Doing Drugs for Science

 

There is a place in Chicago where you can be paid to take mind-altering drugs.

In the Human Behavioral Pharmacology Laboratory at the University of Chicago, psychiatry professor Harriet de Wit studies various licit and illicit mind-altering drugs, from caffeine to Ecstasy, by testing their effects on human volunteers. The purpose of the research is to find out how different people react to different drugs, in order to answer the central question of drug abuse research: Why do some people become addicted to drugs when most people who try them do not?

Study subjects must be between the ages of 18 and 35 and have no history of drug abuse, except those volunteers participating in the studies of Ecstasy, who must already have tried the drug.  After the studies are completed, there is no long-term follow-up of volunteers.

The story in which I first read of these studies was on the front page of the August 7th Sunday Chicago Tribune. The studies are approved by two review boards and the national advisory council of the National Institute on Drug Abuse; yet, reading about the research, I felt a bit uneasy. I believe that research done on human subjects is supposed to have at least a potential benefit to the subjects under study. Will the knowledge gained in these studies really have enough of a potential benefit to the subjects to outweigh the risk? According to the story, “studies have shown that experiments like these do not make subjects more likely to use illicit drugs.” But that does not rule out the possibility that someone who takes part in these studies could thus become exposed and addicted to an illegal drug they might otherwise never have encountered. I vividly recall patients describing to me the stories of how they became addicts the first time they took a drug (cocaine and meth are the two I remember in particular), and I can easily imagine that happening in a study such as those described; in fact the story tells of one subject who was given methamphetamine and liked the feeling of the drug: “I felt extra happy . . . I was cheerful and peppy.”

Am I overly cautious?  Am I too obstructionist?  Is the knowledge gained from these studies worth the chance that even one person might, through participation in the study, become addicted to an illegal drug?  In other words, is this ethical human-subject research?

 

Cybrid-gate in the UK

In last week’s blog (July 26), I highlighted an article from Wired magazine (August 2011) titled “Extreme Science”  in which Wired explores seven “shocking experiments” that scientists could learn from if they were willing to set aside their ethical concerns.  One experiment involves cross-breeding humans with chimpanzees in order to better understand human development.

What I find fascinating about all of this is that the Wired article was written as if unethical experiments don’t occur; as if, in reality, scientists are guided by a moral compass.  But are they?  Just 2 days before I wrote my blog, The Daily Mail (a British publication) reported that over a 3-year span scientists “have created more than 150 human-animal hybrid embryos in British laboratories.”  So, what Wired posed as a hypothetical thought experiment was already happening (albeit secretly) in the UK.

According to The Daily Mail, “155 ‘admixed’ embryos, containing both human and animal genetic material, have been created since the introduction of the 2008 Human Fertilization Embryology Act.  This legalized the creation of a variety of hybrids, including an animal egg fertilized by a human sperm; ‘cybrids’, in which a human nucleus is implanted into an animal cell; and ‘chimeras’, in which human cells are mixed with animal embryos.”  http://www.dailymail.co.uk/sciencetech/article-2017818/Embryos-involving-genes-animals-mixed-humans-produced-secretively-past-years.html

The Human Fertilization and Embryology Act of 2008, Section 4A, contains some of the following prohibitions:

“(1) No person shall place in a woman –

(a) a human admixed embryo,

(b) any other embryo that is not a human embryo, or

(c) any gametes other than human gametes.

(2) No person shall –

(a) mix human gametes with animal gametes,

(b) bring about the creation of a human admixed embryo, or

(c) keep or use a human admixed embryo…”

So far, so good.  Or so I thought.  The Act continues:  It is illegal to do #2 above (i.e., mix human gametes) “except in pursuance of a license.

In other words, it is still possible, with government authorization, to mix human gametes with animal gametes to create an admixed embryo.  The only restriction, according to the Act, is that the admixed embryo cannot be kept or used after the first 14 days of its existence.  Indeed, it is also possible, according to the wording of the Act, to create an admixed embryo, store it (i.e., freeze it) over a period of time, and then at some future point do research on it, as long as it is not allowed to live beyond 14 days.

