Image: Thomson in Primate Research Lab
Jeff Miller  /  UW-Madison file / 2001
Developmental biologist James Thomson says he never expected his work in embryonic stem cells to continue attracting media attention. "It's been seven years now: Get over it," he says.
By Alan Boyle Science editor
msnbc.com
updated 6/25/2005 6:29:14 PM ET 2005-06-25T22:29:14

MADISON, Wis. — Seven years ago, when James Thomson became the first scientist to isolate and culture human embryonic stem cells, he knew he was stepping into a whirlwind of controversy.

He just didn't expect the whirlwind to last this long.

In fact, the moral, ethical and political controversy is still revving up — in Washington, where federal lawmakers are considering a bill to provide more federal support for embryonic stem cell research; and in Madison, Thomson's base of operations, where Wisconsin legislators are considering new limits on stem cell research .

Thomson, a developmental biologist and veterinarian at the University of Wisconsin at Madison, made history in 1998 when he and fellow researchers derived the first embryonic stem cell lines from frozen human embryos. The breakthrough came after the news that a sheep named Dolly was born as the first cloned mammal — and together, the two announcements hinted at a brave new world of medical possibilities and moral debates.

Since then, five of the university's cell lines have been approved for federal funding under the terms of the Bush administration's stem cell compromise of August 2001. Other cell lines have been derived from frozen embryos with private funding, and the bill approved by the House last month would open the way for more.

Not surprisingly, Thomson believes that President Bush should call off his threat to veto the legislation — and that the federal government should put more money into embryonic stem cell research. "If you look at the average budget of, say, one of the major cancer centers, it’s probably about $10 million a year," Thomson told MSNBC.com last week in his Madison office. "Two cancer centers would represent the total federal investment in human embryonic stem cells in the United States. This is just not in balance in any way."

Some of Thomson's other pronouncements might seem more surprising: that supporters of stem cell research are overestimating the prospects for transplantation cures, that the current stem cell lines aren't well-suited for such applications anyway, and that there's no need to resort to therapeutic cloning right now — or perhaps ever.

Critics point out that embryonic stem cells are not being used in any clinical applications yet, while alternatives such as adult stem cells figure in scores of therapies. Thomson acknowledged that the field was still in its formative stage: "There have been companies that have gone into stem cells, but nobody’s made any money."

But he recently helped found a biotech start-up called Cellular Dynamics International that takes a different approach, aiming eventually to turn embryonic stem cells into human heart cells suitable for drug testing. "Nobody’s been able to test heart drugs on heart cells [outside the human body] before," he said. "That will change medicine a lot quicker than actually transplanting those heart cells."

Thomson predicted that in the long run, embryonic stem cells would play a more important role in fundamental research than in transplantation therapies — a view that doesn't sit well with the critics.

"You have to ask the question, why would you destroy living human embryos just to study them?" said Barbara Lyons, executive director of Wisconsin Right to Life.

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In last week's wide-ranging interview, Thompson explained the reasons behind the research, and touched on many other scientific and moral issues as well. Here is an edited transcript:

MSNBC: How do see this research developing in the next few years?

Thomson: I want to make a basic statement first — which almost never gets in the press, but I keep trying — on what I see as the legacy of these cells.

One is the basic science, and simply having better access to the human body. That’s the most important legacy. I’m very hopeful that there will be some transplantation applications for this technology, but they’re going to be very challenging. And it’s been so hyped in the press that people expect it to come the day after tomorrow. …

Ten or 20 years from now, I’m actually currently optimistic that there will be transplantation-based therapies, but even if there was none, and it was a complete failure, this technology is extraordinarily important.

The analogy I like to draw is with recombinant DNA. If you go back to the early ’70s, when people were all excited about this technology, they made a couple of mistakes in the predictions. One was that gene therapy would be pretty easy. Another was the blanket statement that it would solve a lot of problems. Well, here we are, 30 years out, and it really hasn’t changed people’s health in dramatic ways. There have been a couple of small successes, but it’s been very challenging.

I think that transplantation based on embryonic stem cells might have comparable challenges in getting into the clinics. That doesn’t mean it won’t be terribly important someday, but I think there are enough challenges there that there’s a good chance that most things people are trying will fail the first time, and it will take a lot of hard work to get it working.

The other analogy to recombinant DNA is that people completely underestimated how pervasive a research tool it would be. If you think about it, it does things you don’t even realize anymore. If you look at your laundry detergent, there are recombinant proteins in there to make your stuff whiter. Then there’s the O.J. Simpson trial, with PCR-based forensics.

