Medical research ethics

In today's NYTimes, there is an OpEd column by bioethicist Carl Elliott about biomedical ethics (or its lack) at the University of Minnesota.  It outlines many what sound like very serious ethical violations and a lack of ethics-approval (Institutional Review Board, or IRB) scrutiny for research.    IRBs don't oversee the actual research, they just review proposals.  So, their job is to identify unethical aspects, such as lack of adequate informed consent, unnecessary pain or stress to animals, control of confidential information, and so on, so that the proposal can be adjusted before it can go forward.

As Elliott writes, the current iteration of IRBs, that each institution set up a self-based review system to approve or disapprove any research proposal that some faculty or staff member wishes to do, was established in the 1970's. The problem, he writes, is that this is basically just a self-monitored, institution-specific honor system, and honor systems are voluntary, subjective, and can be subverted.  More ongoing monitoring, with teeth, would be called for if abuses are to be spotted and prevented.  The commentary names many in the psychiatry department at Minnesota alone that seem to have been rather horrific.

But there are generalizable problems.  Over the years we have seen all sorts of projects approved, especially those involving animals (usually, lab mice).  We're not in our medical school, which has a distant campus, so we can't say anything about human subjects there or generally, beyond that occasionally one gets the impression that approval is pretty lax.  We were once told by a high-placed university administrator at a major medical campus (not ours), an IRB committee member there, that s/he regularly tried to persuade the IRB to approve things they were hesitant about....because the university wanted the overhead funds from the grant, which they'd not get if the project were not approved.

There are community members on these boards, not just the institution's insiders, but how often or effective they are (given that they are not specialists and for the other usual social-pressure reasons) at stopping questionable projects is something we cannot comment on--but should be studied carefully (perhaps it has been).

What's right to do to them?  From Wikimedia Commons

The things that are permitted to be done to animals are often of a kind that the animal-rights people have every reason to object to.  Not only is much done that does cause serious distress (e.g., making animals genetically transformed to develop abnormally or get disease, or surgeries of all sorts, or monitoring function intrusively in live animals), but much is done that is essentially trivial relative to the life and death of a sentient organism.  Should we personally have been allowed to study countless embryos to see how genes were used in patterning their teeth and tooth-cusps?  Our work was to understand basic genetic processes that led to complexly, nested patterning of many traits of which teeth were an accessible example.  Should students be allowed to practice procedures such as euthanizing mice who otherwise would not be killed?

The issues are daunting, because at present many things we would want to know (generally for selfish human-oriented reasons) can't really be studied except in lab animals. Humans may be irrelevant if the work is not about disease, and even for disease-related problems cell culture is, so far, only a partial substitute.  So how do you draw the line? Don't we have good reason to want to 'practice' on animals before, say, costly and rare transgenic animals are used for some procedure that may take skill and experience (even if just to minimize the animal's distress)?  With faculty careers depending on research productivity and, one must be frank, that means universities' interest in getting the grants with their overhead as well as consequent publication productivity their office can spin about, how much or how often is research on humans or animals done in ways that, really, are almost wholly about our careers, not theirs?

We raise animals, often under miserable conditions, to slaughter and eat them.  Lab animals often have protected, safe conditions until we decide to end their lives, and then we do that mostly without pain or terror to them.  They would have no life at all, no awareness experience, without our breeding them.  Where is the line to be drawn?

Similar issues apply to human subjects, even those involved in social or psychological surveys that really involve no risk except, perhaps, possible breach of confidentiality about sensitive issues related to them. And medical procedures really do need to be tested to see if they work, and working on animals can only take this so far. We may have to 'experiment' on humans in disease-related settings by exploring things we really can't promise will work, or that the test subjects will not be worse off.

More disturbing to us is that the idea that subjects are really 'informed' when they sign informed consent is inevitably far off the mark.  Subjects may be desperate, dependent on the investigator, or volunteer because they are good-willed and socially responsible, but they rarely understand the small print of their informedness, no matter how educated they are or how sincere the investigators are. More profoundly, if the investigators actually knew all the benefits and risks, they wouldn't need to do the research.  So even they themselves aren't fully 'informed'.  That's not the same as serious or draconian malpractice, and the situation is far from clear-cut, which is in a sense why some sort of review board is needed.  But how do we make sure that it works effectively, if honor is not sufficient?

What are this chimp's proper civil 'rights'?  From the linked BBC story.

