Analyze the Jesse Gelsinger casei, mini essay

The Case of Jesse Gelsinger

The Story

When Jesse Gelsinger was growing up in New Jersey, he was diagnosed at the Children’s Hospital of Philadelphia with OTC (ornithine transcarbamylase) deficiency, a rare genetic disorder affecting about one of every eighty thousand babies. An OTC deficiency means a person lacks an enzyme in liver cells that converts the nitrogen, generated when the body absorbs protein, into urea that can be excreted by the kidneys. Unless this conversion occurs the nitrogen builds up in the blood as excessive ammonia, and this causes neurological damage and liver problems. Most babies with OTC deficiency die not long after birth.

The genetic mutation that causes this problem is located on the X chromosome. Women have two X chromosomes, so a defective gene on one of them makes them carriers but with few or no symptoms because their normal gene usually functions well. Men, however, have only one X chromosome, so if they happen to receive the defective X chromosome from their mothers (a 50 percent chance), they inherit the life-threatening OTC deficiency disease.

Jesse’s mother, however, was not a carrier. Doctors therefore attributed his OTC deficiency to spontaneous mutations in some of his liver cells. Hence, his OTC deficiency was mild and his disease was manageable as long as he stayed on a low-protein diet and took his medications.

In September 1998, when Jesse was seventeen and living in Arizona with his father, Paul, and his stepmother, a physician monitoring his disease at a metabolic clinic informed him and his father that researchers at the University of Pennsylvania were working on a clinical trial to see whether they could find a cure for OTC deficiency. The physician described the trial as “gene therapy.” The subject of the clinical trial and “gene therapy” came up again during Jesse’s visit to the metabolic clinic in April 1999. Both Jesse and Paul were interested in pursuing it and, since the family was already planning a trip to New Jersey in June, they agreed to visit the Institute for Human Gene Therapy (IHGT) at the University of Pennsylvania to see whether Jesse would be a candidate for the “gene therapy” clinical trial, which was already under way.

The design of the clinical trial, titled “Recombinant Adenovirus Gene Transfer in Adults with Partial Ornithine Transcarbamylase Deficiency,” was relatively simple. Researchers were engineering an adenovirus (which gives us colds by working its way into our cells) so it would not replicate once it invaded the liver cells. Then they inserted good genes with the OTC capability into the altered virus and infused the altered virus carrying the good genes into the liver. Researchers hoped that the healthy genes in the liver would soon produce enough OTC to overcome the deficiency and prevent ammonia from building up in the body. At this point researchers were conducting only a phase I trial, that is, a trial to see how high a load of the OTC gene-bearing viruses they could safely infuse into people’s livers without causing adverse reactions.

For the phase I trial they were looking to recruit eighteen adults who either had some OTC deficiency or who were carriers. Originally researchers had hoped to try the experiment on babies suffering from the OTC deficiency, but a well-known ethicist who was then at the university, Arthur Caplan, had raised objections to this plan. Caplan argued that the parents of children dying from OTC deficiency would be so devastated that many would agree to enroll their child in a clinical trial out of desperation, and their informed consent would not be truly voluntary. Moreover, the proposed trial was a phase I study where the goal was not to evaluate a therapeutic benefit but to see whether the intervention had unacceptable side effects, a distinction that desperate parents might not well understand.

Researchers planned to divide the eighteen participants into groups of three, with two women and one man in each group. Their plan was to give the three people in the first group a low dose of the altered virus and then monitor them for side effects for at least three weeks. If all went well, they would give the second group of three a higher dose of the altered virus and monitor them for three weeks, then infuse the third group with an even higher dose, and so forth. The women would receive the virus first, and only if the dose did not cause adverse reactions in them would the researchers give it to the man in the group, who would be more seriously affected by the OTC deficiency. Researchers were now nearing the end of the phase I clinical study; Jesse would be the third member of the sixth group, the last person to receive the altered virus.

In June 1999 Jesse and his father met with Dr. Steven Raper at the University of Pennsylvania. Since Jesse turned eighteen that month, he would be old enough to give voluntary informed consent for the clinical trial. Raper, a surgeon involved with the gene transfer trial, explained the procedure to him and his father. He would insert a catheter into the artery leading to Jesse’s liver and a second one into a vein leading from his liver. He would put the modified adenovirus with the healthy genes into the artery leading to the liver. Hopefully the virus with the genes would invade liver cells and thus deliver the good genes. A check of the blood in the vein leaving the liver would indicate how much of the gene-bearing virus remained in the liver. By measuring the viral input and output researchers could determine whether the liver was absorbing the virus with the good genes embedded in it. A week later they would do a needle biopsy of the liver to confirm the results of the attempted gene transfer.

Dr. Raper told Jesse that there were risks involved. He would probably develop some flu-like symptoms after the infusion of the virus and there was some small chance of hepatitis, which he said could be treated. There was also a remote possibility that Jesse might die from the liver biopsy (Dr. Raper told him that the risk of death from a liver biopsy is about one in ten thousand). Dr. Raper also made it clear that the clinical trial, even if it worked as they hoped, would not reverse Jesse’s OTC deficiency because his immune system would reject the virus with the healthy genes in a matter of weeks. On the other hand, if the gene transfer was successful, then it would be a big step forward toward developing a genetic therapy for babies with the OTC deficiency as well as for dozens of other genetic diseases affecting the liver. Both Paul and Jesse agreed to participate if tests showed that Jesse would be a good candidate for the clinical trial.

A month later Dr. Mark Batshaw, another one of the physicians conducting the study, wrote both Paul and Jesse in Arizona about the clinical trial and then spoke with them by phone. According to Paul Gelsinger, Dr. Batshaw said that the treatment had worked temporarily in mice, even preventing death when mice were injected with lethal doses of ammonia. He also said that there were about twenty-five other liver disorders affecting five hundred thousand people in the United States and 12 million worldwide that could be treated with the same technique if it worked and that a recent human participant in the study had experienced a 50 percent increase in her ability to excrete ammonia. In other words, the research was showing signs of therapeutic value that could benefit millions of people. This clinched it for Jesse and his father; they considered this promising news and became excited about participating in the “genetic therapy” research at IHGT.

