The death of a wedge issue

I hope this time I'm finally right about this. I've been hopeful that some strategy of developing stem cells would allow us to bypass the absurd ethical restrictions from those who think one type of destruction of an embryo is worse than another. Particularly promising were spermatogonial stem cells, but they could only be made from men (and the procedure might have been unpopular), and placental/amniotic stem cells, which were limited by the ability to passage them without differentiation, and supply (not everybody freezes back their placentas).

The ideal stem cell would have the following properties.
1. It would be immortal until differentiated - meaning that you could make as many as you want from a single cell
2. It would be totipotent - that means it could make any cell in the body - this can be tested by injection into blastocysts to make chimeric animals or by in vitro differentiation in EBS
3. It would be genetically matched to an individual - that would allow tissues derived from the stem cell to be compatible with a recipient.

Adult stem cells just never were able to meet all three of these requirements. Usually, they would excellent ability to differentiate into what they ordinarily make, but they couldn't transdifferentiate - that is make a cell it wouldn't ordinarily make in the body. Blood stem cells could make endless amounts of blood, but it was unclear if they could effectively make anything else. Mesenchymal stem cells could make things like cartilage and bone really well, but appeared limited in making non-mesenchymal cells, like neurons. And many tissues don't appear to have an adult stem cell population, or, their isolation would not be possible without killing or injuring the donor.

Several news reports from today have been discussing this new advance (Alex Palazzo was hinting about this last week in his coverage of this paper). Here is the new paper (subscription not required) here, and here's Nature's coverage:

Last year, Yamanaka introduced a system that uses mouse fibroblasts, a common cell type that can easily be harvested from skin, instead of eggs4. Four genes, which code for four specific proteins known as transcription factors, are transferred into the cells using retroviruses. The proteins trigger the expression of other genes that lead the cells to become pluripotent, meaning that they could potentially become any of the body's cells. Yamanaka calls them induced pluripotent stem cells (iPS cells). "It's easy. There's no trick, no magic," says Yamanaka.

The results were met with amazement, along with a good dose of scepticism. Four factors seemed too simple. And although the cells had some characteristics of embryonic cells -- they formed colonies, could propagate continuously and could form cancerous growths called teratomas -- they lacked others. Introduction of iPS cells into a developing embryo, for example, did not produce a 'chimaera' -- a mouse carrying a mix of DNA from both the original embryo and the iPS cells throughout its body. "I was not comfortable with the term 'pluripotent' last year," says Hans Schöler, a stem-cell specialist at the Max Planck Institute for Molecular Biomedicine in Münster who is not involved with any of the three articles.

This week, Yamanaka presents a second generation of iPS cells1, which pass all these tests. In addition, a group led by Rudolf Jaenisch2 at the Whitehead Institute for Biomedical Research in Cambridge, Massachusetts, and a collaborative effort3 between Konrad Hochedlinger of the Harvard Stem Cell Institute and Kathrin Plath of the University of California, Los Angeles, used the same four factors and got strikingly similar results.

The improvement over last year's results was simple. The four transcription factors used by Yamanaka reprogramme cells inconsistently and inefficiently, so that less than 0.1% of the million cells in a simple skin biopsy will be fully reprogrammed. The difficulty is isolating those in which reprogramming has been successful. Researchers do this by inserting a gene for antibiotic resistance that is activated only when proteins characteristic of stem cells are expressed. The cells can then be doused with antibiotics, killing off the failures.

The protein Yamanaka used as a marker for stem cells last year was not terribly good at identifying reprogrammed cells. This time, all three groups used two other protein markers -- Nanog and Oct4 -- to great effect. All three groups were able to produce chimaeric mice using iPS cells isolated in this way; and the mice passed iPS DNA on to their offspring.

Jaenisch also used a special embryo to produce fetuses whose cells were derived entirely from iPS cells. "Only the best embryonic stem cells can do this," he says.

Adult stem cell hypers shouldn't claim victory yet. These have major promise but they haven't killed the wedge issue yet (something I really am hoping for). For one, they haven't been able to jump from mice to humans:

But applying the method to human cells has yet to be successful. "We are working very hard -- day and night," says Yamanaka. It will probably require more transcription factors, he adds.

If it works, researchers could produce iPS cells from patients with conditions such as Parkinson's disease or diabetes and observe the molecular changes in the cells as they develop. This 'disease in a dish' would offer the chance to see how different environmental factors contribute to the condition, and to test the ability of drugs to check disease progression.

The second major problem is that two cancer risks are created by these cells. The first is that the retroviruses used to transform the adult cells into ES cells randomly inserts into the genome, causing a cancer risk. The second is that in order to get these genes to be expressed inappropriately, you have to use constitutive promoters to drive expression - in other words, the genes keep on getting expressed even after the cells are re-differentiating - which may be causing cancerous transformations in these cells.

But the iPS cells aren't perfect, and could not be used safely to make genetically matched cells for transplant in, for example, spinal-cord injuries. Yamanaka found that one of the factors seems to contribute to cancer in 20% of his chimaeric mice. He thinks this can be fixed, but the retroviruses used may themselves also cause mutations and cancer. "This is really dangerous. We would never transplant these into a patient," says Jaenisch. In his view, research into embryonic stem cells made by cloning remains "absolutely essential".

So this is not a total victory for ES stem cell research, but it's very hopeful. Ideally they would be able to create this transformation in adult cells by just injecting the proteins these genes make - but the critical issue then is identifying the rare cells that gets transformed.

