"This transcript has not been edited or corrected, but rather appears as received from the commercial transcribing service. Accordingly, the President's Council on Bioethics makes no representation as to its accuracy."

FIFTH MEETING

DR. BALDWIN: Thank you, Dr. Kass. I'm very happy to be here and to tell you how I've been keeping myself busy in implementing this policy. Let me go through a little bit. I don't have handouts of the overheads, but I'd be happy to leave the overheads if you'd like. I don't think I have to go into much detail with this group certainly about what the embryonic stem cells are, their unique properties, their ability to proliferate, and the capability of forming other kinds of cells. So that has importance for basic science understanding of what cells do as well as our anticipation of clinical application as well.

There are many areas that we feel are major questions for us to think about where stem cells are going to influence how biology is done and what the importance will be. Our major activity right now has been to implement the policy that was put in place last August 9th. So the criteria for allowing research with federal funding on human ES cells is shown on this slide. I think we're probably all familiar with this.

They had to have been derived from a blastocyst that was initiated prior to the President announcing his policy. The embryo had to have been created for reproductive purposes and no longer needed which means it came basically from IVF clinics. There had to be informed consent from the donors to use these cells with no financial inducement for the donation.

The way we're implementing this is that having established these criteria our first job was to complete the documentation and ensure that we had documentation, that the available lines met these criteria, and then to post a registry. Once we did that then an investigator could go to the registry and identify a line that they wanted to use knowing that it met the President's policy. So this is front-loading if you will that review process.

On November 7, 2001, we published the NIH Registry. I've given you minimal handouts. You must have 150 pounds of paper to carry back with you. Your handout from me is one single sheet of paper, two-sided. On the front, it shows you the registry. On the back, it shows the stem cell site on the NIH website that has every conceivable document. People are looking around like they don't have it. Do they have it?

CHAIRMAN KASS: I'm afraid there's been a slip up.

DR. BALDWIN: We will get it to you.

CHAIRMAN KASS: Does anyone have these?

CHAIRMAN KASS: They're coming right now.

DR. BALDWIN: Once you go to the stem cell section of the NIH website, basically all of our documentation, information, et cetera is there and is updated regularly. It took us a little while to get the registry up. We wanted to be sure that we had developed it in a way that would be user-friendly and that we had unique codes for the different stem cell lines. It went up November 7th. Then what we did was we started to put in place the things that would be needed for investigators to make use of the registry and actually obtain funding to do this research.

The first thing we did was to realize that we had amissed the posting of the registry so that people could come in for our October 1 receipt date. NIH has three rounds of application receipts. So what we did is extended that receipt date so that anyone who was sitting there poised to do this research still had an opportunity to get an application in.

We then moved on to issue and announcement for Infrastructure Awards so that we could reach out to the sources so we could help them be sure they were actually going to be able to provide stem cells for the researchers who wanted them. We moved on to Administrative Supplements. I'll go into these in a little more detail, but it shows you how almost week by week we were putting in place one or another element that was necessary for us to actually fully implement this policy and make it a reality for the research community.

So Administrative Supplements, Training Potential, all of these pieces. The implementation job was really taking the policy and then saying what are all of the different steps that have to happen to make this actually really work. Let me go back to that one in a minute.

The last one on there is we announced the procedures for how you could use the process that's in place for having research done on human embryonic germ cells. In May 20th, we had the first review of such an application. That's the companion to the embryonic stem cell activities.

As of July 5th when the slide was done, we had made five of these Infrastructure Awards, 13 Administrative Supplements, and one Grant Award. That I think people can look at and say one award. How can this be? But there actually is a fair amount of time that takes place between submitting an application to us, going to scientific review, going to an advisory council, and an actual funding decision made, and an award made.

What you're hearing here is our taking that policy and mainstreaming it in to how NIH does business. We have very sound principles as to how we do business of transparency and peer review. We're bringing stem cell research into that process. At the same time where we've identified what might be a gap or a hurdle or an impediment, we're trying to reach out to that as well whether it's a need for training or a need for infrastructure support.

A few features of this registry. We are listing all of the cells that meet these criteria. You may be interested to know that we've added lines since the President's statement because we found six additional lines that met these criteria. The registry serves two very important functions. It provides a code for each of these and provides the contact information because an investigator that wants to do this research goes to the registry, identifies a line, and then gets in touch with them.

This is the content of the registry. When you go to each one, this is what it looks like if you go to it on the web. You can't read that on the screen. When you click on any one of these sources, you go to a slash screen that's for that particular source. This one happens to be WARF. You'll see that it gives you contact information, e-mail information, their website, and the information about the cell lines that are on there. That is information we're asking the sources to keep up and keep current because it is their information.

What have we found to be the issues for researchers? Well, first is the simple access to the line. Are there intellectual property issues, IRB issues, administrative ones, and ones relative to how they're going to actually get the skills to work with these lines? Let me take these one at a time.

There have been questions as to whether these cell lines are actually available. I think it's important to realize that human embryonic stem cell work is relatively new. Because this was not an area available for federal funding prior to the President's statement, they are largely in foreign sources or commercial entities. So many of these groups were not at the outset thinking about supplying the scientific community. That's why we put infrastructure support out there, so that each of the sources can come to us and apply for funding to help them scale up, better characterize their cells, and make them available.