I think the same things are going to happen with human embryonic stem cells. It will be a pervasive research tool that anybody interested in understanding the human body will use. And that will lead to knowledge, for the development of new drugs or whatever, that has absolutely nothing to do with transplantation. This will change human medicine in ways that don’t make the front pages. And people will not even realize it’s happened. My prediction is that that will be the long-term legacy of these cells.

Thomson: If you think about the kind of transplantation that people talk about — say, Parkinson’s — it’s a very complex disease. The brain is a complicated organ. It may be possible someday to transplant cells and treat that disease. But it’s clearly going to be challenging. When you think about it, that’s a pretty crude thing to do anyway. What you want to do is understand how the disease happens in the first place, and you need to prevent or slow its progression to the point where it’s not going to be relevant anymore.

Up until now we’ve never had dopaminergic [dopamine-producing] neurons from humans that we could study in the laboratory. They simply didn’t exist. So human embryonic stem cells already give rise to these dopaminergic neurons with very high frequency. I hope that they might be useful for transplantation. They may not be. I mean, you have to be realistic about it. But in terms of a basic model to understand what’s happening in the disease, it’s unparalleled. I think what will happen is that people will understand the basic biology of the disease using this model system, and they’ll come up with therapies, and you won’t even know stem cells were involved in creating those therapies. …

I think that’s the theme for most diseases. There are some that really should work, like diabetes. There’s already a transplantation therapy for that. There’s just this mismatch between the availability of tissue and the need: There’s a couple of thousand appropriate pancreases donated in the United States every year for this procedure. You need two for each patient, and there’s over a million people with diabetes. It’s a complete mismatch.

So you’d think if you could just come up with a better cell, then that would go directly into transplantation. And it probably can. The problem is the safety issue. If you take cadaver tissue and take the islet cells out, you’re not forcing them to divide a lot in culture. They’re going directly into a patient. So the chances of introducing a cancer are pretty small. It’s a negligible risk.

But with stem cells, if you manipulate them in culture for a long time, they will accumulate mutations. It’s a fact of life. It’s just a question of differences in the rates. If you accumulate enough of those mutations, you could actually create a cancer.

This has nothing to do specifically with embryonic stem cells. It’s just any cell you put in a tissue culture. But if you’re going to take those cells and put them into somebody’s body, you want to make really, really sure you have some way of dealing with that – because if you’re diagnosed with diabetes and you’re 6 years old, you’re going to live a very long, productive life. It’s a pretty normal life until the end. … But you don’t die from cancer in a couple of months.

So that one is like, “It really should work, and there’s no reason why it can’t work” – but the safety issues are high enough that I suspect it will take a long time to get to the clinics, because you don’t want to create a disease that’s far worse than what you’re trying to cure.

MSNBC: Does it concern you that there are people who say, “We’re this close to solving this sort of disease with stem cells, so let’s pass this legislation”?

Thomson: Yeah, it’s unfortunate. There are clearly exceptions on both sides, but most of the people who oppose this research, and most of the people who support this research, do it with a profound amount of misinformation. It’d be very nice to clear up that information as much as possible. You can still make an informed choice and be for it or against it, but at least it’d be based on the real facts.

When President Bush was elected, there were about eight months when stem cells were on the cover of every major newspaper in the United States, because it was prior to 9/11 and it was a slow news period, basically. Nonetheless, when people did polls right at the end of that period, the average American really didn’t understand embryonic stem cells, despite that tremendous amount of press coverage, because it just became this political question.

I guess the news media aren’t really the media to educate. The news media failed in that role. … I don’t know how to change it, because every time I have an interview with some guy and try to go through what the science is, they talk about curing Alzheimer’s.

Q: I know you’ve given a lot of thought to the moral questions and the issues that the opponents of this research bring up. People who have questions about the research would ask, “Is it really worth it to go down this long road where we don’t see cures just over the horizon, and we’re using components of human life?”

A: You have to take the other point of view seriously. Nonetheless, the bottom line is that there are 400,000 frozen embryos in the United States, and a large percentage of those are going to be thrown out. Regardless of what you think the moral status of those embryos is, it makes sense to me that it’s a better moral decision to use them to help people than just to throw them out. It’s a very complex issue, but to me it boils down to that one thing.

If you really explain what’s happening – that these frozen embryos are ultimately going to be thrown out – almost everybody except those that have to keep to some kind of party line will say, “What’s the problem with this? We should go forward with this.”

