Tuesday, June 07, 2005

Another Stem Cell Explainer

I just got back from a conservative blog that I respect, having read a post about the stem cell controversy.

This is a bit of a follow-up to last week's post. As the embryonic stem cell debate started raging, I noticed that some bloggers with traditional views kept emphasizing the value of adult stem cells (ASC), suggesting that ASC could be just as valuable as embryonic stem cells (ESC). I was perplexed by that. Then I learned that, according to some theological principles, in some circumstances it might be acceptable to bend the rules a little bit, so long as there was no other way to do the job. That assumes that the job to be done has some redeeming outcome. Thus, they would not be able to make as strong of an argument against ESC, unless they could show that the use of ASC could accomplish the same therapeutic purpose as could be derived from ESC. It occurs to me that it may be useful to explain why this is unlikely to be the case.

To understand this, it is helpful to look at a specific example. Read the recent Scientific American article about neuronal stem cells; an excerpt follows, but the entire piece is not much longer:
The discovery that new neurons can arise in adult brains--a feat first observed in songbirds--overturned the long-held belief that a vertebrate's complete supply of neurons is created at birth or soon thereafter. In the new work, Fernando Nottebohm of Rockefeller University and his colleagues investigated how latecomer neurons differ from lifelong ones. The researchers injected two types of dye into the brains of 19 songbirds and collected samples from both types of neurons, which are used in two different pathways in the brain. After analyzing genetic information from more than 3,000 cells from each animal, the team determined that one gene (UCHL1) showed remarkably low activity in the newer, or "replaceable neurons": the longstanding ones exhibited 2.5 times the amount of the UCHL1 protein. "Low levels of UCHL1 appear to be a feature of replaceable neurons wherever they occur," says study co-author Anthony Lombardino of Rockefeller University.
The "latecomer" neurons are nerve cells that developed in an adult brain, growing from neuronal stem cells. Even though many news articles claim that stem cells can grow into any cell in the body, the research cited above chows that the progeny of ASC are not the same as the progeny of ESC. The original brain cells were derived from ESC. They had enough of the UCHL1 protein to be fully viable and functional. The ASC still have the gene that codes for the UCHL1 protein. They still have the ability to generate nerve cells.  But the nerve cells produced by the adult stem cells are not as long-lasting as those produced by embryonic stem cells.  This indicates that ASC are not, with current technology, replacements for ESC.

The difference is not in the genetic makeup. The difference is in how the genes are regulated.   When the gene is expressed, it produces the protein. (UCHL1, in this case.) The regulation of gene expression is rather mysterious at this point in time.

It is possible that, given enough research into gene expression, that we could tweak ASC to act like ESC. But given that you would have to get the expression right for all 20,000+ genes, it is doubtful that we ever would be able to do it correctly by artificial means.

Furthermore, if we are going to figure out how to do that, we almost certainly will have to use ESC to see how it happens in ESC.  Trying to reverse-engineer ASC, to get them to act like ESC, without actually having ESC to study, would be extraordinarily difficult, and likely impossible.

The article that Bill cited on his InDC Journal is here, from WaPo. The author expresses hope that there may be a way out of the ASC/ESC controversy.  In the article, the author states (correctly):
What is different about stem cells -- and what gives them their remarkable capacity to proliferate and morph into whatever kind of cell the body may need -- is the specific pattern of activity of their genes. It is all about which genes are working and which are dormant.
Farther on in the article we see a hopeful sign, hopeful in that it indicates that there may be an acceptable way out of the stem cell controversy:
Working with early mouse embryos, the team has found that single blastomeres, when cultivated in dishes with embryonic stem cells, can become what appear to be embryonic stem cells themselves. Chemicals secreted by the embryonic cells apparently flip the right genetic switches in the blastomeres to make them act "stemmy."
The implication is that it might be possible to remove a single cell from a very early embryo, use that cell to generate a line of cells that are like ESC, although perhaps not exactly the same thing ("stemmy").  If the cell is isolated at an early enough stage, the embryo that had the cell removed might develop normally.  If this works, it may be possible to develop cells that are as good as ESC, without having to try to get ASC to act like ESC, and without diminishing the viability of donor embryos.
If this technique were applied to humans, then a single cell taken from an eight-cell fertility clinic embryo could give rise to a self-replicating line of embryonic stem cells without compromising the donor embryo's odds of someday growing into a baby.
The author points out that the research so far is very early, much of it has not yet been published. That means that it has not been subjected to peer review, and has not been replicated independently.

If everything checks out, this could be a way for our society to get off the dilemma. It's a big if, but...we'll see. If it does turn out as we hope, though, there still could be problems. I can foresee three problems in particular.

First, you would have to get couples to consent to having a cell removed from the donor blastomere prior to implantation. Given that the couple just paid $10,000 for the IVF procedure, and they are desperate for a child, and want that child to be normal, are they going to go along with it? Would it be sufficient to tell them that there usually is no risk in rodent blastomeres?  Well...who knows? It would be up to the couple to decide.

Second, after you get the faux-ESC, and develop something that might be therapeutic, you have to implant them into a human to see if they do the job. To do that, at least in the USA, you need to get the FDA to say it is OK. Perhaps that would be no problem. But getting them to agree to human experiments with "stemmy" cells instead of stem cells would be a somewhat like trying to use a drug that is "penicilliny" instead of using penicillin. Sometimes that really is OK, but it always requires a great deal of hand-wringing to decide.

This may be a surmountable problem, but think of yourself as the patient. You are asked to give permission to have these cells injected into your brain. Do you want the "stemmy" cells, or do you want the real thing?

There are over 20,000 genes in those cells, and most -- if not all -- of them have to be regulated properly for the cell to do what it is supposed to do. Perhaps it will turn out OK if a few of them are not quite right, but if you are like the rest of us, you have only one brain to experiment on.

Perhaps I am being too skeptical here, but after all, I am the guy with a bumper sticker that says "QUESTION SKEPTICISM."

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