(To view The Human Fertilization and Embryology Act of 2008, go to:  http://www.legislation.gov.uk/ukpga/2008/22/contents)

But the story’s intrigue deepens.  The creation of the cybrids” in the UK was apparently done in secret.  As noted in a recent Christian Medical Fellowship blog (July 26): “there seems to be a murky mix of confusion and secrecy from which the true facts and figures are difficult to extract.”  But why the secrecy if research was being done within the guidelines of The Human Fertilization and Embryology Act?

Furthermore, the research was not carefully documented.  It is less than clear the exact numbers of cybrids that were created.  The Christian Medical Fellowship reports that, “According to The Independent “many more cybrid embryos were created – 278.  That large number is naturally of concern, but also of concern is that the numbers don’t match the figure of 155 released last week.  The Government has avoided answering that question.  Moreover, if all funding (apparently) stopped in 2010 and the licence was revoked from the only researcher, when were these 155 (or 278) embryos created?  Were they all created before 2010?  Or are they still being created?  If so, by whom?” http://www.cmfblog.org.uk/2011/07/26/155-animal-human-embryos-created-in-the-uk-%E2%80%93-we-think/?doing_wp_cron

In other words, in spite of government oversight, an assortment of so-called “ethical guidelines,” and the best intentions of scientists, it’s less than obvious that research is done within any firm restrictions.  The CMF concludes that “the glaring discrepancies in the figures issued by The Human Fertilization and Embryology Authority shows it is not fit for purpose when it comes to regulating the scientists.  It is incapable of keeping accurate records and is unable to keep on top of what is going on in research, either with embryos or eggs.”

I ended last week’s blog with the following observation:  “Humans have also demonstrated a natural tendency to push the moral envelope, to give priority to what can be done over what should be done.  Time will tell whether experiments that are now considered unethical will one day be the norm.”  Apparently we no longer need to wait for “time” to make this announcement.

Going where no man should go

In a recent article titled “Extreme Science” (August, 2011), Wired magazine broaches a topic that few mainstream publications would be willing to touch.  What could be accomplished if scientists were prepared to set aside the “moral compass” that guides them (assuming there is one)?  Imagine the advances waiting to be made.  As Wired observes, in the real world (as opposed to the sci-fi world), “Most scientists will assure you that ethical rules never hinder good research – that there’s always a virtuous path to testing any important hypothesis.  But ask them in private… and they’ll confess that the dark side does have its appeal.”  http://www.wired.com/magazine/2011/07/ff_swr/

For example, scientists could separate sets of twins at birth in order to control and monitor their individual environments right from the start.  The gain from such an experiment is a possible solution to the nature vs. nurture dilemma.  Think about a twin study in which both individuals are eventually identified as gay, regardless of their distinct upbringing.  This could offer proof that homosexuality is all nature and not nurture.  In another example, Wired considers the possibility of “womb swapping,” i.e., switching “the embryos of obese women with those of thin women.”  Again, the experiment would determine whether environment or genetic factors determine an individual’s weight.  Then there is an experiment right out of a science fiction movie, one that cross-breeds a human with a chimpanzee.  Wired reports that the technique would be “frighteningly easy” and it would teach us much about human development.

But what actually prevents unethical research from happening?  It could be argued that these experiments are blatant violations of individual autonomy.  But the fact of the matter is that human autonomy is already disregarded with other procedures (e.g., human embryonic stem cell research, abortion, etc.).  In other words, what is the essential moral difference between destroying an early embryo in lieu of subjecting it to controlled research?  One may even maintain that the twins, separated at birth, are at least alive as opposed to embryos that are destroyed.

Then again, one could argue that the main difference is that twins will eventually come to understand their situation and realize that their autonomy has been violated.  On the other hand, destroyed embryos will never know their fate.  Fair enough.  But if morality is governed by utilitarian concerns, as it already is, it would seem that the value gained by subjecting embryos to questionable research outweighs their future concern for autonomy.  And if “awareness of one’s autonomy” is the key moral criterion, then research could be extended to any human lacking awareness (e.g., newborns, coma patients, etc.).

In short, humans have the rational capacity to consider all options to achieve an objective.  Humans have also demonstrated a natural tendency to push the moral envelope, to give priority to what can be done over what should be done.  Time will tell whether experiments which are now considered unethical will one day be the norm.

