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Beyond stem cells

If things turn out the way stem cell pioneer James Thomson thinks they will, embryonic stem cells won't turn out to be the therapeutic marvels many expect them to be.

Instead, there will be a different kind of marvel: You'll give the doctor a sampling of your own cells - perhaps scraped from your skin - and science will transform them into microscopic factories for your own replacement tissue.

Jeff Miller / UW-Madison
James Thomson looks at a stem

cell culture in his lab at the

University of Wisconsin at Madison.

That vision is still years away, but today the vision came a little closer with the publication of research conducted by Thomson and his colleagues, as well as a similar study done in Japan. The research focuses not so much on embryonic stem cells per se, but on genetically modified skin cells that have been dubbed induced pluripotent stem cells, or iPS cells for short. You can read all about it in this report.

Thomson, a biologist and professor at the University of Wisconsin at Madison, says the research released today stands as one of the "bookends" in his decade-long stem cell quest.

The first bookend came in 1998, when Thomson led a team that first isolated human embryonic stem cells. These cells can transform into virtually any of the body's cellular types - an ability known as pluripotency.

The latest research indicates that with the right genetic and chemical prodding, ordinary skin cells could become pluripotent once again. Thomson cautioned that the process has to be studied further to make sure it works as well as it seems to, with no ill effects. The technique has to be modified to eliminate some of the riskier steps - such as injecting genetic material using a lentivirus. That type of virus is widely used in gene therapy for all sorts of benign purposes, but the same class of virus is implicated in AIDS.

If those hurdles can be overcome, IPS cells could become the "panacea" cells for a wide variety of illnesses, according to bioethicist (and columnist) Art Caplan. The ethical debates over human cloning and the fate of frozen embryos could become moot.

The way Thomson sees it, this research reflects the paradigm shift that occurred a decade ago, when Scottish researcher Ian Wilmut and his colleagues created the first cloned mammal, Dolly the sheep. Dolly demonstrated that there was something in the egg that could reverse the cell's "strong arrow of time," Thomson said.

"It was only a matter of time between cloning Dolly and finding out what it was," Thomson told me.

Thomson said he never believed that cloning itself would produce new therapies - and not just because of the moral and ethical qualms about human cloning. "Mainly, it's just hugely inefficient and terribly expensive," he said. Rather, Dolly the sheep - and the pluripotency of embryonic stem cells - pointed to potential treatments that could go beyond cloning, and beyond those precious embryonic cells.

Thomson usually prefers to keep a low profile about his work, but this week he agreed to an interview not just once, but twice (due to a balky audio recorder the first time around). Here's an edited transcript that focuses on some of the bigger questions raised by the new research:

Q: The last time we talked, you mentioned how your work with stem cells was aimed at addressing the mystery raised by Dolly the sheep. …

A: … Or taking advantage of the possibilities that Dolly presented …

Q: … So how do these new findings fit into this larger quest?

A: Dolly showed that that there are things in the oocyte [egg cell] that can mediate cell programming to the embryonic state. We initiated a search to find out what’s there – because once you know what’s there, you don’t need the oocyte anymore. We decided to do that with genes that were specific to embryonic stem cells.

Q: That’s how you identified the genes that you wanted to pursue. But you didn’t start out with just four genes…

A: No, we started out with a very large pool, and we narrowed it down little by little. We cloned over 100 genes that were specific to embryonic stem cells, relative to the cell we were trying to reprogram, and pooled them. We got lucky because the first pool of 14 worked. It worked quite a while ago, but it took us all this time to narrow down which genes were important.

Q: What is the function of these genes in normal cells?

A: Oct4, Sox2, Nanog are the genes we ended up with, and these have been known for a while now to be the key regulators of this pluripotent state. [Another gene, Lin28, appears to play an important supporting role.] It would have made sense if we just tried them to start with, but we were just sitting in disbelief that it could be that simple.

These are the genes that control the expression of other genes. They’re the master control genes of the pluripotent state.

Q: I’m sure a lot of people will be wondering whether this research makes therapeutic cloning a moot issue. Cloning pioneer Ian Wilmut has said that he felt like abandoning the cloning approach and using this approach instead.

A: Yeah, my feeling is that somatic cell nuclear transfer was an experimental technique, and it could have led to a mechanistic understanding of how reprogramming could occur. But I was skeptical that it could ever enter the clinic because of practical reasons.

This may not be the end of the story. These pluripotent cells may not be perfectly like embryonic stem cells. We don’t know yet. But I do think this is the path that people are going to follow now.

Q: How do you think this will affect the political debate over stem cell research?

A: Well, what I hope will not happen is that everybody says, ‘See? We don’t have to do embryonic stem cell research now.’

Just like Dolly was our inspiration to do the screening in the first place, we could not have successfully done the screening without the existence of human embryonic stem cells. The Japanese group, Dr. Yamanaka’s group, used four genetic factors in mice. They had tried the same [mouse] embryonic stem cell culture with human material and it didn’t work. Then they used human embryonic stem cell conditions that had been developed at my lab and other labs.

In our research, we actually used human embryonic stem cells as part of the screening process. So the research itself on human embryonic stem cells led to the next finding about pluripotent cells.

Even though they look just like embryonic stem cells, it could be a couple of years before we find out if there are any significant differences. And the only way we’re going to know that is to compare them with embryonic stem cells.

Q: Do you feel as if you’re going to be following this particular line of research, reprogramming cells, and moving away from working on new embryonic stem cell lines? Or will you still be pursuing new embryonic stem cell lines?

A: Well, we might in a limited way. But we derived five stem cell lines almost 10 years ago now, and we’ve maintained them ever since. We haven’t actually derived a lot of cell lines. We’re just using them for an experimental model. … There might be some limited reasons why we’d want to derive more, but we don’t anticipate deriving a lot of them.

Q: Do you expect we’ll be seeing new cures in the next two years or so because of this research?

A: No, this basically brings us back to an embryonic stem cell state. You know, most of the challenges that were facing us for transplantation therapies have to do with using stem cells as a base. We still have to make the cell type we want, and we still have to get the cell type we want into the body.

One thing it does solve is the issue of rejection. These cells should be perfectly matched with the patient, so the immune system should not attack it. But most of the other challenges are intact.

Q: Would we see these cells initially in applications such as drug testing?

A: Yes, drug testing is one application that embryonic stem cells are already good at, and people are starting to test drugs on embryonic stem cell lines. The important difference is you can get cell lines from specific individuals with a specific genetic background. The existence of a wide diversity of cell lines means you can match the ethnic diversity of a population like the United States. Because drugs act differently on different people from different backgrounds, it’s very important to test drugs early in the process to see if they have different effects on specific groups.

These cells allow you to do that in a much easier way than the embryonic stem cell lines – in particular, the presidentially approved embryonic stem cell lines have very limited genetic diversity.

Q: Looking back, you mentioned that it’s almost been a decade since you first isolated human embryonic stem cells. How do you see this work as opposed to the work that got you started going down this road?

A: In the same way that Dolly initiated the search for reprogramming factors, embryonic stem cells allowed us to accomplish it. I think over time, we probably will drift away from embryonic stem cells. We’ll continue to look upon those cell lines as the gold standard, but it is very satisfying to actually help bring in what I think will replace embryonic stem cells one day.