“The Babies are the Experiment”

By Jon Holmlund

 

The Thursday, Dec 13 edition of the Wall Street Journal carries this headline:  “Doubts Arise Over Gene-Editing Claim.”  The work behind the recent report that the world’s first two gene-edited babies had been born has been publicly discussed, but the details have not yet been published for full scientific review.  Apparently scientists in the gene-editing field are reviewing the public presentation and finding it lacking:

  • Some, but not all, of the cells in the children may have been edited. One would expect changes in all of the cells, and this should be necessary for the overall stated medical goal (protection from HIV infection) to have a chance of having been met.

The edited babies may have variants of the edited gene that have not been fully studied and could have unforeseen health consequences.

The technique used to confirm the gene changes may not be sensitive enough to detect whether other, unintended and potentially undesirable gene changes had been made.

And perhaps most notably, the studies done in mice to demonstrate the feasibility of the technique, before editing the embryos that grew into the full-term babies, involve a different change in the target gene in mice than the change sought in the children. In other words, the animal studies appear not to be representative of the human situation.

This is a common problem for development of new treatments for cancer and other diseases.  Tests are initially done in animals—usually mice—to determine whether the putative new treatment appears to be working.  The animal models used never entirely reflect the human disease.  Some come closer than others.  But the way of handling that uncertainty is to define and limit the risks to people who subsequently have the new treatment tested on them in clinical trials.

In the case of the gene-edited babies, there’s really no way to limit the potential risks, at least not yet, if ever.  Ultimately, one has to strike out and make changes that could backfire for the recipient humans, or be propagated into their descendants with unpredictable effects. 

Accordingly, without good animal models, and appropriately extensive testing in them, then, as professor Sean Ryder of the University of Massachusetts Medical School is quoted as saying, “the babies are the experiment.”  Ultimately, heritable gene editing may just require a leap of biomedical faith.

We should just say, “no, we shall not.”

Sprinting Down the Road on “The Children We Want”

By Mark McQuain

Almost exactly one year ago, this blog asked rhetorically whether your polygenic risk score was a good thing. Jon Holmlund raised this issue again last week, mentioning a company called Genomic Prediction. This company’s claim about the merits of their technology deserves close ethical scrutiny and is my reason for mentioning them yet again.

Genomic Prediction is increasingly calling for IVF clinics to use their version of expanded pre-implantation genetic diagnosis (EPGD), that is using big data analysis to select which embryo to implant – literally choosing the embryo you want based not upon the presence of single point genetic mutations known to be harmful but polygenic sequences (multiple genes, and even multiple upon multiple genes) statistically related to increased risk for complex diseases like heart disease and diabetes. Jon discussed the ethics of selecting “the children we want”, hinting that selecting for eye color or sex was “a step” further down the road.

Genomic Prediction is sprinting down that road.

Just last month, Genomic Prediction entered into discussion with some IVF clinics in the U.S. to screen embryos for “mental disability”. Per the firm’s co-founder Stephen Hsu:

“[EPGD] isn’t accurate enough to predict IQ for each embryo, but it can indicate which ones are genetic outliers, giving prospective parents the option of avoiding embryos with a high chance of an IQ 25 points below average”

This claim is entirely different from a claim that this particular embryo has this particular single point mutation that will cause this particular disease. Rather, the present claim of EPGD is better stated like this: When we saw this same polygenic pattern in some large number of prior embryos, a majority of them had an IQ 25 points below normal. Some questions naturally follow: Did any have above average IQs (and how far above average)? How big is the majority (75%, 85% or 97%)? How many embryos were studied to come up with this statistic?

Gamblers like Las Vegas odds makers are beginning to use big data analysis to better predict the outcome of sports contests. The result is that the Las Vegas odds makers can tell us that when number one ranked University of Alabama plays unranked Citadel in 1000 football games, Alabama will win 999 times. That also means that Citadel will win one of those 1000 games, and, prior to the start of the game, you never know which of those 1000 games you are watching. Last weekend, at halftime, Alabama and Citadel were tied 10-10. At that point, it looked like Citadel was going to win that one game out of 1000 and defy the odds makers.

And that is the point. Many have already decided this it is good to terminate the life of an embryo if he or she has a point mutation for a serious disease. Is it just as good to terminate the life of an embryo if he or she has the mere risk of some non-disease trait we find undesirable like the wrong eye color, sex or intelligence? Do we really have sufficient data to make this decision? How much risk is too much or too little? How do we know if the decision is a good one? Will the decision get us the “Children We Want”? Is it really our decision to make?