Then there are questions about the more human-like animals.  Chimps have received some protections.  They are so human-like that they have been preferred or even required model systems for human problems.  We personally don't know about restrictions that may apply to other great apes. But monkeys are now being brought into the where-are-the-limits question.  A good journalistic treatment of the issue of animal 'human' rights is on today's BBC website. In some ways, this seems silly, but in many ways it is absolutely something serious to think about.  And what about cloning Neanderthals (or even mammoths)?  Where is the ethical line to be drawn?

These are serious moral issues, but morals have a tendency to be rationalized, and cruelty to be euphemized.  When and where are we being too loose, and how can we decide what is right, or at least acceptable, to do as we work through our careers, hoping to leave the world, or at least humankind, better off as a result?

Germline DNA changes and bioethics

The BBC reports that Francis Collins, Director of the NIH, will not allow that agency to sponsor research on germline gene transfer.  Various new technologies seem promising in terms of being able to select a specific part of the genome that contains a clearly defective sequence, and replace that with a normal or healthy sequence.  Much of biotechnology is actually borrowed from what bacteria do naturally, as is the case for a recent approach, called CRISPR.

Genetic engineering has long been seen as the obvious thing to do when a clearly defective gene or genome segment is identified.  We are among the most skeptical when it comes to claims about high predictive power of genotypes relative to many human conditions, but there are clearly hundreds of known genetic variants that seem to have high 'penetrance', that is, are likely to cause disease or a disorder when present, and thus have high predictive power for serious, often pediatric diseases.  These disorders can devastate the person's entire life, so that prevention would be better than therapy once they've occurred. The idea of germline genetic engineering is to prevent the problem--and, indeed, do so permanently even in that individual's descendants.  It is the direct way to treat a defective gene by preventing its consequences in the first place, while other therapeutic approaches only work on the defect once it has been inherited.

Dr Collins notes that these current methods are by no means yet foolproof. Germline engineering also seems to cross an ethical or even religious line in terms of meddling with Mother Nature.  In the BBC story, he notes that embryo screening already can identify those embryos not carrying the harmful genetic material, those that are healthy to begin with (with respect to tested variants, at least), and can then be used without the risk of trying to engineer a change artificially, where mistakes can arise.  The problems with the CRISPR method at present include unwanted or undocumented changes elsewhere in the genome, and these could have serious consequences for the individual (and, again, his/her future offspring).

This seems to be a somewhat ironic, but sound, decision at least for the moment.  The idea of preventing harmful genetic conditions by removing them from our human patrimony is a noble one and has been seen as just around the corner ever since the modern era of molecular genetic technologies.  But genomes are complex, and one tinkers at one's peril, based on what is currently known.

Selective embryo choice has its own ethical issues, of course, as does abortion, cloning, or any tinkering with our nature.  Ethics are not always shared, however, and people vary in their ideas of right and wrong.  Indeed, ethical restraints don't always fare well in competition with selfish interests, which is why institutions and governments impose ethical considerations on research. Even if the NIH prevents germline genetic engineering, we probably cannot stop other countries and private companies from doing it.  Profits are to be made and, to be fair, parents' dreams of normal children will be catered to, hopefully in a positive way.  Generally, it is hard to believe that self-interests will not over-ride ethical interests, as they so often do when money is to be made.  Which is not to say that profit is the only motive--there is good to be done, and lives to improve as well.

Of course, germline engineering of various sorts is taking place in plants and animals for agricultural purposes.  The original level of controversy in terms of feasibility has seemingly waned and cloned animals and plants are routinely being made.  GMO plants are still controversial for many reasons both including potential health issues and, perhaps even more so, the economics of industrialized, highly profitable agriculture, especially as it impacts the developing world and distracts attention from more sustainable, soil-preserving practices.  At present it is hard to sort out the issues there, given the strength and diversity of feelings, and the hard-core economic and vested-interest issues involved. But it is always risky to bet against the power of technology to solve problems, and even to do that in an ethical way.

There are many who advocate genetic engineering for entirely good, moral reasons, related to human improvement.  But there are many also who are not willing to wait until things are shown to be safe.  In any case, at present, Dr Collins seems to be doing what he can to keep the Dr Frankensteins under control.  Whether it's a losing battle, and whether indeed far more good than evil will come from human germline manipulation, remain to be seen.  One can hope that the best will triumph.

