Technical steps to gene-edited babies

This blog has carried several comments about the prospect of heritable human gene editing.  While nearly no one currently supports bringing such babies to birth—and condemns those who would rush ahead to do so—it appears a distinct minority think that we the human race should, if we could, agree never to do such a thing.  The most cautious perspective is to advocate a moratorium.  Others in favor of proceeding argue that, in essence, with the technologic genie (my term, not necessarily theirs) out of the box, a moratorium, much less a ban, is futile; the “rogues” will press ahead, casting off restraint. 

Advocates of research in this area have argued that a clear, careful, regulated pathway is needed to guide the work through necessary laboratory experiments that should be done first, before making a woman pregnant with a gene-edited embryo, in an attempt to be sure that the process is safe and highly likely to yield the intended result.  Even a moratorium would be, by definition, temporary, leaving the question, “when we will know to remove the moratorium?” to be answered.

A feature article in Nature, accessible without a paid subscription, asks “When will the world be ready” for gene-edited babies.  It walks through scientists’ understanding of what the technical issues are.  It is longer than a blog post, so I can only list key points here.  It is worth a reading by anyone interested, and it is written in sufficiently non-technical language that it’s accessible to the general, non-scientist public.

Key concerns are:

  • How would we be sure that genes that were NOT intended to be edited, in fact were not?
  • How would we be sure that genes that ARE intended to be edited are edited correctly?

These two matters have been addressed to some degree, or could be, in animals, but that would be faster and easier than in human egg cells or human embryos, and the results in animals may be different from what is found in the embryos.  (A further question is how many embryos, observed for how long, would need to be studied to support confidence.)

  • Even if the intended gene edit is made, is it clear that doing so is safe and does not induce other health risks? 

This blog recently reported the UK study that suggested that changes in the gene edited in the twin girls born in China last year might eventually reduce life span.  A criterion promulgated in 2017 by the National Academies of Sciences, Engineering, and Medicine was that the edited gene should be common in the population and carry no known risk (including, presumably, no increased risk) of disease.  Such knowledge is lacking for human populations, and what is believed known about the association of genes with risk of future disease has often been developed in Western populations, and may not apply to, for example, Africans.

  • At least some embryos would include some edited and some non-edited cells.  It would not easily be possible, if possible at all, to tell how many of which were present, or needed to be for the editing to work and not cause risks to the embryo’s development into a baby and beyond.  And what answers were obtained would require manipulating healthy embryos after in vitro fertilization.  The outcomes could not be predicted from first principles.
  • What should a clinical trial look like?  How many edited children would have to be born, and their health (and, most likely, the health of their progeny) observed for how long to get provisional answers before practicing the technique more widely?  Or, would the work proceed as IVF did—with dissemination in the general public, and no regulated research?

A US and UK committee is planned to address these questions, with the intent of proposing guidelines in 2020.  This will be important to follow, but with no chance to affect.  Most of us will just be watching, which leads to the last concern:

  • Is the world ready?

If that means, is there an international, or even a national, consensus, then the answer is clearly “no.”  That almost certainly remains “no” if one asks whether there is a future prospect for consensus.  It’s hard to envision something other than different groups and nations holding different judgments, and, most likely, remaining in some degree of irresolvable conflict.

Defense of Abortion as Killing

It is rare to hear a defender of abortion plainly admit that the act of abortion is killing. So, I was curious as to how such an individual would defend that killing. Dr. Sophie Lewis has recently done so in her new book, Full Surrogacy Now: Feminism Against Family. The publisher, Versa Books, has put out a short YouTube video interview, where she outlines her “abortion as killing” defense. The video is just over 2 minutes and she articulates her point clearly. While I have not read her new book, summaries from the publisher suggest the overarching theme is that pregnancy is “gestational work” done by women without appropriate compensation (permission, time, money, recognition…), resulting in their exploitation. Pregnancy (and procreation in general) ought best be done by willing “gestational workers” with clearly defined contractual obligations and recompense. Surrogacy is the answer. There is much to unpack here so I want to focus the remaining blog entry on her defense of abortion as killing as stated in her linked video above.

