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Breakthrough Set to Radically Change Stem Cell Debate

November 20, 2007 at 6:20 PM EDT
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Scientists reported Tuesday that they had succeeded in making human skin cells mimic embroynic stem cells, potentially bypassing the ethical debate over embryonic stem cell use. A cell biologist discusses the research behind the advance.
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JEFFREY BROWN: The excitement today was over new studies that suggest a way around the ethical, practical and financial controversies that have characterized the stem cell debate for so long.

Two teams of scientists, from Japan and the University of Wisconsin, reported they were able to reprogram human skin cells to behave like embryonic stem cells, without using embryos or women’s eggs. Robert Lanza, a leading researcher on embryonic cells, called it a “scientific milestone, the biological equivalent of the Wright brothers’ first airplane.”

On the other side, Richard Doerflinger of the U.S. Conference of Catholic Bishops called it a “very significant breakthrough that would be readily acceptable to Catholics.”

And James Battey of the National Institutes of Health said he saw “no reason on Earth why this would not be eligible for federal funding.”

To help explain this, we turn to Kenneth Miller, a cell biologist and professor at Brown University. He also serves as an adviser to the NewsHour’s Science Unit.

Well, Ken, let’s start with the science here. What does it actually mean to reprogram cells?

KENNETH MILLER, Cell Biologist: Well, what it means to reprogram cells, builds upon essentially a trick. And it’s a trick that our own reproductive cells pull off when a sperm and egg unite to form an embryo.

The cells in an adult body — skin cells, muscle cells, nerve cells — are sort of at dead ends. In other words, that skin cell is going to remain a skin cell; that muscle cell is going to remain a muscle cell.

But our reproductive cells have the ability to go back to stage one, form a single-celled embryo, and then grow into every one of the tissues and cells in the body. That reprogramming is something that happens with us normally between each generation.

What developmental biologists have longed to understand is how that reprogramming takes place. And what this development means today is that we are a little bit closer to understanding how to switch on the reprogramming, take one of our adult cells, trick it into thinking it’s part of an embryo, and hopefully get that cell to develop into cells that we really need to repair or to heal the body.

JEFFREY BROWN: And this work came out of studies that were done on mice, right? We talked about it on the program when that was done. So what’s the advance here?

KENNETH MILLER: Well, the advance here, on one hand, the advance isn’t much. In other words, you could minimize it. You could say, back in June, three laboratories reported that it was possible to pull this feat off, of taking an ordinary adult cell, sticking a few extra genes in it, and reprogramming it to become an embryonic stem cell, and that was done in one species, mice.

The development today is now it’s been done in another species. And you might say, “Big deal.” But that other species happens to be human beings, human cells. And now it’s getting close to having direct application in hospitals and in laboratories.

Avoiding use of embryos

JEFFREY BROWN: All right, so let's talk about the real reason, though, for the excitement is because, as I said in the intro, it allows the potential to side-step -- start with the ethical problems that have been there. How does this allow people to get around those?

KENNETH MILLER: Well, it may allow people to get around those. Let's be very clear about that.

The big ethical dilemma that has faced everyone working with embryonic stem cells is, to get them, you've got to take them out of an embryo. And that usually means that embryo has to be destroyed in the process.

Now, if you're working with human embryonic stem cells, it's a human embryo you have to destroy. And for obvious reasons, that's a problem, and it's a problem more so for some people than others, but it is still a problem.

Now, the important thing to emphasize is that people doing this research have never wanted to destroy embryos. They just want cells that know the tricks that the embryo has mastered. And ultimately what one hopes to do is to understand specifically what genes are activated and how those tricks take place.

So the current technology seems to argue that what we are able to do at this point is to take cells from an ordinary adult, cells just under the skin -- in one case, in the Wisconsin studies, cells derived from the foreskin of a newborn baby -- take those cells, insert a little mixture of just four genes into those cells, activate those genes.

And those cells seem to become reprogrammed to such an extent that they act in the laboratory very much like embryonic stem cells react. And what this means, essentially, is that we may have been able in these two laboratories to produce cells that have all the capabilities and all the potentials of embryonic stem cells without ever producing or sacrificing an embryo.

