as the differentiation limit isn't reached? After animal testing the human trial would be ... well, fraught with peril, I expect. But at some point that will be attempted.

Like I said, I need to find the article (and I can't come up with exclusive enough terms to limit the search to less than 100000 articles. Alas, the Internet isn't always the most cooperative tool.). But I think, if this research proves viable, that it's the only way I see to overcome the strict ethical issues involved here. I'll have to re-read the post to make sure, but it seemed that the two above proposals seek to re-define human life, and that won't ever sit well with some of those in the argument.

And the whole frozen=alive thing is ... just weird. I hadn't heard that. Kind of a dodge, I think.

CS

how many mothers going through the trauma of an in vitro process would be willing to have a few cells sucked off their potential baby? given that failure rates for IVF are already pretty high, how could you possibly justify doing so? and given that a certain percentage of IVF babies will have abnormalities (just like regularly-conceived ones), how can you possibly avoid the tort lawsuits that will rain down when an abnormal baby is born who had cells removed?

frankly i just don't understand this hairsplitting. those who believe that embryos are life shouldn't be satisfied with any of these tricks. once you extract an egg and manipulate it to create stem cells, i don't see how you meet those ethical concerns.

Francis

how many mothers going through the trauma of an in vitro process would be willing to have a few cells sucked off their potential baby? given that failure rates for IVF are already pretty high, how could you possibly justify doing so? and given that a certain percentage of IVF babies will have abnormalities (just like regularly-conceived ones), how can you possibly avoid the tort lawsuits that will rain down when an abnormal baby is born who had cells removed?

Cells are allready removed for research on possible genetical diseases. They take a cell from the embryo, check wether it will grow into a baby with a nasty genetical disorder, and put back an embryo that does not carry the disease. So far no abnormalities in the babies afaik.

d+u: The core of the question is precisely whether what this does is to prevent the dividing, fertilized egg from developing into an embryo, or to cause an embryo to die. As far as I can tell. the embryo-or-whatever develops normally for the first few days.

There's a lot of emotional baggage associated with the word "embryo." , "Develops normally" is also a bit misleading. As near as I can tell, the only thing this process does that is similar to the normal embryo is cell division. Normal, but pretty basic.

Me, I don't care if an actual embryo is used or not. Potential to become a human being seems like a pretty fuzzy concept to be shutting down a very promising medical technology, especially as other nations are only to happy to develop it instead.

If the "humaness" of a clump of cells is indistinguishable with one that has been programmed through a small change in its genetic makeup to grow into the equivelant of a tumour, then I say that the whole "viable potential human being" is a bit abstract.

CS: The freezer idea was just a thought I had. It was prompted by the fact that opponents of embryonic stem cell research oppose using embryos left over from IVF. Many of these embryos are frozen, and despite sporadic attempts on the part of a few anti-abortion activists to get people to 'adopt' them, the vast majority of them will remain in the freezer indefinitely. Still, they are alive, and so harvesting their stem cells would be killing them. Or so the argument goes.

Moreover, there is, as best I can tell, no widespread opposition to IVF that involves the creation of excess embryos, despite the fact that it predictably consigns embryos to this fate.

So, turning this all on its head, I propose that we create (through SCNT or he more normal methods) embryos, harvest as many of their stem cells as we can without actually killing them, and then freeze them. No one who thinks these embryos are alive could regard this as killing them. And no one who does not object to IVF that involves the predictable creation of excess embryos that will be frozen could consistently object to this procedure out of concern for the embryos.

Of course it's ridiculous, but it's a better stupid hairsplitting solution than Hurlbut's, since it avoids silly semantic games about what counts as an embryo, and would allow for the creation of perfectly good normal stem cells.

Of course it's ridiculous, but it's a better stupid hairsplitting solution than Hurlbut's, since it avoids silly semantic games about what counts as an embryo, and would allow for the creation of perfectly good normal stem cells.

I'm really not sure about what is silly, stupid, or hairsplitting about this proposed solution. It deals with the ethics in a reasonable way, and is only hairsplitting if the label of "embryo" is being used in a non-technical way to apply to any biological material of this sort. But as the differences between different states of matter at that level are pretty technical, those terms need to be used with precision. An embryo is the technical term for something that is going to develop into a fetus, not a lump of messy tissue.