The chief investigator in the study was Dr. James Wilson, the head of the IHGT at the University of Pennsylvania. He had become interested in developing genetic therapies for liver diseases after reading about a well-known patient named Stormie Jones, a young girl whose liver cells had a genetic mutation that prevented the liver from removing LDL cholesterol from the blood. This genetic defect allows high levels of the dangerous LDL cholesterol (the “bad” cholesterol) to develop in the body, and most patients suffering from it die prematurely from heart attacks. Stormie was in imminent danger of dying from very high LDL cholesterol levels when she received a heart and liver transplant. The transplanted liver began removing LDL from her blood stream and the healthy transplanted heart gave her a new lease on life. Wilson began to think it would be better for patients if a way could be found to insert normal cells into their liver rather than transplanting a liver.

In experiments on human participants, which began in 1992, Wilson and other researchers surgically removed part of the person’s liver, cultured cells from it in the laboratory, used retroviruses to convey healthy genes into the DNA of these liver cells, and then infused the modified cells back into the liver through a catheter in the artery leading to the liver. Eighteen months after performing the procedure on a twenty-eight-year-old research subject, Wilson reported in 1994 that the genetic intervention was safe and had successfully lowered the person’s LDL level.

Wilson realized, however, that removing cells from a patient, modifying them in vitro, and then putting them back into the patient would have limited use in genetic therapy. A more promising procedure would be the development of what he called “injectable genes.” Doctors would be able to transfer healthy genes directly into the body’s liver cells, perhaps by viruses. If it worked, this would be an in vivo genetic therapy. In animal experiments, Wilson was actually able to lower the cholesterol level of rabbits by injecting healthy genes into their bloodstream.

Wilson soon began working on another genetic disease of liver cells, the OTC deficiency. He thought he could overcome this deficiency by using modified viruses to carry healthy cells with the OTC enzyme directly into the liver so there would be no need to remove part of the liver and add the genes in the laboratory. Scientists and biotech companies were watching his work with great interest. If it worked many people could be cured of diseases caused by deleterious mutations on the genes in liver cells and biotech companies could make a lot of money thanks to patent protection for the engineered viruses that could reverse the diseases.

Jesse flew to Philadelphia on September 10, 1999. Dr. Raper inserted the catheters on the following Monday, and a large dose of the modified virus with the healthy genes flowed into Jesse’s liver. As expected, Jesse suffered flu-like symptoms that evening. Soon, however, things got worse. He spiked a high fever and rapidly deteriorated. Before long he was in a coma, on a ventilator, and receiving dialysis. Then he needed extracorporeal membrane oxygenation. By Thursday he was so bloated that his father hardly recognized him. On Friday morning it was obvious that he had suffered massive brain damage and that his organs were shutting down. After the family gathered and a chaplain said a prayer, a doctor withdrew the life support and Jesse was pronounced dead at 2:30 p.m.

An autopsy failed to identify the cause of the problem that led to his death. Obviously the infusion of the altered viruses caused a reaction that killed him, but doctors could not figure out why. Paul Gelsinger, shocked over the loss of his son, nonetheless supported the doctors and felt that they had done the best they could.

The doctors at IHGT promised to conduct a complete investigation and to inform Paul of everything they discovered. About two months after Jesse’s funeral, Dr. Wilson, the head of the Institute and the sponsor and chief investigator of the OTC deficiency study, flew to Arizona and met with Paul Gelsinger. He explained that Jesse’s death was totally unexpected and still remained unexplained. He spoke of how important the work of his IHGT was, and he sought Paul’s continued support. He asked Paul to come to a three-day meeting of RAC in December that would be reviewing the clinical trial. Paul agreed and flew to Philadelphia where he visited Wilson’s IHGT and then drove to Bethesda, Maryland, the next day for the RAC meetings.

As the RAC meeting progressed, however, Paul began to see another side of the clinical trial that took the life of his son. He heard FDA officials say that Jesse should not have been infused with the virus because his ammonia level was too high at that time. Originally candidates with blood ammonia levels of more than 50 were not considered eligible to participate; later researchers raised that level to 70. When Jesse arrived in Philadelphia for the clinical procedure, his blood ammonia level was 114, and NIH officials said that he should not have been considered eligible for the trial. However, researchers had lowered his level somewhat with medication before they infused the virus.

Paul also learned that researchers had failed to report to the FDA in a timely manner or to inform him and his son that some earlier participants experienced significant side effects from the viral infusions. He also learned that the informed consent form that Jesse signed differed from the one the FDA had approved, and it in fact omitted the important information that two monkeys had died in animal studies after being given high doses of the virus.

Paul now began to think that Jesse had signed the informed consent form without being well informed about possible side effects and risks. He also heard that the viral infusions had not provided any clinically significant therapeutic impact on earlier participants, something that raised questions in his mind about Dr. Batshaw’s remarks that one woman achieved a 50 percent gain in ammonia excretion. Based on that remark, both he and Jesse had thought the research was showing some sign of therapeutic advantage. Paul was also upset to learn that researchers had not provided NIH, which funded the study, or the FDA, which monitored it, or the IRB at the University that oversaw it with other information in a timely manner, as was required by federal regulations.

In remarks to reporters outside the RAC meeting Dr. Wilson objected to the FDA criticisms. He insisted that no data from either animal or human studies foretold that Jesse would die; that the FDA was eventually told of the two participants who experienced the side effects before Jesse was infused, yet it did not stop the study; and that the ammonia level in Jesse’s liver was functioning within the protocol parameters when he was enrolled in the study three months before his infusion. Wilson, however, did not respond to criticisms about the informed consent form and he declined to take questions.

On February 14, 2000, the IHGT responded formally to FDA criticisms and pointed out, among other things, that every patient did give informed consent for the clinical trial; that the two monkeys who died were in a genetic experiment for a different problem, colorectal cancer; and that there was no evidence that the high ammonia level in Jesse was a cause of his death. However, these remarks still left important questions unanswered. Simply because there is a record of informed consent does not mean that the person actually had all the information he needed to give informed consent. And the issue about the two monkeys is not that they received a different gene for a different problem but that they received a similar viral vector to transport genes into their bodies. And it is true that there is no evidence that Jesse’s high ammonia level caused his death, but the point of the FDA criticism was that the approved protocol did not allow researchers to infuse the virus into participants with such high ammonia levels, and researchers are expected to abide by the approved protocols.

After months of publicly supporting the doctors at the university and their research despite the loss of his son, Paul Gelsinger now became their critic and soon sought legal redress. Before looking at what happened next, we consider the case from an ethical point of view.