These are the awards that we've already made. (Indicating.) It's on a rolling receipt date though. It's something that we'll continue to do as long as we have sources that need infrastructure support in order to make their lines available.

There are of course many things that can affect easy access to these lines. In some cases, we have international issues. There's been a change in terms of whether biologic material can be shipped on a passenger airplane. I can't sit here and tell you that it's all simple. This is not Amazon.com where you can just click on it and it comes by FedEx the next day. There are things your investigators have to do in order to get access. They're not qualitatively different from other fields, but they are important in this case.

All of these lines have intellectual property issues associated with them. As I said by enlarge they are either commercial sources or they are foreign sources. There is a U.S. patent on the derivation method. In fact, the sources have to work out their intellectual property agreements in order to make them available.

NIH did something that's a little unusual here. We of course would have to negotiate a memo of understanding for our investigators to have access to these lines. We did the first one with Wisconsin with WARF. What they said was not only would these terms be available to the NIH investigators but they would make them available to other investigators.

That's important to realize because the NIH doesn't get involved in the negotiations between a source and a user. That's their responsibility. But what this has done is made it much easier. In fact, you can go to the website. Those memos of understanding are all on the website. An investigator can just download that, click on it, read it, take it to their tech transfer office, and if they can accept the terms which are pretty straight forward, they're ready. They don't have to negotiate this from the ground up as it were.

We now have four of the MOUs that are available on the website. I'm walking you through each of these steps because I think it's important to understand the different pieces of this puzzle that had to be put in place so that this whole area of research would actually take off. Some of these sources may initially want to start out doing collaborative arrangements, and others are further along in their development and are more ready to make them just generally available. That was clear at the outset that we would have that kind of variability.

This is the flip side of the handout which is the stem cell information site which is absolutely essential if you're interested in this area of research. On it, you will see all of the MOUs are there. We run a Frequently Asked Questions section. We update that as soon as we have anything new to put out there. Background reports, background material, anything a potential investigator or a funded investigator would want to know. We're trying to make it one stop shopping so that it is all out there and pretty easily accessible.

In terms of IRB issues, all of these lines had documented informed consent for the donation of the embryo. One of the follow-on issues though was do any of these lines include identifiable information or not or are they completely anonymized. We worked with the Office of Human Research Protections to clarify the guidance about when IRB review is needed if there is identifiable information anywhere. In fact, this document which of course again is on the website clarifies that there can be a firewall, either it's anonymized or the person receiving the line has no potential to get access to any identifying information then that streamlines what they would have to do within their own institution. OHRP, we would not be requiring IRB review of the use of that line. Grantee institutions may of course have some additional requirements.

There were questions raised about administrative issues in terms of how to think about the facilities and administrative costs if there were eligible research and ineligible research going on to the same institution. Again, we felt that there are already very strong and existing policies about unallowable research. The institutions know how to handle financially unallowable research. Basically this just clarified for them how to do that, again to mainstream how this issue is handled relative to other areas of unallowable activity.

We have this as an administrative issue. I'm not sure that it is. Most research when it comes in it goes through peer review. Reviewers are really looking for preliminary data. In a new field, that's particularly challenging. If it's a brand new field, you may not have preliminary data.

We've taken two tacks there. One is to now just have Administrative Supplements available, but to really go a little further step to advertise their availability. What that means is if you're already a funded investigator and let's say you're working on mouse ES cells and within the basic scope of the research you could add on some work in human ES cells, you can come to the NIH for an Administrative Supplement. They're modest in dollar support, about $50,000. They're handled administratively. But it is a way for probably our most promising cadre of investigators to get started in this field and be able to help develop some preliminary data. We've also tried to deal with that at the stage of review in terms of reminding people that this is an area where it's much more difficult to have preliminary data when you first come in.

One of the difficult issues for us is these are not necessarily easy cells to work with. We've looked at what the need is there. Everyone who has worked with human ES cells has pointed out the need for very careful, meticulous laboratory work and that there's a high degree of variability across labs and culture conditions. So again, we've looked at what would be the tools that we could put out there to help investigators develop those skills.

In some cases, they will get them through the acquisition process. So a source might package some training along with acquiring the cells from them. If you go to them in return for the price of getting the cells, you would also get a couple of days of on-site training for maybe your Senior Lab Technician. But we're trying to look broadly at that. We have an announcement so that an individual investigator who really wants to specialize in this area could come in and apply for funding or an institution that wants to focus on doing some short term training activities that they would make available to others could apply to us for support.

Again, this is really taking the tools that we already have. We already know how to work with a community to build skills when it's necessary. We're just focusing them and applying them to this particular area of science.

The information has been very widely disseminated. Now, we think it's been widely disseminated. Just because we think it's widely disseminated doesn't necessarily mean that it is. I get 350,000 or 400,000 hits a month on my website where this is located. We get more on the NIH website. You can access it right from the nih.gov site.

