Dr. Elias Zerhouni

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• SUSAN DENTZER:

  It's been almost three years now, you all have been three years and a week since the President's Executive Order was issued. Let's start by talking about what advances have been made in the science of stem cell research in this three-year period.

• DR. ZERHOUNI:

  Right, that's the most important question. Clearly, when this field started, then the mystery was, how is it that DNA–which really is the sort of code for everything a cell does–gets reprogrammed or programmed in stem cells? So how do you take one cell, program its DNA in a certain way, then it becomes a pancreatic cell or brain cell?

  The key thing was how we–not that we knew after the discoveries of Jay Thompson, Gerhardt, and others that in fact you could reprogram stem cells and direct them. You'd have to find out what molecular signals were truly responsible for that. The second is what genes really maintain the cell in the stem cell state and what genes control its differentiation. So those are the fundamental questions that we have to address, and we have to have an answer before we can even think of applying it to human beings.

• SUSAN DENTZER:

  So how far along are we in answering all those questions?

• DR. ZERHOUNI:

  I think we've made great progress. I think that if you look at the work in this laboratory, for example, and this was the original stem cell laboratory. Dr. McKay truly, was a pioneer. We have nine laboratories now plus NIH and many more in the universities that are funded by NIH, but what has happened is people have focused on the genes and molecular mockers that differentiate the stem cell that is completely undifferentiated, a stem cell that is likely to be a neuron or a pancreatic cell. So, for example, we've identified genes. There's one gene called nanog, N-A-N-O-G, which seems to be extremely important in maintaining a cell in a stem cell state.

  A scientist, for example, identified about 40 or 50 genes that seemed to be critical to the function and differentiation of these cells, and they're actively working on making sure that the, you know, that the stem cell state is understood. There's a recent paper for mingling, for example, that shows that if, in fact, two genes were to come together and activate some program which we don't know about yet, it seems that then you have a maintenance of the stem cell state which is an important thing to find out because the stem cells are grown like, now mouse stem cells, for example, because mouse stem cells seem to send signals to human stem cells about how to grow and to stay in that state that we'd like to have.

  Well, it turns out that these discoveries are indicating that we're making progress in understanding the molecular signals so that perhaps one day we'll engineer that in a much more powerful way. That's progress for me. Clearly, a lot more can be done. We need to understand how these cells turn malignant because they have the potential of turning malignant, and how to present them from turning malignant we have to understand how they integrate themselves in the organ that we want to repair. That's an important question, and Dr. McKay here, for example, have found ways of making neurons that produce dopamine and the question, then, is how do these integrate within the diseased areas that we want to repair? And how is it not rejected by the human body? Those are all the questions that are right in front of us at this point.

• SUSAN DENTZER:

  Now, a great deal of the controversy that has ensued since August of 2001 has been around the question of how many lines, in fact, were–

• DR. ZERHOUNI:

  Right–

• SUSAN DENTZER:

  –had earned presidential authorization, because they had been derived before–

• DR. ZERHOUNI:

  Well, I think it's important to go back to the genesis of it. I mean I always like to be factual about things, and let's remember where the president was when that happened. There had never been funding of human embryonic stem cell research before. The prior administration, no one had funded this field, and for the reasons that you know, there's a tremendous amount of polarization about the issue of embryos and using embryos for research. There were amendments in Congress that prevented this research from happening.

  So the president had to make a decision. On the one hand, he believes very strongly that there is a moral imperative of not using federal funds to promote the destruction of embryos. On the other hands, you know, you know patients, I know family members who may benefit, and there's a beneficence issue. So he made the decision and said, "Well, I don't want to use federal funds to destroy embryos. How many are there out there in the world that have already been destroyed, that don't have the potential for life?" And the answer was at that time 64. Then we found seven more, so there was 71. And he said, "Well, those I will allow federal funding for and any other I will not."

  At the time when the 71 embryos were–had been destroyed, they had not expanded into cell lines. I think you've seen with Dr. McKay how, what it takes to do it, I mean to multiply them. And you need to have enough of them to be able to send. So in 2002 we had one line that was available for research. Today we have 21 lines. Of the 71 that we have identified as eligible for federal funding, 16 did not expand successfully because it happens, you know, these culture techniques are very difficult, very experimental, and 21 did, and we have two more, and about 31 are still in preserves waiting for new developments to occur.