Ethical Analysis

Situational awareness. We are aware of the following facts in the Gelsinger story:

1. When Jesse was seventeen, both he and his father heard of some important “gene therapy” research at the University of Pennsylvania for people suffering from OTC deficiency, a genetic condition that takes the life of so many afflicted children. He and his father were interested in participating in the “gene therapy” research because they believed it might save the lives of babies and might even lead to something down the road that would help Jesse so he could eat a normal diet and not need medications to control his condition. When he turned eighteen, Jesse visited the Institute for Human Gene Therapy at the University and consented to becoming a participant in the phase I trial. According to his father, part of his reason was to do something that would allow development of a genetic therapy to help prevent future babies from being ravaged by the deadly disease.

2. Unlike most children with OTC deficiency, Jesse’s disease was controlled with medications and a low-protein diet. However, the teenager found taking his medications was a hassle. He did not always take them on schedule or stay on his diet, and he suffered occasional relapses. Dealing with his disease sometimes left him frustrated and angry. At one point, he actually jumped out of his father’s vehicle in a fit of anger while it was still moving, and his arm ended up under a wheel. It is possible that Jesse hoped for a long shot—that enough progress could be made so a genetic therapy might actually benefit him by allowing him to go off his medications and enjoy a normal diet.

3. Dr. James Wilson, chief of Molecular Medicine and Genetics at the University of Pennsylvania and head of its Institute for Human Gene Therapy, was a leading researcher in the field of genetic research on liver diseases. Wilson thought it might be possible to transfer healthy liver genes into patients.

4. Jesse was the eighteenth and last participant in the phase I OTC deficiency clinical trial, and he would receive the highest dose of the viral vector with the healthy genes.

5. NIH funded the clinical trial and the FDA approved it. The FDA provided oversight and required progress reports, especially about adverse reactions if they occurred. There was some hesitation when the trial was first proposed because putting large amounts (trillions) of viruses into people is risky business. Viruses will trigger, and may overload, the immune system even though the viruses have been engineered not to replicate. Actually some earlier participants in the OTC trial did experience some adverse effects that should have been reported to the FDA, but the doctors did not inform the Gelsingers of this.

6. Researchers at the University of Pennsylvania were also doing animal studies that used adenoviruses to transfer genes. Two monkeys in one experiment had died and a third became ill, but the physicians did not inform the Gelsingers of these deaths.

7. Inserting genes into a person’s body is a major challenge. Genes are mostly in the nucleus of our cells, and there is much we do not yet know about the DNA molecule that harbors them. Viruses have the capability of getting into the DNA of our cells (an adenovirus is what causes the common cold), so they are promising vehicles for transferring genes. The trick, of course, is to render the virus harmless and then use it to transport healthy genes into the DNA of the cells.

8. Genetic research is more challenging than drug research because we have to study not only the impact of the agent (the altered genes) on the body but also the impact of the vehicle we use to transfer the altered genes into the body. The vehicle, or “vector” as it is called, is often a virus, and putting massive doses of viruses into a person’s body even without any altered genes can trigger or even overwhelm the immune system.

9. The Bayh–Dole Act of 1980 allows universities to patent their discoveries and then assign patent rights to biotech companies in order to develop the discoveries into commercial products. The universities like the Bayh–Dole Act because it allows them to collect license fees and royalties from the biotech products their researchers develop. Academic researchers like the act because it allows them an opportunity to profit from their research by investing in biotech companies that could support their research and then market what might be commercially viable. Both the university and Dr. Wilson had invested in a company known as Genovo, a biotechnology company that Wilson and others had founded. The university’s equity share in Genovo was 5 percent and Wilson’s share was 30 percent.

We are also aware of numerous good and bad features in the case:

1. Clinical trials with human participants are essential for medical progress, and they have done a tremendous amount of good. Medical research cannot progress very far without them, especially when it comes to drugs, medical devices, and genetic alterations.

2. People who volunteer for clinical trials do so for a number of reasons. Some are dying and will try anything, some do it for money (some trials pay the participants) or free health care, some do it in the hope they will receive therapeutic benefit, and some do it with a sense of altruism because they want to help researchers find a cure for diseases that afflict or kill others. Jesse was not dying and he did not do it for the money. His father indicated that Jesse had a desire to help find a cure for the lethal disease that affects babies as well as hope that researchers might find something that could benefit him. These motivations are morally sound in a virtue-based ethics that focuses on flourishing and helping others to flourish.

3. Medical researchers inevitably find themselves enmeshed in numerous conflicts of interest. A major interest of ethical research is, or should be, protecting human participants from harm, but numerous other interests can conflict with this. First, good medical researchers have an intense interest in accomplishing successful breakthroughs, and this can clash with their responsibility to protect human participants in research from harm. Second, researchers often have an interest in winning recognition for their work and in seeing it published and accepted, and this can clash with protecting human participants. Third, medical researchers, especially if they are trained physicians, often have an interest in finding something that will help many future patients, and this can clash with protecting the small number of human participants in their clinical trials. Fourth, in the more than thirty years since the 1980 Bayh–Dole Act, many researchers and their nonprofit academic institutions have developed an intense interest in profiting financially when they develop something with great commercial value. Obviously the desire to bring a treatment to market rapidly can clash with the responsibility to protect carefully the people enrolled in the clinical trials.

4. Researchers had a moral responsibility to provide adequate and honest information to the Gelsingers when they recruited Jesse for the clinical trial. They also had a responsibility to provide timely information about adverse events to the university IRB, to the NIH, and to the FDA. They also had a responsibility to adhere strictly to the approved protocols for the clinical research. Published reports indicate numerous lapses of their responsibilities in these areas, and this is bad for the participants in the research and it is bad for clinical trials in general because people will not volunteer if they think doctors are acting irresponsibly.

Prudential Reasoning in the Gelsinger Story

Participant’s perspective.Is it morally reasonable for a teenage person in Jesse’s position to agree to enter a clinical trial such as this? Based on the information he was given and the guidance of his father, it is hard to fault his decision to enter the trial. He expected flu-like symptoms that would pass. The informed consent form also noted that the altered virus could be toxic to his liver, but he was reassured that this could be treated. His biggest worry seemed to be the liver biopsy, with its very slight risk of death. The problem, of course, is that he and his father did not receive important information about the adverse effects of the virus transfer in monkeys or in previous participants in the trial, nor did they receive any concrete information about the financial arrangements involving Dr. Wilson, the IHDT, and the University of Pennsylvania. It should be noted that at the end of the eleven-page informed consent form was a statement indicating that both Dr. Wilson and the university had “financial interest in a successful outcome.” The problem, of course, is that Jesse and his father had no idea what that interest was or that it involved millions of dollars.

