Scientists are often viewed as highly ethical, curious seekers of truth. In many cases, this is true. Unfortunately, in pursuit of “truth” some researchers cross important ethical lines, possibly rationalizing their crimes, in a utilitarian manner, as a means to better healthcare for the greater populace.

In June, I wrote a blog focusing on abuses of patients in research trials in a U.S. Veteran’s Hospital in San Diego. This prompted me to further investigate research abuses, and I was disturbed to discover many more well-documented cases of serious ethical breaches in the U.S. and around the world. Though I was familiar with the Tuskegee Syphilis Trial and Mustard Gas experimentation in U.S. soldiers, I was appalled at the number and types of serious beaches in research ethics that have occurred, many with the full blessing of the federal government. This post will review two cases not listed among the 30. One is from two decades ago, and the other is from 2018.

This year marks the 20th anniversary of the Jesse Gelsinger debacle when a research program at University of Pennsylvania made headline news and stayed in the headlines for months. Jesse was an 18-year old man with Ornithine Transcarbamylase Deficiency (OTCD). OTCD often causes death in infancy, but if detected early and treated aggressively with medication and a restrictive dietary protocol, some patients live to adulthood. Jesse was such a person.

Jesse Gelsinger had OTCD, and in his case, it was a milder form, allowing him to live on a low-protein diet and 50 pills a day to the age of 18. He had a few close brushes with death along the way, one of which occurred when he willfully abandoned his regimen and ended up in an induced coma in the ICU, where he remained until his ammonia could be corrected. In most other ways he led a normal life. He was a friendly, fun teenager, and he successfully graduated from high school.

In 1999, when Jesse’s local doctor told him about a potential treatment trial to cure OTCD at University of Pennsylvania (Penn), Jesse contacted them and excitedly flew to Philadelphia to enroll in the trial. Many details of what ensued next were never publicly revealed, but we know he was given a modified virus developed as a vector to introduce healthy OTC genes into his body. If successful, this would then hopefully correct the metabolic abnormality. He was the 18th person to receive the modified virus. Unlike the previous patients who had experienced relatively mild flu-like reactions, Jesse had a severe inflammatory response, proceeding to coma, multi-system failure and brain death all within only four days of the treatment.

Initially his father Paul defended the Penn researchers in the press and in social media. Soon after this, however, a number of issues came to light. The Gelsinger family sued Penn; Dr. James Wilson, who sponsored of the trial; the other two lead investigators; Genovo, the company that produced the vector virus and conducted the study; the dean of the medical school; Arthur Caplan, as the bioethicist overseeing the study; and Children’s Hospital of Philadelphia. The suit was settled relatively quickly, but no one ever publicly apologized to the Gelsingers. Penn eventually “acknowledged mistakes, but vigorously disputed whether they affected the outcome for Jesse.”

Why was the suit filed, and why would an apology have been appropriate?

• Director of the Institute for Human Gene Therapy James Wilson, who was the lead investigator, had a $13,000,000 financial conflict-of-interest, which he specifically denied to Jesse’s father.
• Jesse’s liver functions were impaired within less than 24 hours before the scheduled infusion. This should have disqualified him from receiving the vectored genes, but his doctors overrode the exclusionary criteria and proceeded with the infusion.
• A number of changes were made in the protocol after the Institutional Review Board’s approval, without notifying the IRB.
• The consent process was tainted, as Jesse was not told of the death of several monkeys who had received the viral vector in earlier trials.
• The potential serious outcomes of the trial were glossed over.
• The consent form promised to monitor problems with each cohort and inform the patients of any negative outcomes—and this was clearly not done with Jesse.
• The researchers failed to notify the Food and Drug Administration (FDA) of adverse events in a timely manner.
• This was a phase 1 clinical trial; as such, no suggestion of therapeutic utility should have been made or intimated to Jesse or his family. Jesse and the family seemed to realize this on one level, but statements the family made at the time indicated that they may have suffered from what has been labeled “therapeutic misconception” believing that this might benefit him personally.
• The ethicist, Arthur Caplan, who was supposedly serving as a watchdog on this project, was serving in the department Dr. Wilson chaired. He purportedly did not report directly to Dr. Wilson, but the appearance of internal conflict of interest was strong.

