The 14-day rule: Time to double down?

The “world’s leading scientists” gathered at University College London on 7 December 2016 to explore extending the 14-day limit on embryo experimentation from 14 days to 28 days. Presently the consensus of that meeting is not known. The Guardian has published a nice summary of the background and future implications of the issue (link HERE). Jon Holmlund offered his comments in this blog back in May when researchers artificially grew human embryos to 13 days gestation. Since this issue is back in the news, a few additional thoughts are offered below.

Space does not permit a detailed history of the details of the discussion behind the original 14-day rule endorsed by the Warnock Committee in the UK (see HERE for one such extended summary). The original limit was arbitrary but coincided with the development in the embryo of the primitive streak, a precursor to the nervous system, such that experimentation on an embryo before this stage was believed to eliminate the possibility of that embryo experiencing pain. The implementation of the 14-day rule essentially permitted experimentation to proceed resulting in the successful development of IVF.

Regardless of the ethics, the 14-day rule has been a hard barrier scientifically until just recently. Just because we can breach the 14-day barrier, why go beyond? Allowing experimentation on the embryo out to 28 days would allow scientists to learn about the process of gastrulation, the process that lays down the body plan and where the three tissue layers (ectoderm, mesoderm and endoderm) begin to subspecialize. If we have ethically permitted experimentation on embryos up to 14 days gestation, shouldn’t we just nudge it out a little further?

To quote Jon Holmlund: “In the name of God, forbear!” Interestingly, for different reasons, Mary Warnock agrees with him. Per the Guardian article, she worries:” If we raise the limit, objectors could argue that the 14-day rule has remained intact simply because no researcher had the technique to keep an embryo alive for so long, and that now one has been discovered the rush down the slippery slope will follow. They will say: ‘We always knew that the slippery slope would prove itself.’”

Experimentation on a human embryo at 14 days of gestation is still experimentation on a human being made in the image of God. Perhaps the upcoming debate on extending the 14-day rule will actually result in Warnock’s fear, that we agree that the original 14-day limit was indeed too long to be slipping and sliding?

Zika and Genetically Modified Mosquitoes

Just last week, I received a call from a pollster.  It’s election season and I live in a hotly contested ‘swing state,’ so I wasn’t surprised.   What surprised me were the questions I was asked, mostly about the Zika virus—its spread and possible prevention.  One question especially caught my attention:  Are you in favor of genetically modified (GM) mosquitos?   Bioethics in a poll question!  I could hardly contain my excitement.

Floridians have grown accustomed to mosquito treatments.  (See a recent report from the CDC, here.) The government begins by spraying pesticide and encourages residents to get rid of any standing water.  Screens and insect repellent also are part of the strategy.

There have been some accounts that the pesticide has had undesirable consequences, including the death of bees.  It also produces a concern that pesticide cannot possibly be beneficial to the environment.  If traditional methods used to control mosquito populations have not been successful, GM mosquitoes offer a measure of hope.  Neuhaus and Caplan note, “The mosquitoes are genetically engineered to express a ‘self-limiting’ gene that kills offspring before they reach adulthood.”

The possibility of GM mosquitoes is not new.  According to Ernst, et al., the “Florida Keys Mosquito Control District proposed the first release of a GM mosquito” to help combat an outbreak of dengue fever in Key West, Florida.   Now, with concern growing over the Zika virus, GM mosquitoes have become an issue once again. There will be a non-binding referendum in November for the Keys to express their view as to whether or not the GM mosquitoes should be released.

Neuhaus and Caplan speak out for implementation of this proposal.  They believe it to be in the best interest of the public and the environment.  They base their conclusion in part on the FDA’s conclusion that saw no long-term problems with the release of GM mosquitoes. Others, especially those who live in Key Haven (the site of the release) are voicing their concerns.