It is necessary we answer questions like these if we wish to take on the responsibility to decide who lives and who dies, a decision that we previously relegated, depending on your worldview, to God or Nature.

Abortion by mail, part 2

By Steve Phillips

Last week I wrote about a European organization that has begun providing the medicines used for medical abortions by mail to women seeking abortions in the US following an online consultation. This violates the current restrictions that the FDA has on the prescribing of mifepristone, the primary medicine used for medical abortion. The restrictions exist due to safety concerns with the use of the drug. Those who think that those restrictions should be ended cite FDA statistics that show that serious harm to women who take the drug are quite rare. I concluded that the data indicate that it is hard to support the restrictions based on the risk of harm to a woman who chooses to use mifepristone.

I mentioned that there is another, somewhat perverse, risk that is usually not discussed which enters into the decision about whether the prescribing of should be limited to a certified prescriber dispensing the medicine in a clinical setting. That is the risk to the embryo/fetus. Those who support the use of mifepristone cite an effectiveness rate of 95-97%. That means that over 95% of the time the use of mifepristone in early pregnancy causes the death of the embryo/fetus and along with the use of misoprostol the pregnancy is ended with a medically induced abortion. In the 3 to 5% of cases in which this does not occur, some result in the death of the embryo/fetus, but the products of conception are retained within the uterus and may present some risk to the mother. As noted above, the observed risk to the mother turns out to be quite low. Sometimes when the process of medical abortion fails the embryo/fetus may survive. Mifepristone is an anti-progesterone. We know that medicines which alter the hormonal environment of an embryo can cause congenital anomalies. Therefore, there is a risk that if an embryo does not die and a subsequent surgical abortion is not done an infant may be born who suffers from congenital anomalies due to exposure to the medicines which were intended to cause a medical abortion. To prevent this, it is recommended that women who take the medicines for medical abortion who do not abort within the usual period of time have a surgical abortion. That would be the primary reason to support the FDA’s requirement that these medicines only be dispensed in a clinical setting by a certified prescriber. The role of the certified prescriber is to make sure that no embryo who is exposed to mifepristone survives to be born with the possible congenital anomalies.

Thus, we have a situation in which our society, as represented by the FDA, has decided that it is permissible to give a pregnant woman a medicine that will kill the embryo/fetus living inside her, but only if the medicine is dispensed in such a way that it can be assured that the embryo/fetus will be killed and not survive with an abnormality caused by the medicine. I said this was perverse. It is what we get when we have a society that puts a higher value on avoiding suffering than the value placed on human life.

Wir wussten nicht

By Mark McQuain

It has been said that “the only thing necessary for the triumph of evil is that good men do nothing.” Implied in this statement is that, first and foremost, the good men and women must be aware of the evil before they could be held morally obligated to act against that evil. There are subsequent issues associated with that obligation, such as does one even have the ability to act and, if so, how much personal harm or risk must one endure before being morally absolved of the responsibility to act. Regardless, knowledge of the evil is a requirement before moral culpability to act against that evil can be expected or assigned.

Therefore, a claim of “we did not know” would certainly absolve people of any moral responsibility from failing to act. But only if that denial is true. Challenging the validity of such a denial is reasonable because the denial is the easiest way to escape moral culpability. Consider the following two examples where claims of “not knowing” were possibly used to avoid moral responsibility.

When the Dachau concentration camp was liberated by the U.S. Seventh Army at the end of World War II, it was reported that the local German townspeople denied that they knew what was going on at the camp, claiming “Wir wussten nicht” – “We did not know”. General Walton Walker started the practice of bringing local townspeople to view such camps by ordering the Mayor of the town of Ohrdruf and his wife to visit the Ohrdruf labor camp. After the visit, it was reported the Mayor and his wife returned home and killed themselves.

Did they really not know?

Recently, the movie “Gosnell: The Trial of America’s Biggest Serial Killer” was released with minimal coverage by Hollywood or mass media. Reportedly, the producers had to resort to crowdfunding to initially get the project off the ground. Kermit Gosnell was a physician in Philadelphia who operated the Women’s Medical Society Clinic where he performed late term abortions. He and his clinic had multiple complaints and legal actions related to unsafe office practices as well as several procedure-related deaths prior to eventually being raided on unrelated drug dispensing charges. What the investigating officials found upon raiding the facility would fairly be described as a “House of Horror” for the unsanitary conditions, use of untrained staff, expired medications and multiple fetal remains randomly strewn around the clinic. Dr. Gosnell was convicted of first degree murder in the deaths of three infants, involuntary manslaughter on one female patient and 21 felony counts of performing illegal late-term abortions. During the trial, state and city regulators were repeatedly called out for their failure to act sooner, given the high volume of prior allegations and complaints.