Parent’s perspective. Jesse’s father, Paul, provided a great deal of guidance and support for his son. It is hard to fault his role based on the information he was given. Later he pursued legal action against the researchers, which also is morally reasonable in a case such as this because the researchers did not disclose important information and great harm was done: the clinical trial caused the death of a relatively healthy teenager who had no need of genetic therapy to control his genetic disease. Paul has continued to speak and write about the tragedy, and this has served to call attention to the need to improve patient protection in clinical trials.

Researchers’ perspective. There are good moral reasons for doing research with human participants designed to develop genetic therapies correcting mutations in human liver cells. Someday genetic research might lead to a significant revolution in medicine that will help many human beings. It is not morally reasonable, however, for researchers not to meticulously follow the approved protocols; not to inform prospective participants of adverse reactions in previous subjects, or of animal deaths in viral transfers, or of financial arrangements relevant to clinical research; and not to provide timely information required by the protocols and by regulations to the NIH, the FDA, and the local IRB that oversee the clinical trial.

University’s perspective. Officials at the University of Pennsylvania were aware of some of the conflicts of interest between Wilson’s work as a university faculty member and his significant financial stake in Genovo, a company he cofounded to market the products of his research. In 1994 the university’s Conflicts of Interest Standing Committee (CISC) had looked into the conflicts of interest that would exist between Wilson’s research and the potential for great financial gain for him and his company that the research could generate. The CISC made an effort to reduce the potential negative impact of this conflict by imposing some restrictions on Wilson: he could not sit on Genovo’s scientific board, he could not be paid for his work as a consultant for Genovo, and he could not do clinical studies funded by Genovo. Yet the university allowed Dr. Wilson to own 30 percent of Genovo stock, and it accepted an equity share in Genovo for itself. The university also agreed that the IHGT could accept $4 million a year for five years from Genovo for genetic research, and in return it allowed Genovo to seek licenses and patents and to earn profit on future developments by the IHGT or its researchers. They also agreed to accept $25,000 a year from Genovo toward the salary of Arthur Caplan, the well-known bioethicist then at the university. Professor Caplan was professor of bioethics in the Department of Molecular and Cellular Engineering, which Dr. Wilson chaired at that time.

The Aftermath

In December 1999 the NIH and the FDA held the hearings in Bethesda regarding the clinical trial, and Paul Gelsinger attended. After investigating the circumstances surrounding Jesse Gelsinger’s death, the NIH reminded all researchers with similar genetic experiments that federal regulations required them to report adverse events that occur in the trials. Up to that point 39 adverse events in genetic experiments had been reported; after the NIH reminder the number suddenly jumped to 691! Clearly scientists were routinely disregarding the NIH reporting regulations.

On January 21, 2000, the FDA shut down all clinical genetic trials at the University of Pennsylvania due to numerous regulatory violations.

In August 2000 Targeted Genetics Corporation, a biotech company, acquired Genovo. Published reports indicate that Wilson’s equity interest in Genovo brought him $13.5 million in Targeted Genetics stock and that the university’s equity interest in the company was worth $1.4 million at the time of the sale.

In September 2000, one year after Jesse died, his family brought a wrongful death/fraud/intentional misrepresentation lawsuit against the university, the Children’s National Medical Center (CNMC) in Washington, the Children’s Hospital of Philadelphia, doctors Wilson, Raper, Batshaw, and Kelley (the dean of the medical school), Genovo, and the bioethicist Arthur Caplan. The suit alleged, among other things, that the informed consent process was seriously flawed because the defendants failed to inform Jesse and his family of the risks to him suggested by the illness and death of the monkeys and failed to disclose the adverse effects the virus had caused in some earlier human participants. It also alleged that the defendants failed to disclose adequately the conflict of interest that existed on the part of Dr. Wilson and the university due to their financial interests in seeing Genovo succeed by bringing the viral vector to market as rapidly as possible. The implication of the lawsuit was that the researchers and the university cut corners in the clinical trial in their haste to develop what would be a blockbuster biotech product.

The defendants in the lawsuit decided not to defend their actions in court. About a month after the lawsuit was filed, they quickly agreed to settle the case out of court and paid the Gelsinger family an undisclosed amount of money, estimated by some reports to be in the neighborhood of $10 million. Both the FDA and the Justice Department continued their investigations,

In February 2002 the FDA formally notified Dr. Wilson that he had failed to address adequately numerous issues that the FDA had raised about the clinical trial, among them:

• The study was not stopped as required by the approved protocol after some participants developed grade 3 or higher toxicities.

• Researchers injected the virus into subjects that did not meet the criteria required by the approved protocol.

• Researchers injected the virus into a male as the second person in a group of three despite written agreement that the sequence in each group of three would be two females followed by one male (males with the disease are more at risk than female carriers).

• Researchers failed to perform prestudy ammonia tests on three days and one day before the viral infusion on all participants as required by the protocol.

• Researchers failed to submit accurate and timely reports to the IRB. In the annual report to the IRB in August 1997 Dr. Wilson stated that the first person in the study developed mild anemia probably because so much blood was drawn and that the next two participants did not develop anemia after the amount of blood drawn was reduced. In fact, however, those two participants actually did develop grade 1 anemias, but this was not reported. In the annual IRB report of August 1998, after the first ten participants had received the virus, Dr. Wilson stated that “there have been no significant treatment-related or procedure-related toxicities,” when in fact a significant adverse event had occurred on June 25, 1998. Also, the 1998 annual report did not present a table of adverse events according to the protocol; this information was not submitted until the 1999 annual report. In the annual report of August 1999 Dr. Wilson stated: “No serious adverse effects have occurred as a result of this study.” The FDA alleged this statement is false because the record shows there were some serious adverse effects, namely, grade 3 toxicities in six participants.

• The protocol stated that researchers will halt the study if a single participant develops a grade 3 or higher toxicity, yet they did not halt the study despite instances of grade 3 toxicities in dose cohorts 4, 5, and 6.