Now should be the winter of our discontent

The idea of ethics, including bioethics, is essentially to find rules that restrict what we can do.  Ethics otherwise has little meaning. But while we all like to talk about bioethics, and the Genome Institute has something like 3% of its budget statutorily dedicated to such issues, is this really more than 'safe ethics'?  Is there really much meaningful self-restraint, much less external constraint, on what we in genomics will do?

Exhumed skeleton; Richard III; Source: Univ Leicester

It is controversial enough what we find ways to permit ourselves to do when it comes to research on animals.  The protections exist, but if you were a mouse king you'd think them horribly weak.  The rationale always is that what we do to animals we can't do to humans (a questionable justification for sentient beings!) but also that, yes, well, it is horrific for the animals sometimes but it saves human lives!  Or, to be more exact and realistic about most, though clearly not all, of what is done to the millions of laboratory animals around the world, the results might plausibly, sometime in the 23rd century, make a difference to someone.  Perhaps.  A bioethical point of view might argue that stricter strictures might force much more serious attempts at using cell culture or other means to address the same problems.  With genomic technologies, that doesn't seem too fanciful.

When it comes to what we do to humans, we do have restrictions (we can't do some of the things the Nazis and earlier eugenicists did---though recent Israeli attempts to chemically sterilize types of Jewish immigrants they didn't find too savory raises disturbing echos about lessons not learned even yet).  But science is clever enough to find ethical-sounding ways to get around awkward issues like sharing profits or patents with study subjects, confidentiality, truly informed consent and the like, to enable us to do the work we are determined to do. These are subjects open to much fair debate, and there are legitimate, serious, even ethical, reasons to defend various sides.

But today we're writing about a different kind of bioethical self-restraint--or, rather, its absence.

A what? A what?  My kingdom for a headline??
If you have rights when you are alive, such as of privacy and confidentiality, do such rights follow you after death?  Native Americans, for example, do have collective tribal rights to control what is done with burial finds of their ancestors, but how generalizable should such rights be? 

We are responding to the Big Splash story of the purported finding of the bones of King Richard III (of Shakespeare and Bosworth Field fame).  A skeleton "deformed, unfinished, sent before my time" whose various anomalies could be interpreted as those referred to historically in RIII's context was found, and DNA testing done to see if he is (or might be) RIII himself.  The DNA testing was of mitochondrial DNA from what is in the news stories, and apparently showed a direct descent of the skeleton through the same female lineage as the investigators confirmed in a living descendant.  Since there may be other relatives lying around in this part of England, so to speak, there is always the possibility that RIII isn't really RIII, but the attribution seems likely.  And while it's true the skeleton was "rudely stamped and not shaped for sportive tricks," whether it really was Richard is somewhat beside our point.

Exhumed skull of famed Danish astronomer Tycho Brahe, CREDIT: Jacob C. Ravn, Aarhus University [Full Story]

RIII isn't the only celebrity unearthed by the grave-robbers.  We have recently seen Tycho Brahe excavated (we blogged about this at the time) and there have been others done or suggested (Abraham Lincoln, King Tut, Billy the Kid, the final Russian Tsar's family).  The key to is here is that these individuals are publicly named and whatever is found is splattered across the pages.  Without the personalization, there's no story.  But don't these people deserve privacy not just from scientists poking with great relish around in their remains, but also from announcing their findings publicly?

"Sent after my time", too
We think so.  We think that the dead should retain their privacy.  If ancient burials are allowed to be excavated, as they have been and are worldwide, it should be enough to characterize group traits and individual traits that are, perforce, anonymized because we don't know the individuals' names.  Unlike modern donors of DNA samples, they did not provide any sort of consent for their privacy to be invaded.  For King Richard, being gawked at in his own time was more than enough, thank you.

Do we now not "seem a saint when most we play the devil"?

Mummy of King Tut; Source: National Geographic

This is juicy attention for the scientists and, perhaps, even worth a grant or two.  We're only human, and naturally respond to praise and attention.  The stories lead to nice sales for journals, magazines, and television programs.  Naturally, as is reported, the journalists and scientists call this an 'historic'  or 'dramatic' discovery that could  "bring about a reassessment of his reign." It's the usual hype, but it's more than that.  We just can't resist milking every possible story for melodrama, a subtle or not-so-subtle way of enticing the public.