Did they really not know?

Wir wissen nicht. (We do not know.) And, perhaps, we will never know.

Bioethics & “Three Identical Strangers”

By Neil Skjoldal

I recently had the opportunity to watch the 2018 documentary Three Identical Strangers, which tells the story of triplets Bobby Shafran, Eddy Galland, and David Kellman.  They were separated shortly after birth in the 1960s and adopted by three different families through the Louise Wise adoption agency in New York City.  The way they happen to find out about each other in 1980 is fascinating.  It created a media sensation at the time, including an appearance on The Phil Donahue Show.

The documentary starts by sharing their thrill of discovery, which included the many similarities that the brothers have, even though they spent the first 19 years of life apart.  However, it eventually moves to some of the larger and darker questions that lingered for each of the adoptive families—the biggest of which was, “Why weren’t we told that there were siblings?”  And as you might suspect, the agency representatives did not provide many helpful answers.  The parents’ feelings of anger and bewilderment resonated with me as an adoptive parent.

Eventually the brothers came to find out that they were part of a “twins study” conducted by noted psychologist, Peter Neubauer.   The study involved the brothers being interviewed and filmed individually every year through the first few years of their lives, with them not knowing that their brothers even existed.  Their parents were told it was a study of adopted children, not a study of twins.

The documentary leaves little doubt where it stands on the ethics of this matter.  From some of those interviewed, it appears that the purpose of the study was to address the classic “nature vs. nurture” question.  However, the harm done to these brothers (and the others who were unknowingly involved in the study), making them feel like ‘lab rats,’ undermines any positive value that the study may have had.  That Neubauer’s research remains sealed at Yale until 2066 adds fuel to the fire that something unethical was done.

In a blog post on www.psychologytoday.com, Dr. Leon Hoffmann asks whether it is reasonable to expect researchers of previous generations to follow our contemporary standards.  He asserts that both the original researchers and the producers of the documentary are guilty of self-deception.  This is a point worth considering as we look back; however, this case is from the 1960s and those impacted are still very much alive.

It is difficult for me to disagree with the assessment of reviewer Neta Alexander of www.haaretz.com:  “’Three Identical Strangers’ is thus a faithful representation of the spirit of the times. It’s about the way in which the authorities and those with power – headed by a charismatic and respected psychologist – abuse their powers in the name of science.”  Three Identical Strangers stands as a timely reminder that there should be safeguards and limits to research.

Abortion by mail

By Steve Phillips

A recent article on the CNN website reports on a European organization called Aid Access which has recently made the medicines used for medical abortion available to women in the US by mail. The organization utilizes telemedicine in the form of online consultations to prescribe the abortion drugs from a pharmacy in India to be mailed to the woman desiring an abortion in the US. It is clear that this violates FDA regulations. To ensure the safe use of mifepristone the FDA currently requires that the drug, which has no medical indication other than induction of abortion, is only available to be dispensed in clinics, medical offices and hospitals, by or under the supervision of a certified prescriber. At issue is whether those restrictions should be lifted to allow more open prescribing of mifepristone.

The appropriate reason for the FDA to have additional restrictions on certain drugs is safety. Those who advocate lifting the restrictions on mifepristone argue that the safety of this drug has been established and cite FDA statistics that the risk of death from using the drug to induce medical abortion is only one in 155,000. This makes its use much safer than either surgical abortion or continuing a pregnancy to term. Those who oppose lifting the restrictions counter with concerns that the unsupervised use of the drug may also lead to failure to diagnose ectopic pregnancy and can result in situations that require surgical intervention, which may have increased risk in an unsupervised patient.

While there are risks to the use of mifepristone, it is hard to make the case that the risk of harm to the mother is high enough to warrant the additional restrictions that currently are required for this drug. That makes it hard to justify limiting access due to true concern about the risk to the woman whom uses it. This is not the case for another regulation regarding abortion. Laws that require abortion clinics to meet the same standards as outpatient surgery centers have a clear justification. Surgical abortion has similar risks to other outpatient surgeries, so it is reasonable to require the same safety measures for an abortion clinic and an outpatient surgery center.

There is one risk related to the use of mifepristone, which is not usually discussed, which does support the additional restrictions on its distribution, but in a somewhat perverse way. That will be the focus of my next post.