  The question, obviously, is, is this enough, or can we sustain the research that needs to be done at this point? That's the core issue. Right now what we see is, we see a marked increase in the activity of stem cell research here. I think we've funded about $10 million in 2002; $25 million in 2003 alone, and growing as we go forward in making

  ommitments or expending the investments. Scientists are coming to us and saying we want those cells. They've been shipped to a lot of laboratories. Here at NIH we've built a laboratory that Dr. McKay runs to characterize all the cell lines that are available, and it's not clear how many lines you really need at this point in time, and we are still evaluating that. There are still issues that need to be worked out.

  But it's fair to say that from a purely scientific standpoint, you know, the scientists who are making the point about more lines say, well, the experiments that we'd like to do but just can't do with the one lines that we're already deriving (ph) in 2001. And that's a valid scientific point. But the problem is, you know, this issue that comes at the intersection of science and society, and I think the president wanted to walk before anything else and understand that he has an interest in advancing the basic science and feels that it's important also not to force the use of taxpayer funds for something that many people object to.

• SUSAN DENTZER:

  So you're saying, in effect, that if science were the only objective here, we'd have a lot more lines.

• DR. ZERHOUNI:

  Again, there's nothing that evolves in a vacuum. I think you have to have a consensus, that, you know, federal funding is coming from taxpayers, and taxpayers express their wish. And this is the issue. These are the core issues of when is it appropriate to use taxpayer funds to do something that many have found objectionable, that no prior administration had ever funded. That's the core issue, and I think we need to be factual about this. The message I tell my scientists everywhere, said mostly we're a science agency. We want to accelerate this field while we're remaining factual, not factual nor fictional in terms of promising things that–that may be exaggerated.

• SUSAN DENTZER:

  Specifically, on the issue of the potential need for more lines, the number one argument seems to be that there will be insufficient genetic diversity in the lines that people want. What is your perspective on that? What is the ultimate–

• DR. ZERHOUNI:

  The answer, it's an argument that you hear, and it's certainly a valid argument to pose. The question is, when is that argument going to be very critical. Genetic diversity is an issue that become very important if we have found the way to use these cells in different populations. And the only way you can make them transplantable, if you will, without rejection, without being, you know, rejection becomes tissue matching. So if that's the case, then you need to have a–just like we do in bone marrow transplantation today, you need to have a matched cell. So that, certainly, from a scientific standpoint is something we need to evaluate, and at this point no one knows whether we'd be able to devolve, like the universal donor cell, like in blood, you know, when you are O-negative blood you can't give to everybody. So we don't know that yet. But it's certainly a valid question from a scientific standpoint.

  And again, we–we have been very careful to say, look, everyone is free to do research that they wish to do to demonstrate the different anatomy of research that is not demonstrable with the federally-funded lines, using private funds in parallel. And we do not–there's a misconception out there that if you use federal funds you can't use private funds. We've been extremely collaborative with the institutions to make sure that they could conduct the research in parallel, but with private funds.

• SUSAN DENTZER:

  The big criticism that we heard –in fact, we heard it again yesterday from Jamie Thomson–is that the number one problem with the president's policy isn't so much that it's been an actual barrier to the conduct of research, but rather a perceived barrier to the conduct of research; that scientists are worried that there's a cloud over this; that federal funding in the future might be insecure; that our younger scientists have been reluctant to stake a claim in this area of research; that institutions don't want to get out in front on this.

• DR. ZERHOUNI:

  Yeah, I hear that, too, and, frankly, you know, personally, you have to compare that to a base. We have no base of scientists in 2001 who–that have never been funded, so what has happened since? There are a very small number of scientists who knew how to work with stem cells. As I said, we had one laboratory here, and now we have nine. If you look at the demand out there of the number of grants that went from zero to 120, we have funded many new investigators in the field. And we have no lack of demand of people coming and saying, we want to do some lines that you have, we want to work with them.

  But they also–there is also a time lag in terms of training. So the question is, are people seeking training in this field? And that's what I've told our staff to track: How many people are signing up for training courses? So we have five training courses, they're booked solid, double booked. So that tells me that there is a huge interest.

  When I talk to the directors of laboratories who do stem cell research, remember, most of the stem cell researchers in this country, if not all, are funded by NIH, so we know a lot, and when we talk to them, we say, do you have problem attracting post-doctoral fellows who want to do the course of study? They don't record that, they say they have a lot of candidates that come. The question is, is this enough of a base, and are we going to grow the base to the point where we have critical mass that is going to look at that size relative to the applications. So that's a tough question to answer because you really don't know what is the normal trajectory. But what I can tell you is that based on the data that we have, there is a great interest; our training courses are solid; there's demand for the federal cell lines; there's demand for federal funds, it's almost doubled in one year between '02 and '03, and we're continuing.