We know some professional associations have been pulling up those Frequently Asked Questions and sending them back out to their constituencies. One of the things you can certainly help me with is if you can think of any other strategies that we might use to make this information widely available. That appears to do it. I wanted to go through that fairly quickly so that you would have a chance in my time here to ask questions. If anything that I've gone through was either too quick or didn't make sense, please ask me now.

CHAIRMAN KASS: Dan Foster and then Janet.

DR. FOSTER: I don't work on stem cells. One of questions I think fairly broadly asked in the scientific community regarding the research is given now the 80 cell lines, how many of those are in some sense adequately characterized to be useful in research. You know much better than I do, there's been considerable skepticism about the adequacy of these cell lines for the research that we want to do.

DR. BALDWIN: Well, it's a little difficult to give an exact number. It's certainly in excess of two dozen on there and are pretty well characterized and we know they're available. I understand the question. I understand the concern.

I think that we're equally concerned to see that investigators do get started working with the lines that are available. That's going to be the best test of how good those lines are. We won't know until people use them and test them and compare two lines from different laboratories.

There's a tremendous amount of basic work that simply has not been done. While that's certainly an interesting issue to pursue, I'm at the implementation side. I'm asking are the grant applications coming in. Are we funding it? Are we building up a base of knowledge about those lines? I think we really have to do that.

DR. FOSTER: Well, I think that's probably the only answer you have. We oftentimes say the only way you can answer these questions is to do the experiments. We had been talking about that earlier today.

DR. BALDWIN: Exactly.

DR. FOSTER: I think just myself that you've done a wonderful job on this infrastructure so far.

CHAIRMAN KASS: Janet, would you like to begin?

DR. ROWLEY: Well, I'd like to carry on with the first question that Dr. Foster asked you. Backing up just a bit. Have you or have you in conjunction with the sources come up with a set of standardized procedures that you're going to do to characterize these lines? Is everybody karyotyping their lines and doing some molecular analysis of them and what kind of studies have they done for longevity of the lines, et cetera?

DR. BALDWIN: First off, the next enhancement if you will of the registry is to encourage our sources to provide additional data. The sources vary as to how much information they have and how much they're posting on those websites. To encourage them to go ahead and site either their published articles or the research that's being done with their lines, that's the area of enhancement that I'm looking for next.

The next area I think will be for us to bring those sources together. They really form a very unique network. It will be bringing them together really as a group that I think would be most valuable, for them to share their experiences as to the most valuable information or where their information appears to be discordant. We've just made those awards within the last 60 days, so it's just a little early for that. That would be the approach that I'd be inclined to pursue.

DR. ROWLEY: In terms of the Infrastructure Awards that you have made to individuals, you indicated in your very brief overview that you are asking or providing financial support to the sources to do some things.

DR. BALDWIN: Exactly.

DR. ROWLEY: I guess the question is in your infrastructure grants is there some commonality of information that you are hoping that they will use that support for to provide answers to some of these questions. Or is it just you have X number of cell lines and it costs X amount to do something.

DR. BALDWIN: No. It's not that. But the first way that you phrased it, I think it would leave the impression that we're saying here's a list of things we want to see, do each of these with each line. We really haven't done that. They have come forward, not just give us money and we'll do more, but to say what they will do and that goes through peer review to say is that an appropriate strategy and are they going to be useful tests.

I guess my experience has been especially in a new field bringing those investigators together so that four or five of them sit down and say here's the way I'm going to do this and here's the information that would be valuable. Having them talk that out to drive it toward some common sense of what is the most appropriate or the useful measures is usually preferable to us saying at the outset the specific ones we want to see.

I know that's a taste in preference. Some people like a little harder edge at the outset. I guess my experience has been I prefer to draw some of that out of our sources as opposed to imposing it on the outset. But I understand your question.

DR. ROWLEY: You're aware of the article in Nature suggesting it be some of the cell lines. Presumably all of these are grown on mouse feeder cell layers or virtually, a number of the cell lines are grown on --

DR. BALDWIN: Many, yes.

DR. ROWLEY: So that the possibility that there are mouse-human hybrids is real. Those would obviously have limited or no usefulness for the kinds of investigations that many people are interested in. I guess I'm a cytogeneticist, so the first thing we do for cell lines is karyotype them.

DR. BALDWIN: Yes.

DR. ROWLEY: I would have thought that it would be an important early parameter for the study section to have required that each one of the grantees do.

DR. BALDWIN: It is. I think what you're raising to me may be one of the things that we could do would be to extract from those Infrastructure Awards a little more of the vision of what the sources are proposing to do even in advance of them having the results and having the data to post. Obviously the abstracts are available. But we haven't thought about doing that as an extract to see where that common sense of the group as to the most useful activities would be.

They have latitude under a grant application. It isn't that they're locked into doing one thing. If six months from now it's clear there's something valuable to do, they could add that to it. That would be a very useful suggestion for this. I think I see something to go back and do.

DR. ROWLEY: Okay. Let me just pursue two other aspects of this. I think it's marvelous that in your dealings with the sources that you have made arrangements for other investigators to get some of the same kinds of expedited access to the lines under the memorandum of understanding. I think that's marvelous because certainly these material transfer agreements can be painful and to do each one for private investigators is difficult.