Her central defense of abortion as killing is as follows:

…looking at the biology of the hemochorial placentation helps me think about the violence that, innocently, a fetus meets out vis-a-vis a gestator. That violence is an unacceptable violence for someone who doesn’t want to do gestational work. The violence that the gestator meets out to essentially go on strike or exit that workplace is an acceptable violence.

The gestator going on strike or exiting the gestational workplace is the act of abortion. In her view, pregnancy is gestational work that can result in workplace violence or, at least, unacceptable work conditions that exceed those previously agreed upon. At that point, Dr. Lewis believes it should be permissible for any woman to leave the workplace, even though that exit causes an ultimate violence to the fetus – the killing of that fetus. She holds the placental attachment to the uterus as a sufficiently biologically violent condition that should permit a biologically violent defensive reponse with the abortion.

It is hard to make these acts either biologically or morally equivalent. Biologically, there is nothing violent about a placenta developing an attachment to a uterus. In fact, using Dr. Lewis’s workplace metaphor, it is the job of the placenta to attach to the lining of the uterus and it is the job of the uterus to receive such an attachment – it is what both were designed or evolved to do. Even if we accept her workplace violence metaphor, it is rare for the violence of the placental attachment to the uterus to result in the death of the mother just as it is equally rare for the violence of the abortion NOT to result in the death of the fetus. These are hardly biologically equivalent events.

Morally, it is hard to argue, even in her terms, that the mother’s choice to terminate gestational work is equivalent to the baby’s placental attachment, even if we grant her claim that both are equally violent. The mother always has the choice in deciding to terminate the pregnancy – the fetus never has a choice or intentional control of the placental attachment process at any point during the pregnancy. After all, intentional choices are made by persons not fetuses. I doubt that Dr. Lewis wishes to cede further moral ground by granting personhood to a fetus.

Maybe that is why Dr. Lewis stipulates that the baby’s violence is innocent. Frankly, the obvious innocence of the baby makes it even harder, if not impossible, to morally justify the violence she desires us to find acceptable.

More gene-edited babies on the way

It is reported this week that a Russian scientist plans to edit the genes of more human embryos intending to bring gene-edited babies to birth.  As with the case in China last year, the intent is to edit a gene called CCR5 that is responsible for a receptor that facilitates initiation of HIV infection.  The stated reason is to prevent transmission of infection from the mother, not the father, as in the Chinese case.  Maternal transmission of HIV is a real risk, but there are other ways to prevent it, with medications.  And, as recently reported on this blog, the risks of editing this gene are not understood, nor are the long-term risks of heritable genome editing.

The science press is saying that someone should put a stop, now, to bringing edited embryos to pregnancy and birth.  But it is unlikely that effective action can be taken.  The public will has not been engaged, necessary medical research controls are not in place, and no one can say just who would have the authority to take what sort of action.

So for the moment there is little else to say.  We will hear of more cases.  We will find out later how we will respond.  Clarity and consistency of that response seem unlikely. https:/

Pragmatism and principle regarding human gene editing

You may have seen in the general press that the gene-edited twin girls born in China last year may have had their life expectancies shortened in the bargain.  The doctor who edited the babies’ genes specifically edited one gene, that is associated with susceptibility to HIV infection.  Their father is HIV positive, but that does not put the babies at any health risk.  Further, the gene editing potentially could have increased their future risk for other infections.  Now, a group in the United Kingdom have analyzed mortality data for about 400,000 people who volunteered to have their genetic information placed in a data bank.  They reported that people who have a gene mutation similar—but apparently not identical—to the change made in the Chinese babies had a 21% lower chance of living to age 76 than people without the mutation.  Now, the average age of the people who volunteered their information for the data bank is said to be 56.5 years, so the implication is that there is a shortening of life expectancy after middle age, for people who have lived at least that long. 

One should interpret the U.K. analysis with caution, but the argument seems to be, “see, we don’t know the risks of human gene editing, so we shouldn’t be doing it.”  And indeed we do not know the risks.  But the argument in fact is, “…we shoudn’t be doing this—at least not yet.”  As Joy Riley pointed out on this blog a few days ago, the goal of a moratorium on human genome editing appears to be to allow the scientists working on the technology to take time to build public trust and consensus for it.  “We shouldn’t be doing this, ever” does not appear to be an option.  Long-term readers of this blog may recall numerous posts over the last few years describing this process of gradual acceptance in the scientific community.  The scientists draw an analogy to the 1975 Asilomar conference on recombinant DNA work, which established guard rails around that work.  But the analogy is flawed.  The risks of the work addressed at Asilomar were more readily defined, with shorter time frames to results, than can be addressed with genome editing.  400,000 middle-aged people’s mortality due to any (unspecified) cause over the ensuing quarter-century?  How many edited people, studied for how long, over how many generations, with what consent process, to determine the risks?  There can be no acceptable definition of the risks prior to actually assuming them.  “The babies are the experiment.”