  We're putting in a national stem cell bank because the researchers are telling us: We need easier access to quality cell lines. We're organizing symposia. We had like 40 people three years ago. The last symposium was 1,400 people at these meetings. Last year it was 600. So it's hard to prove that there is, in fact, such a dampening effect, but I wouldn't question that, in fact, this is potentially an issue. I don't dispute that, but I don't know what the evidence is.

• SUSAN DENTZER:

  The other point of concern that is raised is that much of this research is going to flee or has already fled overseas.

• DR. ZERHOUNI:

  Right.

• SUSAN DENTZER:

  And some people pointed to the fact that it was the South Korean researchers who first did the schematics of nuclear transfer to creative stem cell line is something that would have happened here had the policy not been what it is.

• DR. ZERHOUNI:

  You know, it's a very typical saying about science. I mean scientists do not want to have restraints, fundamentally, to the kind of experiments that they think may be of benefit to patients. Society, on the other hand, always says, well, we want to do this, but–and provide the benefits–but in a way that does not jeopardize some of our moral beliefs and ethical beliefs.

  So in the case of going overseas, we again cannot see that in, you know, factual terms. For example, in the United States is the country with the larger number of widely available publicly-funded cell lines. Everybody brings the example of England, so I'm very aware of the policies there which are, obviously, different than ours, but how many lines are available in England? And the number is either one or two, depending on the last status. They use a lot of our lines to do the research, and every time they need funding they have to go to a federal–I mean a government license to do it.

  So when I look at publications, there's still the largest number comes from U.S. laboratories, patents, and it's something we have to be sensitive to, and we are. And we are carefully monitoring that situation to see if, indeed, there are fundamental advances that are escaping us. But at this point I don't see patents that are, you know, coming out away from the U.S. or publications coming out in disproportion. And I don't know if the examples–I can tell you examples both ways–we have scientists from overseas that are flocking to our laboratories here to do science and stem cell research. And of the scientists that I know about –Dr. Peterson, who went to England from California because of the, admittedly, because of the restrictions. So again, it's not a clear picture, either way, but a picture that we are monitoring and are more sensitive to.

• SUSAN DENTZER:

  You brought up the stem cell bank.DR. ZERHOUNI: Right.

• SUSAN DENTZER:

  Tell me what NIH is proposing to do and why.

• DR. ZERHOUNI:

  Right. Okay, this is a–this is something that came out of the symposium that we ran into, and when I became director of NIH, one of the things that I was asked to do was to make sure that all the progress that can be made in stem cell research is made. And that was directly from President Bush. He said, "I don't want any restriction on the funding of this research of what we can do." His restrictions are based on the number of lines that had been already, embryos that had been already destroyed in terms of potential for life. That was his position.

  So I put a stem cell task force together, and we monitored what was happening, because, you remember, these lines don't belong to the federal government, they belong to private sources. So the first thing we did is we said, if you're willing to expend those lines and make them widely available, we'll be willing to fund to the culture facilities, essentially, and we did. So we have nine infrastructural grants to different sources. And that's how we went from one line in 2002 to 21 into 23. That's what happened.

  However, when you do this, and you realize how tricky and difficult the culture of these cells is, number one, then you realize that you need qualify control; you need comparability.

  The second is what–what we did here at NIH over a year ago. We said, you know, nobody knows exactly what the line A better for than line B, and we don't really know what the characteristics are. And nobody knew exactly how to characterize them, so Dr. McKay is doing that now for 10 lines. And we thought then, heard from the researchers, you know, the single point of contact with good technical support that helped us, if you will, and good characteristics of the line with standardized method would help us, because then will be able to compare results, and we will be able to pick which of the lines is better for diabetes research, or Parkinson's disease research and so on. So we're responding to the need that the scientific community has identified and that we at NIH have identified as well, and doing that in a way that, hopefully, will continue to facilitate both quality cells and easy access to these cells, which is what is needed right now.

  We need more experiments to be done to understand what I told you about the molecular signals that reprogram DNA is what we need to know.

