“Safe” gene editing

The New England Journal of Medicine carries a brief article about “Controlling CRISPR-Cas9 Gene Editing” (subscription required).  The upshot: RNA used as a medicine, as in the case of “CRISPR” to edit genes, can hang around well after administration, and alter genes other than the ones intended to be altered.  These “off-target” effects could lead to unwanted clinical side effects.  You’d like to be able to shut the RNA medicine off.  Pharmaceutical companies that make and develop medicines from short RNA sequences have been doing just that—creating “antidotes,” if you’ll pardon the expression (bad use of the word, really—an antidote is to a poison, and the medicines are not poisons)—to reverse unwanted off-target effects of their medicines, should such effects occur.

Using CRISPR for gene editing to treat known genetic disease raises a similar concern, and the NEJM article cites a recent experiment indicating that such a “reversing agent” for CRISPR, if needed, might indeed be feasible.  So, suppose you are trying to treat someone with genetically-caused blindness, and there’s a risk that other genes might be affected.  You could give the “reversing agent” to block that.  Cool.  You’d want to get it into the right tissues—the right parts of the body—but the work described in NEJM suggests that might all be reality eventually. 

One challenge is: these RNA-based agents don’t always get into the parts of the body, or into cells, all that well.  The NEJM writer says that this new work into “controlling” CRISPR-based gene editing “of course, depends on the [reversing agent] delivery problem being solved, but that is a topic for another day.”

It’s been some time since your correspondent worked for a drug company making RNA-based drugs, and I’m not close to the work these days, but I would say that is most definitely a topic for another day.

So, why bring this up in a bioethics forum?  Because it’s one more matter that would need to be considered and addressed before charging into gene editing that can be inherited from generation to generation.  This, as the present writer has repeatedly held, is something that that the human race should never do.

But it’s bowling along.  The latest reports are that attempts to edit genes babies of deaf couples to prevent them from being born with genetic deafness are nigh in Russia.  Understandable, laudable goal, but we should not think that control of the process is nigh.   edium

Should Abortion be a Trivial Event?

A recent NEJM Perspective by Drs. Jane Henney and Helene Gayle is calling for reduction in the current restrictions on Mifepristone, previously better known as RU-486. Mifepristone, a progesterone blocker, which effectively opens the cervix of the uterus, when combined with misoprostol, which promotes contractions of the uterus, forms the two-pill combination marketed as Plan C – an effective, safe, self-administered home medical abortion. Arguing that the drug has been shown to be far safer than originally thought, and because many US women are accessing foreign internet sources of potentially suspect quality Mifepristone, Drs. Henney and Gayle are encouraging the FDA to make the drug available from regular US pharmacies rather than at special medical/surgical clinics from a restricted set of doctors as it is presently distributed.

At the time of its initial FDA approval in 2000, it was unknown whether mifepristone would have a high risk of excessive bleeding or incomplete abortions so it was approved under FDA Subsection H, which required that the drug be dispensed directly from a physician (rather than a pharmacy) who can provide blood transfusion or surgical abortion. Drs. Henney and Gayle argue that numerous studies since 2000 support that this level of restriction is unnecessary. This is not to say that the risks of Mifepristone are zero but rather, as one of their arguments goes, there are many other medications available from a pharmacy via prescription that have higher risks so why single out Mifepristone? They are not specifically calling for the medication to become “over-the-counter” (meaning available without prescription) but they list other countries where this is the case.

Their concern about the ease of obtaining Mifepristone (or Plan C) over the Internet is not exaggerated. A quick search of the Internet shows one advocate website called plancpills.org providing a report card where their own secret shoppers grade various Internet sites offering Mifepristone for sale. Another popular site called AidAccess.org offers an informative video, telemedicine consultation as well as foreign sourced Mifepristone and this site is presently one of the least expensive sources of the drug.

