A Death in the Laboratory: The Politics of the Gelsinger Aftermath
Authors: Ira H. Carmen
Journal: Molecular Therapy (2001)

"Tragedy at Penn; boy, 18, dies in gene therapy experiment." "FDA says gene therapists don't tell research subjects the truth about potential risks." "Congress wants to know why 18-year-old died in Penn trial." "Gelsinger's father sues Penn and its geneticists." "FDA puts hold on HGT research." These paraphrases of trumpeted newspaper and journal article headlines reveal gene therapy's current public image. They send shivers up the backs of human subject researchers everywhere, particularly biomedical scientists. And rightfully so. The delicate balance required for human gene therapy to go forward—the balance between research innovation and communal responsibility—has suffered a severe jolt. We have already learned certain lessons from the Gelsinger episode, some of them the hard way. The first lesson is that when a government agency insists that gene therapists provide legitimate documentation, be it patient eligibility forms, informed consent statements, or adverse reaction data, there is a burden on principal investigators to do more than produce "bare-bones" feedback. That is, gene therapists must construe their public responsibilities broadly, not narrowly, and if anything, "overfile." This is not as easy as it sounds. Drawing upon my 4-year tenure (1990–1994) on the NIH's Recombinant DNA Advisory Committee (RAC), I can report, as I have reported elsewhere (1Carmen I.H. Human gene therapy: A biopolitical overview and analysis.Hum. Gene Ther. 1993; 4: 189-193Crossref Scopus (7) Google Scholar), that some gene therapists do not have the energy or sense of commitment to the routines of bureaucratization to do what needs to be done. All too often I heard—and still hear—usually with arms uplifted toward the heavens: "How many forms must I fill out and how much detail must I include?" Permit me to provide a political scientist's retort: "My friend, you are in the world of politics whether you like it or not, so you better play the political game and play it well." The second lesson involves the matter of adenoviral toxicity. While on the RAC, I was privileged to listen to a "great debate" between Ronald Crystal and Harold Ginsberg on this agenda item, the discussion centering around the safety of the former's proposed cystic fibrosis protocols. The RAC subsequently approved Crystal's proposal, and in so doing implicitly agreed with his calculation of the risk–benefit ratio. Though adenoviral vectors have become a standard weapon in the gene therapist's tactical arsenal, there is mounting evidence that its optimal role lies in the realm of cancer gene therapy, not genetic diseases per se (2Brenner M. Reports of adenovector "death" are greatly exaggerated.Mol. Ther. 2000; 1: 205Abstract Full Text Full Text PDF PubMed Scopus (12) Google Scholar). This is precisely the sort of expertise we need to keep the science on track in a responsible way in contradistinction to post-Gelsinger headlines which read: "Adenoviral vectors kill people." Indeed, it is the only antidote to the biases and the ignorance triggering these headlines. All of which raises a quintessentially political question, namely, how do we institutionalize the process by which we funnel such unfolding expertise into the arena of research protocol formulation? (I shall say more about this in my concluding paragraph.) The third lesson learned is that the bioethical implications of these experiments are not ethereal subjects of philosophical discourse but political subjects of empirical discourse. If one thumbs through the pages of The Hastings Center Report, one can find any number of ethical commentaries on the propriety of human germ-line gene therapy, just as 15 years ago one could find similar commentaries on human somatic cell gene therapy. These discussions can be useful guides to theory building, and they are fundamentally harmless. It is quite another exercise when bioethicists instruct geneticists in whom to treat and whom not to treat. Evidently, the Penn gene therapy team had decided to enroll as human subjects precisely the subjects one would think at first impression ought to be enrolled, OTC-deficient babies who faced a clear and present danger of demise. But because babies cannot consent to anything, the principal bioethicist on station advised the researchers to substitute stable "adults" who could consent. As for parents who normally tender approval in the name of their youngsters in order to authorize far more invasive procedures than the one at hand, the bioethicist found that they would be "coerced by their child" and hence could not provide informed consent (quoted in 3Miller H.I. Gene therapy on trial (letter).Science. 2000; 287: 591-592Crossref PubMed Google Scholar, see also 4Marshall E. Gene therapy on trial.Science. 2000; 288: 951-957Crossref PubMed Scopus (168) Google Scholar). The Penn team acquiesced, and so did the U.S. Food and Drug Administration (FDA). The upshot was that when Jesse Gelsinger's father sued all Penn parties involved, he even sued the bioethicist (5Science. 