Gene editing for genetic enhancement

By Steve Phillips

I appreciate the prior posts by Jon Holmlund and Mark McQuain regarding the recent announcement of the birth of genetically modified twins in China. Much has been written about why this should not have been done, but something very significant has been left out of most of those responses. They have failed to mention that the scientist who created the genetically altered twins was doing a form of genetic enhancement. As I have noted before, the only real reason for anyone to do research on the genetic modification of human embryos is to enable the possibility of human genetic enhancement. The scientist involved in this situation has recognized that and directly pursued it. I suspect that his open pursuit of enhancement is one of the reasons why he has received such a negative response from those who otherwise support the permissibility of using human embryos for experimentation on germline genetic modification.

The primary argument presented for why this was wrong is that he has subjected two healthy human infants to the unknown risks of genetic modification without any corresponding medical benefit to the infants. The modification was disabling the gene that codes for a cell membrane receptor that the HIV virus commonly uses to gain entry into cells it infects. The hope was that these infants would have enhanced resistance to HIV infection, although not complete immunity to such infection. The infants themselves would not have been at increased risk for HIV without the modification, but the parents had a desire to have children with increased resistance because their father has HIV and is aware of the difficulty of living with the disease. Thus, the modification was being done to provide an enhancement desired by the parents and was not being done to infants would have otherwise suffered from a genetic disorder.

Most who support current research to develop effective techniques for human germline genetic modification take the position that the safety of doing this has not been established well enough to use the technique to create infants and that when the research does reach the point that genetically modified human infants are created it should only be in situations in which those infants would otherwise have had serious genetic disorders. They are correct that this technique is currently unsafe but fail to realize that we will probably never be able to establish the safety of this type of genetic modification, because that would require safety data from multiple generations of these infants’ offspring. The idea of restricting this technique to infants who would have been born with serious genetic disorders and the idea that this technique could be used to rid the world of these genetic disorders does not make sense. If a couple desires to have children and know that they are at risk to have a child with a serious genetic disorder and have no moral concerns about the destruction of human embryos involved in such things as genetic modification, they can pursue selection of an unaffected embryo using PGD and have no need to take on the additional risks of genetic modification. Using genetic modification to eliminate genetic diseases would require a Brave New World scenario in which all human beings are artificially conceived and natural conception is prohibited. Therefore, the only reason to pursue the genetic modification of human embryos is for the purpose of human enhancement.

Let me be clear that I agree that what the scientist has done is wrong because he has subjected these two infants to significant risk without any significant medical benefit. That is always wrong. However, the strength of the negative response from those who generally support research to develop human germline genetic modification is likely due to the fact that he has opened up to public scrutiny the real purpose of such research. He has also shown that it is not true that we can ignore ethical concerns about enhancement because we could regulate the use of genetic modification so that would not occur. Enhancement was the goal of the very first use of this technique to produce human infants.

The Genetic Singularity Point has Arrived

By Mark McQuain

November 2018 will go down as one of the most pivotal points in human history. Jon Holmlund covered the facts in his last blog entry. Regardless of what you think about the ethics of He Jiankui’s recent use of CRISPR to alter the human genomes of IVF embryos and his decision to intentionally bring those genetically altered twin girls to full term, one thing is perfectly clear – we humans are in charge now. Whether you believe in God or Nature as the Entity or Force that previously determined the arrangement of our genes, humans now sit at the adult table and will be gradually (rapidly?) making more of those genetic decisions. Like Kurzweil’s upcoming Singularity Point when computers develop sufficient artificial intelligence to design the next computer, humans have now reached the point where we can and are willing to design the next human.

The Genetic Singularity point has arrived.

While there are some scientists who are frustrated that our Institutional Review Boards and ethics committees have held us back this long, most of the rest of us are frankly stunned and uneasy that we have reached this point. But anyone who thinks our stunned uneasiness will prevent a repeat of this experiment or prevent a push to alter increasing portions of our human genome to change other genetic sequences will simply remain more frequently stunned and persistently uneasy, ethical arguments notwithstanding.

My reason for expecting this to be the case is I believe we will hear increasing demands of the form that now that we have the ability to change our genome, we have the responsibility to change our genome. In fact, it would not surprise me to see, in the not-to-distant future, insurance companies paying for the cost of IVF/CRISPR to modify your child’s genome to prevent disease/condition X to avoid paying for the later treatment of disease/condition X. Oh, you won’t be forced to do this. But, if you choose to rely on God or Nature for your baby’s genetic pattern, “we” won’t be responsible for his or her care. And, if big data can eventually be married to IVF/CRISPR to statistically improve one’s chances of having a smart/beautiful/athletic/successful baby, wouldn’t you want the same for your child? Since it will be our responsibility, how could a parent not choose to make their child the best that they could be?

This will be Gattaca writ large.

Being at the Genetic Singularity point, by definition, means we humans choose our next step. We have reached the point where we believe we are ready to select our future direction. It is up to us now to chart our own course. Our genetic trajectory is our responsibility. Our success or failure, or more broadly, our future good or bad, is finally ours to determine – really ours to assign.