The correct conceptual framework for human genome editing is not benefit-risk analysis, it is deeper reflection on where we should not let engineering encroach on the human organism.  “Keep your ambition off our bodies,” I suppose.  And when we think in those terms, we should quickly recognize territory where we fear to tread at all, not just slow down.

Oh, Those Darned Terms (Part 3)

It is hard to keep a good theme down as terminology is back in the news. It seems National Public Radio (NPR) is concerned about proper terminology as a recent “Guidance Reminder: On Abortion Procedures, Terminology & Rights” post by NPR Standards and Practices Editor Mark Memmott on NPR.com suggests. This link is one of periodic commentaries by Memmott on standards expected by journalists at NPR based upon their Ethics Handbook, which is also available on their website. The stated goal of the Ethics Handbook and the periodic commentaries is to be as accurate and unbiased as possible with reporting at NPR, which is obviously an appropriate goal in reporting the news, particularly potentially controversial topics. Read Memmott’s commentary link and see if you think NPR is meeting that goal.

I think there is room for improvement.

For one thing, while there is an appropriate “We-They” throughout the article describing NPR’s word choice versus the word choice of groups favoring “anti-abortion rights” (approved term), I failed to find a similar “We-They” within the article describing NPR’s word choice versus the word choice of groups favoring “pro-abortion rights” (not approved term). Perhaps I missed it?

Additionally, NPR favors the term “fetus” over the term “unborn”, despite the fact that fetus means “unborn offspring of an animal” per Wikipedia or “unborn or unhatched vertebrate” per Merriam-Webster. The Latin sounds more accurate but fewer people are speaking Latin these days. Nonetheless, NPR believes that “[i]ncorrectly calling a fetus a ‘baby’ or ‘the unborn’ is part of the strategy used by antiabortion groups to shift language/legality/public opinion.” I wonder if the Mayo Clinic realizes their interchangeable use of the terms “fetus” and “baby” on their fetal ultrasound web page is not only incorrect but places them squarely in the antiabortion movement trying to shift language/legality/public opinion?

Finally, NPR does not like to use the term “abortion clinics” but rather “medical or heath clinics that perform abortions”. That may indeed be more accurate but why stop there? Why not list all the procedures that a specified medical clinic performs, including the total number of each of the procedures performed, and let the reader decide how he or she wishes to categorize that particular clinic?

It is wrong to purposely select terms feigning accuracy so as to appear unbiased, particularly if the goal is to bias by use of those very same terms.

Proposed moratorium on human germline: Asilomar analogue?

The Editorial Board of The Washington Post (WaPo) recently published their opinion  on regulation of heritable genetic changes in human eggs, sperm, and embryos. The authors expressed some measure of relief that organizations such as the National Academies in the U.S., the Royal Society in Britain, and the World Health Organization are beginning to consider the daunting topic of human heritable genetic changes. The board advised, “The goal must be a framework that will enable genuine scientific advancement but avoid reckless fiddling with the source code of life.”

The WaPo editorial board further recommended “something of similar scope and power” to that of the Asilomar Conference on Recombinant DNA Molecules, held in February 1975. Asilomar, as that conference came to be called, was convened to evaluate the risks posed by the novel technology of genetically modifying organisms. The public perception of Asilomar has been primarily one of scientists shouldering the “social responsibility of science.”

Further, the WaPo article pointed out that one of the authors of the March 2019 Nature commentary calling for a “global, temporary moratorium on clinical uses of human germline editing” was Paul Berg, a Nobel laureate, and one of the organizers of the Asilomar conference. The Nature commentary, authored by Eric Lander, Françoise Baylis, Feng Zhang, Emmanuelle Charpentier, and Paul Berg, described the consensus for a moratorium thusly:

The 18 signatories of this call include scientists and ethicists who are citizens of 7 countries. Many of us have been involved in the gene-editing field by developing and applying the technology, organizing and speaking at international summits, serving on national advisory committees and studying the ethical issues raised.