2000; 289: 2017Crossref Google Scholar). And why not? I am not arguing that Gelsinger's father should have collected had the lawsuit gone to trial, which it never did. Rather, I argue that if a bioethicist is going to assert his credentials in the formal decision-making process, and if the decision is actionable in a court of law, then the bioethicist is a proper party to the litigation. The notion that the bioethicist is simply advising his colleagues, a form of counsel inferentially protected by either academic freedom or the First Amendment's free speech guarantee, is frivolous (5Science. 2000; 289: 2017Crossref Google Scholar). More fundamentally, since when does a sick child "coerce" its parent into silence, thus constituting a per se waiver of the opportunity for, if not treatment, at least experimental benefit in the good Samaritan sense? Perhaps the parent—and the not-spoken-for child—would prefer a plain and simple death and perhaps not. Who knows? I happen to prefer the politics of individual autonomy to the politics of paternalism, and the lesson presented here is that gene therapists had better appreciate the implicit politics in bioethics. Finally, I concur in the view that the FDA did not come to the process with clean hands. The fact that it signed off on the protocol, and hence Jesse Gelsinger's participation in it, ought to counsel in favor of a temperate reaction on its part (3Miller H.I. Gene therapy on trial (letter).Science. 2000; 287: 591-592Crossref PubMed Google Scholar), not one essentially banning the Institute for Human Gene Therapy at Penn from executing HGT protocols. The final lesson is the most important lesson, at least from a political science point of view. Put boldly, there is a basic flaw in the way American national government oversees human gene therapy. In point of fact, the problem is of much broader scope, which bears witness to its importance. That is, there are basic flaws in the way the U.S. government oversees all controversial human genetic engineering experimentation (HGGE). This broader problem needs to be addressed before we can put the smaller, gene therapy, problem into perspective. When politicians feel the need to do something—usually because an interest group with clout is up in arms—but don't much care whether that something is ever done or not, they farm out the task of writing up a set of recommendations on the subject to a group of experts. If the commission's findings comport with political reality, there is a chance that action could ensue. If the findings do not comport with political reality, then the report can readily be filed away and forgotten. Over the past several years, committee recommendations on the hot topics of HGGE have received the appropriate fanfare and then disappeared. I turn to several examples. How many observers remember the ill-fated Human Embryo Research Panel, charged with investigating the experimental status of human preembryos? That blue-ribbon NIH group determined that it was ethically and socially responsible to permit the allocation of Federal money to create and employ preembryos for certain research purposes, a practice long considered necessary and proper in the United Kingdom. Unfortunately for the committee, its salient recommendation was not politically acceptable to President Clinton, who vetoed it out of hand even before the NIH Director had had an opportunity to assess the proposal. Of course, some Congressional Republicans didn't like the idea either, so down the drain it went (6Carmen I.H. Washington politics and genetic engineering research: When worlds collide.Hum. Gene Ther. 1996; 7: 97-108Crossref Scopus (1) Google Scholar). To make political life more manageable for him in this area, President Clinton established a National Bioethics Advisory Committee (NBAC) to which he could assign "hot" HGGE topics as they arose. Naturally, the panel could hardly bring back "solutions" that it knew Mr. Clinton—based on his public pronouncements—would reject. A classic case study arose as a result of Ian Wilmut's success in cloning Dolly. Clinton's immediate response was to issue an order forbidding any Federal agency from spending money to implant preembryonic human clones into a woman's body. He then directed the NBAC to investigate the matter and report back to him. More than taking the hint (because, of course, the panel might simply have legitimated his order), the committee proposed that Congress pass a law criminalizing the use of somatic cell nuclear transfer to create people. The recommendation received some support in Congress; others wanted to enact even more restrictive legislation. Generally, however, the genetics and reproductive research communities were appalled, while ethicists and social scientists were divided. (For a review of the arguments concluding that the NBAC's analysis was seriously flawed, see 7Carmen I.H. Should human cloning be criminalized?.J. Law Politics. 1997; 13: 745-758Google Scholar.) No action has been taken to date, and the report has become a dead letter. More recently, the NBAC has struck out on its own, initiating a study of the policy implications of human embryonic stem cell research. In a report delivered to President Clinton on September 13, 1999, the committee recommended that the Federal government fund not only this research but also the production of cell cultures from human embryos. Earlier, the NIH had opted for a more modest approach: funding for research, yes; funding for cell-line production or derivation, no. Not content with asking Mr. Clinton to choose between NIH preferences and NBAC preferences, the panel also threw down a challenge to Congress itself, recommending that it modify its ban on the use of Federal money for embryonic experimentation. The President's response was swift and decisive: the NIH and Congress had it right and the NBAC had it wrong (8Marshall E. Ethicists back stem cell research, White House treads cautiously.Science. 