So Man created mankind in his own image, in the image of Man he created them…And Man saw everything he had made, and behold, it was very good…

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 that 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.

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.

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.

Reducing Abortion Regardless of Roe v. Wade

By Mark McQuain

The selection of the next Supreme Court Justice has perhaps naturally unleashed a flurry of op-eds describing the post-apocalyptic world that will result from any partial or complete reversal of Roe v. Wade. In the July 18th, 2018 Perspective in the NEJM, Dr. Julie Ingelfinger offers the tragic case of a foreign nursing student she befriended while both were training in New York in the late 1960s. The student was finishing her final nursing year and was engaged to be married when she became pregnant despite the use of contraceptives. Per Dr. Ingelfinger, neither the student nor fiancé had “the means to provide for a baby, so they reluctantly decided that terminating the pregnancy was the only choice.” The only abortion option available at that time, pre-Roe v. Wade, was a “back-alley abortion.” After the abortion, the student developed sepsis, resulting in a hysterectomy and kidney failure. Dr. Ingelfinger oversaw the dialysis and despite appropriate medical care, the student died suddenly from complications of the dialysis. Dr. Ingelfinger’s reason for sharing this story now is to remind us that back-alley abortions resulted in similar complications in many other young women pre-Roe v. Wade and warn that if Roe v. Wade is overturned in the future, young women seeking abortion will again suffer the same fate as her nursing student friend.

In a similar vein to Dr. Ingelfinger’s editorial, there is a second op-ed on CNN website on May 5, 2018 by Danielle Campoamor entitled “Why Supporting Abortion is a Pro-Life Position”. She fears any future restrictions in Roe v. Wade will result in the suffering or death of young women seeking an abortion and wants everyone to have the “safe, affordable and relatively easy abortion” that she experienced:

“I wasn’t subjected to mandatory waiting periods, forced counseling or an abortion provider required to regurgitate state-mandated, inaccurate information. I didn’t have to travel long distances, worry I was getting there too late in the pregnancy, find money to pay for child care or walk past angry or intrusive protesters. Instead, I went in pregnant and, a few hours later, came out with my future back in my control.”

In both articles, the focus is unilaterally on the health and life of the mother. Ms. Campoamor’s position is easily challenged, if not decimated, by including the health and life of the baby in her calculus. Dr. Ingelfinger’s premise requires more unpacking.

Her position appears to be that all future unwanted pregnancies in an overturned-Roe v. Wade world would require a pre-Roe v. Wade “back-alley” surgical abortion. Many Latin American countries have never legalized abortion yet their illegal abortion fatalities have dropped as medical abortifacients (morning after pills) have replaced surgical abortion methods. Interestingly, both the author of the previously linked article on the Latin American experience and Dr. Ingelfinger cited economics (and not legality) as a main reason for choosing abortion. Analysis of the statistics on why women in the US choose to abort challenges this assertion. A clear understanding of these statistics might help identify strategies that lead to a voluntary reduction in the number of abortions, absent changes in the legal status of abortion.

There is a nearly 15-fold increased risk to carry a baby to full-term than it is to have an elective abortion. We have “successfully” divorced sexual activity from the risk and responsibility of bearing and rearing a child, as long as we are willing to use abortion as the definitive stop gap in maintaining our birth control. From my standpoint, this success and this control has come at a terrible price, namely the deaths of over 60 million babies in the US alone. Sadly, I pessimistically do not believe that there will be a meaningful change in the Federal law regarding abortion, regardless of who becomes our next Supreme Court Justice (link requires subscription). There are simply too many women and men who have come to rely upon the type of control of their future activities that abortion provides. Therefore, I ask Dr. Ingelfinger, Ms. Campoamor and all of those on the other side of the abortion divide: must all unwanted pregnancies end in abortion (medical or surgical), regardless of the status of Roe v. Wade?

Human limitation and ethics

By Steve Phillips

I recently read Cody Chambers’ article “The Concept of Limitation in Emil Brunner’s Ethics” in Ethics in Conversation from the Kirby Laing Institute for Christian Ethics. The article is well done and you need to read it to get the full impact of what he has said. What resonated with me was the idea that being limited is a part of what it means to be human and that our limitations are essential for our relationship with God and each other. It is our limitedness that helps us see that we need both God and other people and that we were made for those relationships. This is central to ethics because it is in our relationships with God and other people that we find our understanding of what ethics is.

This understanding that we are in our nature limited beings created by an unlimited God could not be more different from the conception of human beings held by many in the culture around us. They desire to see human beings and particularly themselves as having unlimited potential and freedom with no creator at all. That desire for personal freedom dominates contemporary ethics and shows itself in all areas of bioethics.