Public health officials must always consider the public good.  They wrestle with possible unintended consequences and must think beyond solving the problem of the moment, by consider the long-term effects of their decisions.  I agree with Ersnt, et al, who observe, “Novel public health strategies require community engagement.”  If the Mosquito Control Board finally decides to proceed with GM mosquitoes, many will be watching to see what, if any, long-term implications will follow.  Perhaps you might have a genetically modified species in your neighborhood in the not-too-distant future.

Public discussions on human gene editing

On August 3, the National Academies of Science, Engineering, and Medicine posted online the slides and talks from its July 12 meeting to discuss public implications of the Human Gene-Editing Initiative.  A total of four meetings plus a related workshop were held: an introductory discussion in December 2015, followed by three more substantial meetings plus the related workshop in February, April, and now July of 2016. 

I’m still working through the materials, notably Francis Collins’ slide set from the July 12, 2016 meeting, addressing regulatory processes, in utero gene editing, and other topics.  But what first caught my eye was a brief written statement from the same meeting, from Ron Cole-Turner of Pittsburgh Theological Seminary.  In it, he states that Christian opinions on human gene editing are not monolithic; that, far from being reflexively in opposition, those opinions are quite open to editing even of the human germline as long as safety concerns are addressed, embryos are not sacrificed in the process of research, and therapy rather than enhancement are in view.

I must say the statement disappointed me.  The “safety argument” is the most prominent ethical concern raised in discussions of whether editing human genes in heritable ways is ethically permissible.  We certainly want assurances that we would not put the “edited” individuals at risk, and we really would want some level of certainty that the downstream effects would not be disastrous.  But of course, the latter may be impossible to assess, since adverse consequences could be subtle and might become apparent over many generations.

Beyond that, I thought Cole-Turner’s statement was too limited, with no mention of questions of informed consent, and with no deeper reflection on how human germline editing might (I would say, would) alter the way we look at ourselves, each other, our children, and the human race in general.  The push would be further toward seeing humans as plastic, alterable entities without limit, and, beyond questions of “simple” justice (how would we keep from making benefits available only to the rich?), would create a class of, as C.S. Lewis suggested, “conditioners,” or as contemporary European thinkers have put it, a class of engineering humans who work on other, engineered humans.  Finally, Cole-Turner did not really engage the concern that there is a constant eugenic temptation in humanity that would likely re-assert itself with force.

Cole-Turner’s statement was not proud; he opened by admitting that no one person could speak for all Christians.  And maybe brevity was necessary on the occasion of the committee meeting.  But I still would hope for more robust “religious” inputs at sessions like this.  Otherwise, one gets the feeling that all that is sought is a token religious imprimatur on the most cutting-edge biotechnologies of the “brave new world.”

Follow the link in the first sentence of this post, and the statement by Cole-Turner, as well as other materials from all the meetings, may be reviewed in detail.  It is good that these are posted, because, although it’s easy to say that a thorough public discussion of transformative biotechnology should be held with all stakeholder groups, only so much is generally done to achieve that.  Even interested parties, like your humble correspondent, have limited time to devote to the details.  But more of us in the general public should labor to make time to dig in deeper.

ADDENDUM: After posting the above I went back to the link (top of this post) and read through the slides from Dr. Collins.  Readers of this blog should by all means do so as well.  At the end, he muses about the level of acceptability of 28 current or possibly future interventions, placing them on a grid of when they will be in practice vs. level of ethical concern they prompt.  The slides are self explanatory and worth musing over.–JTH

The surprisingly small benefit of some very (expensive) Big Ideas

Last week, JAMA published online a Viewpoint provocatively titled, “What Happens When Underperforming Big Ideas in Research Become Entrenched?” The overarching Big Idea to which the article refers is the “narrative positing that a combination of ever-deeper knowledge of subcellular biology, especially genetics, coupled with information technology will lead to transformative improvements in health care and human health.”

