The following are excerpts from two interviews that The Daily Pennsylvanian obtained in the past week with gene therapy researcher James M. Wilson.
These interviews mark the first time since the 1999 death of Jesse Gelsinger in a clinical trial Wilson was conducting that Wilson has spoken with the DP.
Wilson granted the interview on the condition that he would be informed ahead of time about the nature of the questions to be asked, and that all questions would pertain to his preceptorial this semester or to how the Gelsinger case was discussed in the class.
Wilson would not comment on the Food and Drug Administration's investigation into his clinical research practices that stemmed from the well-publicized Gelsinger trial.
Part 1 of the Interview: Daily Pennsylvanian: Basically, just to get us started, I wanted to know why you agreed to give this preceptorial in the first place when the preceptorial board approached you? What were ideas going forth with it?
Wilson: The students met with me after sending me an e-mail about helping to organize a preceptorial on gene therapy. I felt that it was important to be responsive to the students, that I enjoy teaching. I wish we had more interactions with undergraduates, we being the faculty of the Medical School, and I welcomed the opportunity to spend some time with the undergraduates. I also was pleased to learn that those students who would participate would be those who expressed a desire and would have to enroll through, I guess they do it through the registrar. So I thought this was a great opportunity to just spend some time in an informal setting with some students
DP: What ideas about gene therapy, in terms of the science and the ethics of these studies, are you trying to get across?
W: Gene therapy has been, it's a field it's still somewhat in it's infancy and I believe has substantial promise in the practice of medicine. The fact is that it's in its early days and many people that I've had a chance to interact with are very interested to learn about the promise and the reality of gene therapy. So the challenge, though is to try to communicate what the technical realty of gene therapy is so that the listener can form their own opinion about how interesting this is and what its potential is. So, what I've spent some time doing in the preceptorial up until now is really try to discuss the scientific basis for the field, number one, and number two, to chronicle the history of the field which is useful, I think, to the students so that they can get a perspective on the trajectory of the science and really any important lessons that were learned along the way. This is an obvious thing for me to do and one that I'm well equipped to do since I was involved in the field of gene therapy as a post doc[toral student] really when it began in the sort of early to mid '80s. So I've lived this field from the beginning, shows you how young the field is, and I can give not only the historical perspective, but then what we hope to do in the next session is to talk about the future, challenges, where the field shows promise.
DP: How successful do you think the first two classes have been in terms of getting your students to understand what you've been trying to get across?
W: I think in the first class we attempted to get everyone on the same page with respect to a rudimentary understanding of the technology. I tried to illustrate that through examples that I have participated in over the about two decades that I've been involved in this field. The second class was an experiment, and what we tried to do was show them what it meant to participate in a science. We did that by setting up stations that the students rotated through so that they could. see how the concepts I described in the first session are reduced to practice at the bench. And I find that this is important because it gives them a frame of reference to remember what it is that we discussed, but also for them to get a sense for what a scientist does, especially operating in this field. It turns out, though, that a number of the students are committed to science in terms of their degrees. There are a lot of science majors in the course, though there are some that aren't, I think there's a Wharton student, who's in the Wharton School. But they come to it with various different backgrounds and interests in science.
. In the first session we were talking about the technology, which really has to do with vectors - vectors are the gene delivery vehicles - and how do we get the genes into the cells? And then what have been examples in which this has been attempted, what has been the outcome, what have we learned?
. DP: Is there anything else you want students to take away from the course? For the students who do not study science, what do you want to get them to understand?
W: Well. I think about undergraduate education a lot. I'm actually a trustee at the college I graduated from, which is Albion college. I'm more involved in undergraduate education than probably you may think. And I think about what it means to learn science as an undergraduate, and it worries me that the world that you guys will shape, in the future, is going to be so heavily influenced by technology that some understanding of that technology becomes important just to function in society in an increasing way. So, I think a lot about the importance of providing, in the context of a liberal arts education, an understanding of the key aspects of science. And so, just because the students are not science majors, I can get excited by that, because this may be one important opportunity for them to expand their knowledge and experience of science. It's also exciting to have people interested in science because that's what I've dedicated my life to and obviously surrounding yourself with those types of people is really fun.