That’s separate from creating embryos. That offends a lot more people, and I can understand why. You’re creating something that’s a tool, and you’re making a tool out of this thing. I haven’t seen polls, but just in my personal conversations, using things that are about to be thrown out offends almost no one, including fairly devout Catholics – whereas actually making something into a tool offends a much larger percentage of the population.

From a public policy point of view, it makes a lot of sense to separate these two issues. Part of what’s happening, and the reason why things kind of stalled, is that nuclear transfer and therapeutic cloning was intermixed with trying to make new cell lines from pre-existing embryos. They’re very separable. There are some scientific reasons why nuclear transfer and therapeutic cloning might have merit, but most of the value of this technology can be captured simply by making cell lines with existing embryos. There’s a diminishing return the more deeply you get into it, and if society is not quite ready for both – well, at least take the one where there’s a great advantage now and move on with it.

So what Congress did recently and what the Senate is trying to do is a good thing and would actually help a lot. I hope President Bush reconsiders his veto. It would change the field dramatically.

Q: The people who use nuclear transfer generally say that the technique is optimized for producing the stem cells rather than making babies. They would not want to equate this with the process that produces embryos that were fit for implantation, and they’d argue that they’re using the reproductive process differently …

Video: South Korea makes stem cell advance

A: See, you’re trying to define it away, and it doesn’t work. If you create an embryo by nuclear transfer, and you give it to somebody who didn’t know where it came from, there would be no test you could do on that embryo to say where it came from. It is what it is.

It’s true that they have a much lower probability of giving rise to a child. … But by any reasonable definition, at least at some frequency, you’re creating an embryo. If you try to define it away, you’re being disingenuous.

Q: One of the facets of nuclear transfer research is that you get around the tissue rejection issue, and you have the genetic makeup tailored to the patient. That was one of the implications of the research coming out of South Korea. How do you address those issues with frozen embryos? Does it go back to the idea of stem cells as a means of learning about the human body rather than being strictly used for transplantation?

A: Well, it goes back to both. … There’s a mismatch between how close we are to clinical applications and the nuclear transfer work. If the therapeutic applications were ready to go today, nuclear transfer would probably make a pretty big impact. … The trouble is that most of these transplantation therapies are going to take a while to get to, and my personal guess is that there will be other technologies that go around the need for nuclear transfer. But it’s a personal guess, I may be wrong. So my own lab looks at other things.

Q: What are some of those guesses about other technologies?

A: Well, if you take a nucleus and you put it into an oocyte [egg cell], the oocyte knows how to reprogram things. That’s a problem that we can study, to understand how that happens. We don’t really have a lot of information about how that works, so it’s hard to predict how long it’s going to take to solve that problem. I’d be surprised if within 10 years we didn’t have another way to solve the problem, but it could be that it’s a very, very hard problem and it’s going to take a long time to do it.

Q: To find a way for a normal cell to reprogram itself?

A: Right. The message of Dolly is less about cloning, that we can clone Dolly or we can clone people or even do nuclear transfer to make embryonic stem cells; it’s that the differentiated state is in principle reversible. And while that was known for a lot of model organisms, and there was even some evidence for that in mammals, Dolly really drove the message home that it was simply a question of time before we understood how to do that.

Prior to Dolly, we thought it was just impossible, we thought biologically it was not a reversible process. So Dolly does have implications for cloning animals and people, but really the biological message of Dolly is that the differentiated state is reversible under some conditions. …

Q: What’s your view of the idea that the moral issues may become moot because of the things people might be able to do in the future, with blastomeres, or embryos that are altered so that genetically they cannot get beyond a particular stage?

A: I’ve talked to the guy from Stanford [William Hurlbut] who has been a big proponent of that. The basic problem is that we haven’t really thought through the implications of Dolly. It will take a while to do that. It was 1978 when the first IVF [in-vitro fertilization] child was born, and basically all these issues have to do with that, they have nothing to do with stem cells. It all goes back to IVF. The problem with IVF is that it affects a relatively small part of the population, so society pushed it to the side and didn’t deal with it, even though it was controversial at the time. With embryonic stem cells, that affects most people, and suddenly society has to deal with it. So most of the issues go back to IVF and the creation of embryos, and nothing has changed. The moral debate hasn’t really changed. If you read the Warnock Commission report, sometime in the ‘80s, all those issues were brought up.