Where do I Store the Name of your Dog?

Following a long office day of wrestling with my current nemesis, our office electronic medical record (EMR), I was pleased to read a lovely article by Dr. Taimur Safder in the current NEJM entitled “The Name of the Dog”. I’ll not summarize it as the link is free and the article is short and makes the point of today’s blog wonderfully.

I realize the EMR is not actually alive and, lacking agency, is unable to act as my archenemy and cause my downfall, or that of my patients. Further, I have a degree in electrical engineering so the technology of the EMR is not the issue either. I will grant that current and future data mining of the EMR may benefit untold numbers of patients. I will also concede that EMRs will (eventually) be bolstered with AI tools that will improve diagnostic accuracy and reduce or eliminate costly unnecessary testing.

My concern is that the EMR causes me to focus so much on the data collection that I spend less time getting to know my data source (my patient) as more than the sum total of discrete data points. There really isn’t any good place in the EMR to put the name of my patient’s dog. If I am going to treat my patient as more than a something, perhaps as a someone, then more than just reductionistic data acquisition and processing will have to take place.

With that in mind, please take a moment to view one of my favorite paintings by Sir Luke Fildes at the Tate Gallery called “The Doctor”. The painting depicts a country doctor sitting at the bedside of a young patient, with the child’s parents in the background. One can imagine the concern of the child’s father and almost feel the anguished prayers of the child’s mother, but both are interestingly relegated to background positions in the painting. The focus of the painting is the focus of the lamp in the painting – the country doctor and his patient.

Medicine in the 19th Century was limited in terms of meaningful data collection and limited further by actual effective treatments. In other words, the EMR of the 19th Century could have been completed in mere minutes and the diagnosis and treatment, such as it was, rendered in a few minutes more.

Given those limitations, perhaps not surprisingly, one gets the sense that the depicted outcome was far from certain and also that the country doctor had been in the home a while – there was at least time for tea at the table. What on earth was he still doing there? Maybe in absence of a definitive diagnosis and immediate cure, what the doctor could provide was his time, his empathy and his focused, loving concern. One gets the sense he would likely remain with his patient and the family as long as he was needed to offer what help and hope he could.

That seems like a reasonable example of how one imago Dei might care for another.

Would that I could consistently convey that level of steadfastness, that empathy and that loving concern to all of my patients without frantically looking for that special place in my EMR to store the name of your dog.

Noninvasive prenatal testing and sex-selection abortion

By Steve Phillips

The National Health Service in Great Britain has decided to implement the use of noninvasive prenatal testing (NIPT) and that has raised some concerns. It would seem natural for there to be concern about this test used to detect prenatal genetic conditions such as Down syndrome, which commonly leads to the choice to abort the fetuses with those conditions. However, according to a recent article in The Conversation by Jeremy Williams one of the major concerns is the use of this technique to facilitate sex-selection abortion. Williams states that one of the major political parties has proposed a policy of banning the use of NIPT for sex determination and has described sex-selective abortion as “incredibly unethical”.

Williams concedes that the idea that sex-selection abortion is morally wrong and ought to be prevented is widely held even by those who otherwise have no moral objection to abortion but suggests that taking that position is problematic for those who believe that a woman has a right to choose to have an abortion. Williams lists several reason that people give for why the sex-selection abortion is wrong. These include idea that sex selection abortions are done due to a trivial preference, concern that sex selection abortion constitutes unjust discrimination against female fetuses, concern about women being coerced into this type of abortion, and that it teaches that the lives of girls are not as important as boys. He is concerned that if these reasons are accepted they would apply more broadly than to just this one type of abortion, and he is right. Many abortions are done for reasons that seem trivial compared to the value of the life of the fetus. Any abortion that is done because of the characteristics of the fetus, including having a genetic disorder such as Down syndrome, are both unjust discrimination against those who have such a disorder and express a message that people who have such a disorder do not have the same value as those who do not. Many women are pressured into having abortions, and do not actually freely choose them.

The problem with what Williams has written is that sex-selection abortion is just clearly wrong. It is wrong to kill a fetus because that fetus is female and end the life of the girl and woman who that fetus would have become just because she is female. That is a clear violation of women’s rights. The fact that this helps us see that abortions in other situations are also clear violations of more universal human rights should make people question whether those abortions are also wrong. It does not mean that sex selection abortion is permissible.