This description appears to differ substantively from one Berg gave of the Asilomar analogue. In an 18 June 2011 video interview by Larry Goldstein, Berg had this to say about the success of Asilomar:

We made some decisions that were smart in retrospect. For example, one of the things we did not do – and did not include in any way in the agenda was the ethics. We didn’t talk about genetic testing… we talked about real experiments, and what the impact of those experiments would be in the field (10:40-10:58)

Of the five authors calling for a moratorium on human heritable genetic changes, only Françoise Baylis is an ethicist. A 2004 article penned by Baylis and Jason Scott Robert, “The Inevitability of Genetic Enhancement Technologies,” gives insight to her views. The paper concludes with

. . . we maintain that accepting the inevitability of genetic enhancement technologies is an important and necessary step forward in the ethical debate about the development and use of such technologies. We need to change the lens through which we perceive, and therefore approach, the prospect of enhancing humans genetically. In recognising the futility of trying to stop these technologies, we can usefully direct our energies to a systematic analysis of the appropriate scope of their use. The goal of such a project would be to influence how the technologies will be developed, and the individual, social, cultural, political, economic, ecological, and evolutionary ends the technologies should serve. It is to these tasks that bioethical attention must now fully turn.

It appears that 1) Paul Berg’s previous concerns about “ethics” being involved is not a problem to date in this enterprise; and 2) the called-for moratorium is truly only a “speed bump” on the road to converting future generations into our own laboratory experiments. The “individual” ends such experiments will serve are likely to be the individuals who are paid handsomely to do such experiments or who hold the patents to the processes utilized – not the individuals formed. Despite the extensive embrace of heritable human genome editing by the principals cited here, we need to remember that this is not a road that we must travel. Future generations are not our playground. We need to rethink this “moratorium”:  It should be an outright ban.

Emerging attempts to control gene editing

Recently, it was reported that the panel convened by the World Health Organization (WHO) to develop standards and guidelines for gene editing will ask the WHO to establish a registry for any projects on heritable human gene editing.  The idea is that, to get research funding, a project would have to be registered, and there would be a required review in order to get on the registry in the first place.  The net effect would be to control the flow of money to such projects.

Also, according to Nature, the Chinese government is looking at amending its civil code, effective March 2020, to in essence make a gene editor liable for health outcomes by declaring that “experiments on genes in adults or embryos that endanger human health or violate ethical norms can accordingly be seen as a violation of a person’s fundamental rights.”  The idea here appears to be to make gene editors think twice about whether they are sure enough of their work to accept essentially a permanent risk of being sued for all they are worth if anything goes wrong in the future.  Your correspondent knows nothing about Chinese civil procedure, but in the litigious U.S., the risk of really big, unpredictable lawsuits at some entirely unpredictable time in the future, with no limit, can make even big companies shy to pursue something. 

So maybe these approaches, by “following the money,” as it were, would at least slow down heritable genome editing, short of a ban.  Skeptics of the utility or wisdom of a ban argue that the “rogues” will just find work-arounds anyway, and that entire states can “go rogue,” limiting the effects of the ban to only the nations willing to enact and enforce it.

That’s a reasonable argument, but it still seems that, by only requiring a registry—with noncompliance always a risk—or trying to up the ante in court—a risk that some entities might take if the perceived reward is big enough to warrant it, and they can hire enough expansive lawyers to limit the risk—there is an admission that heritable genome editing is going to go forward.  And, indeed, maybe there’s no stopping it.  But it seems like promoting a stance toward human life that refuses to accept heritable gene editing is still something we should do.

When should physicians provide a good death?

A recent New England Journal of Medicine (NEJM) Perspective by Deborah Denno, Ph.D., J.D., entitled “Physician Participation in Lethal Injection” (subscription or limited free access required) discussed physician involvement in state-sanctioned capital punishment by lethal injection. Some of the arguments for physician involvement in euthanasia (“a good death”) or Physician-Assisted Suicide (PAS) would seem to apply to some degree to lethal injection and is the subject of this blog entry.