• Researchers failed to obtain proper informed consent in accord with federal regulations. The FDA requested that Dr. Wilson inform participants not to donate blood or gametes, and he confirmed in writing that he had added that information to the consent form when in fact this information was not in the informed consent form. Researchers also failed to inform potential participants that higher doses of the virus were associated with DIC (disseminated intravascular coagulation—a life-threatening generalized bleeding that is hard to stop) in monkeys and might cause a similar problem for humans. Three monkeys received viral vectors in late 1998; one received the same virus vector as the humans and the other two a different vector, but all three developed DIC. Yet the consent form was never changed to reflect this important fact, and Jessie did in fact develop DIC after he received the virus. Researchers also failed to inform the later participants in the trial that, in addition to “flu-like symptoms,” they were likely to experience significant periods of chills, nausea, and vomiting. Moreover, the protocol said that they would be given only Tylenol for discomfort when in fact researchers had to use other pain medications to reduce the discomfort participants were experiencing.

In April 2002 Wilson relinquished his post as director of the IHGT. In September 2002 Dateline NBC did a program on Jesse’s death and the family’s search for answers. In February 2003 BBC Two devoted a program to the tragic story.

In February 2005 the US Department of Justice announced a civil settlement in the case that the department had brought against the institutions and the researchers involved in the OTC trial. The Department of Justice had accused the researchers (Wilson, Raper, and Batshaw) and their institutions (the University of Pennsylvania and CNMC) of violating the civil False Claims Act between July 1998 and September 1999 by (1) submitting false statements and claims on the grant applications, progress reports, and annual reports submitted to the NIH; (2) submitting false statements and claims to the FDA, which was monitoring the research; (3) submitting false statements to the IRBs, which reviewed the research over a period of several years; and (4) submitting false statements and claims that prevented the human research participants from giving properly informed consent.

In the settlement with the Department of Justice the University of Pennsylvania agreed to pay a fine of $517,496 and CNMC agreed to pay a fine of $514,622. The Department of Justice settlement did not require Dr. Wilson and the other physicians to pay fines, but it did impose restrictions on their work. Dr. Wilson, as the sponsor of the FDA-regulated clinical trial paid for by NIH, had to agree not to participate in research involving human subjects until he completed training in protecting human subjects. He also had to accept severe restrictions on his research with human participants until February 2010. Dr. Wilson also agreed in the settlement to lecture and write an article on the lessons learned from the OTC study, and to include statements from the Gelsinger family in the article. Wilson’s article on lessons learned from OTC trial in which Jesse Gelsinger died was published online and in print four years later, in 2009.

Two other physicians involved in the research, Mark Batshaw and Steven Raper, were also required to complete training in protecting human subjects, and both had restrictions placed on their clinical research for three years. As is customary in this kind of settlement, the accused parties (the two institutions and the three physicians) did not admit the allegations and contended that their behavior was at all times lawful and appropriate.

In January 2008 Dr. Wilson, as the editor-in-chief of the journal Human Gene Therapy, wrote an editorial on adverse events in gene transfer trials in which he encouraged “genetic therapy” organizations to put in place more effective ways for human participants in clinical trials to have “a full and unbiased understanding of the risks and benefits of their participation.” The editorial mentioned the adverse events in the severe combined immune deficiency (SCID) and arthritis trials discussed in the next section but did not mention the adverse events and the death of Jesse Gelsinger in his OTC trial at the University of Pennsylvania.

In the same issue of Human Gene Therapy, two authors recommended the appointment of advocates to help people considering participation in genetic experiments to understand the risks of genetic research and to advise them whether participation in a study is truly in their best interest. Yet more than a participant-advocate was needed in the Gelsinger case. Jesse needed to know about numerous major problems in his clinical trial—namely, the failure of researchers to provide information about the recent monkey deaths; the failure of researchers to inform him (and the IRBs, the FDA, and the NIH) of the earlier adverse events experienced by people enrolled in the study; the failure of researchers to abide by and eventually to stop the study in accord with the approved protocol; and the failure of researchers to mention the extent of the financial gain that Wilson and the university stood to receive if they could market the viral transfer procedure.

Ethical Reflection

The story of Jesse Gelsinger ranks with other landmark bioethics cases such as Quinlan, Conroy, Cruzan, and Baby Doe. Investigations into Jesse’s death by the NIH, the FDA, the Department of Justice, and attorneys representing the Gelsinger family uncovered numerous instances of actions and omissions on the part of researchers that appear less than admirable from a virtue ethics perspective and that are contrary to federal regulations guiding research on human participants. We cannot flourish as human beings—that is, develop moral integrity—by being less than fully honest with other human beings in matters that affect their health and well-being, and by failing to manage well conflicts of interest where the well-being of research participants collides with the potential for huge profits and the desire for scientific acclaim. Jesse’s death was the first time someone in a clinical trial involving gene transfer died, and it serves as a wake-up call for everyone involved in genetic research involving people.

The Gelsinger story also raises our consciousness about a whole new set of ethical issues that arise in the entanglement of campus-based research funded by the NIH with the commercial biotech industry funded with venture capital and looking to make a profit for its shareholders sooner rather than later. The desire to make serious money all too easily conflicts with the moral responsibility to protect human subjects and to treat fellow human beings with honesty and decency. There is clearly a conflict when both the nonprofit universities and the researchers who work for them have an interest in the potential financial gain that could be generated from the federally funded research.

There is no way to root out all conflicts of interest in medical research. Researchers, especially if they are physicians, generally have an interest in helping mankind by curing disease. But they also often have personal interests (they want public acclaim and awards), professional interests (they want to expand scientific knowledge and discover something new), and financial interests (they want to make money). If we cannot root out conflicts of interests what can we do?

One suggestion is disclosure: some insist that researchers should disclose their conflicts of interest to potential participants in their studies. As Theodore Friedman, who served as chair of the NIH RAC, wrote in the journal Science after the Gelsinger tragedy, “The single most important mechanism for ensuring patient protection from inherent risks of clinical experiments, unrealistic expectations, and potential conflicts of interest of the investigator is accurate and full disclosure of potential risks and benefits and a well-executed informed consent process.” This is a step in the right direction, but it is not enough because informing potential human participants does not adequately protect them from being harmed by the inherent risks or financial conflicts of interest.

