More thoughts on IPS Cells

This week we learned about the latest results from the emerging field of induced pluripotent stem cells (IPS cells). I just wanted to give a few links and my latest thoughts on the subject.

What this field has given us is the ability to study how cells are programmed and how they are deprogrammed. I agree with Thomas Robey who writes:

.... most of science is not about designing cures! It's about asking questions and answering them. Goal-oriented science and translational research is what pays the bills because it captures our imagination. But when it comes down to the bottom line in biomedical research, we need to understand mechanisms and systems before we go and use some new-fangled therapy in the clinic.

That doesn't mean that this line of research has no eventual clinical applications but as PZ writes:

What the investigators have accomplished is to discover the reset button for the cell, but the way they currently press it is by hitting it hard with a ball peen hammer.

Yes, there are many problems with the technique - including the fact that the the procedure involves the introduction of 4 active genes into the cell to be deprogrammed. To accomplish this task, DNA from 4 active genes were inserted into the cells with retroviruses, which promote the random insertion of the foreign DNA into the genome. This is a standard technique for getting DNA into cells, but for anyone who has been following the progress in gene therapy it becomes obvious that this is a big problem. Random insertion of genes can promote genetic defects and cancer. This obstacle won't be easy to overcome as the reprogramming event takes weeks and thus probably requires these genes to be turned on for long periods. It seems likely that we won't be able to get around this problem by inserting mRNA or proteins into cells - we'll need continual production of the factors. In addition the reprogramming event is quite rare - only one in a few thousand cells are reprogrammed.

In any case the whole line of experimentation has hit the political circuit and the religious right and certain researchers are quite happy. (see Nisbet's entry). Some claim that IPS cells now make embryonic-stem cell (ESC) research obsolete. That's nonsense. In addition, other ridiculous statements are being made. From a NY Times article:

On Tuesday, senior aides to Mr. Bush said he drove the experiments by holding his moral ground.

"This is very much in accord with the president's vision from the get-go," said Karl Zinsmeister, a domestic policy adviser to Mr. Bush who kept the president apprised of the work. "I don't think there's any doubt that the president's drawing of lines on cloning and embryo use was a positive factor in making this come to fruition."

That's just crazy. Nick Anthis from the Scientific Activist writes:

... by doing everything in his power to prevent embryonic stem cell research from happening, George Bush is now inexplicably its savior. The Administration is able to claim this with a straight face despite the fact that (1) this isn't the end of the embryonic stem cell debate (see below) and (2) one of the two studies reported yesterday (and the original work that directly led to these breakthroughs) comes from Japan!

PZ isn't impressed either.

Yes it would seem that the religious right wants a simple answer and a silver bullet. And then they want to take credit for it. I just wish that the public discussion of this topic was more level-headed. We need research on all fronts. Our ability to make IPS cells come directly from studies on ESCs.

I would like to make one last point regarding the *potential* future of stem cell research, should the religious right be optimistic?

I've touched on this in an earlier post, and I'd like to restate it here.

Paradoxically the dogma that fundamentalist Christians hold dearly is undermined by the very same research they are now celebrating. You see the religious right believes that a "soul" is created at the time of conception. Using this framework, the religious right equates abortion and ESC research with murder (or at least "soul"-i-cide). But if activating 4 genes now produces IPS cells that can give rise to an entire new organism, it becomes obvious that conception is not required to generate "souls". So when does the "soul" enter the body? It is not so clear anymore (that is, if you believe in a soul). Perhaps the "soul" enters the body when the organism acquires a central nervous system? Perhaps only when the CNS is fully formed? Perhaps birth? Following this line of reasonning - if the creation of a "souls" doesn't take place upon conception, why would anyone be against early term abortions or embryonic stem cell research? As usual the world is never black and white despite all our preconceived notions.

In the meanwhile, we the scientific community will continue to perform experiments. We will learn more. And inevitably we will be amazed by the incredible beauty of what it means to be alive. In the process we will gain knowledge that, we hope, will improve the lives of those who are less fortunate.

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iPSCs aren't capable of forming complete embryos - they are amenable to becoming chimeras or cybrids when inserted in embryos.

Like embryonic stem cells, IPSCs are pluripotent but not totipotent. They can't make the trophoblast.

As it currently stands we will be able to make make a complete organism with IPS cells. It is true that the cells must be injected into a blastocyst - however as the Jaenisch lab has shown, if you inject the cells into a tetraploid blastocyst whose cells do not incorporate into the organism, the resulting organism will be derived completely from the IPS cells. In their hands the embryo made it to a very late stage in development, but I'm sure that live animals will be produced soon (or have been produced but are yet to be reported on). In contrast, the tetraploid cells differentiate into trophoblasts, which forms the sheet of cells that surrounds the developing organism but do not incorporate into the embryo. Thus once born, the animal is composed solely of IPS cells.

Again as I wrote in the comment section of a previous post, you could only conclude that the "soul" is found in the trophoblast layer, but that is equivalent to saying that the most important part of the candy bar is the wrapper.