The article highlights three technologies that are integral to the Big Idea but that have not lived up to their promise. The first is genetics/genomics; as an example of unfulfilled promise, the authors trenchantly observe, “Sixty years after the discovery of the genetic defect, no targeted therapy has emerged for sickle cell anemia” — one of the simplest genetic diseases, caused by a single gene. The second is stem-cell therapies; the authors point out one analysis of studies of stem cell therapies, in which the supposed effectiveness of the therapy was directly proportional to the number of factual discrepancies in the published study. The third is electronic health records (EHRs), which have cost billions, but have not realized either the improved care and cost savings that were their major selling point.

Despite the lack of evidence of real benefit, these three technologies have received vast amounts of NIH and government monies. The article recommends changes such as the “NIH should fund many more high-risk, unconventional ideas instead of supporting the same familiar highly funded research fronts.” It also calls for accountability for funded studies to show real benefit.

The article’s title asks what happens when underperforming big ideas become entrenched — vast amounts of money and energy are wasted — and suggests solutions. But the article does not address why those Big Ideas have become entrenched in the face of all evidence, and this must be addressed before solutions can work. I do not pretend to have a definitive answer. But I think there is an even Bigger Idea that overlies all of these lesser ideas: the idea that more technology is inherently good, and in higher-tech medicine will be our salvation.

For example, look at those things that have been shown to make “transformative improvements” in mortality, morbidity, and life expectancy: Quitting smoking. Getting off the couch and doing a bit of exercise. Eating your fruits and veggies. Getting immunized.

Now, which sounds more exciting for research funding: stem cells that we confidently assert can cure Parkinson’s even though we can’t quite prove but it’s pretty obvious that they should, or finding ways to get more grocery stores into poor neighborhoods whose most affordable food source has golden arches in front of it?

Organ Harvesting in China

On June 13, 2016 the House of Representatives passed HR 343, “Expressing concern regarding persistent and credible reports of systematic, state-sanctioned organ harvesting from non-consenting prisoners of conscience in the People’s Republic of China, including from large numbers of Falun Gong practitioners and members of other religious and ethnic minority groups.” )  In part, the bill “calls on the United States Department of State to conduct a more detailed analysis on state-sanctioned organ harvesting from non-consenting prisoners of conscience in the annual Human Rights Report.”  This is a welcome response to a horrific practice.

Newsweek  reports that according to The Falun Dafa Association, “[I]n China patients aren’t waiting for organs. Rather, organs are waiting for patients.”    This is because executed prisoners provide a constant supply of organs.  The international community must continue to voice its strong disapproval of this practice.  We look forward to the June 22nd report of David Kilgour, former Canadian Secretary of State, investigative journalist Ethan Gutmann, and Canadian human rights attorney David Matas on China’s organ transplantation industry.  It is to their great credit that they are shining a bright light on this troubling issue.

Organ donation is a scientific marvel and a great blessing to those who have received life-saving organs.  Executing  prisoners of conscience and harvesting their organs is beyond the pale of ethical conduct.  It defies human dignity and scandalizes the international community.  It needs to stop.

Mitochondrial replacement boosterism

A new Viewpoint article (available for free, without a prescription) from the Journal of the American Medical Association (JAMA) asserts that the United States is acting too slowly to advance mitochondrial replacement techniques (MRTs), the so-called “3-parent baby” approach that would seek to prevent mitochondrial DNA disease, which is transmitted maternally.  The authors approve of the recent recommendations by the afore-named Institute of Medicine (IOM), but are dismayed that, for now, recent federal legislation blocks FDA from further consideration of MRT applications.  This runs counter to the principle of beneficence, they argue, by foreclosing the possibility of reproductive relief for the estimated 800 US women affected each year.  This is their number, not mine, and presumably refers to 800 attempted births per year by women affected with these mitochondrial diseases, which are inherited and so present in an affected individual for life.  Again, the goal would be to allow these women to conceive and, one hopes, give birth to an unaffected offspring. 

In any event, the authors of the article in question find the IOM’s recommendations thoughtful, but the aforementioned legislation thoroughly unreasonable.  Besides blocking the advance of science in the U.S., we are ceding ground to the U.K., where it’s full speed ahead for clinical applications of MRTs.