You raised the question of cost. I wonder is there a fair variability. It seemed to me that as we were approaching WARF it was several thousand dollars to get a single cell line.

DR. BALDWIN: Because of the network of agreements really, I think that's going to be pretty standardized, the $5,000 for access. I'm talking about academic researchers not anyone who is accessing for commercial purposes. Then you can't just download an MOU and go to work. That's very different if you're setting out to develop them for a commercial activity. My interest is here, what we can do for the basic research community.

DR. ROWLEY: Now, also in dealing with WARF, the MTA did include statements that any discoveries we make with those cell lines the intellectual property reverts to WARF. I don't know whether in more recent memorandum of understanding whether that's --

DR. BALDWIN: (Off the microphone.)

DR. ROWLEY: Okay.

CHAIRMAN KASS: Could I just ask a question because this is an important question to lots of people? Could I have Janet ask the question again and could I hear the answer again so I know what we've just had?

DR. ROWLEY: Well, I was raising the question that it was my impression that as we approached the Wisconsin Alumni Research Foundation that were we to buy the cell line --

CHAIRMAN KASS: Right.

DR. ROWLEY: Which is $5,000 and we did research with it, any intellectual discoveries that we made then became the property of WARF, not of us. There are a lot of these MTAs that have what are called pass-throughs. This was the question. Whether I was mis-remembering or whether possibly your memorandum of understanding is maybe a bit different than I recall from maybe four or five months ago because I haven't paid attention to this recently.

DR. BALDWIN: I don't think that has changed in that time. I do have a copy and I'd be happy to leave it with you. I think you may be thinking of when you're obtaining the cell lines for a commercial development.

DR. ROWLEY: No, because this is strictly university research. That's an important issues as to whether as you are making new discoveries they're your intellectual property or reverts in some way to the source of the cell lines. The fact that's not part of this is I think excellent. I assume that as people come in with R01s that the cost of the cell lines and things can be included as costs within the grant.

DR. BALDWIN: Oh, absolutely.

CHAIRMAN KASS: Again, just for my clarification. I gather the answer to that question is that reversion applies only if these things are sold to commercial organizations and not to university researchers. Is that right?

DR. BALDWIN: Yes.

CHAIRMAN KASS: Okay. Thank you. Janet, are you complete for now?

DR. ROWLEY: Yes.

CHAIRMAN KASS: Thank you. Rebecca Dresser.

PROF. DRESSER: I wanted to ask about a couple of things. First, I was interested in how you decided about whether the informed consent requirement had been made in some countries far away. Did you ask for just some documentation or how did you approach that?

DR. BALDWIN: We had documentation from all of the sources. We also had visits to a number of the sources. All of the sources at the time the registry first posted had come and visited at the NIH, so we had discussed these things with them specifically. We also have had visits to many of these other labs. So it's not just a paper review. It's primarily a case of them presenting the documentation which is always the case. That's the heart of it. But we have gone further than that.

PROF. DRESSER: Right. I understand. The other thing I wanted to ask about is a little bit off the track but I understand that Dr. Gearhart recently got an award to work on stem cells from fetal tissue.

DR. BALDWIN: Right.

PROF. DRESSER: And that it went through a review process under the earlier NIH guidelines for stem cells which applied to both embryonic stem cells as well as fetal stem cells.

DR. BALDWIN: Yes.

PROF. DRESSER: So I understand that it went through a review process, and all the very detailed requirements were met. I wondered if that was the same review group that reviewed that protocol as the one that was earlier put up during the prior Administration, the group the Janet Rowley mentioned this morning.

DR. BALDWIN: You mean the composition of that review group.

PROF. DRESSER: Right.

DR. BALDWIN: No.

PROF. DRESSER: How did that work?

DR. BALDWIN: Let me explain what happened there. We had these guidelines that covered both derivation from germ cells, from fetal tissue to generate the embryonic germ cell lines and also for embryos. So the expectation had always been there would be more interest in the embryonic research at that point. A group had been put together, but it had never actually met and functioned.

So when the President's policy came along that really superseded this whole section on embryo research. So we rescinded that portion of the guidelines. But the only rescinded that portion of the guidelines. We left in place prohibited. We left in place the fetal tissue side of it. Now we had a very different creature because we knew the scope of that would be much narrower than was originally construed.

So we basically went back and rebuilt that process. I mean, we didn't change any of the elements of review. We didn't change any of the rigor. But we did make that an internal NIH review. Obviously dealing with appropriate conflicts of interest so that there was actually someone who would be on that group who would have been from the funding institute. We had them absented from that review because of potential conflict.

But we took that group which was very mixed in terms of their science background, ethics background, et cetera, to review that proposal and to align it with the guidelines that were in place. They did meet. That was a public meeting. We announced that in the Federal Register. We did approve that project.

That process only begins when there is an application ready to be funded. So someone comes in, we knew the Diabetes Institute was ready to make an award through their Beta Cell Consortium. That's what prompted that meeting. It happens in conjunction with the Center for Scientific Review Advisory Council meeting.

PROF. DRESSER: So is the group all then NIH employees?

