4:10 p.m. December 19, 2012

UC Davis Researchers Illegally Infected The Brains Of Terminally Ill Patients

It’s been a rough year for UC Davis. First came the pepper spray incident where a campus police officer was filmed calmly blinding student protesters. Then, the wildly egregious violation of academic freedom in which a faculty member was disciplined for his position on prostate-specific antigen testing, which differed from that advertised by an event at the university. And now, federal regulators are blasting the U.C. Davis Medical Center in a recently-released review of three experimental surgeries performed at the institution.

As reported by Marjie Lundstrom and Sam Stanton of the Sacramento Bee, a 92-page report issued by investigators from the Centers for Medicare and Medicaid Services found that hospital administrators failed to properly enforce federal regulations regarding the experimental surgeries performed by neurosurgeons Dr. J. Paul Muizelaar, chairman of the department of neurological surgery, and Dr. Rudolph J. Schrot, an assistant professor and neurosurgeon with 13 years experience working under Muizelaar.

The experimental surgeries in question involved opening the skull of and deliberately infecting the brains of cancer patients with the bacterium Enterobacter aerogenes, without FDA or Institutional Review Board (IRB) approval, and without compelling scientific evidence in support of the immunological hypothesis that a brain infection in glioblastoma patients could improve outcomes.

From the SacBee:

“[M]edical staff were kept in the dark about the doctors' work or failed to follow hospital policies and professional standards, the report stated. "These failures put all surgical patients at risk for injury and harm, including death," the report stated. The federal watchdog agency went so far as to say the neurosurgeons, Dr. J. Paul Muizelaar and Dr. Rudolph J. Schrot, may have been responsible for "contributing to or causing the death of at least one patient."

So what happened? Sure, the concept of evil surgical experimentation is a well-worn cinematic trope, but this is no 80’s horror flick. In reality, when something like this happens, it takes much more than an intrepid ingenue with teased hair to piece together the who, what, and how from the wreckage of mishandled administrative duties, patient deaths, and copious amounts of blame, fresh for designation.

To understand this case, you need to understand a little of this history of biomedical research in the US, and how the events that transpired led to the patient protections we have in place today.

In 1972, after five years and two official protests, a 32 year old U.S. Public Health Service (PHS) epidemiologist named Peter Buxtun leaked information to the press exposing the decades-long Tuskegee syphilis experiment. In the now infamous study, conducted from 1932 to 1972, PHS enrolled 399 African-American men infected with syphilis in a trial to assess the natural process of the disease. All information regarding syphilis (diagnosis, transmission) was withheld, PHS knowingly used targeted incentives (free medical care, food, transportation) to ensure participation, and subjects were actively kept from receiving treatment.

When the longest non-therapeutic human experiment on in history was brought to light in 1972 it caused a powerful and angry public outcry, the aftermath of which helped lead to the establishment of public bioethical policy in the U.S.

In this case, the physician-investigators involved in trial recruitment clearly exploited their position and influence as physicians to win the trust and respect of trial participants. They knowingly obfuscated any semblance of informed consent and relied on patient neediness and the physicians’ respected status in the community as medical professionals to ensure compliance. Obviously, their actions were highly unethical; the researchers deliberately undermined the autonomy of their research subjects, blatantly used the men as a means to an end, exposed them to unnecessary harm and suffering, and explicitly exploited a vulnerable population.

Which brings me to the Belmont Report. Passed in 1974, in response to the public outcry over the Tuskegee syphilis experiment, the National Research Act established the National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research (CHPS) and issued the mandate that PHS establish regulations for the protection of human research subjects.

The 1979 report from the CHPS Commission, “The Belmont Report: Ethical Principles and Guidelines for Protection of Human Subjects of Biomedical and Behavioral Research” provided a summation of basic ethical principles and guidelines for use in resolving the ethical issues inherent in scientific research involving human subjects. The report provided three principles to serve as strict ethical guidelines central to the proper conduct of human subject research: respect for persons, beneficence, and justice.

The principle of respect for persons means that individual people should be treated as autonomous agents. In circumstances of diminished autonomy, the affected persons are entitled to protection.

Beneficence means that ethical treatment involves not only autonomy and protection from harm, but demands that efforts are made to ensure the best possible outcome for the participant.

The final principle, justice, requires the careful consideration of who benefits from the research in terms of who bears the burdens and risk.