For those without access, the article explored a recent Supreme Court rejection in Bucklew v. Precythe of a Missouri death row inmate’s appeal for protection from lethal injection under the Eighth Amendment’s prohibition of “cruel and unusual punishment”. In short, Russell Bucklew has a rare vascular condition making venous access both difficult and potentially more painful to use lethal injection as the means to execute him. It was argued that his medical condition necessitated at least medical training to guide the injection process, if not actual physician/surgeon training, such as possessed by an anesthesiologist, to provide the actual vein access for the lethal injection. In rejecting his appeal, the Court responded, in part, “the Eighth Amendment does not guarantee a prisoner a painless death – something that isn’t guaranteed to many people, including most victims of capital crimes.” The Court added that methods prohibited are those that “superadd terror, pain or disgrace to their executions”, though as the article points out, the Court does not specify as to how to test those limits, and left unanswered whether physician involvement was legally required to guarantee satisfaction of the Eighth Amendment.

The article discusses the fact that national medical associations generally strongly discourage their members from providing guidance for lethal injection. The American Medical Association’s (AMA’s) own amicus brief for the case listed above states that the AMA opposes capital punishment. The American Society of Anesthesiologists (ASA) takes a similar position opposing participation of its members in lethal injection. Both the AMA and the ASA agree that capital punishment is not the practice of medicine and the ASA goes further to challenge the Court to look elsewhere for any lethal injection skills.

Interestingly, both organizations are less precise on their position regarding physician involvement in euthanasia or PAS. The AMA sees PAS as causing “more harm than good”. The ASA has no official published position on PAS that I could find on their website. Their Statement on Palliative Care does not mention euthanasia or PAS. This is important, as there is a growing demand for physician involvement in euthanasia/PAS, the implication being that there is additional benefit with physician involvement in achieving a good death.

For the record, I have always believed that physicians are uniquely the worst choice for killing people under any circumstance as our training universally focuses on honing skills that avoid causing death to our patients. We are effectively trained at not killing and would therefore provide dysthanasia – a bad death. But, perhaps, I am mistaken. There is growing demand to involve physicians in actively and purposefully killing their patients, with many holding the contrary belief that physicians uniquely have the best skill set to provide for euthanasia – a good death.

So, even though Russell Bucklew failed to make a successful legal case for physician involvement in lethal injection, did he make a sufficient moral case? If physicians and their unique skills are necessary for euthanasia/PAS, are they not equally necessary for state-sanctioned execution, particularly given that the latter involves the non-voluntary death of an individual who is guaranteed Eighth Amendment protections, and especially given our inability to provide any scientific evidence that we are satisfying those protections?

If physicians really are the best at providing euthanasia, doesn’t moral justice demand we require a physician to similarly provide a good, physician-assisted, state-sanctioned, death (PASSD) despite the stated objections of the AMA and ASA? Anything less arguably opens the door for adding “terror, pain or disgrace” to the execution.

Parental responsibility in childhood immunizations

Last week I wrote about the issue of parental responsibility and medical decision-making for children. We have good reasons for having parents be the primary decision makers for children who are not capable of making their own medical decisions. However, as I discussed in the last post, there are some situations in which parents make decisions that are not in the best interest of their child. When those decisions reach the point at which the child’s life is in danger, society clearly has a moral obligation to intervene to save the life of the child.

Parental refusal of recommended immunizations for their children raises similar issues but is more complex. We can clearly demonstrate that it is in a child’s best interest to receive at least most of the commonly recommended immunizations for children. Those immunizations help to prevent a child being affected by diseases that can be serious and have a very low risk for serious adverse effects. However, the chance of an individual child being affected by many of these diseases is relatively small and the situation is quite different from a child whose life is in immediate danger due to a parental refusal of treatment. Since the risk to an individual child is relatively small and there is some possible risk to the child from receiving the immunization, it is not clear that a parent who refuses immunizations for a child is being negligent in the same way as a parent who refuses treatment for a life-threatening illness. It can be argued that the best way to deal with this type of situation is education. Many times, parents refuse immunizations for their children because of misconceptions about the risks and a lack of understanding of the benefits of doing the immunizations. It can be difficult to counter widespread misconceptions, but physicians have the responsibility of trying to do that the best that we can. However, this is not the only issue involved in determining whether society has an obligation to intervene and mandate childhood immunizations when parents refuse.