One of the statistics offered in support of abortion, especially medication-based abortion such as Plan C, is that these processes are safer for women from a morbidity and mortality standpoint than actually being pregnant, particularly the labor and delivery of birthing a baby. Of course, it (always) goes without saying that the same processes are nearly universally fatal for the baby. But, for arguments where the morbidity and mortality of the child are excluded, abortion, particularly medication-based abortion, has become a relatively safe process.

I have no doubt that the present restrictions by the FDA on access to Mifepristone will be reduced for the reasons Drs. Henney and Gayle have provided, perhaps eventually to point of making Plan C available over the counter.

Abortion is becoming a trivial event.

Abortion kills a human being.

Killing a human being should not become a trivial event.

Embryonic Legerdemain?

Developmental biologist Lewis Wolpert is credited with saying, “It is not birth, marriage, or death, but gastrulation which is truly the most important time in your life.” Gastrulation, simply put, means the embryo develops an axis and distinctly different cell layers. In the human embryo, gastrulation takes place during the third week post-fertilization. Formation of endoderm occurs over days 14-15, and the mesoderm begins to appear on day 16 (see Figure 1-11 here).  Ali Brivanlou, of New York’s Rockefeller University, identifies gastrulation, or the breaking of symmetry in the embryo, as the “major Holy Grail of developmental biology.”

Why is this so? During the third week after conception, the embryo has burrowed into the mother’s womb, and the peering eyes of scientists cannot visualize the events there. With the 14-day rule in place regarding embryo research, laws or guidelines in various locales outlaw or discourage (as in, do not fund) laboratory culturing of embryos beyond that point. So, Brivanlou’s lab “came up with a model of human embryos that is developed outside of the womb and is not the product of sperm and eggs, but the product of human embryonic stem cells that self-organize into complicated structures.”  These embryonic stem cells have formed what appears to be an embryo, but in Brivanlou’s terms, “could never become a baby.”

Dehumanizing the embryo is one of the essential components of making research on embryonic humans more palatable to the public. It will also be en essential step in a workaround of the 14-day rule. It appears that “model embryo” will join other terms such as “embryoids,” “gastruloids,” and “SHEEFs” as some element of humanity that scientists do not recognize as humans worthy of legal protection. Regarding Brivanlou’s “model embryo,” Harvard Medical School’s Dean George Daley calls it a “remarkable tool in a petri dish.” The “tool” with which Brivanlou and others concern themselves is both human and alive; otherwise, would they be interested?

Let’s think about this, using an analogue. If well-trained scientists could produce men and women without chests, what would be allowed? Would they have to call such men and women without chests “human”? Could they use men and women without chests for experiments?  Would the experiments have to be approved by institutional review boards?  Would the rest of us pay the scientists – handsomely – to do this? Could they win prizes?

Reclaiming the Lost Art of Dying

As I continue to reflect on the recent CBHD bioethics conference, there are several of the sessions that stand out to me. One was the presentation by John Kilner at the conclusion of the conference that I wrote about last week. Another was the very first presentation as the conference began. Lydia Dugdale spoke on the topic of “Reclaiming the Lost Art of Dying.” Many of us have recognized that there is a tendency for people in our current culture to die poorly. Dr. Dugdale suggested that our difficulty in dying well is related to our level of medical technology. Because modern medicine is able to do so much in treating and curing diseases, the allure of a cure can keep people from accepting the reality of death. She gave as an example a case of a woman with incurable cancer who never addressed the reality that she was dying because every time one treatment failed another was recommended.

She reminded us that there was a time in the middle ages when people were taught the art of dying well through a text titled “Ars Moriendi.” This booklet was published in the 1400s following the ravages of the bubonic plague in both literate and illiterate versions to help people prepare for death. It included instructions on preparing willfully for death and accepting it gladly when the time came. It spoke of avoiding temptations such as impatience, despair, pride, and doubt. It included a catechism pointing to the truths of the Christian faith and prayers for those who were dying.