So Dolly came along, and that did change the moral argument in ways that people haven’t fully appreciated. The bottom line is that any cell in your body has a latent potential to form a human being. If I told you there was a frozen cell in liquid nitrogen, and I thawed it out, and I manipulated it, and I put it back into a woman’s uterus and it formed a child, could you infer what the moral status of that cell was? Well, no – because that could be true of any cell in your body now. Granted, you have to do a fair amount of manipulation. But in terms of potential, the potential is there. There’s no inherent reason why a liver cell can’t form a baby.

So arguments based on potential alone are kind of suspect now because of that. It’s becoming increasingly difficult to say, “OK, you have this one-cell embryo, how is it fundamentally different from another cell in your body?” If you have a one-cell embryo in a freezer, you have to intervene to actually make it become a child. You have to do a lot to it. …You have to thaw it out under very technical conditions and you have to prepare the mother. There are a lot of interventions there. So I think the fundamental problem is that people haven’t come to terms with that. This idea that you’ll pre-engineer it to fail seems disingenuous to me. At what point is it failing, and just because it’s failing, why is that not an embryo? I don’t know.

Q: Then there’s the issue of interstate and international competitiveness: Sometimes you get the feeling that there’s a race to capitalize on this technology, and then you have the countervailing moral arguments. It’s easy to get into this situation where you feel like “we’re going to have one hand tied behind our back, because the South Koreans or the British have this line…” I assume that you view it differently?

A: Well, yes and no. There is some advantage about people being worried about the rest of the world getting ahead of us in this. I’d still say that most of the decent papers come out of the United States, but that’s changing. Britain, for example, has these very liberal policies, but they’re implemented in a way that’s actually slowed them down, and they don’t have a lot of money to do it. So in spite of these liberal policies, it’s still not this golden place to do stem cell research. In Asia, Korea and Singapore are making major investments in this area, and China too. California managed to get the money flowing from Proposition 71. That’ll make a big difference. So competition does ultimately make the world go round on one level or another, and that’s not a bad thing, I guess.

Q: Does that enter into the argument over what sorts of procedures would be acceptable for pursuing this?

A: It certainly should. The United States is just odd. Basically, if you do things with federal money, you’re pretty restricted in what you can do. If you do things with private money, you can do whatever you please, even things that would offend most people. So it doesn’t appear to me that it represents sound public policy.

Q: In terms of stem cell technology, there was an advance in getting beyond the mouse feeder cells, but there are still some animal components that need to be used to support human embryonic stem cells. Do you think that problem is solvable?

A: I think there are going to be a couple of things that will ultimately change federal policy, though we might have to wait for three years. One is that my group and quite a few other groups are developing culture conditions that are much better than the original culture conditions. … My prediction is, within the next year there will be at least one and probably several publications demonstrating that: completely defined conditions, no animal products, no feeder layers of either human or animal origins.

The other thing, which is already happening, is that more and more clinically relevant lineages are being published. People have published work with dopaminergic neurons, motor neurons, heart cells – quite a list now. That means that although we’re not ready to put these cells into patients yet, the clock is ticking.

And the original cell lines, while they can be put into patients if you jump through enough hoops, they’re clearly not the safest things there, because no matter how much testing you do, you might have missed something. If you derive stem cells from day one in completely defined conditions, in the appropriate GLP [Good Laboratory Practice] conditions, there’s simply going to be a higher level of safety. So if I were a patient – say, 10 years down the line when the therapies come on board – which cell line would I want? I wouldn’t want the original ones.

When we derived those original cell lines, I was very consciously making them just for experimental purposes, because I figured other people would derive them under these GLP conditions and I wouldn’t have to deal with that. We’d just do the experiments. Little did I know that we’d be stuck with these cell lines.

It hasn’t bothered me yet, because we didn’t really know how to make them better. But the field is changing now. We’re getting very close to where we can make them under completely defined conditions. And as I said, I suspect there will be multiple people publishing on that. So I hope that that will drive the political process. Congress now is attempting to pass this law to derive more cell lines from these existing embryos, and I hope President Bush can actually consider changing that veto.

In the first four years, it was entirely about the basic science. Although a lot of the scientists have been very vocal about the compromise [announced in August 2001], I’ve been kind of quiet about it. And the reason is that, in a kind of “silver lining to the dark cloud” thing, it’s almost better that Bush was elected. I don’t know how to say this without offending someone, but it’s a little bit like Nixon going to China. Nixon didn’t suddenly become a Communist.