1999; 285: 502Crossref PubMed Google Scholar, 9Shapiro H. Ethical dilemmas and stem cell research.Science. 1999; 285: 2065Crossref PubMed Scopus (14) Google Scholar). Ultimately, the NIH promulgated new guidelines implementing its previously articulated position (10Vogel G. NIH sets rules for funding embryonic stem cell research.Science. 1999; 286: 2050Crossref Scopus (6) Google Scholar). More recently, President Bush has indicated a marked distaste for human embryonic research in all its forms, but like his predecessor, seems prepared to defer to NIH and its superior unit on the organizational chart, the Department of HHS. Where does all this leave the NBAC? It is exactly this dismal record of HGGE policy formation and implementation by impotent advisory committees that I submit is at work in the context of human gene therapy today and, furthermore, that reared its ugly and unfortunate head in the Gelsinger affair. Commencing in the mid-1970s, the NIH, through the RAC, governed the gene-splicing field as it was then known, and thus, commencing in the late 1980s, it essentially inherited human gene therapy. The RAC had developed a set of rules (the NIH Guidelines) and applied them the way the United States Supreme Court applies the Constitution. Geneticists who wanted to perform relevant experiments submitted their protocols to the RAC; the RAC would accept them, amend them, or reject them in the light of the guidelines and "case law," that is, precedent. Such hearings sometimes required the RAC to interpret its "constitution" and sometimes even amend it, just as our highest judicial panel "amends" the U.S. Constitution. Recombinant DNA researchers took the RAC very seriously. Sitting in judgment on their work were the most prestigious of their peers plus scholars with expertise in the legal, ethical, and social implications of genetic research. The RAC's decisions had what passed for the force of law in this field of "dos and don'ts." Rarely did the NIH Director overrule the RAC, and then only because he believed it was too permissive, which most scientists thought it never was. Because HGGE investigators knew the RAC had teeth, they did a pretty good job, within the limits of their training and energies, of cooperating with RAC terms and conditions (see my comments above on this point). As time went on, this most prestigious of blue-ribbon scientific review panels slowly—though in fits and starts—loosened its oversight grip, generally in a prudent manner. The RAC also proved highly adaptive, forsaking subject matter areas which seemed less provocative or which seemed better placed in others' hands (e.g., field testing) and addressing new controversial subject matters as they arose (e.g., gene therapy). (For expansive treatment of these themes, see Refs. 1Carmen I.H. Human gene therapy: A biopolitical overview and analysis.Hum. Gene Ther. 1993; 4: 189-193Crossref Scopus (7) Google Scholar, 11Carmen I.H. Cloning and the Constitution. Univ. Wisconsin Press, Madison1985Google Scholar, and 12Carmen I.H. Debates, divisions, and decisions: Recombinant DNA advisory committee (RAC) authorization of the first human gene transfer experiments.Am. J. Hum. Gen. 1992; 50: 245-260Google Scholar.) All this changed in 1997. The then-Director of NIH made known the fact that he wanted to abolish the RAC; eventually, he agreed to a kind of compromise. The RAC could no longer stop a project in its tracks, but rather it would continue to review protocols and provide advice to the FDA. It was also charged with the task of convening conferences on key issues in the field. Essentially, the RAC—an NIH instrumentality—became the ethical, legal, and social instrumentality of the FDA, which is not even housed in the Department of HHS, much less sharing housing with NIH. Even more significantly, the Director had managed to turn the RAC into just another advisory committee. Why the change? I cannot write with a high degree of certainty, but I will hazard two reasons based on my proximity to the scene. The first reason was that the then-Director did not approve of NIH's role as a research regulator; he saw the NIH as a research supporter. I shared his view 15 years ago, believing that the conventional forms of governance, including the judicial process, should provide the appropriate balance between a researcher's rights and obligations (11Carmen I.H. Cloning and the Constitution. Univ. Wisconsin Press, Madison1985Google Scholar). I still think that that is the correct approach were we writing on a blank slate. But I am not a purist. I appreciate, in the grand spirit of American pragmatism, that once we start down a road, and the results over time generally prove satisfactory, it does more good than harm to stick to that road. I fear that, like Supreme Court Justice Antonin Scalia, the ex-Director is a purist in these matters (purists can come in all sorts of ideological shapes and forms). He ripped up 20 years of a tried-and-generally-true procedure in the name of a more grandiose vision of scientific accountability. The second reason was pressure from certain principal investigators in the gene therapy field who had grown tired of running the RAC–FDA