Now, the IOM recommendations were anything but slapdash, reflecting careful thought leading to conclusions with which one may yet disagree.  What troubles me about the JAMA piece is how cavalier the authors are in embracing MRTs as the camel under the tent for doing anything and everything to the human genome.  They write (emphases are mine, not theirs):

“[The recent] developments [regarding MRTs] are nothing short of historic and their significance multifaceted. First, mitochondrial replacement therapy represents the sole example of state-approved germline gene therapy in the human. Second, it comprises the only known intervention with the potential to reduce the burden of mitochondrial DNA diseases. Third, it constitutes the first case in which organelle and, indeed, whole cytoplasmic cellular replacement are being contemplated. Fourth, it irrevocably alters assisted reproduction by placing it at the center of future genome editing efforts. Fifth, it acts as a test case for the regulatory adjudication of other emerging reproductive innovations. Examples include but are not limited to editing the genome of the human embryo and the prospect of using somatic (eg, skin) cells to generate eggs and sperm in a laboratory dish.”

I encourage readers to let this paragraph sink in.  The thinly-veiled argument is that putting breaks on these technologies is illegitimate not only because it violates the principle of beneficence, but more importantly because it could delay the day when humans are fully engineered.  The authors and their apologists will object that I am putting words into their mouths, but I think their enthusiasms are showing.

Read the whole thing.

Medical errors and more medical errors

Last week the BMJ reported that annually, there are 251,000 hospital deaths due to preventable medical errors in the US. There’s some debate about the calculations that they used to arrive at that number, and about what exactly constitutes a medical error. However, rather than quibble over the fine points, let’s acknowledge that medical errors are an ethical problem that must be addressed. In this post I would like to widen the conversation beyond the hospital walls. Below is a sample of some deaths due to preventable medical errors that weren’t included in the BMJ calculations (most of these ones happen outside of hospitals); nevertheless, they too affect thousands of people annually. I will also attempt to provide a taxonomy of the relevant errors.

Deaths due to the inability of the patient to obtain medical care because they couldn’t afford the care or the insurance — unknown number. The medical error here is a systemic one, the rationing of health care on the basis of who can pay for it.

Deaths of patients due to their being the subjects of human research — unknown number. This is peculiarly prevalent among embryonic patients (as Jon Holmlund wrote about last week). The medical errors include the failure to extend to embryonic research subjects the protections enumerated in the Declaration of Helsinki. There is also a category error: classifying embryonic patients as something other than human beings.

Deaths of embryonic or fetal patients through elective induced abortion — 977,000 (2014 data). The same category error as previous comes into play here: the failure to recognize the humanity of the unborn human.

Deaths of patients from drugs prescribed by their physician for the purpose of suicide — the numbers data is incomplete. The number is relatively low but projected to grow as more jurisdictions legalize physician-assisted suicide. The errors here include a professionalism lapse (forgetting that the professional status of medicine was established, among other things, on the dictum that doctors do not give deadly drugs, even if asked to do so). There is also the error of hubris: the belief that doctors can decide that someone should be allowed to kill themselves.

Preventable medical errors, all.

Experimentation on nonviable human embryos

Nature News recently reported that a second Chinese research team has done research on non-viable triploid human embryos in which they used CRISPR-Cas9 genome editing to introduce a mutation that cripples the immune cell gene CCR5 and would make individuals with the mutation resistant to HIV. This research raises a multitude of ethical concerns. Should we be pursuing such research when we have not decided whether using these techniques to create individuals who would be brought to birth would be permissible? Does the fact that only 4 of 26 human embryos targeted were modified and that those were not modified on all of their chromosomes and there were a large number of unintended mutations indicate we are nowhere near ready to try this technique on human embryos? If this could be done effectively would we want to make children with an impaired immune system, but who are resistant to HIV?