This is true, but how do you imagine that experiment done with humans? We know that if it can be done in mice, it is only a matter of tweaking the method a little bit to make it work with humans, but to the religious, this is not enough...

And I don't think the sociopolitical climate right now will allow for anybody to do that experiment...

By Georgi Marinov (not verified) on 24 Nov 2007 #permalink

I'd guess that this makes more trouble for fundamentalist Christians in that even their skin cells might give rise to life. Think of how many potential lives gets lost every day! This should pose a serious moral dilemma for them.

BTW, the Christians aside, I am wondering whether the trick can only work with fibroblasts and if it works with other cell types, what would be the required proteins? I don't have the entire papers in my head, but I don't recall any of the groups trying something other than fibroblasts

By Georgi Marinov (not verified) on 24 Nov 2007 #permalink

GM,

I know for a fact that people are trying the 4 gene protocol on many different cell types. One idea that has been kicked around is that the conversion rate is so low because it is only the adult stem cells that are converted. I'm sure that we'll soon know the answer to that question as well.

Thanks for the clarification, this makes sense (the adult stem cells); if this idea is true it should be possible to test it with purified adult stem cells, which would exhibit a higher conversion rate?

By Georgi Marinov (not verified) on 25 Nov 2007 #permalink

Again as I wrote in the comment section of a previous post, you could only conclude that the "soul" is found in the trophoblast layer, but that is equivalent to saying that the most important part of the candy bar is the wrapper.

As a scientifically-minded individually I of course am inclined to agree it is unlikely that the soul is located in the trophoblast layer. However you raise an interesting point.
I don't think the trophoblast theory of the soul would be quite as trivial as you suggest. One who believes in souls (and belief is indeed what is required in the absence of any evidence) no doubt would make the argument that the soul must be transferred from mother to child through some means - the trophoblast would be a logical choice as the physical vehicle for this transfer. Once you accept vitalism, it seems a fairly reasonable next step that any vital life force must somehow be passed through direct transmission from parent to offspring. An appealing consequence of this theory would would be that no pluripotent cell line, such as IPS, could ever have a soul. So, a new vitalist theory that accommodates the IPS results would be:
IPS/ESC+maternal trophoblast=organism with a soul

Maybe one might even predict that if one made a physically complete organism somehow in a trophoblast-independent manner, it would lack a soul (whatever that is exactly. maybe a person that just stares blankly at the wall??) Now there's something I'd like to see Jaenisch do.

To me, all this discussion simply underlines the point that stem cell science and science in general have nothing to tell us about whether souls exist or not. There's been no evidence presented to data to my knowledge that such a thing exists. It seems unlikely there ever will be, as the definition of a soul, at least as I understand it, places it outside the realm of experimentation - a soul is not something you can physically detect. So either you have faith in the belief that souls exist or you limit yourself to a scientific outlook and you don't. Stem cell biology seems unlikely to change anyone's mind.

bayman,

With the trophoblast story I am just pointing out how our pre-conceived notions are not always correct. I view the whole argument of "conception = generation of a soul" very simplistic. Now we find out that we can reprogram cells and create a new entity by turning on 4 genes - although you still need a blastocyst. So using this logic we confine the "soul" to the trophoblast, which are not even part of the embryo per se. What happens when one day we discover how to differentiate IPS cells into trophoblasts? Then where does the soul go? All I am saying is that this new research points to the fact that reality is not black and white and that people should rethink their positions. The whole idea of "conception = soul generation" looks more and more arbitrary.

I think there is a definitive experiment that will settle the issue (is there a soul or not) once and forever, although it is only theoretically possible and actually pure sci-fi as of now:

We know that the day when a synthetic bacterial cell will be made from stock chemicals is not that far in the future. Now imagine creating a human zygote from stock chemicals and developing it into an adult human. I predict that it will be perfectly normal and indistinguishable from humans conceived the traditional way.

Of course, assembling the chromatin, with all the epigenetic marks at the right places, ensuring the proper three-dimensional organization of the nucleus and all the membranes, and the accurate distribution of proteins in the cell so you can boot up the system is a mind-bogglingly difficult task. Neither will anybody be given the huge amount of funding necessary to do this in a society ruled by religious superstition. But this is the definitive experiment IMO.

By Georgi Marinov (not verified) on 26 Nov 2007 #permalink

with all the epigenetic marks at the right places, ensuring the proper three-dimensional organization of the nucleus and all the membranes, and the accurate distribution of proteins in the cell so you can boot up the system is a mind-bogglingly difficult task

Yes, it is. Our currently total epigenetic states are the results of a > billion year assembly process. How much faster can we do it? A million times faster? Still means it would take 1000 years (for example).

But this is the definitive experiment IMO.

Assuming one created a seemingly human organism by such an approach, you still have not shown that it has a soul. What experiment would you propose to prove whether said organism indeed has a soul?