President Clinton did not fund this research. It’s nice to yell at the Republicans, but moderate Republicans have been some of the biggest supporters of this. Even though it’s a compromise, and even though the compromise does not represent good public policy, it got the field going, it got federal funding going for the first time. Scientists suddenly knew that if there was a change in administration, it wouldn’t stop – whereas if Bush didn’t allow it to go forward, the policy could flip-flop every time a Democrat or a Republican takes the White House. So even though we have to go beyond that policy, it did get the field started, and I think that’s a positive way of looking at it.

During that first four years, it probably didn’t hurt things that much – it did create this funny bottleneck about cell lines, which did slow things down, and that’s unfortunate. But going forward another three years, it could actually hurt people. Just because it’s going to take us 10 years to derive these new therapies doesn’t mean we don’t want to have the cell lines now.

Thomson: It’s a long-term process to really characterize these lines well. The existing cell lines have been around for seven years, and people are gearing up to want to do clinical trials. They’ve been arguing with the FDA all this time over the original cell lines. Well, that means we want the new cell lines now for some therapy that’s going to be 10 years out.

A three-year difference could really hurt people now, because the [culture] media has gotten qualitatively different. Just deriving the same old cell lines with the same problems made no sense to me, but once those conditions are really defined and safe, then it makes sense to go back and derive more. So I hope public policy allows that.

Current public policy in theory allows it, because you are allowed to use private funding, but the reality is that the federal government, the National Institutes of Health, is the funding that drives basic research and research into new therapies in this country. And if you exclude that, then you’re basically stuck. …

Q: How do you respond to the claim that we have these other sources of stem cells — adult stem cells or cord blood — and there’s no need to turn to embryonic cells?

A: We don’t. The most studied cell in the whole body, in terms of stem cells, is the hematopoietic stem cell. It can’t be grown. So what you do when you do a bone marrow transplant is you take some bone marrow out of you — actually, we do peripheral blood — and we put in another patient without expanding it. There’s a clinical need for that expansion step, but it can’t be done right now. And hundreds of labs for 30 years have studied that adult stem cell, and that’s the one we know the most about.

If you go to these other ones, most of them are known by indirect methods, and nobody can actually isolate and expand and grow them in useful ways. But we can already make blood in very reasonable quantities from human embryonic cells. …

So if you think about particular things, you can find a stem cell that might work for that application, but this ability to expand these cells in an unlimited, stable developmental state is essentially unprecedented among stem cells. … People can do mesenchymal stem cells [from bone marrow] pretty well, and neural stem cells kind of well, but neural stem cells is a good example. If you try to make dopaminergic neurons from fetal neural stem cells, you get a burst of that activity, and it goes away. Nobody’s been able to sustainably make dopaminergic neurons from an adult stem cell, or a fetal one, period — whereas with embryonic cells you can do it already. Over time that might change. But a lot of good groups have tried very hard and failed, to date.

And again, getting back to the basic science thing: If we study the embryonic stem cells, we learn the basic science. That knowledge is just as likely to be applied to adult stem cells as to the embryonic stem cells. The knowledge goes back and forth. And in the case of the blood, people have failed at growing that cell for three decades. Well, studying that lineage with embryonic stem cells, we might learn the clues to make it growable, and it might be that we still want to use adult stem cells to do that because there are a lot of advantages to that, but the knowledge might come from embryonic stem cells.

This divide about adult vs. embryonic, it’s a political debate, it’s not a scientific debate. Scientists choose the model for a question that fits the question. … So people who have focused on adult stem cells historically are using embryonic stem cells now. It doesn’t mean that’s what they think will be the therapy, but they see it as a more useful model to understand the questions they want to ask. …

Q: Thinking back to when you did your first work with embryonic stem cells, did you have any expectations about how things would look seven or 10 years later? And how has the reality matched those expectations?

A: Dolly had just been published, so I knew this would be a media thing. But the thing that has most surprised me is how long the media attention has lasted.

It’s been seven years now: Get over it. We derived a few cell lines, and that’s kind of neat, but what I anticipated is that there would be this media storm that would last, I don’t know, three to six months. And then people would just get on with their lives and do something else, because they have short attention spans. But it’s seven years in now, and it’s still this lively topic of discussion.

A lot has to do with the fact that we have this particular president. I think if the political process were just a little bit different, we wouldn’t even be talking today.

What do you think? Share your opinion on stem cell research with Cosmic Log.

An earlier version of this report referred incorrectly to the timing of the first reports about the cloning of Dolly the sheep.

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