• SUSAN DENTZER:

  Now, to help our more general interest viewers I'd like for you just to explain two things quickly.

• DR. ZERHOUNI:

  Sure.

• SUSAN DENTZER:

  When we say "stem cell line" often people are confused about what that means. What does it mean?

• DR. ZERHOUNI:

  All right. "Line" means that it's a series of cells that have come from one single embryo. Now, the way it happens is embryos grow, and there are–there's a sub-population of cells early on which have the potential to turn into any organ cells. It could be neurons, it could be heart cell, it could be anything. And when you take that little group of cells, you then expand them by multiplying them in culture. The whole population of lines that comes from–of cells that comes from single derivation is what we call a line. So there may be billions of cells in the line, you see, because it's coming out of this number, one single embryo, and it's derived from that. And that's what we mean by lines.

  So a line means you can have billions of cells coming of one line, and we have 71 different lines that came from 71 derivations that have been already done by August 9, 2001. That's the basis of the public policy and the description of the lines, as we speak.

• SUSAN DENTZER:

  And you used a word earlier that's commonly used in this field, to "characterize" the lines.

• DR. ZERHOUNI:

  Right.

• SUSAN DENTZER:

  What do scientists mean when they talk about characterizing lines?

• DR. ZERHOUNI:

  So "characterize" is exactly saying, for example, if someone is six feet tall and can run 10 seconds for the 100 yards, you know, that's what we mean by characterization. What are the molecular characteristics of the cell that tells us that it is likely to be stem cell, or it's likely to have characteristics of a neuron cells, a brain cell, or pancreatic cell, or muscle cell. So these markers, these molecular signposts is what we call "characteristics of lines."

  And we need to have, essentially, almost a registry of them. And so line 3 is very good at doing this because it has these markers and this definitely is stem cell, but, oh, by the way, it's no longer a stem cell because, see, it has a marker here that shows that it's already a neuron. So don't try to make that one into a pancreatic cell. Do you see? This is–we're filling in the puzzle is purely what this exercise involves.

• SUSAN DENTZER:

  Has the president–we know, of course, there have been a number of meetings with members of Congress, with people in the Oval office in the White House, to discuss this policy and evaluate it over time, to discuss whether it should evolve. Has NIH been specifically asked to give some advice about some of the specific legislative proposals to evolve the policy?

• DR. ZERHOUNI:

  We're constantly asked to provide scientific updates on what is happening in sciences. I constantly provide the Department or the White House staff with information about what is happening, what are the issues. For example, the issue of small stem cells came about, so the question comes up, so is this really a sine qua non or absolute no-no? I mean should we not do any research on these? And we then go back and provide that information. So there is a constant stream of informational requests, information hearing about the scientific field.

  In terms of legislation, it's not a role, really, to develop legislation

• SUSAN DENTZER:

  Right, understood.

• DR. ZERHOUNI:

  Right.

• SUSAN DENTZER:

  But in terms of commenting, for example, one of the popular legislative proposals now is to at least allow federal funding of work that could be done on newly-derived stem cells. Those would not be derived with federal funding, but they would be newly derived from embryos discarded at IVF clinics–

• DR. ZERHOUNI:

  Right. When that came up, we said, "Okay, give us an exactly what happens in an IVF process, for example. What are the proposals talking about?" And we're very good, if we do not know the area information about getting the information and describing exactly the process. For example, if in vitro fertilization, for the White House and the president to understand the details of that. So that's what we do.

  And we've been asked to do that, obviously, to support the analysis of the policies.

• SUSAN DENTZER:

  You wrote a letter in response to some lawmakers this spring in which you said, as you said earlier, that from a purely scientific perspective–

• DR. ZERHOUNI:

  Right.

• SUSAN DENTZER:

  –there's a clear argument in favor of more lines.

• DR. ZERHOUNI:

  Right.

• SUSAN DENTZER:

  The more lines the better. And a lot of people read that as your perspective being that the policy should evolve in that direction.

• DR. ZERHOUNI:

  Yeah.

• SUSAN DENTZER:

  Could you clarify what meant by that?

• DR. ZERHOUNI:

  There was a lot more that was read into it. Typically, you know, in Washington you write something, and it's interpreted 10 different ways. What I wanted to do there is really reflect the administration's position that, you know, we want to be factual about this. The administration and the president did say, "I am absolutely convinced that all science can be done with my policy." This was portrayed by others as being the president.