DR. BALDWIN: Yes.

PROF. DRESSER: I mean, one of the things we're interested in is if you're going to have review of some of these kinds of things who should be on the group. I was just curious about that. So you see this group more as going down the requirements and checking off to make sure everything was done as opposed to making some sort of ethical judgement about whether it's good enough to go forward.

DR. BALDWIN: Well, they're explicitly not to review the science again.

PROF. DRESSER: I understand that.

DR. BALDWIN: The science is reviewed on a separate track.

PROF. DRESSER: Right. So what is their role?

DR. BALDWIN: Their role is to in fact look at the requirements which have many different components and to see whether the documentation that's presented to us is consistent with the requirements that we've put out there. If you go back to your first question, it's really not terribly different from the review that we've done now on the materials submitted on the embryonic stem cells where we basically had the President's policy and it was our job which was in fact an NIH staff-level review as to whether the documentation was appropriate.

PROF. DRESSER: Right.

DR. BALDWIN: We were trying to look for some parallelism there.

PROF. DRESSER: But the initial proposal when this was going to cover both kinds of stem cells, I just know some people who I believe might have been put on the earlier group. I know it wasn't all NIH. It was more diverse.

DR. BALDWIN: Oh, no. Right.

PROF. DRESSER: So was that group seen more as making conceptual, ethical judgements more than this one is?

DR. BALDWIN: That group really had a much larger task because that was where we were envisioning prospective establishment of embryonic stem cell lines.

PROF. DRESSER: Right.

DR. BALDWIN: So they were going to really be reviewing the proposals or the strategies for developing those lines. With the President's statement, that decision was made. No prospective work, only retrospective. It's only those lines that meet these criteria fixed in time and space. I think we felt from the beginning that was going to be the much more challenging area and likely to be the volume of work would come in from the embryonic side. But that was a judgement call on our part to bring that a little more in parallelism with what we were doing on the embryonic side.

PROF. DRESSER: Thank you.

CHAIRMAN KASS: Bill Hurlbut.

DR. HURLBUT: Apropos of that question in a slightly different perspective. Are there provisions in the way things run now for opening to new apparent embryonic-type pluripotent stem cells that aren't from embryo sources? For example, suppose that something like Catherine Verfaillie cells are shown to be truly pluripotent or maybe even totipotent. Are there possible ways to review that which would allow new lines to be admitted if they didn't come from embryonic sources, either from above or below in the sense that by de-differentiating something that was differentiated or producing something that was slightly differentiated from below? Do you see what I'm saying?

DR. BALDWIN: But de-differentiating from an adult cell is not covered by this at all. Maybe I'm not understanding your question.

DR. HURLBUT: One of the hopes is that you'll be able to take an adult stem cell or maybe a somatic cell using the proper cytoplasmic factors and bring it down to pluripotency.

DR. BALDWIN: But you could do that. That would not be covered by this because you're not starting with an embryonic or a fetal line.

DR. HURLBUT: My point is there are going to be some potential ethical questions around that, and they will be the equivalent of embryonic stem cells in a certain sense. I know that they're sources not embryos, but they're potential is what's also in question. Isn't it?

DR. BALDWIN: Well, that's --

DR. HURLBUT: I mean, you or the current policies would not approve for example the artificial creation of a zygote from above if you will. You could add the cytoplasmic factors.

DR. BALDWIN: I understood your question as to whether there would be specific requirements to generate an apparently pluripotent stem cell line starting from an adult cell. We would not have coverage over that. I think you're probably really asking other questions about what you would do with that cell after you got it, perhaps.

DR. HURLBUT: Yes. I'm trying to get at the moral question of whether the current provision has possibilities for reviewing new creations that are being worked on at this time.

CHAIRMAN KASS: Bill, I think if I understand what is here being implemented is something that is tied specifically to these authorized embryonic stem cell lines.

DR. BALDWIN: Right.

CHAIRMAN KASS: And that while there might be other things coming along that give rise to all kinds of myriad questions, that's not the bailiwick of this body. Am I misunderstanding?

DR. BALDWIN: No, you're absolutely correct.

DR. HURLBUT: So they were not principles put in place. It was the cell lines only.

CHAIRMAN KASS: Yes. Here was for the first time authorization, permission to go ahead with these lines. Nothing was in place to make that possible. The NIH has had the pleasure and burden of making this happened as expeditiously as possible. That's not without its difficulties and bugs. That's partly what we are learning about I think. What happens with other things that come along, that would require different kinds of structures or might already belong to different kinds of places. But that seems to be not the issue before us here.

Could I ask a question. It's probably too early to tell because the number of proposals is still few. But what are you hearing from the investigators who want to get up and running, granting that there might be the usual kinds of impatience between researchers and funding and assistant sources? But with respect to the procedure, with respect to the obstacles, what are you hearing from the investigators who say at last? Are there certain chronic obstacles at the moment? If so, what are they?

DR. BALDWIN: Well, I'd say the obstacles are not big obstacles, but they are certainly issues to deal with. They are really the ones that I've mentioned. You do have to deal with the intellectual property issues. I mean, this is something and that's true for many products that are out there in research that you do have to deal with and MOU. You do have to think about the intellectual property issues.