STEPS in the wrong direction

One of the major tasks of bioethics since its inception has been to ensure the ethical conduct of scientific experiments involving human subjects.  One of the cornerstones of ethical experimentation (indeed of all medical treatment that respects the human dignity of the patient) is the concept of informed consent:  the study participant should know up front the purpose, potential benefits, and potential risks of participating in the study.

In the 1990’s, Parke-Davis, the manufacturer of the anti-epileptic medication Neurontin (generic name: gabapentin), conducted a trial called Study of Neurontin:  Titrate to Efficacy, Profile of Safety (STEPS).  This was a Phase 4 trial (performed after the medication was already on the market) whose professed objective was to study the efficacy, safety, tolerability, and quality of life among gabapentin users as the drug’s dose was increased.  Parke-Davis recruited physicians to enroll patients into the trial;  in all, 772 physician-investigators enrolled a total of 2759 patients into the trial.  The study resulted in two published papers.

It all sounds innocuous enough, no?

Recently, through legal action, all of Parke-Davis’s internal and external documentation relating to STEPS became available for review.  In these documents, a different picture of the trial’s objective comes to light.  A few quotes from the company’s internal memos:

– “Some indicators of [the study’s] success include 20% increase in new patients’ starts in March and a 3% market share in new prescriptions. . .”

– “STEPS is the best tool we have for Neurontin and we should be using it wherever we can.”

– “. . .at the very least, we should be looking to place as many managed-care patients as feasible in [STEPS] to prevent Lamictal [a competitor’s drug] starts.”

– Multiple strategic planning documents cite the STEPS trial itself, not the trial’s findings, as a key marketing tool for gabapentin.

– Parke-Davis monitored and analyzed the physician-investigators’ prescribing habits, finding increased prescribing of gabapentin among STEPS participants compared to a control group of non-participants.

Apparently, contrary to the trial’s stated objective, the purpose of STEPS was not science, but marketing;  the true subjects of the trial were not the patients, but the physicians.  The most important measured outcome of the trial was not the safety or efficacy of gabapentin, but whether and how much doctors changed their prescribing behavior as a result of participating in the trial.

Is this an ethical trial?  Some might say, sure, there was nondisclosure of the true intent of the trial, but c’mon, it wan’t Tuskegee, right?  I mean, nobody was hurt (unless you count the 11 patients who died, the 73 who experienced serious adverse events, and the 997 who experienced less serious adverse effects).

No, this was an unethical trial.  There could not be informed consent, as the true purpose of the trial was not revealed to physicians, patients, or IRBs.  In addition, using any human being in such a deceptive manner for monetary ends is inconsistent with respect for human dignity.

 

An article that reviewed STEPS and provided the quotes above appeared in the June 27 Archives of Internal Medicine;  the abstract can be accessed here.

 

The Imago Dei Has Something to Offer

In their case the god of this world has blinded the minds of the unbelievers, to keep them from seeing the light of the gospel of the glory of Christ, who is the image of God. – 2 Corinthians 4:4

The Rapport sculpture, Reynolds Medical Bldg., TAMHSC

In my two years of involvement in the ethics community at a state medical school, I’ve found that the Christian concept of the imago dei speaks to unaddressed problems in bioethics.  The philosophy of materialism so dominates medical study and practice that descriptions of the individual do not rise much past the biological system that is the body.  Theological and, to a large extent, metaphysical explanations are excluded.  This leaves ideas on ethical behavior merely as encouragement to be nice or to ensure individual choice.

The Bible uses many terms to describe the human being, including nephesh, ruach, lebh, basar, psyche, soma, and sarx.  None of these descriptions falls into a neat, Western, body-soul-spirit framework.  These words instead speak of a richness that extends far beyond any reductionist view of the person.  The doctrine that people are created in the image of God (Gen. 1:27, 9:6) gives us insight into human purpose and ethical behavior toward others.

Last fall, I presented a poster at a symposium and included in it a paragraph on using the imago dei as a basis for a theory of personhood.  A medical researcher nearby left her poster and asked me what data I used to support my conclusions.  I explained that my paper examined the theoretical constructs we use when treating our patients.  It never occurred to her that she had, or might need, a philosophical framework in order to interpret her own data.  Medical practitioners need to recognize the body as one aspect of the whole person formed in a way to reflect God, even to represent Him in the world.  Ultimately, an understanding of our humanity in terms of the imago dei points to the new Adam who in His blameless life was, and is, the image unmarred.