. The other thing that has been nice is the informal nature of the structure of the preceptorial, that you get to spend time with students [when] grades don't make the difference, which really takes that stress out of the relationship. And those that step forward are doing it because they're genuinely interested rather than it's kind of an important part of what it's going to be to take you guys, to take them to the next step, whether it be a job or medical school.
DP: Can you give me an idea of what's going to be discussed in the next session?
W: Well, the next session in part will be determined by what the students want to learn, what more they'd like to hear about. We'll talk about where the field is now. We sort of left off on that in the first session. We brought them up to kind of where we are now. One part of the [final] session will be to discuss the future, where we think the successes will be, where it's going to be more difficult. And we'll also take the opportunity to discuss the science of the trial related to OTC deficiency and what we learned scientifically from that experience.
DP: Can you explain what the OTC deficiency is?
W: Yeah, uh, OTC deficiency is a genetic disease, it's rare. It is due to a gene defect that inactivates a gene product. A typical clinical situation is. that the mother's a carrier of the defective gene, and they're usually not affected, but they're carrying the gene. Frequently they don't know they're carrying the gene. It's passed on then to their son, who is usually born fine, without any problems, but the problem with this disease is that the individual affected by it is unable to break down protein. And so if you can't break down protein, then protein substances will build up in the blood that are toxic and it can lead to coma. So the way that this usually manifests is that the baby's born fine, no problem, but the first time that they take a meal - formula or breast milk - is the first time that they get protein, and then they can't break it down and they get very sick. And it's my understanding that of those affected, boys who have a severe gene defect, 50 percent do not survive. They don't leave the hospital. They die from the genetic defect.
. So what gene therapy is, it's an attempt to deliver the normal version of that gene into the liver so that now the gene would take up residence in the liver and then program the liver to be able to break down the protein. So that's basically it in broad strokes.
DP: And this was the experiment going on at the time of Jesse Gelsinger?
W: Yes.
DP: A lot of the students I talked to mentioned that they wanted to hear about the Gelsinger experiment and the news surrounding it. How you're going to discuss it with them and what will you try to convey about the case?
W: Well, I'm going to try to describe accurately the disease, the strategy for treating this disease, the data generated to support testing this in humans, the clinical trial, how it was designed, the discussions that we had had with individuals within the group, outside the group, about how to structure the trial, how the trial proceeded, the data that were generated from the study, what we observed with respect to what happened when the doctor was administering to Jesse Gelsinger. And that two years of work in which we've dedicated ourselves to try to understand the basis for the severe mutant reaction that was observed in Jesse Gelsinger. Now I'll accept that's a lot to go over, but it's an important story and it's one that we're going to try very hard to inform the students about.
DP: Why did you decide to speak out about the Gelsinger case now, and to the students? What do you want to accomplish by speaking to the students about the case, and what are you feelings about the secrecy surrounding this preceptorial?
W: It's an important question and I respect your asking it, and I'm glad I have a chance to respond. I feel that we have been as responsive as we can to assure that anything that we've learned from this experience that we get out, and communicate with the scientific community. And we have been aggressive at sharing with the scientific community any and all aspects of this case, both before the data that we generated during the trial and since then, with the hope that this information will be useful to others in assuring that this will eventually be successful, and hopefully to avoid any similar circumstances in other trials. I'll give you an example. This happened in the death of Jesse Gelsinger happened in September of 1999. We informed the regulatory agencies and made a commitment to the Recombinant DNA Advisory Committee to make a public presentation at their next meeting which was December, early December, in December 1999. We worked very hard between mid-September and early December to try to assemble as much information as we could. We were not obligated to present at that meeting. That meeting is open to the public, and they had taped it to various other sites. We went and we presented all the information that we had..