The enforcer of these principles, and core component of the National Research Act, is the requirement that all research protocols involving human research participants are reviewed and subject to approval by an Institutional Review Board (IRB). The purpose of the IRB is to protect the rights, safety, and well being of all participants in research involving human subjects, especially in cases involving vulnerable subjects such as children, prisoners, minorities, the elderly, pregnant women, the terminally ill, and/or persons with diminished capacity for autonomy.

The IRB review is charged with determining, both in advance and by periodic review that the rights and well-being of human research subjects are protected per the ethical principles outlined in the Belmont Report. An IRB review must assess a proposed research protocol for the potential and perceived risks involved, ensure measures are taken to promote fully informed and voluntary consent from participants, and carefully weigh ethical matters of justice, inequity, and exploitation.

Straightforward and necessary, the IRB review basically says that if you are going to experiment on people, we are going to make sure that all work is done in an ethically rigorous fashion. Informed consent must be obtained, professional objectivity must be maintained, and the study participants need to all be treated like they are somebody’s sweet Grandma. Essentially.

Now, back to Muizelaar and Schrot infecting people's brains at UC Davis.

The SacBee first broke the story in July when they reported that two UC Davis neurosurgeons accused of experimental surgery had been banned from human research. The surgeons did not have IRB approval to perform the deliberate infections of operative wounds, which is especially significant in light of the fact that they were dealing with patients of an easily exploitable class: the terminally ill. Without the protection of the IRB review, patients were at the mercy of a completely untested experiment parading around as “innovative treatment”.

Nature reported that in 2008, Muizelaar had Schrot query the FDA about their intent to deliberately infect a postoperative wound in a glioblastoma patient using the bacterium E. aerogenes. The FDA said that animal studies were needed prior to the experimental treatment's use. Muizelaar ordered the requisite cultures, arranged for testing to be done in rats, and did not infect the patient whose case he discussed with the FDA. However, he did use the bacteria obtained for the rat testing to infect three other patients. You read that correctly: the cultures ordered for testing in a rodent model were used in patients. This is not okay.

The first patient was infected in 2010. Schrot contacted the director of UC Davis’s IRB to ask permission to perform a one-time procedure on a patient, not intended as research. This was deemed to fall under the umbrella of “innovative care”, which unlike experimentation with human subjects, is not subject to FDA and IRB scrutiny and approval. However, the director did say that further work would need to be reviewed. Muizelaar and Schrot continued their experimental work, treating three patients total. When the surgeons sought approval from a non-IRB, non-FDA ethics committee to treat an additional five patients, the IRB director intervened, issuing a cease and desist, instigating an internal investigation. UC Davis self-reported the transgressions to the FDA, and the two neurosurgeons in question were banned from research on humans

For more information about the science involved in this case, I spoke with Jonathan Eisen, Ph.D., a Professor at U.C. Davis. Eisen holds appointments in the Department of Medical Microbiology and Immunology in the School of Medicine and the Department of Evolution and Ecology in the College of Biological Sciences. A staunch supporter of transparency and open-access in science, Eisen has an impressively curated collection of links relating to this case on his blog, The Tree of Life.

The project, “Probiotic Intracranial Therapy for Malignant Glioma”, was aimed at using deliberate infection to stimulate a protective immune response in the brains of glioblastoma patients. Glioblastoma is an incredibly deadly, incredibly aggressive form of cancer: from diagnosis, the average survival time is 12-14 months. It is nearly always fatal. "From a research point of view, [the hypothesis] seems very interesting and these cancers are horrible."

In the face of such a devastating prognosis, the need for treatment is certainly intensely compelling. “I don’t want to judge clinical care because you are treating someone with this horrible cancer and they say well, what can you do for me? Is there any experimental treatment? And so it’s up to the medical professional involved to at least be very careful with what they’re doing.” How, then, did we go from brain cancer to deliberate infections?

According to a brief survey of relevant literature, it all goes back to four case studies described by researchers at Mississippi Medical Center. In these cases, there was a regression of malignant brain tumors that occurred concurrently with infection. “As far as I can tell from reading the literature, there’s certainly no evidence that those particular microbes caused any particular effects. They have correlations in terms of what they pulled out of the brain. And it’s fine, it’s a reasonable theory that infections in the brain might protect from these cancers because of the immune response.”