She asked if something like this were possible for us today and suggested that bioethics could be a framework for learning how to die well. It can help us recognize our finitude and the limits of medicine. It can also point us toward community which can provide the support needed for those who are dying to die well. This may be as far as those in a secular setting, like the one in which Dr. Dugdale works, can go. However, those of us who share Christian faith should be able to take this farther. She challenged us with a quote from Jean-Claude Larchet’s book The Theology of Illness in which he says, “Ask God not in the first place for the return of health, but for what is spiritually most useful.” That points us back to what was understood in the days that the Ars Moriendi was written. Dying is an important part of our spiritual life, and we can grow spiritually through the experience of our own death as well as how we care for others as they die.

Good from Evil

I was given an article by a student of mine following his one month elective rotation with me in which we spent some clinical time discussing bioethical issues. The May 2019 web article by Sharon Begley from Statnews.com had to do with an interesting medical dilemma first presented in 2016 by Dr. Susan Mackinnon from Washington University in St. Louis. I have briefly summarized Begley’s article in the first part of today’s blog and extended her point at the end.

Dr. Mackinnon had a patient who was having severe leg pain following multiple knee surgeries. Dr Mackinnon was providing the final surgical attempt to isolate the nerve presumably being compressed by scar tissue in hopes of surgically decompressing that nerve to permanently relieve the patient’s severe pain. If the surgery was not successful, the only other option at that point was to amputate the leg. During the surgery, she used an old anatomy book called The Pernkopf Topographic Anatomy of Man, which unambiguously has the best illustrations of nerves around the knee, and successfully located and decompressed the nerve in question and successfully avoided an amputation.

So, what was the dilemma?

As Begley points out in her article, it came to light in the mid-1980s that the illustrations used in the Pernkopf atlas were based in part on the bodies of people executed by the Nazis in the late 1930s. The moral dilemma for Dr. Mackinnon was therefore:

“…even now, the Pernkopf illustrations are unsurpassed in their accuracy and detail, especially their depiction of peripheral nerves…and although a few journal papers may have an equally good, single illustrations, finding the right paper takes time that Mackinnon did not have as she stood over her patient.”

Dr. Mackinnon had been given the Pernkopf atlas as a graduation gift in 1982 but the Nazi history behind the atlas was not known until the mid-to-late 1980s, the full history of which only became known to her after the surgery. Should she continue to use an atlas that contains illustrations of the bodies of people executed by the Nazis? If used, is there a duty to inform a current patient about the nature of the atlas? Can sufficient good be derived from the atlas given the unspeakable evil required to create it to permit its ongoing use?

She posed her dilemma to Rabbi Joseph Polak, the Chief Justice of the Rabbinical Court of Massachusetts, who consulted Prof. Michael Grodin of the Elie Wiesel Center for Jewish Studies at Boston University. Their opinion became known as the Vienna Protocol, due to the origins of the Pernkopf atlas. Their response may be found in this link, which I believe is better read in the full context of the Vienna Protocol than summarized by your humble blogger. For those of you who must read the opinion before reading the entire protocol, please follow the link and scroll to the 4th to last page at number 12 in section C entitled “The Protocol and Recommendations”.

The evil that created the Pernkopf atlas was the Nazi occupation of and executions that occurred in Austria during World War II. It is no longer occurring. No one in the present is suggesting that we resume executing people to gain more anatomic drawings to complete additional volumes of the atlas. Any good resulting from the current use of the atlas isn’t being offset by any ongoing evil of creating more atlas. The evil of the Pernkopf atlas is contained in the past and, in that sense, finite. Containing the evil seems to be a necessary step in obtaining good from that evil.

I mention this in closing as I believe there are current analogies of activities performed in the name of scientific good where we condone ongoing evil. Studying fertilized ova until sacrificing them on Day 14 (an evil) in the name of learning about human reproduction (a good) is one modern day example. In Vitro Fertilization done to obtain a healthy baby with genetic traits we want (a good) that results in the death(s) of other fertilized eggs we don’t want (an evil) is another. There are other examples we have discussed within this blog. I believe we need to contain and hopefully discontinue these and other practices if we want to claim the information we gain can honestly be called good.