I would like to focus on a more basic ethical concern. The researchers in this and the prior Chines study reported in April 2105 justified experimenting on human embryos by using embryos that were non-viable. They obtained from a fertility clinic early human embryos that were triploid, meaning they came from eggs that were fertilized by two sperm and contain 69 chromosomes rather than the normal 46. This is a fatal condition. Most naturally occurring triploid fetuses miscarry in the first trimester and the very few who survive until birth seldom live more than a few days after birth. Embryos created during IVF that are identified as being triploid are not implanted since those doing IVF desire a healthy child, not a disabled one. The researchers contend that the fact that these embryos will not survive makes it permissible to use them for genetic research because it removes the concern that a genetically modified human being could be born.

However, does the fact that a human embryo is destined (almost always) to die prior to birth mean that it is permissible to use that embryo as a research subject? If a human embryo is a human being who has been made in the image of God, then the life that the embryo is living has value and should be respected even if that individual will never be born. When we do research on children who are not able to voluntarily consent to being research subjects we restrict that to research that either has minimal risk to the subject or is being done to try to benefit a child for whom no other treatment is available. Embryos are not able to consent to be research subjects, yet this research is being done on them with great risk to the life that they do have and with no intent to benefit them. If these two sets of researchers do not believe that human embryos deserve this type of respect, then why not use normal embryos instead of triploid ones? In both cases they would be experimenting on living human beings who are incapable of consent and are being killed and the end of the research. Why would it be more acceptable to do that with human beings who are more disabled and have a shorter life expectancy?

We have made significant ethical advances over the past century in our understanding of how we should conduct human subject research. We need to remember that human embryos are human subjects when they are used in research.

“Imago Dei” by any other name…

William Shakespeare reminded us that an object’s essence is not determined by the label we assign to it. No one has since proven Shakespeare wrong. Despite this fact, nowhere have labels been more strongly asserted than in the bioethical debate of abortion. Exactly what or who exists in the uterus of a pregnant human female? The list of labels is long and includes: “baby”, “the pregnancy”, “embryo”, “fetus”, “the products of conception”, “the unborn” and “potential future person”. These labels may honestly reflect an individual’s sincere belief or understanding of the essence of the object in question. But the labels can impede an honest discussion of and agreement upon the essence of that very object. Termination of a baby carries more moral alarm than termination of a pregnancy even though both refer to the same event. We even have different labels to identify the opposing groups on the abortion issue that avoid naming the procedure; Pro-Life and Pro-Choice.

With abortion being the third rail of social politics, it should surprise no one when we see our politicians on both sides of the aisle politically injured when mishandling the subject. When asked if a pregnant woman should be held liable for seeking an abortion in some hypothetical future where abortion is illegal, Mr. Trump eventually suggested she might be subject to “some form of punishment”(1), though later walked back the statement after realizing his assertion upset both Pro-Choice and Pro-Life groups. Since this was a legal rather than ethical question, a non-lawyer could similarly struggle to rationalize how one presently can be held criminally liable for the unintentional death of the fetus of a pregnant woman via a motor vehicle collision(2) but not held criminally liable for the intentional death of the same fetus under current (read: legal) abortion laws(3). No discussion was undertaken from an ethical standpoint to explain why punishment might be deserved in the first place.

Within a week of Mr. Trump, Ms. Clinton caused a different abortion controversy by “referring to the unborn as a person”, drawing the ire of her Pro-Choice supporters(4). The label “person” usually carries moral protection prohibiting, for instance, potentially fatal surgical procedures without informed consent, and abortion is certainly fatal, at least from the standpoint of the unborn, particularly when promoted to a person. Similar to a previous statement above, aborting a person carries more moral alarm than aborting the unborn.

For the Christian, the essence of the pregnancy, products of conception, embryo, fetus, unborn or potential future person must include the Image of God, the Imago Dei. It is this essence that provides moral boundary and ethical guidance regardless of other human attributes, whether potential or realized. See this recent blog entry for further detail.