I haven't heard any particular concerns other than the anxiety around how much emphasis we'll place on preliminary data in a field that's going to be a little hard for them to develop preliminary data. When we know that there are more lines being shipped then we're seeing applications for, it says to me that probably what is happening or what I am speculating is happening is that some investigators are going ahead, getting the lines, lines they know will be eligible for our funding, but working on them some before they apply to us for funding. That's not anything we're imposing on anyone.

Most researchers like to put the best application forward that they can and knowing the difficulty in working with these lines, knowing that it's not simple may want to buffer themselves with some time before they actually come in with an application that goes into peer review. That's really my speculation from bits and pieces that we've heard.

I think we have six intramural labs that have now received cells. This is all really very new. I mean, I don't know how people's cosmic time sense here is but for me this is very fast for this much of a roll-out of a very new, exciting, difficult, and high profile area of science. I've been asked 100 times am I satisfied with the flow of applications, do I think there should more. You always want to see more good applications. Always. It's not been a flood. But given the circumstances, I'm not really all that surprised.

CHAIRMAN KASS: Could I ask a follow-up? To pick up on Dr. Rowley's question before on the question of the characterization of many of these lines and also on the -- Well, it really goes to the question of the purity of these lines as well. Is there anything further that can be done through NIH, either on that or on the access questions? Are you being asked by the investigators to lend a hand there? Is there a hand to be lent?

DR. BALDWIN: Well, we're only partway through this implementation. I mean, we haven't stopped the helping hand out there to work with these sources or to put funding out there for training activities. This is certainly a high profile issue for us because we know that we're doing things that almost sound contradictory. Somehow, I don't think they are.

One is we want to mainstream the process so the we stay connected to our fundamental principles and strategies of how we do business and use the tools. Applications still have to go through peer review. These things don't happen overnight. On the other hand because it is such an exciting area of science, there really has been a concerted effort. We have a contact group with all of the institutes involved. We're working very closely with them to use every tool that we do have.

So we're trying to balance those two things. I guess our instinct is that's the right strategy, but we have to keep the pressure on and we have to keep it a high profile issue for the NIH. And we are.

CHAIRMAN KASS: Thank you. Janet and then Frank.

DR. ROWLEY: I'd like to follow on with two questions. One of which relates to your earlier answer to me that there are about two dozen cell lines that have been characterized and again, how you would define characterization.

DR. BALDWIN: Well, I think part of the problem is I don't think there is that clear of a definition.

DR. ROWLEY: Okay.

DR. BALDWIN: There's not tab six that is the clear definition of what everybody would accept as characterized. That's the figure that we've been using of the ones where there is considerable information about the characteristics of the lines.

DR. ROWLEY: But it's different probably for each one of the six.

DR. BALDWIN: It is a little.

DR. ROWLEY: So that there isn't a standard.

DR. BALDWIN: But you're now challenging me to go back and see the extent to which we could line up some of that information and even use that network that we'll create with those sources as a way to drive it towards certainly some basic understanding. But I don't think that exists right now. I don't think we can say here are the six things you definitely should have done.

I think the field is moving pretty fast. It's important for us not to foreclose anything. I think when you're working in a new field one of the riskiest things for us to do as funders is to inadvertently foreclose or tighten it down too soon.

DR. ROWLEY: I certainly agree with that. As you say, it's as investigators use the lines they may also through their use find either additional features or additional problems that hadn't been appreciated before. So all of that is going to be important information. You indicated you were probably going to get at least some or all of the sources together to discuss these. What kind of timeframe do you see for that?

DR. BALDWIN: I really don't have a timeframe on that. We've only made five of the Infrastructure Awards. We still have more to deal with. The new sources are very new to us. It's just too early for me to say.

DR. ROWLEY: So it would be more like a year from now rather than say six months.

DR. BALDWIN: Probably in between that.

DR. ROWLEY: Okay.

DR. BALDWIN: If you had prompted me, I probably would have said maybe nine months. But we do not have a specific date on that.

DR. ROWLEY: Okay. I'd like to change gears if I can but also take advantage of your long association to senior level at NIH. If you could help and I think this is related to the question that Rebecca was asking, we are aware that when Harold Varmus was Director of NIH he had a working group under Shirley Tillman looking at pluripotent human stem cells and reviewing some of the procedures to use that. I think when you said that the focus of the present is narrowed down obviously the focus of that larger group under Shirley did include some derivation of embryo research using IVF.

One of the concerns of this group as well as others is how you would see a somewhat broader group either of the pluripotent stem cell review group for example that was envisioned in 1998 to 2000 that group was composed of ethicists and lawyers as well as scientists. At least that's my impression. I believe the membership was appointed by the Secretary of HHS. I'm not positive about that, but that was my impression. Whether such a review group would be an appropriate regulatory body to actually give responsibility to if for implementing and reviewing certain aspects or setting certain guidelines for embryonic stem cell research.

DR. BALDWIN: What kind of guidelines do you have in mind? Do you mean for areas of science that would be instituted?