We need more than disclosure; we need protection for vulnerable human participants entering the world of clinical research. In addition to disclosing conflicts of interest, we can insist on better oversight by IRBs, the NIH, and the FDA and better procedures to protect vulnerable human participants who do not really understand how the research culture is driven by money as well as by the desire to achieve breakthroughs in science and medicine.

Some have suggested that people considering enrollment in clinical experiments involving genomics and genetics should be provided a knowledgeable advocate who will help them understand the science, including the relevant studies on animals, and the financial background of the research so they can give fully informed consent before becoming human subjects in these experiments. This is an idea worth exploring because the implications of scientific genetics are difficult to grasp and serious money is often involved in the ties among researchers, universities, hospitals, and the biotechnology industry.

Most importantly, we can work to ensure that another interest receives serious attention in the way we educate future researchers—the ethical interest whereby researchers realize that the most important thing in their life is not discovering a cure or making a lot of money but flourishing as decent human beings; that ethics trumps personal, professional, and financial success; and that character integrity cannot be achieved unless we treat other people with respect and decency.

In addition, more accurate language in genetic research will help. The phrases “genetic therapy” and “gene therapy” are ubiquitous in both the professional and popular literature, but they are terribly misleading. At this point (2015) no genetic therapies exist in the United States, and we should not speak or write as if they do. All we have is genetic research and genetic experimentation. Calling an institute the Institute for Human Gene Therapy, for example, when the institute’s primary function is not providing any therapy for anyone but conducting experiments on human beings, is misleading and another example of the “therapeutic misconception,” a common ethical problem in human subjects research. A more accurate title would be something like the “Institute for Human Gene Research.” Human beings enrolled in clinical research involving gene transfers can easily misunderstand what is going on if they are told they are participating in genetic therapy trials rather than in genetic research. As was stressed in chapter 3, inappropriate language often distorts understanding and moral reasoning. Unfortunately, the NIH Genetics Home Reference Handbook contributes to the misunderstanding. It asks “What is gene therapy?” and replies “Gene therapy is an experimental technique that uses genes to treat or prevent disease,” thus conflating therapy or treatment with experiment or research.

Finally, we can also rethink the ethics of conducting research on children. The advice of the well-known ethicist Arthur Caplan to researchers at the University of Pennsylvania when they wanted to conduct the OTC deficiency research on babies carries some weight. Caplan said that research on babies would be unethical because parents, distraught over hearing about the lethal disease affecting their child, would not be able to give truly voluntary and informed consent on behalf of their children. He advised enrolling only people over eighteen, who are capable of giving informed consent, and this is how Jesse Gelsinger became involved. Caplan’s advice captures an important insight: we cannot morally permit desperate parents to volunteer their babies for risky research. However, there is another way to look at the research.

The federal regulations governing federal funding for research on children focus on minimal or almost minimal risk, and Caplan’s objection to enrolling children in the OTC genetic trial focused on parental voluntary informed consent. But maybe the focus in cases like this should be on whether the research has a reasonable balance of possible benefits for the participant and for others compared with what is at stake for the children already dying of OTC deficiency. If we focus on this, we might see the OTC research in a different light. We might see it as more appropriate to enroll babies than adult survivors like Jesse. This is so because adults in a genetic experiment who have survived the disease are actually at much greater risk for harms from the research itself than the babies who are already dying from the disease. It was the research itself that exposed the few adult males in the study to great harm—their lives were at risk from the experiment and not from the usually lethal disease that was not threatening their lives. On the other hand, the lives of the babies with the OTC deficiency are already at high risk from the lethal disease and will almost certainly soon die from it. They are already in harm’s way, and if the experiment caused their death it would be bad but less harmful than if it caused the death of somebody not at risk of dying from OTC deficiency.

There is something of analogy here with people who may be dying of cancer and who want to try a risky experimental treatment. They have a lot less to lose than a person who is not dying, so it is reasonable for them to take greater risks than a person who is not dying. So too, dying babies with OTC deficiency have a lot less to lose than adults such as Jesse who are surviving with mild forms of OTC deficiency. Even if he were fully and properly informed of the research, which he was not, it still might have been more reasonable not to admit him because he had so much to lose. The more reasonable approach here might have been to allow parents to consent for their dying babies, as Dr. Wilson wanted to do in the first place.

This does not mean we can use babies or children as guinea pigs for medical research. What it does mean is that, in some cases, a reasonable prudential argument could be made that, just as dying adults might think it is reasonable to enroll in a risky clinical trial hoping against hope that it may help them and, if it does not, that researchers might learn something that will help others, parents in extraordinary situations might think it reasonable to enroll their dying children in risky research that would not be reasonable if the children were expected to survive.

A final remark: one can argue that it would be morally admirable for researchers to offer families of those harmed or killed in a poorly conducted clinical trial at least an apology for their various failures, especially after the litigation was settled. The FDA, the NIH, the Department of Justice, a settled civil lawsuit, and widespread ethical commentary found numerous lapses with the way the university, Wilson, Roper, and Batshaw conducted the Gelsinger clinical trial, yet no one is on record as apologizing for the misdeeds and omissions. The lack of an apology has continued to bother Paul Gelsinger years after the tragic death of his son.

Other Deaths

Jesse was the first person to die in a genetic research trial but not the last. In 2005 several of the eleven children enrolled in a clinical genetic trial in France developed leukemia-like disease, and one of the children died. The children had a form of SCID, an inherited genetic disease that leaves patients without a functioning immune system. White blood cells lack an enzyme needed to maintain the immune system, and without it they cannot fight off infections of any sort. There really is no good treatment for the problem. Researchers led by Dr. Alain Fischer of the Necker Hospital in Paris were experimenting with a retrovirus to introduce genes with the enzyme into blood stem cells to see if they could provide a functioning immune system.

For a while it seemed to work. In April 2000 Fischer reported in the journal Science that two babies in his study had normal immune systems ten months after receiving the gene transfers. On April 28, 2000, Gina Kolata reported in the New York Times: “For the first time, gene therapy has unequivocally succeeded, scientists say.” Eventually eight of eleven children receiving the gene transfer showed marked improvement. The gene transfer looked like a success. In 2002, however, a serious problem appeared: one of the children developed T-cell leukemia. Soon a second child developed the same problem. In January 2003 the FDA temporarily halted all twenty-seven SCID trials in the United States that were similar to the trial in France. Eventually four of the eight children who initially benefited from the gene transfer developed T-cell leukemia. Then, early in 2005, tragedy struck: one of the children in France died from the leukemia. In effect, the genetic transfer did reverse the SCID but at a very high risk of leukemia and death in a few years. The hype about a successful genetic therapy was premature; the “therapy” was really an experiment that provided a functioning immune system but brought with it an unacceptable risk of cancer and death. In late 2007 it was reported that a child in a somewhat similar trial at the UCL Institute for Child Health in London also developed T-cell leukemia.

