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Stanford Report, October 2, 2002

Paul Berg: Use cloned embryonic stem cells to cure disease

By MARK SHWARTZ

Q: More than 20 years after you proposed a moratorium on recombinant DNA experiments, there is a call by the White House panel to have a moratorium on stem cell research. I can see there are differences, but there may be some parallels.

A: Oh, there's a very fundamental difference. The moratorium, as it has been advocated by the Kass commission, is for four years and gives no path to resolution. And the reason it can't give a path to resolution is because the fundamental issue is a moral one. So the question is, if you have a strongly held moral view, as many of those who voted for this, they're not going to change their views.

Q: They're talking about trying to achieve some sort of consensus in those four years.

A: OK, we've had a year since the president ruled, and a year before that in which we've been discussing stem cell research, and you still have the divisions that existed then. There are the people who are strongly opposed, because they view that stem cell biology involves killing embryos. They equate an embryo to a person. So if you make a blastocyst by inserting a nucleus from a skin cell into an egg, they say you've created a person. That person is entitled to all the protections of the law, and if you try to destroy it in order to get stem cells from it, that's murder.

Where is the give? The Kass commission was set up with a very large group of people who already held that view; they never changed that view. They heard all of the evidence, all of the discussion that the National Academy of Sciences brought to bear on it -- they did not change their views.

Q: Although when the report came out, the press touted it as somewhat contradictory to President Bush's own point of view, in that they were saying, "We're not going to advocate an outright ban on [federally funded] embryonic cloning."

A: But they did! It's just a ploy. In effect, it is a ban. There is nothing going to happen if that's approved over the next four years, except a lot of people hacking away in conversations, talking past each other. Nothing's going to happen.

If you have such great moral concerns about this type of work, let's put in place a regulatory process in parallel. Let's have everybody who's going to be working on this being registered. Everything they're going to do is approved by oversight committees. After all, we have institutional review boards. I could go to an institutional review board and say, "I need to make stem cell lines of the following type. I can do that by taking nuclei or cells from this individual. I can collect eggs, and I can do the following experiment. I can isolate the stem cell lines for this purpose." It would all be in a database where everybody in the world can look at it and see who's doing what and where and when.

But not according to the moratorium. It's really the same as the bill they can't get passed.

Q: You're referring to the bill introduced by Sen. Sam Brownback.

A: Yeah. They can't get the Brownback bill passed. The question is whether the Hatch and Feinstein version [can pass], which says, "We all agree. Let's prohibit attempts to clone a person, but by god, let's not cut off the possibility for capturing the benefit of this technology for treating millions of people's diseases." Maybe that can pass. If it doesn't pass, there's nothing.

Q: Is there any place today for a bioethics equivalent of the Asilomar conferences you helped organize in the 1970s?

A: Our concern [at Asilomar] was, are we going to be spreading some kind of infectious agent, which is going to do great damage to the environment and to people? It was not a moral argument; it was not an ethical thing -- "Are we entering into an area where we're going to discover new kinds of things that challenge the very essence of humanity, blah blah blah" -- all of that. That was not a factor.

The Asilomar conference was solely to evaluate, is there a public health risk? The answer out of that conference was that we really didn't have enough information to make a definitive judgment, and so we advocated that we establish an oversight process -- a set of guidelines and a series of committees and a series of passages and approvals, so that the early stages of this work would be monitored to make sure that nothing untoward came up.

The great thing at Asilomar was that people came open minded. Everybody wanted to find a way to resolve the issue: worry about safety; how do we do the science. Bill Hurlbut sat through all of the scientific discussions [at the White House Bioethics Council] and it made zero impact. Why? Because he holds deeply as part of his faith a view that says, "We dare not sacrifice a life for any purpose."

If you hold that view, you can go to 10 Asilomars and it's not going to make any difference. Leon Kass would not change one iota. That's why he was chosen by the president. The fact is, the president didn't wait for the Kass commission thing. He had a White House lawn party for all his base to tell them he was never going to allow this kind of work to go on, so what the hell was the point of the Kass commission?