But is it right to do this at others' expense, who did not agree to it?   Are we here just taking advantage of our blogospheric rights in an over-the-top rant?  Well, consider this:  suppose the findings were of a close relative of yours, say, your deceased child, father, or grandfather--depicted, analyzed, related to rumors, portrayed as a curiosity, and named in the world's media.  Would that make a difference?  If so, what about, say, your great-grandmother?  At what point in your genealogy does naming names and personalizing a finding become legitimate sport for the media?  Put another way, if for moral, religious, or ethical reasons you feel that the sanctity, or even just the dignity, of a deceased person is important, then just when does a person become just a 'body'?

There is another point.  The attribution could be wrong, subjecting RIII to needless public scrutiny.  The reported source of the confirming DNA is a 17th generation descendant, the end of the line apparently, who lives in London and gave a sample of his DNA.  He has a perfect right to provide DNA to identify his own characteristics, but--and this raises all the well-known confidentially issues about DNA analysis!--in our view, he has no right to give his consent for his DNA to be used to identify and characterize his relatives, be they dead or alive.  Assuming no lab errors or over-interpretation of the sequence results, in principle we could trace the DNA sequence back to some original ancestor carrying that sequence, and then forward along the tree of descendants, including RIII's branch.  But lots of other people would likely had the same sequence, lived in the same area at the time, been close or distant collateral relatives engaged in the same battle, and so on.  So while the evidence is consistent, it is not definitive (as the authors did acknowledge).

We may have extreme views on this.  Indeed, we are just about the only people in the world who seemed to have thought that the best selling and widely lauded book about Henrietta Lacks, an African-American cancer victim whose HeLa cells are available, used in research labs worldwide, was a travesty -- she was exploited in life, and exploited in death.  The media loved it, and only a few voices other than our own reacted about this as a deep intrusion into her privacy and that of her relatives.  We blogged about that here. 

What is bioethics?
Is it yet another indicator of the manifest lack of serious ethical constraint of even bioethicists (who don't seem to complain much about these things)?  Indeed, the main concern of bioethicists, if you get right down to it, is not getting too cross-wise with the scientists they are supposed to constrain.   Nobody admits this publicly, of course!  Bioethcists' jobs should not in any way depend on that congeniality, nor on having some salary paid from anybody's grant.  To apply real ethical constraints, professional ethicists should be prohibited from being paid on any grants whatever, unless they be from purely disinterested parties.   But that, of course, would be a genuinely ethical policy that universities, especially medical schools of all places, who need the overhead and don't provide safe, hard money to pay ethicists, cannot abide.  If we can't even constrain scientists from sporting with the departed, how can we expect ethical self-constraint in anybody else?

Whose microbiome is it? Take an educated guess

Carl Zimmer's articles in the New York Times are usually a treat.  Indeed, he's one of the best science journalists around.  But his op/ed piece on Sunday told only part of the story.

Called "Our Microbiomes, Ourselves", Zimmer describes the efforts to sequence entire populations of microbes -- the microbiome -- in various orifices of the human body, and he considers the ethical questions this is bringing to light.  Long considered to be separate from us, recent understanding has shown that many bacterial species are vital to our survival.  The bacteria in our gut are the classic and best example: we can't live without them in our intestines because our digestion depends on it.  So they may have their own species name, but in a very real way, and evolutionarily as well as today, their genome is really our genome, too (and to some extent vice versa).

Zimmer proposes a scenario whereby the microbiome of someone's nostril is sequenced, and a unique microbe is identified, and found to have pharmaceutical uses, and industry goes on to make millions from the new drug that results.  If it was found in your nose, he asks, do you deserve a share of the profits?

It is a tricky question, because it defies our traditional notions of property and justice. You were not born with the germ in your nose; at some point in your life, it infected you. On the other hand, that microbe may be able to grow and reproduce only in a human nose. You provided it with an essential shelter. And its antibiotics may help keep you healthy, by killing disease-causing germs that attempt to invade your nose.

Welcome to the confusing new frontier of ethics: our inner ecosystem.

But, while the specific scenario might be new, the question of who profits from stuff going on in or coming out of other people's bodies certainly isn't.  As a recent book reminded us all, Henrietta Lacks' tumor cells have been used since the 1960's for various profit-making purposes, but she and her family got nothing from her unwitting donation of cells.  From best-selling books written about neurological case histories to clinical testing of new drugs to the reaping of cells for research, there's nothing new here.