In July 2007 there was yet another death associated with genetic research on human beings. A thirty-six-year-old woman named Jolee Mohr, who was enrolled in a clinical trial by Targeted Genetics (the company that bought Dr. Wilson’s Genovo), died after receiving an injection of adeno-associated viruses carrying genes into her arthritic knee in a phase I/II (safety plus the possibility of improvement) trial. Her rheumatologist, Dr. Robert Trapp, injected the adeno-associated virus into her knee on Monday, July 2. The next day her temperature was 101. She continued to get worse and on Saturday, July 7, she went to the emergency room with a temperature of 104.1. She was sent home under the care of her primary care physician. Aware of the virus injection, he called the rheumatologist and told him of the adverse reaction. Dr. Trapp assured him that the virus was safe. Jolee got worse and on Friday, July 12, she was admitted to the local hospital. On July 19, she was transferred to the University of Chicago Hospital where doctors, learning of the gene transfer, notified the FDA of the adverse reaction. Targeted Genetics also notified the FDA the next day, and the arthritis study was halted. After life support was withdrawn from Jolee on July 24, she died twenty minutes later, leaving behind her husband and five-year-old daughter.

The FDA immediately halted the trial and other similar research studies, but then it lifted the ban in December 2007, a move that seems to indicate it believed that the genetic transfer was not the cause of her death. On the other hand, NIH’s RAC reviewed the case and said it could not rule out that the genetic transfer via the viral vector was a factor in her death due to lack of data. Hence, in this case we are left not knowing whether or not her death was related to the gene transfer.

Even if her death was unrelated to the gene transfer, this clinical trail raises important ethical issues. First, the move to treat arthritis, which is not a lethal disease, by experiments using gene transfer with large doses of viruses is morally controversial. It raises ethical concerns because risking a person’s well-being or life in connection with a nonlethal disease is seldom a prudent or reasonable thing to do. Moreover Jolee’s husband said, according to published reports, that she was only mildly affected by her arthritis and was living a relatively normal life. In fact, she had spent the weekend before she received the injection of the virus boating with her family.

Second, it should also be noted that she was recruited for the study by Dr. Robert Trapp, her rheumatologist. Patients tend to place great trust in what their physicians suggest, and this could have biased her consideration of the risks. She also signed the consent agreement immediately after he told her of the clinical study. It would have been more prudent for Dr. Trapp to insist that she take the document home, read it carefully, and then think about it and talk it over with her husband. The document, by the way, did speak of “unknown side effects” and “in rare circumstances, death,” but the language was buried in the middle of the fifteen pages.

A third ethical issue in this case is that her rheumatologist did not provide an important piece of relevant information: Targeted Genetics was paying him for every patient he recruited for the study. At least there was no mention of this in the informed consent document. It seems reasonable that many people would want to know whether the doctor recruiting them for a clinical experiment is being paid for having them sign up; otherwise they may think their doctor is recommending their involvement solely for their best interests. Many researchers, however, continue to think that it is not ethically relevant to explain what their financial interest is in recruiting research subjects or in obtaining results quickly from trials that will bring them or their companies financial profit.

A fourth ethical issue is the IRB review in this case. Targeted Genetics did not use an IRB at a hospital or university; it submitted the protocol to a private commercial IRB under contract with the company. The IRB was approved by the FDA, but the problem is that these for-profit IRBs risk losing business if they are too demanding about studies that biotech companies want to pursue. Hence, there is yet another conflict of interest here; the IRB has a financial interest in approving studies for the biotech companies as well as a regulatory interest in protecting human subjects, and the danger is that the former interest might overshadow the latter.

Germline Genetic Research

One particularly thorny ethical issue centers on future research that would alter either what are called germline cells or gametes (the cells of sperm and ova forming the next generation) or very early embryos before any cells, some of which will become germ cells, become differentiated. Alterations of DNA in germ cells of parents and in early embryos will pass into the bodies of their children and then will be inherited by their children’s children and thus modify a whole line of future generations. Alterations of DNA in all our other cells—the somatic cells—usually affect only one person and not any children.

Altering only somatic cells is both an advantage and a disadvantage. It is an advantage because it confines any unintended and unwanted consequences of the genetic alterations to one person. If something does not turn out well, and this often happens in medical research on human participants, then the problem will affect only the patient and not future generations.

Yet it is also a disadvantage because successful genetic alteration of somatic cells will only help the research participant or the patient and does not correct the mutation children will receive from parents through the germ cells that form the fertilized ovum. It would be nice to correct the genetic error in subsequent generations as well as in the actual patient. It would be nice, in other words, to develop effective gene therapy for germ cells so that deleterious inherited genetic mutations can be stopped once and for all. The fact that germline gene alterations, unlike somatic alterations, would alter the DNA of future generations is what makes it so promising—and so dangerous. Germline research and therapy could prevent disease in future generations, but it could also introduce unwanted alterations in the gene pool that could haunt future generations. The stakes are so high that no germline research has yet been approved, although some scientists do want to try it.

Germline genetic alterations could occur either in ova and spermatozoa before fertilization or in early embryos. Alterations to cells in early embryos are also germline alterations because the cells are not yet differentiated; that is, not yet functioning as specific cells such as brain cells, or kidney cells, or blood cells, or sex cells, and so forth. Any alterations made in the undifferentiated cells of an early embryo, then, will appear in all those cells’ daughter cells, and some of the altered daughter cells will eventually become differentiated and function as germ cells—spermatozoa or ova.

An intense ethical debate about germline therapy is now gathering momentum. The 1982 President’s Commission report Splicing Life took a dim view of germline alterations but was not overly concerned because at the time germline genetic engineering seemed a long way off. But as time went on concern began to rise. In 1997 most European countries took a strong stand against germline alterations by signing the Convention on Human Rights and Biomedicine, which states: “An intervention seeking to modify the human genome may only be undertaken ... if its aim is not to introduce a modification in the genome of any descendants” (Article 13).