Fertility Fraud

By Neil Skjoldal

Last week, Canadian fertility specialist Dr. Norman Barwin lost his medical license after complaints that he had used his own sperm to artificially inseminate his patients without permission. Bionews.org reports that there were understandably strong reactions from the families affected by his horrific actions.  And now it has come to light that he had done this at least 11 other times.

This case brought to mind a case that came to prominence last year.  Dr. Donald Cline, an Indiana fertility specialist, used his sperm to artificially inseminate his patients and is said now to have more than 50 biological children.  Apparently, up until recently, there were no laws stating that it was illegal for a physician to do so. In light of the Cline scandal, Indiana passed a fertility fraud law which singles out fertility doctors who use their own sperm.  Theindychannel reports:  “The law, which takes effect July 1, makes it a level 6 felony if someone makes a misrepresentation involving a medical procedure, medical device or drug and human reproductive material.”  

It is truly sad that it takes a law to ensure that doctors will not artificially inseminate patients without their consent.  However, I am glad that Indiana did so.  (California has a more general law). If individuals are unable to regulate their behavior based on their own personal morality and ethics, it becomes incumbent upon society to investigate the matter to determine whether a law is needed or not.  This is what happened in this case.

Bonnie Steinbock takes an interesting perspective on the Cline case.  While acknowledging that the doctor was unethical, Steinbock questions whether or not the children born from this unethical behavior were actually harmed by him:  “What makes the lawsuits of the children Cline sired problematic is the fact that, but for Cline’s use of his own sperm, none of these children would have existed.”  She concludes, “If there are to be any medical malpractice suits against Cline, these should be limited to the parents, not the children.”

These unethical acts demand our attention. What can be done to stop them? And what of those who were victimized by this behavior? At the very least, they deserve answers. I hope that Indiana’s law might make a difference. Hopefully other states are taking notice.

Ending well

By Steve Phillips

This past week I attended the CBHD summer conference. This year’s theme was “Taking Care: Perspectives for the End of Life.” As usual, the conference was filled with thought-provoking sessions and many good personal interactions. While I have much to think about from many of the sessions the one that impacted me the most was the concluding plenary session by John Kilner titled “Dignity and Life on the Line: Ending Well.” This session impacted me in a number of ways. Not the least was remembering how much Dr. Kilner has impacted my life as I listened to him talk about the end of life from the perspective of one going through his own end-of-life journey. It also came at a significant time for me as my wife and I have been grieving the recent death of her father.

However, even without those very personal things, what Dr. Kilner had to say about the end of life was significant. He reminded us that the dignity of human life that exists because every human being has been created in the image of God applies as much or more at the end of life as any other time. Since God has intended in our creation for us to be an internal reflection of him, death is truly an enemy. However, death is an enemy that has been defeated by Jesus in his resurrection. Our approach to death can be wrong if we fail to recognize either of these things. If we do not recognize death as an enemy, we may not pursue appropriate treatment, or we may pursue intentional killing as a means of avoiding suffering. Either of those is wrong. We should intend life and not death. If we fail to recognize that the enemy death has been defeated, we may try to avoid death at all costs and pursue over treatment that increases suffering because we have made life on this earth into an idol.

He also reminded us that the process of dying can include things that are positive. All human life is worth living. The life that we are living as we are in the process of dying can be of benefit to God, others, and ourselves. As we in our weakness put our lives in God’s hands and allow his body, the church, to care for us, we bring glory to God. We allow others to be blessed by serving as they care for us. In the weakness of dying we can find the hope and joy that come from God whose strength is manifested in us in our weakness. I pray that when the time comes God will help me to end my life well in this way. I also pray that I will be able to help others end their lives well.

Thank you Dr. Kilner for all that I have learned from you by your teaching, your encouragement, and the example of your life.

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:/