As per Shakespeare, we cannot ignore the smell of the rose, regardless of how we choose to label it. Would that we could not ignore the essence of the Imago Dei, regardless of our ethical, social or political beliefs.

 

The pertinent portion of note 3: “If the mother can intentionally terminate the pregnancy at three months, without regard to the rights of the fetus, it becomes increasingly difficult to justify holding a third person liable to the fetus for unknowingly and unintentionally, but negligently, causing the pregnancy to end at that same stage. There would be an inherent conflict in giving the mother the right to terminate the pregnancy yet holding that an action may be brought on behalf of the same fetus under the wrongful death act.”

Translational Science as an Ethical Imperative

An acquaintance recently sent me a copy of an article from the December 7, 2015 edition of The New Yorker magazine, describing efforts of a neurosurgeon to use an unconventional approach to treating terminal brain cancer.  Follow the link and read the article for the whole story, but the physician in question was acting on anecdotes of people whose brain tumors had improved dramatically after serious post-operative wound infections. (Surgery is the front-line, but generally inadequate, treatment for these tumors.)  The physician purposely infected the wound of one of his patients with Enterobacter aeroenes, a bacterium normally found in the bowel and in human feces.

The first patient had a dramatic improvement and lived for a few years after—a highly unusual, positive result.  The second one did not do so well.  There was a small number of people treated in this way, and results were mixed at best.

From the article, it seems clear that this was a good doctor trying to help his patients—one who had done a practice-changing clinical trial and who understood that some treatments may “work”—that is, have a biologic effect as expected—but not help the patient—that is, the effect does not translate into any actual clinical benefit against the disease.  This is a common problem in the development of new treatments, especially for cancer, where clinical trials often do no better than showing “a correlation with a correlation with something you care about,” as a former senior official of the National Cancer Institute put it to me (not about this neurosurgeon’s approach, but about something else) some years ago.

“Innovative therapy” is not the same as “clinical research” or “human subjects research.”  The former is performed by a licensed physician using his clinical judgment to try to apply available means for the best care of his patient.  The latter tries to collect generalizable knowledge and, one hopes, help the study subjects in the process.  Often in clinical trials, especially the earliest trials of the newest approaches to therapy, the latter (“direct benefit” to subjects) is not attainable, but the former (the “indirect benefit” that may translate into future direct benefit for other people, or for society at large) is.  In early cancer trials, overoptimism, implicit or explicit, is often a concern, leading to something called a “therapeutic misconception.”

In this case, the doctor took pains NOT to create a therapeutic misconception.  He didn’t oversell the idea to his patients.  With the first case, the local IRB—the ethics board—did not think its oversight was needed, calling the approach “innovative therapy.”  As the number of patients receiving the attempted treatment increased, the IRB started to think it should get more involved.

To make the story short, enough was done without formal IRB review or FDA regulatory review that it was decided, in retrospect, that several people should be disciplined for, in essence, getting out over the end of their skis with the idea.  The author of the article contrasts this case with the Duke University studies into using a modified poliovirus to treat brain cancers, something that was the subject of a widely-noted report on 60 Minutes last spring (subscription required to view online).  That approach was studied in the laboratory for years before being tested in patients.

A big challenge with “alternative” or unorthodox treatment approaches for desperate diseases is that they are typically blind shots.  Now, if you know you don’t have long to live, you might be willing to let a blindfolded marksman shoot a wild animal off your head, knowing he might hit your head instead.  And, frankly, many new treatments are still “semi-blind” at least.  But (and leaving aside for now the whole question of how much of what kind of regulation is best) there is something of an ethical imperative for doctors exploring new treatments to perform the most disciplined scientific research they reasonably can to try to understand what is going on with their new idea, how to improve their chances of success, and how to limit undue risk to their patients.  It’s part of integrating medical research into good patient care, and it’s called “translational,” trying to translate a set of observations or laboratory results into a defined treatment with some reasonable estimates of the risks and benefits.