Alternately, the promoters could be changed from constitutive to drug-activated, so only with administration of tetracycline the genes will get expressed. That way, once they're differentiating, the genes can be shut off, avoiding the cancer transformation.

They also will need to deal with the problem of random retroviral insertion into the genome as retroviruses can cause cancer all on their own. This could be bypassed with an integrase system (which may work ideally) that allows for insertion into a distinct and safe chromosomal location, or possibly a different viral system could be used - like adenovirus - that doesn't lead to genomic insertion.

I'll need to make time to fully read the paper and I'll post again with a full review of this article. I'll also have some fun going through the adult stem cell hypers who will inevitably start taking credit for something they had nothing to do with (and is still far from replacing embryo-derived ES cells).

Tags

More like this

As promised, I'm going through the three papers from last week about the re-programming of adult cells into an embryonic-like phenotype. Since it is three papers I'll go through first what's common to all three, and then what each group did special. First of all, let's summarize the method one…
You guys might have noticed I've been quiet lately, that's because I've scheduled a thesis defense and am under deadlines. However, I couldn't let these two (1) papers(2) on reprogramming of human adult cells into stem cells slip by without some comment (NYT piece here) These reports are a follow-…
Today three papers came out, two in Nature, and one in the inaugural edition of Cell Stem Cell, that basically confirm the results from last year's landmark manuscript by Kazutoshi Takahashi and Shinya Yamanaka (for details on this paper, see this post). Just to remind you, in that original…
That could easily have been the shared title of a pair of articles in today's New York Times discussing the science and political implications of two very significant stem cell papers published online yesterday. The biggest offender was Sheryl Stolberg: It has been more than six years since…

While it would be good news if this enables research heretofore unfunded, we should not make the mistake of thinking that it will eliminate this kind of wedge issue. The future of biotechnology is going to continue stepping on the fundamentalists' toes in a large variety of ways. It will be to our own detriment if we let these kind of religious taboos draw the boundaries around what kind of science is acceptable.

I agree with Russell. The lunatic meandetings of the Fundamentalists should not even enter the discussion. Theirs is a political position, and not a scientific one, and thus their objections should remain in the realm of pilitics, preferably tucked away in the fringe.

By valhar2000 (not verified) on 06 Jun 2007 #permalink

Thank you for a balanced presentation of this story. I look forward to what you think of the scientific merit of the papers and your digest. These reports emerged from my own evaluation relatively unscathed, unlike previous reports from different groups about amniotic stem cells and bone marrow stem cell transdifferentiation. I particularly appreciate your quoting Rudy Jaenisch (in bold no less) as saying,

"This is really dangerous. We would never transplant these into a patient." In his view, research into embryonic stem cells made by cloning remains "absolutely essential".

My concern is that people will not pay attention to this appeal. This debate is being framed as adult vs. embryonic stem cell research, when really it should be adult AND embryonic stem cell research. The public wants to fund research. They want to fund embryonic stem cell research, they want to fund adult stem cell research. (I hear that they do not want to fund a war.) That this is being presented as an either-or argument kindof makes me sick! More verbose arguments along these lines can be read at my blog.

Yes, this is a fascinating development, but I highly doubt the stem cell issue will be going away any time soon. Earliest I'd guess might be 20 years with a generational change. But the same nonsense rationality for social conservatives on this issue now, when it's already a true non-issue if you learn anything about it, just isn't going away soon. Much to sadness.

Other stem cells have always been able to do the three, but many proponents of hES have refused to believe it. (hES are not totipotent, btw. Only the zygote is, and a zygote is not a stem cell.)

A fundimental difference in stem cell perception is that biologists need to have everything replicated in lab, a process that slows therapeutic research far more than any political restrictions could - but adds enormously to full knowledge of what cells can and cannot do ... in lab.

Embryonic differentiation, though, is a process by which subtle chemical changes occur throughout the cells migration in (particularly) the early stages of development. This is nearly impossible to recreate in cells from a deconstructed embryo and unnecessary in cells from a more mature individual.

Two fundimental properties of embryonic stem cell make them unlikely for therapies in the near future. Tumor formation & patient rejection of the cells are the primary paradox limiting their therapeutic value. To avoid tumors, the cells must be differentiated to their final tissue, with no stem cell quality remaining ... and this tissue is as if it came from any other donor, requiring a lifetime of immunosuppressing drugs.

SCNT has been proposed to get around this issue, but primate biology is different than the SCNT successful animals - for example, primate centrosomes are paternally derived. There is increasing evidence this may never be achieved. Furthermore, SCNT is inefficient, and puts women's health at risk acquiring research materials. Furthermore, in animal studies, therapies using SCNT derived ES have not worked to date, with success coming cells are harvested from a 'clone' is matured to the level of a 5-month old infant.

Though stem cells from a variety of mature tissue are pluripotent, I disagree this is necessary from a therapeutic stand. The closer to the final tissue the more stable/safe the cells from which it is made. Indeed, 'adult' and berashis stem cells exist for the purpose of seeking/repairing body damage and it is a mistake of biologists to ignore this important process is to the future of less invasive/stressful medicine.

It's too bad that this debate has become an us (biologists) vs. them (medical professional), with the therapeutic value of hES in the next decade overhyped for fears the public won't understand the value of the knowledge gained from this work on early cells.