Pheh. When it comes right down to it, those who are opposed to this type of medical technology are not going to be satisfied by any other solutions either, especially harvesting from embryos that are then frozen to prevent further development.

"It deals with the ethics in a reasonable way, and is only hairsplitting if the label of "embryo" is being used in a non-technical way to apply to any biological material of this sort."

I really don't think so. It makes changes in the cells before it is an 'embryo' such that when it becomes an embryo it won't develop properly. You are still damaging the human embryo, you are just doing the damage before it is an embryo. By analogy, it would be like saying that DDT didn't effect eagles because it changed their eggshells before they were hatched--i.e. before they were really eagles.

Hi -- for the record, I am reliably informed that it's not, in fact, possible to remove a few embryonic stem cells from an embryo (actually, technically, I think it's a blastocyst) and have it still be viable.

Sebastian: It makes changes in the cells before it is an 'embryo' such that when it becomes an embryo it won't develop properly.

Nope. Changes are made to the genetic material from gametes, and then injected into an egg. It is never an embryo, or a zygote for that matter. Teratomas, which this proposal is modelled after, form parthogenetically. They can even form in males (and you really don't want the details of that, trust me).

Sorry, make the above "Changes are made to the genetic material from gametes, and then injected into an egg that has had its nucleus removed."

H: That's why the article stuck in my mind, because the removal of stem cells without loss of viability would be such a big achievement. (I'm still looking.) And you're right - the appropriate embryonic stage is the blastocyst. If you have an article on why it's not possible, I'd appreciate a link. Otherwise I'll ask the biologist down the hall tomorrow. I do need to review my biology.

As for the frozen embryo thing - not to get too off-topic, but I've seen several posts (one at Ricky West's site, as memory serves, several months ago) where the question of frozen embryos was raised. I don't think they are stored indefinitely, owing to space restrictions. They are kept for a long time (ten years?) but eventually discarded. If I'm wrong - well, something else to look up. (My inability to find the article has me doubting my other memories on the subject.) But the question was, why aren't pro-life advocates calling for legislation banning multiple fertilizations, if the potential babies are going to be frozen and (most of them) discarded? I've been waiting for that to hit the airwaves.

Back to the hunt -

CS

PANCREAS CELL: We're DEAD?!?

Moreover, there is, as best I can tell, no widespread opposition to IVF that involves the creation of excess embryos, despite the fact that it predictably consigns embryos to this fate.

In my (Dutch) hospital you had to sign before the treatment that you would be willing to freeze excess embryo's. If you did not want to, they would take less eggs in the puncture-procedure to create less embryo's. In the Netherlands they only put back one or two embryo's, so without freezing they would not retrieve more than approximately six eggs and try to fertilize those.

Hi -- for the record, I am reliably informed that it's not, in fact, possible to remove a few embryonic stem cells from an embryo (actually, technically, I think it's a blastocyst) and have it still be viable.

I was referring to . Though according to the religious tolerance site I link to it might still be unacceptable for some.

> hope this fixes it. Preview, preview.....

Dutchmarbel -- yes, that's possible; but that's a different (earlier) stage than the one at which stem cells are harvested.

"Moreover, there is, as best I can tell, no widespread opposition to IVF that involves the creation of excess embryos, despite the fact that it predictably consigns embryos to this fate."

Wrong.

One of the key objections to IVF at the time it was being introduced was that it produced embryos which were not implanted and which would later be destroyed. Furthermore another key worry at the time was that scientists would be tempted to use such embryos in experimentation.

Both concerns have been proven correct.

Sebastian: the words 'is' and 'widespread' were key to that sentence :)

Well, I don't know if anyone else is still reading this, but I wanted to apologize. I can't find the article I remember. My girlfriend suggests that I might have read an article on Pre-Implantation Genetic Diagnosis, where a cell is removed VERY early from the divided egg (at the 8-cell stage I think) and screened for genetic abnormalities. I'm certain that's not what I read, but I can't retrieve it in any event. And she didn't save her copy either.

Sorry. I'll try and do better next time.

CS

Dutchmarbel -- yes, that's possible; but that's a different (earlier) stage than the one at which stem cells are harvested.