DR. ROWLEY: Well, my impression is that the working group under Dr. Tillman came up with a series of guidelines, some of which you've already incorporated or were incorporated into the embryonic stem cell lines that they had to be derived with donor consent and things of that sort. The guidelines also have prohibited areas of research.

DR. BALDWIN: They're still in place. We did not rescind the prohibited areas of research.

DR. ROWLEY: And our discussions here and the evolution of science in the last few years has really suggested that some of those prohibitions might be removed. Then whether a review body of such as a broadly constituted body would look at the prohibited areas. For example, the prohibition says no somatic cell nuclear transfer. That's now an area that's been supported by the report from the National Academy of Sciences amongst other things. Is that up to NIH and the Secretary to remove that prohibition or would there be a broader constituted group that might look at that?

The other thing that's prohibited is actually developing embryos specifically for research. This is an issue that we've discussed back and forth. At least some individuals, members of our Council, believe that it should be allowed under certain circumstances and with certain guidelines.

DR. BALDWIN: Well, you have certainly outlined a very difficult and evolving area of science and ethics. The current group, the human pluripotent stem cell review group is definitely not envisioned as a group that would be taking on issues such as you described. That is a group that is really there to address the adequacy of any plans to use fetal tissue. The prohibitions that were in place in the original guidelines are still prohibitions that are compatible with administration policy.

So what we might do in the future is really not something that I could comment on here. I can say that's not the kind of issue that would be remanded to that advisory group. But we always have the capacity of putting in place other advisory groups if it's warranted. We don't have any specific plans at this time.

Dr. Zahuni (PH) the current NIH Director certainly views this as a very important area of science and one that requires our due diligence and careful attention to what our steps should be. So it's certainly not something that's going to get any less attention. But I wouldn't be able to comment further than that.

CHAIRMAN KASS: Frank Fukuyama.

PROF. FUKUYAMA: A brief question. Is there any possibility of these approved lines any of them dying out as a result of mistakes and handling or inexperience? You said that they are very hard to keep going.

DR. BALDWIN: That's very speculative. I don't know. Of all of the things I worry about in this line --

PROF. FUKUYAMA: That's not it.

DR. BALDWIN: That's not on my worry list. Maybe you gave me something new to worry about.

CHAIRMAN KASS: Robby George.

PROF. GEORGE: Just very quickly. A point of clarification. In reply to Dr. Rowley's last question about who would have authority to lift or alter the prohibitions that she discussed such as somatic cell nuclear transfer, can you tell us again who's authority would be exercised there? My understanding is that would require an action by the President or the Congress, not any advisory body. Am I wrong about that?

DR. BALDWIN: No. You're not wrong.

PROF. GEORGE: I'm right about that.

DR. BALDWIN: Yes. Anytime an issue is up for discussion there's frequently a desire to have an advisory group's comment on them.

PROF. GEORGE: Absolutely.

DR. BALDWIN: And we don't have a group in place that is doing that. I'm not anticipating any changes in that.

PROF. GEORGE: Right. But apart from discussion or advise the policy --

DR. BALDWIN: That's why I said those prohibitions are compatible with Administration, with our current policy. So I'm not envisioning any changes.

PROF. GEORGE: Is that your understanding as well, Dr. Kass?

CHAIRMAN KASS: Yes. That's my understanding. This is perhaps a strange question to put to you. This group as you know has been asked by the President to monitor stem cell research and to think about offering guidelines for it. We have spent a fair amount of our time on human cloning as you probably know. But we have had presentations from Dr. Gearhart and Dr. Verfaillie. We are trying as best we can to keep up with what is going on through the NIH.

From the point of view of your activities and what you hear from the researchers in-house and extramurally, are there things that you would like brought to this body that might deserve our special attention? We've been trying to learn really about the implementation policy and finding out how easily and well are things moving. Apart from the request that the President should become more liberal and allow more lines to flourish which I understand would be a perfectly natural opinion of the scientific community, within the policy as now stated or in relation to that policy that we would have to consider, are there not so much advise but questions and concerns that we would be remiss in not attending to from the point of view of the people that you speak with and the research that you're trying to help develop?

DR. BALDWIN: I don't know whether this is a direct answer to your question. I think what I see most need for right now is scientists just getting down to work with the lines that are available. There are many questions that need an informed debate. I think that debate will be better informed if it can come from not a speculation about what might happen and whether this is a good enough line or those work are enough but really more concrete, empirical evidence as to what happens when researchers get in there and work with these lines.

There are very different views out there as to are they enough, they're not enough, they're good enough, they're not good enough. But they're a little hypothetical for my taste right now. If they could be better grounded in experience we may find that people have terrible problems working with these lines. We may find all kinds of terrible problems. On the other hand, we may not.

Certainly if you look at the mouse ES experience, it started out with a lot of lines and it shook out to where there were a few that seemed to be the most valuable, most useful. Will it be the same way in the human lines? I don't know. We won't know unless we get investigators willing to get in there and in the trenches and starting the work with them.

We're trying to put every conceivable mechanism out there to help that move along, but we still have to get the applications in from the research community. I guess if you say what's the one thing that I most want to see happen, I think that's it because I just think it will just make the discussions the we could have six months, nine months, ten months, and 12 months from now so much more empirically grounded. That would be my issue right now.