So we've been open, and I'll tell you why. First of all, it's the right thing to do. But when we undertook this study, as well as any of these studies, we make a commitment that we will learn as much as we possibly can to assure that this will ultimately succeed. We can't promise that any one strategy is going to be the one that will ultimately be successful, but our obligation is to assure that we learn from the experience and share the information. And we have been true to that. It began with a presentation to the [Recombinant DNA Advisory Committee]. We have two papers that we've written up describing the clinical trials that are in the process of being reviewed. We have published a number of papers describing studies that we've done since the trial was done, to sort out in the animal models what it is that stimulated this immune response, and in an attempt to try to figure out why Jesse Gelsinger was so sensitive to the therapy - more sensitive than what appeared at least in one of the other patients. We published those papers, and we presented them at every scientific meeting that will let us get to the podium. So we've tried to get the information out, and we will continue to do that.
DP: What do you think the public's perception of these kinds of trials is, and what their perception is of the universities that sponsor this kind of research? What do you think the scientific community can do to let the public know what the purpose of these studies is?
W: Well, it's a hard one., but I will say that anything that an institution like the University of Pennsylvania can do to absolutely minimize the risks to patients and assure compliance with all federal regulations they ought to and are doing, and that's good. And it's also a time when, a very exciting time, when we're reaping the benefits as a society of the substantial investment that has been made about that research with respect to broad new areas of biology that could impact on the way we treat or prevent disease. So the opportunities are growing exponentially. Gene therapy, the impact of genomics on developing drugs, stem cells, and as these opportunities grow, as well as their applications, the major universities are appropriately putting in place as many safeguards as they can.
DP: Why did you decide to close the class to the press?
W: That's a good question. One thing I've always dreamed of being is a teacher and a professor, and I love it, and I consider it a privilege. And the classroom is a very, very special place where we try to encourage the open exchange of ideas ad discussion, and anything that would potentially stifle that would be something that I'd want to discourage. And having press present in the classroom I feel would deter from the educational experience. And there's a time and a place for everything - speaking with members of the press is also important, teaching is important, mixing the two, if you can avoid it, I think [is important].
Part 2 of the Interview: DP: What was discussed in the final meeting of the preceptorial?
W: So last night we talked about sort of the broader picture of how you develop therapeutics, which is gene therapy, from the beginning - the discovery, to the development of a product that someone would distribute. And that was important to find some context to the sorts of program that we have developed here at Penn that go from gene to vector to animal studies to initial clinical trials and how this is a reitirative process. They try to learn along the way that would help you improve your strategies and learn about your strategies. And the difficulties often in modeling what you eventually see in humans based on animal experiments is that there are limitations, and until you actually evaluate a new therapy in a human you sometimes don't know how well the animal trials could have predicted it.. And then I ... had about six or seven slides and we talked about the OTC trial.. We started from what were we thinking when we first began to develop this program, how did it evolve in the animal studies. We reviewed the animal studies, talked about the dialogue that ensued when we began to develop a clinical trial, what type of patients should be involved, what's the most appropriate structure for the trial, what weighed in on those discussions, what were the point-counterpoints, and then what we learned in the trial, what we thought happened in the case of Jesse Gelsinger, and then the work we've done over the last two years to try to better our understanding. And then we opened it up for questions... students just asked a lot of questions and they were interrupting me quite a bit during the presentation. I felt that the students really warmed up during the three sessions, started to feel much more comfortable with the group.
DP: You had said you were also going to look at the future of gene therapy in the course. What prevented you from doing so?
W: I think we ran out of time and I wanted to make sure that I answered their questions. I really wanted to let them go with it in terms of what direction they wanted to go because I said you can ask me whatever questions you want, and then we had about another half hour where we had an open discussion. But boy, talking about the future of gene therapy is something that I'd love to do and it's easy for me to do because it's all speculative.
DP: What were the main points concerning the present state of the industry?