I thought stem cells were harvested from embryo's 0-4 days old? IVF embryo's are no older than 4 max 5 days?

Marjolein (who's IVF embryo's were not good enough to freeze after the best two were used for IVF. So the remaining 6 could be either destroyed immediately or after 14 days of research: our choice)

Hilzoy, sure but the context was that pro-lifers have been ignoring the issue. In the sense that we can tell when we have lost a battle and know when to focus on things that might have some chance of doing good you are correct. But in the sense of not worrying about it you aren't.

dutchmarbel: more like 6 days, I think.

Most info is very vague about the specific number of days I find. But if they mention them, it is usually 5 days max - at least in the sites I found.

I started from here.

It seems a moot point though, the one or two days difference. I just link to the ISSCR since they describe the newer methods too.

dutchmarbel: As I understand it, preimplantation diagnosis is done by removing a cell from an embryo when it's at about its 8-cell stage, and looks like this. Stem cells are taken at a slightly later stage, when it looks like this. At this stage, it has over 100 cells, and you can see both the trophectoderm (the sphere which will become the placenta) and the inner cell mass (the bump that will become the fetus). The stem cells are taken from the inner cell mass. But at the earlier point when PGD is done, there is no inner cell mass, hence no stem cells.

tnxs Hilzoy, for the clarification.

What a difference those two days can make ;-)

Does this mean that PGD is something that is controversial too? Since the removed cell could become a completely new embryo?

I will not read your answer for two days though: it is past 4 in the night here and I am away for the weekend.

Well, it looks like some people are still reading this.

Another reader of this thread actually tracked down the article I was trying to find! (Thank you K!) Here it is:

http://www.corante.com/loom/archives/the_morula_solution.php

I KNOW this was the right article, because I posted a comment there the day I read it - November 3. The researchers take a cell from the morula - a stage about four days after fertilization - and induce it to develop into stem cells, while the rest of the cells in the morula continue to develop normally. This makes sense to me, as taking an undifferentiated cell from this very early group would be akin to one of them dying. The other cells, which have not yet reached any stage of differentiation, would keep dividing to replace the missing cell and continue. You would have to supply nutrients, I suppose, to make up for the lost mass, but it's an intriguing and promising possibility. I hope it bears further results.

CS

CS: As the comments on the blog you refer to note: that would be similar to the PGD procedure I mentioned here. And might lead to the same protests, since the cell taken away *could* become a viable embryo.

If they let it replicate and grow more, it *is* in actual fact an embryo I guess, an identical twin from the original.

Which makes me wonder about wether PGD is approved of by everybody, for that same reason.

Though I agree with the comment that it should first grow into a viable embryo before people see it as one, that feeling is no different from my feeling that the embryo should first grow into a viable fetus, implanted and all, before I see it as babylike. For some the *potential* is enough to declare it a human being if I understand it correctly.


Agreed. I had mentioned PGD earlier in this thread as well. And the question does come down to whether you have a potential twin in the removed cell, or something akin to a donated organ that grows back. This would be one focus for argument.

As for approval - isn't PGD already available and used as a viable diagnosis technique? Or is it still experimental?

CS

As for approval - isn't PGD already available and used as a viable diagnosis technique? Or is it still experimental?

It dates from 1989 (UK). In the Netherlands it was a known technique (though rare, only one center that performed it, due to costs and necessery skills/resources) when I had my IVF 7 years ago. Currently there are 4 centers. So it seems to be viable enough, but I don't know how things in the USA are. When I was actively researching infertility treatment options (9-7 years ago) I found that this seems to be one of the area's where Europe often goes faster than the States.

PGD is in fairly broad use. It's only helpful for a small fraction of IVF patients: those who produce enough eggs (and then enough strong embryos) to risk the reduction in numbers from the procedure itself, and from having to wait for a day 5 transfer. Usually it's used for people who know there are genetic issues (both parents are CF carriers, e.g.) or after repeated miscarriages with no other known cause. Not all clinics do it.

It's assumed by some that Julia Roberts did PGD, mostly because the genders of the babies were announced when she was only 9 weeks pregnant.

I've linked to a big collection of bulletin boards for IVF patients: a fine place to see how practice is racing ahead of philosophy... note particularly the boards broken out by procedure, which might give you some idea of what's really being done out there.

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