gauntlet. To them the FDA was a necessary evil; the RAC, however, was expendable. As stated, that reason is incomplete, however. The FDA was not a passive player in the process. The fact is that the FDA has a fairly long, and in my view a fairly suspect, reputation as a turf grabber. It claimed that it had the power to regulate the tobacco industry, and it took a Supreme Court decision to slap it down. It claims it can regulate human cloning, though nowhere in the NBAC report is there one sentence even debating the merits of FDA jurisdiction. Because the FDA has no ethical, legal, and social tentacle, it simply profited by the ex-NIH Director's purism and researcher discontent to expropriate the NIH's expertise in this area for its own purposes. The result, to repeat, was and is the emasculation of the RAC, much to the detriment of enlightened human gene therapy oversight. Let us look more closely at this emasculation. In 1999, the RAC had placed before it Richard Hurwitz's retinoblastoma protocol. Actually, Hurwitz hadn't even bothered to submit his papers to the RAC, filing only with the FDA; the RAC entered the picture after the FDA had already tendered its approval. While Hurwitz said later that not submitting to the FDA and the RAC concurrently was a plain and simple oversight, I guarantee he would not have committed such an oversight 5 years earlier when everyone knew the RAC had clout. According to one witness, "the committee turned thumbs down on [the] gene therapy protocol" (13Garber K. RAC nixes plan to treat retinoblastoma.Science. 1999; 284: 2066Crossref Google Scholar). Said Hurwitz in a published reply: "Our protocol was not 'nixed' by the RAC" (14Hurwitz R.L. Brenner M. Poplack D.G. Horowitz M.C. Retinoblastoma treatment (letter).Science. 1999; 285: 663-664Crossref Google Scholar). The issue here is not the proper definition of rejection. The issue is the degree to which the RAC was perceived by all the major players as the committee of last resort in its jurisdictional mission, the committee that called the ethical, legal, social, and scientific shots. To the degree that the RAC is today believed to be just another advisory committee, its messages get garbled and its place in the gene therapy scheme of things becomes murky. The Hurwitz tale and the James Wilson tale have much in common. In 1996, the RAC approved the Penn study including the researchers' choice of adult rather than infant subjects. The RAC did insist on one important change: the adenoviral vector must be inserted into a peripheral vein, not the hepatic artery. The protocol then went on to the FDA, which overruled the RAC on this point. That is, the FDA permitted its experts to trump the RAC's experts. But just why did the NIH Director accede to this pecking order? Why didn't the RAC have just as much know-how as the FDA, if not more, on the point at issue, namely, the likelihood of vector migration to germ cells? In fascinating and instructive déjà vu, Wilson, just as Hurwitz would do a bit later, failed to inform the RAC that he was "taking FDA's advice" (4Marshall E. Gene therapy on trial.Science. 2000; 288: 951-957Crossref PubMed Scopus (168) Google Scholar). Nor does it appear that the FDA bothered to inform its "partner" agency either. Already the RAC was on the road to second-class bureaucratic standing. The best way for the political system to respond to Jesse Gelsinger's death is to revitalize and rearm the Recombinant DNA Advisory Committee. The old NIH Director is gone; even he was threatening to rethink his decision in the light of the Hurwitz episode (13Garber K. RAC nixes plan to treat retinoblastoma.Science. 1999; 284: 2066Crossref Google Scholar). The process of education is somewhat daunting; key players don't see the critical political problem. The Biotechnology Industry Organization puts its faith in the FDA; in its view, the RAC should brainstorm about ethics but shouldn't be permitted to disapprove of anything (15Werner M. Gene therapy oversight creating stir on Capitol Hill.BIO News. 2000; : 3Google Scholar). Furthermore, important members of the gene therapy research community, though recognizing that the RAC is an open forum while the FDA is a "closed shop," still think the latter is the "appropriate regulatory agency" for political oversight (16Friedman T. Principles for human gene therapy studies.Science. 2000; 287: 2163-2165Crossref PubMed Scopus (44) Google Scholar). In a field where public concern is endemic, where that concern is freighted with ethical, legal, social, and especially political implication, and where give-and-take between scientific peers is maximized, I fail to see why the FDA's power-to-veto is more "appropriate" than the RAC's proposed power-to-veto (7Carmen I.H. Should human cloning be criminalized?.J. Law Politics. 1997; 13: 745-758Google Scholar, 17Steele F.R. Gene therapy on the RAC.Mol. Ther. 2000; 1: 1-2Abstract Full Text Full Text PDF Scopus (5) Google Scholar). I conclude by asking these various observers this question: Under what theory of governance are the people better served by the FDA acting alone and in secret in its jurisdictional capacity where a viable alternative is the FDA and the RAC acting jointly in their respective jurisdictional capacities? It is certainly not the theory of separation of powers augmented by checks and balances, our time-honored constitutional paradigm that one would think could offer instruction here.