While adamant to stress that he is not a clinician and was not going to speak to the intricacies of treating the terminally ill, Eisen expressed shock at the wild jump from a correlation straight into untested therapeutic use. “From a microbiology point of view, the logic of what they did, as far as the documents I’ve seen, borders on the ludicrous. There’s a report in the literature that some patients, who were surviving for a long time with this cancer, were shown to have infections in the brain. Of those infections, in a few of them they were able to assign something in their brains to a taxonomic group. They don’t know that’s what was causing the infection per se, but they isolated something in the brain from those patients. And three of those things that they isolated were classified to this one organism, Enterobacter aerogenes.”

Eisen noted that in talking to colleagues within the department, it’s was very clear that many people did discuss the hypothesis that an infection in the brain could stimulate the immune system in a way that would the help fight the cancer. “There’s been a pervasive innuendo in the community about this, but that’s very different from actual evidence”

Eisen reviewed the available literature on the topic and found nothing, nothing whatsoever that would lead him to think that there was enough evidence to warrant the use in humans and the choice of culture.

“You can see their rationale that this might be an interesting research topic. So, let’s just say that a bacterium does something interesting. What did they do? They went and ordered bacteria with the same name from a culture collection. As far as I can tell, not giving any consideration to the fact that in most species of bacteria there are thousands of different strains, some of which may have a positive effect, some of which may have a negative effect. But they called this a probiotic treatment, as though these were known to be good microbes and you just add them and you get better. And that’s not remotely close to what they were doing.” Eisen stressed that the unknowns were significant, seemingly bewildered that the jump was so quickly made to clinical use with so little understanding.

“There’s a correlation in that one study of some patients surviving long who happen to have infections, and that’s it. That’s pretty sparse.”

Which brings me to informed consent. If the surgeons involved were unwilling and unable to procure IRB and FDA approval, what makes anyone think they would be willing or able to ascertain full and informed consent from their terminally ill patients? Not to mention the horrendous fact that they were referring to this treatment as “probiotic”. Probiotics! You know, like the things you put in yogurt that are great for you and make you poop and keep you from getting cheesy crotch infections when you take antibiotics. The term probiotics carries all the dangerous connotations of gummy vitamins. And if my doctor recommended an experimental probiotic treatment, I’d assume it was well-researched, harmless, and the right thing to do. Especially in the face of terminal cancer. Death or probiotics? Easy.

Patients should have the right to get the care they want, be it traditional or experimental, so long as they are truly informed as to the nature of their treatment. Patients need to feel comfortable that the information they receive from their physicians adequately encompasses the scope of the treatment and the potential risks and benefits inherent in the treatment. And patients that belong to vulnerable parties demand even more careful and thoughtful delivery of care-related information.

There are, however, difficulties inherent in navigating consent in the midst of the tenuous relationships involved in the physician-investigator-patient triangle. In one corner, you have the physician, with all the culturally sanctioned powers that entails. We are habitualized to trust our physicians, and typically for good reason. They are the guardians of our health and well-being, the gatekeepers between cherished, biologically-operational human life and the decaying lumps of meat and shit of which we will all eventually become. They tell us to take strange pills because it will fix things, they use technology and sharp objects to peer inside our bodies, to understand us, to heal. And we give them this power over us, to inform our decisions about our own bodies and how we care for them, because they ostensibly know better.

In the other corner, you have the investigator. The investigator wants to know, wants to find out, wants to push the boundaries of human knowledge. Where the clinician is bound by the honorable Hippocratic Oath, the parameters of investigation are traditionally more focused on statistics, rigor, and replication. Blending the ethics of seeking knowledge and the ethics of healing bodies creates a slew of delicate conflicts, perhaps none so great as those faced by the patient.

What do you do when your doctor wears two hats? Investigation and medicine are so intimately linked, yet for the patient, delineating between treatment and trial can be fraught with misunderstandings and issues of consent. When things are good, the physician-investigator is a valiant superhero, savior to patients bereft of treatment options. Flip the coin and the physician-investigator is just as easily pegged the villainous snake oil salesman, impacted with hubris and ruthlessly profiting from nefarious and lucrative dealings with pharmaceutical giants. The reality of the situation is that delineating between the doctor-patient and investigator-participant relationships requires dedicated consideration of the diverse ethical, social, and legal implications inherent in this ambiguous fluidity of the two roles.

But within all the nuance and ambiguity of these relationships, one thing is for certain: No one, not even brain surgeons, should ever be allowed to experiment on humans without the oversight of the persons and institutions we entrust with patient protection.