The FDA took quick action investigating Jesse’s death. Penn had “immediately and voluntarily” halted Jesse’s trial, but the FDA officially put a hold on the trial and soon after froze all human gene therapy at Penn. James Wilson was barred from human subject research for five years. The two primary investigators, Drs. Mark Batshaw and Steve Raper, were barred from human research for three years. In the end, however, Wilson remained the head of human genetic research at Penn, and he recently launched a gene therapy startup company, Passage Bio. Dr. Raper continued on as an associate professor in the Department of Surgery at Penn, went on to obtain a law degree and is now Vice-chair of Quality and Risk Management, Department of Surgery. Dr. Batshaw received several promotions and is now Executive Vice President, Physician-In-Chief and Chief Academic Officer at Children’s National Health System.

The biggest recent ethics controversy involves He Jiankui, PhD, a Chinese biophysicist who is neither a physician nor geneticist, when he recently announced “the birth of twin girls with edited genomes.” His stated intention in performing this genome editing was to protect the girls from HIV, which their father has. His work was presented at one conference, but subsequently has been discussed by Dr. He only in YouTube videos or news interviews. The whole idea of germline editing was a venture into uncharted territory. Any changes Dr. He has made in the girls’ germlines will be passed on to their children, grandchildren and so on. This has not been done in any other lab as far as we know, primarily because of the inherent danger and irreversibility of such an intervention.

Since Dr. He hasn’t published in peer-reviewed literature, it is difficult to say exactly what he has or hasn’t done, but a number of questions are raised. The safety of this procedure has not been documented, so no one can assess the risks versus benefits.

• It is unclear which, if any, IRB reviewed Dr. He’s protocols prior to implementation.
• He failed to follow standard procedures in procuring participants.
• His consent process, as reported, appears to be highly inadequate. When questioned, the parents thought their daughters were receiving a vaccine against HIV.
• He used coercive penalties in his consent, which would financially penalize any participants who dropped out of his study.
• He forged ethics review documents during recruitment of participants, and he swapped blood samples to skirt laws against allowing people with HIV to use assisted reproductive technologies.
• He essentially practiced medicine without a license.

His university has fired him, and he has been censured by the health ministry in Guangdong Province, where he worked. He has been ordered to “stop doing science,” and he may be tried as a criminal based on the above, though that is yet to be seen. If the children suffer any ill effects, it is reported he could be sentenced to between three and 10 years in prison. However, to complicate this issue, some damages to the girls may not show up for many years, and some ill effects may not show up for many years, when they are detected in the girls’ children.

So what have we learned (or re-learned) from these cases?

• IRBs serve very important functions, but if they are kept in the dark about negative outcomes or breaches of protocol, they can’t do their jobs.
• It can be really hard to police all the specifics of complex studies after the trials are in progress.
• The dangers of clinical trials need to be honestly and completely delineated in consent procedures.
• While some conflicts of interest are inevitable, these must be carefully monitored and clearly presented in their entirety to study participants.
• If any adverse outcomes arise from clinical trials, they must be immediately reported to the appropriate authorities.
• Once an IRB approval has been reached, the specifics of the trial protocols cannot be altered without a follow-up review by the IRB.
• Whenever someone says, “It’s not about the money,” it’s probably about the money.

Tracing the origin of well-known quotes can be difficult, or even impossible at times, so I can only say without attribution (though scholars say it was not Thomas Jefferson), “Eternal vigilance is the price of liberty.” Another version of the quote concludes, “Power is ever stealing from the many to the few.”

The protection of the vulnerable is an ethical principle honored throughout multiple societies for millennia. The liberty to pursue scientific human research on vulnerable persons comes with the high responsibility (price) of comprehensive, ongoing, informed vigilance. Those unwilling to pay the high price should not be granted the privilege of conducting human research, and they should be severely censured if they do.