W: What I wanted to describe was the process from making a discovery, like we all do here at Penn frequently, to making that a clinical realty, and that's not a process that we normally think about in an academic environment. What we frequently do is develop our science through gain of new knowledge in animal studies or in cells and frequently what happens is you bring the science part up along to the point where there's really nothing more to do. I mean, if you cure a mouse of a disease that simulates a human disease and you do it repeatedly, that's it. Then you're sort of done, and the question is what do you then do, and the goal is what do you then do, and that's the interface that we talked a bit about - transferring this technology to the pharmaceutical industry because that's what they do for a living. And we talked about some of the challenges of that, the importance of developing mechanisms to facilitate that to happen. And then we discussed that at times it may be useful, on a limited basis, to actually move the science a little bit further and demonstrate effectiveness. in early human experiments within an academic environment funded by foundations or the National Institutes of Health. I think it was important for the students to understand that once you cure a mouse, you're not finished. It's sort of only a beginning, and there's a lot of work that goes on subsequent to that. And in gene therapy there has been no product yet approved for sale, it's still in the research stage.
DP: Why and how did you discuss the OTC trial and the ethics involved in choosing Jesse Gelsinger as a subject with the class?
W: I thought that was an important thing to discuss because it had been discussed and I felt that spending dedicated time for dealing with the OTC trial was a very appropriate thing to do because we learned a tremendous amount about the research in the field and the technology. To start from the beginning. there's a mouse model of OTC deficiency where you put the vector in and they would no longer die if given high protein, so we had done a lot of animal work. But then you get to a point where you then have to decide can and should we test this on humans. And then there are a number of questions you have to address, one of which is what would be the structure of the clinical trial and who would be the patients? So what I did was I told the story up until then and then I asked the students for their advice - what would be your thoughts about how this clinical trial should be structured? - trying to give them as much background as I could, and that was one of the reasons why at the beginning I talked about bench to bedside and what some of the issues would be so that they'd at least have some background. And that was nice because it stimulated really a dialogue, not me sitting there telling them how it played out. But once students started committing themselves, I think you should do this or you should have done this, and some agreed with the way it had proceeded and some hadn't, but once they committed themselves then the discussion really started to go. So the issue was that the majority of affected individuals with OTC deficiency are newborn boys because it's x [chromosome]-linked. They're newborns and when they inherit the defective gene from their mom, they have no enzyme, so that they're unable to break down protein and when they take a protein challenge, which is their first meal, whether it's breastmilk or formula, and then they just can't tolerate the protein and they go into coma and 50 percent of those kids die. So then the question is who do you enroll in the initial trial and there was discussion when we were reviewing this and also last night that it would be the children who come into the hospital who are diagnosed with this disorder at a time when they're very sick and we discussed how that was in fact the view of a number of individuals involved in the study initially, but then it was an important enough decision that we had expanded the discussion, (this is back when we were actually doing it, not [Tuesday] night), and to ask another individual, because we didn't want this to be a decision made in isolation.. Art Caplan was involved in the discussions... and he voiced a counterview which is, since this is the first time this vector would ever be tried in humans and we don't know what the risks are, that it may be better to enroll patients who aren't very sick with the disease, who may just be carriers of the disease, and for them to be adults, the reason being that they can provide their own consent, you don't have to go to a guardian, that they're healthy, that they're there really just to participate in gaining new knowledge, but are relatively healthy, not that they're going to get something out of it which we couldn't guarantee at that point. And they felt, several felt, that bringing this clinical trial forward into situations where there is this newborn boy who is born without problems and three days later is about to die would be a coercive situation. And the doctor runs into this room and says there is this experimental therapy that [parents are] almost in a position where they can't turn it down because they're faced with some really terrible circumstances. So, from an ethical standpoint, when you look at informed consent to provide so that the person participating in it can provide the clearest decision possible and minimize any coercion that's inherent to the situation, not that we would try to coerce, to go with adults. And that was debated; I mean that was a point of debate. In fact, I wasn't involved directly with the patients, but the other physicians, Mark Batshaw and Steve Raper, with other members of the bioethics community, met with patients group to discuss, and they concurred that it would be best to proceed forward with carriers, with males who only have a partial defect and weren't as sick as those unfortunate kids who basically would die. So we talked about that and that there wasn't any right or wrong answer. At the time we were trying to make the best decision based on what we knew at the time.