Q: When the president made his decision a year ago, initially there was a lot of positive feedback from the scientific community: "There are 60 or 70 embryonic stem cell lines we can work with." But very quickly that changed.

A: When you actually say, "Where are these cell lines?" "Oh, they're not really cell lines. Some of them are just sitting in deep freezes and have never been looked at."

Oh, really? Can we get access to them? Suddenly you find out there are intellectual property issues. The method for making stem cell lines is patented by [the University of] Wisconsin. They claim they have an iron patent. You want a cell line from them, you've got to sign a document about what you're going to do with them. You're going to report back your findings. Any commercialization, you have to deal with them.

My guess is, today there are certainly far less than 10 lines that might be usable, but even those are not available except for one line from Wisconsin. So they derived five or six lines -- they're only shipping one.

I've given talks to a zillion different citizens groups, and the usual response has been, "What's wrong with [using discarded embryos]?" George Shultz said to me, "It's a no-brainer." If you're going to destroy these structures in any case, and there is no solution to continuously storing them, why is it that somebody would be opposed to capturing the benefits? The president obviously can't stomach the idea, so he said, OK, 75 embryos have already been sacrificed and the stem cells are sitting there, so you can work with those and no new ones.

What the president didn't realize is that the ones he approved are useless to achieve the goal for which he made that decision, which is, if you want to develop therapies to help the people who have all this array of diseases that might be helped by them, you'd certainly want to do everything you could to make the technology match to that endpoint. But no. He says, "You can only work with these cells, because that's the only thing that saves my moral ground." If you can't do what you said you did it for, then what's the point?

It's like him saying, "I'm authorizing the construction of this new kind of weapon or bomb, but I'm not going to authorize the means for delivering it." So there we are. We're stuck.

Q: So, in the meantime, is embryonic stem cell research going full bore in other countries?

A: Yes, not only full bore, but in Canada, they, too, are going slower -- prohibiting cloning stem cell lines -- but they can get all the stem cell lines they want. They can go to IVF [in vitro fertilization] clinics and get those embryos, bring them back and make their own. We can't do that. We were never able to do that, even under the Clinton administration, because the legislation that authorizes the appropriations from the NIH [National Institutes of Health] has in it what's called the Dickey amendment, which says you cannot use federal funds to work on human embryos.

This building [the Beckman Center], for example, gets indirect costs from the federal government. Every inch in this building is viewed as being supported by NIH. We can't do any experiments here that violate Bush's edict or this Dickey amendment.

Q: So, when the opponents of embryonic stem cell research say, "You're free to do it in the private sector," that's really not much of an argument for universities.

A: Ask yourself, where is the major intellectual energy and ability -- in the private sector or in the huge biomedical enterprise that's funded by the NIH? Where do all the discoveries that have brought us to this stage come from? They haven't come from industry; they haven't come from the private sector. They've come from the NIH.

The other thing that's really important is, think about an investigator. I'm booming along, having a very successful research program. Now there's a big breakthrough: "God, that's exciting. Maybe I ought to get into that. Wait a minute. This thing is filled with politics, a whole lot of controversy. I don't even know if it will last."

If I get to the point where I actually develop something interesting and I find out I can't go beyond, why do I want to get into this kind of field? I'm going to stick with what I have. I'm getting lots of publicity. My papers are being accepted. I'm getting grants. I'm learning a lot. Why do I want to get into this?

Q: It's a chilling effect.

A: It's a very chilling effect.

There hasn't been a thing happening [with embryonic stem cells] this year. The NIH is sitting there saying, "Well, the investigators don't seem to be that eager to get into this."

Of course they're not eager to get into it! It's going to take you a year before you get any money, if you get any money -- and if you get any money, can you get the cell lines? And if you can't get the cell lines and you can't make them, what I am getting into?