Immunizations are unique in the way that they work. They help protect the individual who is immunized, but they also help protect the community as a whole when we can achieve sufficient levels of immunity to halt the spread of an infectious disease within the community. This is sometimes called herd immunity. We have an excellent example of how this works with the current measles outbreak in the United States. Measles happens to be one of the most easily transmittable infectious diseases that we know of. It also can be deadly in a small percentage of the people who acquire the disease. It is also primarily a disease of children and is transmitted by children. When about 97% of children have been immunized in a community the disease will not be transmitted through that community and those who have not been immunized or cannot be immunized are protected from acquiring the disease. This level of immunity was accomplished in the United States about 20 years ago and for some time the only cases of measles that were seen in the United States were cases that originated elsewhere. However, because of parents refusing to have their children immunized for measles in significant numbers in some parts of the country, herd immunity is no longer present and we are having outbreaks of measles this year that are more than we have seen in 20 years.

That raises a different question. Should we mandate immunization of children for diseases such as measles and override parental decision-making not solely for the benefit of the children whose parents refuse to have them immunized but for the common good of the community? There are some children and other individuals who cannot be immunized or for whom immunizations would not be effective who are put at increased risk when herd immunity is not achieved in the community. This makes the decision about whether to immunize a child not just a decision about what is best for that child but also a decision about what is best for the community. For Christian parent it makes the decision about whether to immunize a child a decision about love of neighbor. Immunizing one’s own child helps to protect the child, but it also helps to protect the most vulnerable in the community. If we truly love our neighbor, we should do that even if there is a small risk to our own child. The final question is whether we as a society should require children to be immunized for these diseases when a parent is not willing to authorize it out of either concern for the best interest of the child or concern for those who are vulnerable in the community.

Parental responsibility in medical decisions for children

The 2 posts on this blog this week by Neil Skjoldal and Mark McQuain raise issues related to parental decision-making for the medical treatment of their children. Neil raised this issue related to parental refusal of life-saving treatment for acute leukemia and Mark raised it related to parental decisions not to have their children immunized for measles. There are some similarities in these situations and some differences. An obvious similarity is that in both of these situations parents are making a decision to refuse treatment for their children that is the recommended standard of care. Both situations raise issues about who should make decisions about the medical care that children receive and how those decisions should be made.

One thing we should be clear about is that this is not a conflict between the principle of respect for autonomy and the principle of beneficence. Respect for autonomy says that a person should be able to make decisions about what happens to his or her own body. It says that it shows disrespect to an individual as a person to insist a person receive recommended medical care when that person has the capability of making his or her own decisions and does not consent to the recommended care. This principle does not apply to decisions about the medical care of young children. Young children are not capable of making decisions about their own care and the parents are not the ones receiving medical treatment, so respect for autonomy does not apply to these situations.

What is involved is our understanding of parental responsibility for making medical decisions for their children. Because young children do not have the ability to make their own medical decisions, someone needs to serve as a decision-maker for them. We generally understand that parents ought to be the ones making those decisions. We have good reasons for that. Decisions about the medical care of young children should be made based on what is in the best interest of those children. God has created us as human beings to be dependent during the early part of our lives. He has put us in families with parents who have the responsibility for providing for the needs of their dependent children. Parents should love their children unconditionally as a precious gift and make decisions for their children based on what is best for each child. This usually makes parents the people who care the most about doing what is best for a child and makes them the best medical decision makers for their child.

However, sometimes parents do not fulfill their parental responsibilities as well as they should. None of us are perfect, but there are times when it is clear that the decision being made by a parent is not what is best for a child. When the potential consequences for the child are serious enough it can become the responsibility of the rest of us to intervene for the benefit of the child. We should not violate parental responsibility lightly, and it needs to be done in a controlled and orderly way, but when the child’s life is in danger, we have a responsibility as a society to intervene to protect a child. We should do this in any type of severe neglect or abuse.  We should do it when parents refuse medical treatment for a child who is likely to die if without treatment and the treatment has a good chance of saving the child’s life.

That appears to be the case in the situation in Neil’s post. The concern about parents refusing immunizations for their children has some similarities, but is more complex. It will take another post to address that.