CHAIRMAN KASS: Well, thank you. Just a tiny addendum. We are also trying to plan our own agenda for the remaining 17 or 18 months of our existence under the existing Executive Order. I know there's no real answer to this question. But order of magnitude. If we wanted to be good monitors of this and of the research and how it's going along, do you think a year from now there would be stuff to monitor?

I mean, are we going to be able to do what we're supposed to do or are we at the end of this time say let the research go forward, we'd like to know what's happening? And I'm not going to hold you to the answer. But it matters to us I think in thinking about how to plan our own agenda what kind of time table we ought to be expecting to have some kind of data coming in. I know it's absolutely unpredictable.

DR. BALDWIN: Several things I do know. One is this all takes longer than anyone thinks it does at the outset.

CHAIRMAN KASS: Right. Rowley's Law.

DR. BALDWIN: If you had said anything less than 12 months to tap back in and see how implementation was going I would say I really think that's too soon. I mean, if you look at a timeline from when these agreements are in places or when we've actually started to move money to a source for infrastructure support, we're measuring things in matters of weeks and months here. Science just takes time.

In a year's time I think we'll certainly have a better sense of the rate of applications. We'll have a better sense of some people's early experiences in working with these lines. But I would not want to over promise as to how definitive that will be. Less than a year, I wouldn't do it. In a year's time, I think it would be a fair question to say come back in a year or send someone back in a year and say how has it progressed and how many more investigators, what's the experience from those.

We'll have 13 Admin. Supplements. Those are going to be experienced investigators who are probably our bellwether, our leading edge. In a year's time, I think we'll have a much better feel for how difficult this has been for them or how quickly the sources given infrastructure support have gotten more common information available about their lines and whether in fact we have any lines that turn out just to not appear to work at all. In a year's time, I think that would be a reasonable question to put to us. I would hope I have some answers for you.

CHAIRMAN KASS: Well, thank you. Would you allow me one more?

DR. BALDWIN: Sure.

CHAIRMAN KASS: In connection with your own heavy responsibilities to this activity, is there someone as part of this project also keeping up with what is being done in the private sector on this activity to the extent to which that information is forthcoming? In other words, if one wanted to say is there somebody at NIH who sits really in command of --

DR. BALDWIN: Asking the private sector to tell us about what they're doing with their own money and not ours? No.

CHAIRMAN KASS: I don't mean that. But there are things that are published too.

DR. BALDWIN: Yes, certainly. We have been attentive to the meetings that occur. We have staff at any of the national meetings or regional meetings, et cetera who are staying apprised of where the interesting work appears to be done. I just have to draw that little line. There's always work that's going on in the not federally funded sector that we don't always know about.

CHAIRMAN KASS: Of course.

DR. BALDWIN: There's nothing new about that. But no. We are definitely staying on top of where the developments are to the extent that we can.

CHAIRMAN KASS: Thank you. Alfonso Gómez-Lobo.

PROF. GÓMEZ-LOBO: This is an information question. Maybe it's out of your domain. I know that at NIH quite a bit is being done on adult stem cell research. Right?

PROF. GÓMEZ-LOBO: Now, is there any way of comparing volumes? I mean, is there a lot more being done in adult stem cell research?

DR. BALDWIN: Oh, yes. That's a much more established field, yes.

PROF. GÓMEZ-LOBO: Okay. Thank you.

CHAIRMAN KASS: Well, it looks like you have answered our questions for now very forthrightly, very fully, and very helpfully. We're very glad.

DR. BALDWIN: I'm happy to take any other questions that you would like to probably channel them to me. E-mail them to me and I will try to get an answer for you if there is anything that I have not gone over. Again, virtually every piece of information that we have put out there, every announcement, every piece of guidance, every helpful hint all is accessible on the website. If you would prefer to receive that as hard copy, I'd be happy to pull together a briefing book and send it to you if the Members would like that.

CHAIRMAN KASS: Well, we thank you very much. Dr. Lee Zwanziger, would you stand please? Lee is a research director on the staff and the person most interested in the stem cell aspect of our work. I'd like at least you and she to say hello. We can keep a communication open in that direction.

DR. ROWLEY: I mean, I think that would be very helpful particularly to the extent that we would have some understanding of the cell lines that have been reasonably well characterized. For example, are most of them derived in the U.S.? Are most of them derived elsewhere? Issues like that would certainly be helpful.

DR. BALDWIN: You sort of challenged me to do an update on that. So it gives me something to do.

CHAIRMAN KASS: Thank you.

DR. BALDWIN: Thank you.

CHAIRMAN KASS: We are finished a little early. Thank you very much, Dr. Baldwin. Is Ted Friedman here? If we started a little earlier, people could finish a little earlier. I don't want people who are coming from out of town just to hear you talk miss the beginning. But we are now ten after. What if we reconvened at 2:30 p.m.? Then we just finished a little earlier. Would that be all right? We'll take a break until 2:30 p.m. Off the record.

(Whereupon, the foregoing matter went off the record at 2:09 p.m. and went back on the record at 2:36 p.m.)