I think the year has been very slow because what the president said he was giving us was a big fig leaf. It could never have achieved the goal of the Senate, which was to try to develop new therapies. And then he cuts off any opportunity of making new stem cell lines that might be able to do it. Why? Because he's offended by it.

Not only that, he and others who are strong advocates of the Brownback bill are saying as well, 280 million Americans are not going to have access to any therapies developed using this technology no matter where it was developed in the world. So if the English develop a cure for juvenile diabetes, with that bill, it would be criminal for you to try to treat somebody using that protocol.

If you think about the arrogance of it, you'd say, my god, these 500 guys sitting in Washington -- a majority of them -- have said, "We're not comfortable with this way of doing things. It offends my sensibility," or whatever. And therefore, nobody in this country can have access to this therapy.

Q: So how could privately funded embryonic stem cell research go on?

A: Privately funded stem cell research can go on. There's no prohibition on that; if you want to make cloned stem cell lines by this nuclear transfer technology, that is still possible today. But if the Brownback bill passes or the moratorium passes, they're dead in the water themselves -- everybody. Specifically, the moratorium recommendation is that not only the public sector but the private sector be prohibited.

  Q: You've been quoted as saying that you regret having the word "cloning" being used in relation to stem cell research.

A: Oh, yes. I think one of the very unfortunate things is, of course, that stem cells have sort of joined up into the cloning debate. But in the end you have to admit and say, look, we use the word "cloning" all the time. We clone molecules, we clone cells, we clone viruses, we clone bacteria. It's not a new term for us, so we live with the word "cloning."

The general public, who read The Boys from Brazil or have been given some specter of automatons marching in unison, mindless, having been created for nefarious purpose as clones -- that's what the public thinks of. So when people who are not educated -- and I include most of our congressmen -- hear the word "cloning," they can't go out to their electorate and say, "I approved cloning."

We've tried to use other terminology: "somatic cell nuclear transfer." That's what we do; that's the operation -- take the nucleus from a somatic cell, you put it into an egg and you make stem cells. The fact is that, in doing that, you're going through a stage, which is also one that, if you tried, you could try to implant in a uterus to make a person. So, the path is common up to the point where you have the blastocyst. The blastocyst is used to make stem cells; the blastocyst could be implanted to make a life.

So, we're all agreed this part of it should be prohibited, but why do you have to prohibit everything? It's reasonable enough to recognize that what we are doing is cloning stem cells. Every cell in your body is potentially an embryo. If we just take any cell from your skin, the inside of your cheek, whatever, and fuse it to an egg, we can make what somebody will call is a person.

Sen. Orrin Hatch, whose credentials on right-to-life and conservatism are unchallengeable, he's got a history going far back of conservative causes. He comes to the conclusion that a blastocyst in a petri dish is not the same as a blastocyst in a uterus. It's simple for him, it's simple for many -- when they understand it. But most people don't understand it. I gave a lecture once and people said to me, "I thought you had to go into a woman's belly and rip out the embryo in order to make stem cells." If that's the level of understanding --

If you want to have what the president wanted, to be able to cure diseases, then you're going to transplant the products of stem cells. They have to be matched to the recipient. OK? That's the name of the game. If I want to transplant parts of liver to fix up something, or your heart, I can't put in somebody else's cells. I can only do it with cells that can be matched to your type, and the only way I can make that is to start with your nucleus and make stem cells from there. It seems to me so obvious and straightforward -- except for the fact that it goes through a stage that somebody calls a "person."

Q: There are all these fears about embryo farms being generated.

A: That's the "what-ifers." You name me any technological advance for which somebody couldn't sit down and describe to you misuses -- dangerous misuses, offensive misuses. You don't see the country banning guns. Guns are used to kill.

But if you have a law that says you can't take this blastocyst beyond the 14th day and it is a criminal offense for doing so -- it's like every other thing for which we have laws to prohibit something which is murder, robbery or racketeering. We have laws. There will be abusers. When you catch them, they go to jail.

Q: What about their argument that adult stem cell research is really where it's at -- that that's the best protection for breakthroughs, that we don't really need embryonic human stem cell research?