However, the United Kingdom and, of course, the United States, did not sign this convention, and some scientists in these countries have been advocating research involving germline modifications. In February 2014, after a two-day public meeting, the FDA said that more studies are needed before it can give any approvals for germline human trials. One way to prepare for this is to modify the germ cells of animals and then track their offspring for several generations to see what happens.

Great Britain is moving ahead more rapidly; in February 2015 it legalized a procedure that will affect the human germline. The procedure is variously called “mitochondrial replacement,” “oocyte modification,” or “3-parent IVF.” It was designed as a way for women with deleterious mutations in their mitochondrial DNA to have healthy genetic children. Only mothers pass on mitochondrial diseases; the father’s spermatozoon loses its mitochondria during fertilization, so its mitochondrial genes are not inherited by his offspring.

At the end of the last century some researchers had tried to overcome maternal mitochondrial defects by adding healthy mitochondria from a second woman’s egg to the cytoplasm of an egg from the woman with mitochondrial mutations and then fertilizing that egg with the husband’s sperm in a typical IVF procedure. Between 1997 and 2000 several children were actually born after this mitochondrial modification, but two of the sixteen babies had chromosomal disorders. There were no clinical trials to assess the safety and effectiveness of this procedure, and the FDA halted it in 2001.

The mitochondrial replacement procedure that became legal in Great Britain in 2015 now allows clinical trials to begin there. These trials will use newer techniques. One takes an egg from a woman without deleterious mitochondrial mutations, removes its nucleus, and replaces it with the nucleus from an egg of the woman with mitochondrial disorders. This creates an egg with a nucleus of DNA from one woman and a mitochondrial DNA (thirty-seven genes) from another. The modified egg is then fertilized by the husband’s sperm in an IVF process. A child born from this procedure will have three genetic parents: a father, a mother (whose egg provided the nuclear genetic material), and a second woman (whose egg provided the thirty-seven genes in the cytoplasm of the egg). A second technique uses the husband’s sperm to create two sets of IVF embryos, one with eggs from his wife and a second with eggs from a woman without deleterious mitochondrial mutations. The nuclei of the embryos derived from the mother are then inserted into the enucleated embryos derived from the other woman, and some of these can be transferred to the mother in the hope of establishing a pregnancy.

The good news is that the children will not have any inherited mitochondrial diseases. Bad news, however, arises on several fronts. One is that children might be harmed by this early genetic engineering. A second and even greater concern is that mitochondrial replacement will change the germline, and we really do not know how dangerous this might be. Not only will the genetic makeup of the child be modified but the modifications in the mitochondria will also be passed on to all female descendants in her family line for generations. A third concern is that once we begin changing gametes or newly created embryos to produce genetically altered children, there will be some who will want to use germline alteration techniques for enhancement—to produce more intelligent, better-looking, taller, and stronger children—and the era of genetically designed babies will be upon us. This will produce two main kinds of children in the future: genetically modified children and nongenetically modified children, or, to put it another way, children with designer genomes and children without designer genomes, or, to put it yet another way, superior children and inferior children.

Most ethicists encourage caution with germline research, but some do advocate moving forward because they believe the potential benefits will outweigh the possible harms. Typical arguments favoring germline research and therapy include:

• The desire to avoid producing children with inherited genetic flaws,

• The desire to correct a genetic defect in a preimplantation embryo,

• The desire for cost-effective ways to reduce inherited genetic diseases in the population, • The desire of researchers to explore all modes of treatment, and

• The desire of clinicians to offer patients the most effective treatments. And typical arguments against advancing germline research and therapy include

• The desire to avoid causing unintentional problems in the DNA of future generations,

• A claim that discarding a genetically defective embryo is better than altering its genome with the attendant risk of causing deleterious mutations in future generations,

• The social injustice of germline alterations—they are so expensive only the rich could afford them,

• The limited impact of germline therapy on the population—only a small percentage of IVF embryos will benefit,

• A claim that germline interventions will amount to eugenics in the pejorative sense—the effort to cleanse the race of “bad” genes, however they might be defined,

• A claim that germline alterations would be used to breed various classes of human beings well suited to provide various desired services such as warriors or compliant workers with a diminished sense of autonomy (if this sounds far-fetched recall how some groups once castrated young boys so they could sing soprano in choruses and choirs, and how some societies today still practice female genital mutilation),

• A claim that children have the right to receive from their parents DNA that has not been subject to tampering, and

• A claim that germline research for therapy will inevitably slide down a slippery slope toward germline research for enhancement—that is, for genetic alterations to achieve desired characteristics such as good hair, tall build, thin body, blue eyes, blond hair, and so forth in children.

This last argument, the slippery slope argument claiming germline interventions will inevitably move from therapy to enhancement, is suggestive. After all, the need for germline therapy is really quite limited compared to many other more common problems affecting human beings. Given the limited therapeutic opportunities for germline genetic therapy, then, one does wonder why there is such considerable interest in pursuing it. One answer may be the large role the market plays in American health care. While the need for germline genetic therapy is limited, there is a vast potential market for germline genetic enhancement. It promises to make your children taller, stronger, brighter, more handsome, and more beautiful. Since a lot of parents find this so appealing, commercial interests see a huge potential market for germline genetic enhancement. Such enhancement, of course, is not really about health care because, unlike possible germline genetic therapy that would try to make defective genes normal, germline genetic enhancement would try to make normal genes better.

This chapter was unusually long due to the complexity of genomics and genetics as well as the rapidity of developments in these fields. Good practical decision making presupposes a grasp of what is going on, and we all need to learn what is going on, especially as sequencing whole genomes and exomes moves rapidly thanks to the incredible drop in costs, from research settings governed by federal regulations and IRB oversight to clinical settings and to direct-to-consumer commercial markets that make it available for almost everyone. Some polls have found that people readily admit they do not really know much about DNA, genomes, exomes, genes, genotypes, phenotypes, germline cells, and the issues they generate. But the same people often just as readily offer firmly held opinions about genome screening, genetic testing, and genetic modification for both therapy and enhancement of germ cells as well as of somatic cells. Opinions based on ignorance are not good. We need to learn something about molecular biology and the ethical, legal, and social implications of genomics and genetics before we can make morally prudent decisions about how to use this deluge of truly revolutionary information and technology for personal and social good.