  The position of the president was not that. It's, you know, we recognize that other things may need to be done, but they'll have to be dealt with with private funds. His position was, you know, his policy was predicated on his moral and ethical position: "I just don't want to use federal funds to encourage or, you know, stimulate destruction of embryos any further than what has happened before August 9, 2001."

  So I'm the scientific director of–I mean a scientist and director of NIH, and my job is to provide factual information, not distorted information. And it's clear that in that sentence I'm extracting facts; that if you talk to any scientist, other experiments you could envision that you could do with cells that, yes, you can. Would they be helpful? Who knows?

  And so it's a statement of fact, and it's not a statement of, you know, policy-setting, because policy is not set by me, it's set by the president.

• SUSAN DENTZER:

  Of course, this has become a very political issue, and just this past week–

• DR. ZERHOUNI:

  Sure.

• SUSAN DENTZER:

  –the convention, among others Ron Reagan, Jr., gave a speech talking about the ability of individuals to have a personal, biological repair kit at the local hospital that would, essentially, be embryonic stem cells. What is the actual status of the applicability of all of this to patient care? How soon might we actually see some results in that vein?

• DR. ZERHOUNI:

  I'll tell you, if you ask scientists who are not involved in factions about this, who really think about it, thoughtfully, and know from prior experience what it takes to develop a new line of therapy of any kind, we know they are confused. Even a simple drawing that would be developed today would take 10 years, 12 years before we can truly make sure that it's safe and effective and so on and be approved and so on.

  So it's a little bit–we–I just want to make sure that we provide the information and make sure that hope doesn't go ahead of the science here, because then it becomes hype. And I'm concerned about the over-promising. So when you ask me that question, I want to be very careful. We are going to accelerate the understanding of the very basic steps that need to be resolved before we can even think about what form of therapy and how. That's my job; that's what I'm trying to do at high speed.

  And how many years that's going to take, it's impossible to predict. But, if you, just for example gene therapy, genetic therapy is something that came about 20 years ago, very promising. It's been successful in a few applications, a limited number of patients, but it's not yet widely successful. So I don't like to underestimate the difficulties, but I also, like everybody else, I'm a physician, I want to cure people's ills. And so we're all very hopeful that we can find a shortcut some day and make it happen. But it's years, it's not weeks.

• SUSAN DENTZER:

  Coming back to the point about the grants that NIH had given out, you said $25 million, roughly $25 million for '03.

• DR. ZERHOUNI:

  Right.

• SUSAN DENTZER:

  We don't yet know what the total will be for fiscal '04.

• DR. ZERHOUNI:

  Right.

• SUSAN DENTZER:

  But as I understand it, there's no upper bound on the amount of money that NIH is willing to put into this.

• DR. ZERHOUNI:

  That's a–that's another misconception out there that I hear a lot about. It's not factual. There is no limit of funding, and there is–the president has not banned any funding for–for, you know, in terms of the amount, has not limited the amount of funding that we could dedicate to this area of research.

  And again, we're looking at it in a wide–with a wide spectrum. We're looking at embryonic stem cells, cord blood, we're looking at adult stem cells. No one at this point who is truly looking at the science can tell you where progress is going to come from. So we need to invest across the board, and there's no limit on our investment itself in that regard.

  But there's a limit in the sense that we want quality research to be done, so we have quality applications, we fund them. We have applications that do not pass the scientific quality test that we have here at NIH peer review, which is done not by NIH scientists; it's done by outside scientists who are independent from the government, and they tell us: Look, this research is just not of good quality for you to spend federal dollars on that we want. By, by and large, all of the top scientists in this field I hope have been funded now by NIH since 2001-2002.

  So the issue is not funding; the issue is access to federal funding for material, a new set of lines. That's the core issue.

• SUSAN DENTZER:

  There is a perception, and I would say probably even a growing perception that if the president is re-elected that policy will be revisited after the election.

• DR. ZERHOUNI:

  Well, I wish I could read his mind, but that's not the signal that–I mean the president's very clear that today his policy is based on his moral and ethical beliefs, and he's restated that. I don't know what the perception–there are always perceptions in politics, as you know, but I can't speculate on that.

• SUSAN DENTZER:

  And you have no information that would suggest that that's the case?

• DR. ZERHOUNI:

  No. No.

• SUSAN DENTZER:

  Nor does it sound as if you are expecting that that is the case.

• DR. ZERHOUNI:

  No. That's sort of above my pay grade, really.