A: There are a lot of holes in that story, and the only system which holds up in which adult-derived stem cells have been proven to be therapeutic are bone marrow stem cells and placental cord blood, which is very rich in hematopoietic stem cells. And people are claiming they can make nerve cells, brain, you name it, but would the FDA accept a therapy on the basis of a claim as unverified, unduplicated, non-peer reviewed? No way! But it makes great press to say, "We don't need embryonic stem cells."

But let's be gratuitous and all say, "OK, adult stem cells have some promise. We don't know how much. It's still vague, a lot of dispute, it's contentious -- my god, let's push ahead. Let's start studying adult stem cells."

It would be an absolute disastrous blunder to say, "Let's work only on adult stem cells," and five years down the line find out that they're inadequate. And you say, "You know, we lost five years." We can't afford to bet on the wrong one.

Q: And it could all turn out to be not as promising --

A: It could all turn out to be not as promising as we think, [but] you can already see a number of experimental lines of research that could be extraordinarily valuable and exciting.

We know today that people who inherit certain mutations have a strong disposition toward producing serious disease -- cancer in particular. You can go to a person who's born with a [cancer-causing genetic] mutation, take some skin cells and make an embryonic stem cell line which has that mutation -- and now you can begin to study what the consequence of that cell having that mutation is on successive development. Not making a person!

We know that there are lots of mutations that predispose people to late-onset diseases that come on later in life, so what is it that has to happen? Why does that take so long? So there's a lot to learn about developmental biology. Sen. Hatch had it right. He said, "Look, as far I'm concerned, right-to-life means giving life an opportunity to tens of thousands of millions -- not worrying about the fate of a small, undifferentiated clump of cells in a petri dish."

Q: You've met with Sen. Hatch?

A: I've met with him and his people.

Q: Are you actively consulting to Congress?

A: I testify, I write [laughs], I answer letters from congressmen, yes.

Q: This doesn't seem to be a big partisan issue. Like you said, you've got Hatch, Feinstein --

A: The trouble is, it is partisan to a certain extent, because Republicans in large part do not want to embarrass the president. So you've got a few people who are willing to go out. I think there are 10 Republicans who are willing to stand up and say they are willing to vote against Brownback.

Q: Are you optimistic or pessimistic?

A: You have to understand that nothing's going to change overnight for the following reason. Nobody in the academic community who has to rely on federal funds can do any work even when there's no prohibition, because this Dickey amendment that's in the appropriations bill says you cannot work on embryos.

Let's say tomorrow Brownback is defeated and the Hatch-Feinstein bill gets passed. Great. You can't clone a person but you can do nuclear transfer experiments. Bush vetoes it. He doesn't even have to veto it, because the House passed a bill, which does what Brownback would do. So, the Senate passes one bill, the House a different bill, and they have a conference. What comes out of that conference, god only knows -- dangerous ground. All the scenarios are: There's not going to be any federal funds available.

The commercial sector will do their thing, which is in secrecy. They will go only in those directions that can make money and leave unexplored or undone those things which don't have markets. That's really what I forecast.

Q: Not very optimistic.

A: It's not optimistic, not optimistic at all.

If you think back 20 years ago when IVF was first proposed -- and I happened to be at a conference where one of the developers of it from Cambridge, England, gave a talk -- he was nearly lynched. The idea that someone would have the arrogance to try to make an embryo and then implant it where you couldn't predict the outcome, and say, "God, what kinds of things would be born? Are you prepared to accept the responsibility for devastating births?"

Today, you go and talk to any audience now, particularly elderly people, they will say, "I have two wonderful grandchildren." I was talking to George Shultz, and he says, "I have two wonderful grandchildren born by IVF. I wouldn't have that if it didn't exist."

I think biomedical research is moving into territories that are going to encounter more and more of these oppositions, because when you're dealing with human life, you're beginning to deal with things that people can't even begin to articulate. The comfort level goes away.


Paul Berg

Paul Berg