Some bioethicists, Zimmer says, believe that people's private microbiomes should be kept private, just as people's genomes should be, because the microbiome may hold clues to future illness.  But, there's nothing new here, either.

And,

As scientists get to know the microbiome better, they are also looking for new medical treatments: after all, most antibiotics were first discovered in bacteria and fungi. Michael Fischbach, a biologist at the University of California, San Francisco, and his colleagues have discovered a wealth of promising druglike molecules made by microbes in human bodies.

Zimmer adds that microbiomes may be harvested from subjects in poor countries, because of their potential usefulness to pharmacology or to understanding disease risk.  But that's an old story, too -- pharmaceutical companies have been doing clinical trials in poor countries for decades because it's cheaper and there's less regulation.  And agribusiness has inflamed many countries for raiding them of commercially modifiable plants and then selling them at high cost to farmers, making them dependent on buying seeds annually, rather than beneficiaries of royalties.

Sequencing the microbiome of an entire town's sewage system might reveal a lot about the entire town's health, but, Zimmer asks, would permission be required from each person living in the town?

The microbiome poses another bioethical balancing act, between the interests of microbe hosts and the public at large. If scientists become too consumed with protecting the individuals they study, research on the microbiome could slow.

So, Zimmer poses some interesting questions about the ethics of microbiome research, but there's nothing new here.  The same questions of who owns what and who should profit apply to all biomedical research. And, we're willing to bet that, as usual, the answers will favor the researchers.

'The' gene? For what?

There is yet another story in the news these days, about a diabetes drug that apparently raises the risk of heart disease. In this case, the chemical known as rosiglitazone binds to a receptor called PPAR-gamma in fat cells. Variation in a PPAR-gama gene has been found by several studies to be associated with higher risk of type 2 (adult-onset) diabetes, the form of the disease in which cells do not respond to circulating insulin, thus leading to elevated glucose in the blood, and to pathological consequences.

However, there is some evidence accumulating, according to the news stories, that rosiglitazone may increase the risk of heart attacks.

Whether or not this turns out to be true, it is but one of many stories about side effects. Indeed, as a follow-up story suggest, there are some boys-will-be-boys elements of questionable ethics--where the company was hesitant to accept or acknowledge at least one study that showed the elevated heart-attack risk--resembling many other stories of yielding to heavily vested interests, an aspect of the ethics of science that could use some serious scrutiny. Again, we see the news stories but can't claim to know what the preponderance of the facts are in this case.

Separate from any ethical questions, most drugs, if you read the small print, can have many side effects. The small print in drug inserts may contain several anti-lawyer rather than true biological effects of the drug, since if an effect is rare in a drug trial it will be difficult to prove a true casual connection.

Above is one image of one section across one stage (mid-gestation) of a mouse embryo, stained (purple) to show cells expressing PPAR-gamma. This is from the great gene-usage site GenePaint.org that shows the mouse mid-gestation expression of around 20 thousand genes. Go there and you can look at all sections in two different mouse embryos available for this gene (here's one).

The point is that even at one stage in one strain of animal, the gene is expressed in many tissues. Ironically, but not necessary atypically, the gene is not expressed in the heart at this stage. However this is part of a system of energy-related cellular functions that are used by most if not all cells, and the gene is in fact expressed in most cells at some level (see Wikipedia for PPARg).

Regardless of how the drug-reaction story turns out, it and many other like it show a point that we tried to make in The Mermaid's Tale, and that we were by no means at all the first to observe: many genes--probably the vast majority of genes--are expressed in several different tissues at different times or under various circumstances. Signaling and related cell-communication and gene-expression regulating systems (of which PPAR is an example), are often used in many different types of cells. It is not the gene, but the combination of genes, that has functional effects.

Thus, it is totally to be expected that a drug that targets a gene product can, or probably will, have multiple effects. The effect may be positive relative to disease in one type of cell, but harmful in other cells. Usually, doses are adjusted to minimize such effects, but humans and our experiences and cellular contexts are so variable that it is difficult to avoid some cost for a given benefit.

This is part of the way life is organized. It's how life evolved. It's how organisms with many different tissues and organs evolved--because an organism is the result of exquisitely complex and highly stereotyped cell-to-cell interactions.

Attempts to target just one gene in one type of cell are a real challenge as a result. That's why even targeting a mutant gene in a given type of cancer has proved to be so challenging, as another story in the NY Times has discussed.