And I think that's good news, regardless of how one feels about the ethics of conventional embryonic stem cell research.

Potential risks involved

JEFFREY BROWN: The researchers were clear about the potential drawbacks here. Talk a little bit about that, including the potential of introduction of cancer?

KENNETH MILLER: Oh, absolutely. The trick in both laboratories -- one laboratory in Kyoto and San Francisco -- they were collaborating jointly -- and the other at the University of Wisconsin -- each laboratory used a slightly different trick.

But in both cases, they took four genes and inserted them into human cells by using a virus. Viruses are, in effect, little packages of protein and DNA that are specialized at getting genes into cells. So it's a logical choice.

But the first problem is the virus itself goes in, and you don't know where those genes, that DNA is going to insert. So that could cause unpredictable damage to the cell into which these genes are inserted.

The second problem is that one of the genes that was used by one of the groups is known as the MYC-oncogene And the MYC-oncogene is strongly associated with a variety of types of cancer.

And in an earlier study this year in mice, the Japanese group showed that mice regenerated by using this technique -- in other words, to prove that these things really had the capability of embryonic stem cells, that these mice actually had a much higher incidence of cancer than mice that were produced by other ordinary methods.

So this is a powerful technology, but all powerful technologies are dangerous. And both groups of researchers have expressed an eagerness in their respective publications to find a way to do the same genetic trick without involving viruses and without involving genes that have the potential to do harm. So this is a tricky technique.

Significance of the study

JEFFREY BROWN: They did seem to suggest that they thought there was ways around this, that they would solve the problem. So where are we? Remind people of the promise here. And given this, how soon might that day come?

KENNETH MILLER: I'm not going to venture a guess on how soon the day will come. I'm going to talk about this from the point of view of basic biology.

What we have wanted to know about in cell biology are what the tricks are that are used to reprogram cells to bring them into an embryonic state where they're capable of everything. So that, for example, if someone has a heart attack, and the cardiac muscle cells begin to die in the heart, or stroke and nervous tissue in the brain begins to die, we'd like to be able to take cells and give those cells an instruction, "Become heart muscle cells and fix the heart attack, or become brain neurons and fix the damage from a stroke."

Embryonic cells seem to be capable of doing that. What this research suggests is it might be possible to take cells from an adult human -- no destruction of an embryo -- insert in a relatively small number of genes, and then persuade those cells to, in fact, become nervous tissue cells or to become heart muscle cells.

And in the Japanese study, in fact, both of those cell types were produced in culture, which is very, very exciting. All the dangers that you mentioned are still there, but what it means for every laboratory in the world doing this research is that we are now a technical step closer to actually being able to try these techniques out and work out the kinks in them, so that they become safe and effective.

JEFFREY BROWN: You know, a scientist -- I know you know him -- Douglas Melton at Harvard, he had a great quote today that I want to read to you. He said, after he saw the results, he said, "Once it worked, I hit my forehead and said, 'It's so obvious, but it's not obvious until it's done.'" I thought that's a great way of thinking about how science actually works in a case like this.

KENNETH MILLER: I think it's absolutely true. And all of this goes back to work that was done in Shinya Yamanaka's lab at the University of Kyoto almost a year-and-a-half ago. And what his laboratory did was to take embryonic stem cells and very carefully analyze which genes were expressed at higher levels in those cells than you might expect.

He got about 24 candidate genes. And then, one at a time, very systematically, his lab knocked them out until they found four genes that were absolutely essential, couldn't get rid of them, to maintain the stem cell state. Now, that was a stunning finding. And everybody who read it, myself included, thought, "It can't be that simple."

But a year later, three laboratories, the one in Kyoto, one in California, and one in Massachusetts, did the logical experiment, which is to take mouse cells, throw in those four genes, activate them, and see if they act like embryonic stem cells. Lo and behold, they did. Hence Dr. Melton's surprise. Now we know that that very same trick works in human cells, as well, which is truly an exciting development.

JEFFREY BROWN: All right, Ken Miller, thanks a lot.

KENNETH MILLER: My pleasure.