Avoiding advanced dementia, part 2

By Steve Phillips

Last week I wrote about one of my moral concerns regarding Norman Cantor’s proposal to avoid advanced dementia, which he views as being intolerably degrading, by using an advance directive stating that when he reached a certain level of dementia he no longer wanted to eat or drink so that his death would result. My concern with this was that the person caring for him would have to concur with him that his life at that time was no longer worth living in order to justify following his directive and cease to feed him and give him fluids to drink. An independent assessment that another person’s life is not worth living is required of any physician or other caregiver who participates in euthanasia or assisted suicide. Such a determination that another person’s life is not worth living is something that we should never do and the need for that determination is a fundamental reason why euthanasia is not permissible.

Dena Davis in her article “Avoiding Dementia, Causing Moral Distress” agrees with Cantor that a person ought to be able to use an advance directive to end his own life to avoid advanced dementia, but sees a flaw in Cantor’s plan. She writes, “As long as the demented person is enjoying her diminished life, it will be psychologically and emotionally difficult, perhaps impossible, for most people to withhold food or even simple medical interventions. Even if they believe they ought to comply with the advance directive, the moral distress is simply too great.” She concludes that since a person cannot rely on others to follow an advance directive like Cantor’s, the only way to avoid advanced dementia is preemptive suicide. The article “A Debate over ‘Rational Suicide’” in the New York Times describes 80-year-old Robert Shoots doing just that.

My second concern is that it is wrong for us to choose to end our own life by rational suicide even if no one else participates in that act. Autonomy and personal liberty are important, but there are some things that can be wrong to do even to ourselves. This is easier to see from a Christian perspective. Christians understand that our lives belong to God and we do not have the authority to end our lives. That authority belongs to God alone. We have been commanded not to kill any innocent human being because we have all been made in the image of God. That includes a command not to end our own lives.

It can be harder for someone who does not understand that his life belongs to God and has value because he has been made in God’s image to see why rational suicide would be wrong. However, all of us are relational beings. We are connected to our families and the rest of humanity. What we do to ourselves impacts others. Those who contemplate rational suicide to avoid things such as advanced dementia forget how their deaths impact others. They have a desire to avoid a part of life they do not want to live and may want to relieve those who love them from the burden of caring for them but caring for those we love when they become dependent is an opportunity for us to be more fully human. Caring for a loved one with dementia is very hard but is one of the ultimate expressions of human love. We should not take that away from those who love us.

Avoiding advanced dementia

By Stephen Phillips

Norman Cantor has prompted widespread discussion with his recent article “On Avoiding Deep Dementia” in the Hastings Center Report (link is to the abstract only). In his article he states that he finds the possibility of living through progressive cognitive dysfunction and helplessness an intolerably degrading prospect. As a result, he has proposed using an advance directive stating that when he would reach a certain level of cognitive impairment, which would include having lost the capacity to make his own medical decisions, his advance decision to voluntarily stop eating and drinking would be implemented resulting in his death. He argues that it would be morally proper for those caring for him at that point to follow his prior instructions even if he showed no appearance of suffering at that point in his life.

There are many moral concerns related to Cantor’s proposal. I would like to address two concerns. Today I will address a concern that his proposal has in common with any form of euthanasia or assisted suicide that requires the assistance of someone other than the person who is choosing to die. In a later post I will address the issue of true rational suicide in which no assistance from a second party is required.

By proposing a strategy for avoiding advanced dementia that involves waiting until after he is unable to make decisions on his own, Cantor has required that someone other than himself who is providing care for him must implement his instructions. He sees that as respect for his autonomy, but whenever a second person enters into an act of euthanasia that person must make an independent decision that it is reasonable to agree that the life of the person who is to die is not worth living. This is true whether the act that is being requested of them is active euthanasia, assisted suicide, or cessation of eating and drinking. We are not morally obligated to do anything that another person requests of us. One qualification for fulfilling a request from another is that the request be reasonable. If there are any circumstances under which it is morally permissible to participate in ending another person’s life it could only be when that person’s life is no longer worth living. While it might be maintained that a person could make that determination about his or her own life, anyone assisting in that death needs to make an independent decision that the person’s life is not worth living in order to determine that this is a reasonable request which should be granted. However, we should never make a determination that another person’s life is not worth living. Our concepts of human equality, universal human rights, and justice all depend on the idea that every human life has value. All of that is undermined if we can say that there are some human lives that no longer have value.

Cantor’s proposal requires that someone caring for him after he has been become unable to make his own decisions agree with his previous determination that when his dementia reached that point his life would no longer be worth living and should be ended. That is something that we should never do.