Chambers looks at how this impacts thinking about gene editing. Those who advocate doing human germline genetic modification see it as the freedom to create a child who is made to be what the parents creating the child desire the child to be. This is usually expressed in terms of creating a child free from genetic disease, but there are simpler ways to have a child without a disease carried by the parents (including adoption). It is ultimately the desire to be free of natural human reproductive limitations and create a child we have designed and chosen. Being limited helps us to see that we need each other and must respect others, including our children, as they have been made by God. Our natural lack of control over the characteristics of our children leads to an understanding that those children are a gift from God that we should accept unconditionally. Using technology to try to take control of the creation of our children leads to creating children that will fulfill our desires and a loss of the unconditional acceptance that is the foundation of a positive parent-child relationship.

Freedom in the proper context is good. The desire for unlimited freedom leads to putting ourselves above others and ultimately controlling and subjugating others, including our children, to our desires. Proper ethics requires an understanding that our freedom is limited.

Britain’s experts on gene-edited babies

by Jon Holmlund

Some of the cable news shows ran segments on the report released this week by Britain’s Nuffield Council on Bioethics, “Genome editing and human reproduction: social and ethical issues.”  Full disclosure: I have not yet read the full report, only the short summaries (all of which are available for free download at the link here).

The TV teasers—”U.K. bioethics council says that gene-editing children may be morally acceptable” were accurate.  The key conclusion is that “the use of heritable genome editing interventions to influence the characteristics of future generations could be ethically acceptable in some circumstances” (emphasis theirs).  But the news folks made it sound like an attempt to birth an edited baby is around the corner, or at least fully green-lighted by Nuffield.

The summary of the report reads more modestly, acknowledging that such attempts are currently banned by law most places, and that making them legal could require “a long and complex legislative pathway.”  But the Council does take the view that at least some attempts, such as those to try to repair a lethal disease gene such as the dominant gene for Huntington’s disease, might be justifiable.  This blog has considered such an argument in the case of sickle cell anemia—single gene defect, well understood, circumscribed attempt to repair only that gene.  An argument can be made.

The Nuffield Council’s summary really is a list of general statements that, taken individually, are hard to take issue with, and are in some cases almost platitudinous.  The overall impression is, “yes, heritable human gene editing could be ethical, and probably should be considered, but only after a long public deliberative process, appropriate regulation, etc., etc.”  Nuffield offers two stipulations for ethically acceptable heritable human gene editing:

  • “Intended to secure, and is consistent with, the welfare of a person who may be born as a consequence” of the effort, and
  • Social justice and solidarity are upheld; that is, discrimination or social division should not be a consequence.

These statements are both too broad to be helpful.  In the first case, the Council acknowledges that some efforts could be attempts to enhance a person’s natural characteristics, not just treat a recognized disease, and that, except for the most genetically straightforward cases, the scientific and technical challenges are substantial.  In the second case, it would seem that pressures for discrimination based on social attitudes or economics (ability to pay for the procedure, medical insurance reimbursement issues) will be unavoidable.

Scientifically and socially, there will be unintended—or at least undesirable—consequences.  These may be known but considered acceptable.  For example, how many human embryos will need to be created and destroyed to perfect the procedure?  How many generations will need to be followed to rule out some late complication?  Can we really guarantee that “having babies the old-fashioned way” won’t become a thing of the past?  And, in spite of the laudable desire to bring healthy children into the world, wouldn’t this be a wholesale acceptance of the basic assumption that only the people we want to be born, should be born?

For these reasons and others previously articulated on this blog, heritable human gene editing falls into a small but critical group of biomedical undertakings that should not be pursued.

And, BTW, the remaining bugs in the system include, as reported this week, that gene-editing techniques appear to introduce errors more frequently than previously appreciated.  Given that heritable human editing involves more than just a few cells in a dish, a “presumption to forebear” should apply.

The TV news gave this about 5 minutes this week.  That’s the breadth and depth of our “public deliberation” beyond a few experts.  At the end of one segment, the host looked into the camera and said, “next up: are liberals or conservatives happier?”

As Neil Postman said:  “now this…”

Risk and reproductive freedom

by Steve Phillips

A recent article in The Atlantic titled “The Overlooked Emotions of Sperm Donation” discusses concerns about the emotional problems and conflicts that can occur in families that turn to sperm donation is a way of creating a child amid infertility. The article focuses mostly on heterosexual couples dealing with male infertility who have used sperm donation. In those families there are commonly emotional problems faced by the man when the couple has a child to which he is not genetically related, and there are problems that can occur between the couple who is raising the child and the sperm donor and his family when a known or related donor is involved. The author expresses concern that many couples who choose sperm donation are not aware that these emotional problems can commonly occur and fail to reflect carefully about these concerns or do preventive counseling to deal with them.

The article is well-written and raises concerns that people need to be aware of, but there are some things that are missing. The author briefly addresses the emotional concerns of the child and mentions that there have been some children’s books written to help children deal with those concerns, but the emotional difficulties for a child conceived in this way are very significant. There is also no discussion of whether concern about the emotional difficulties for all the parties involved including the child, the parents raising the child, and the donor and his family might be a reason to consider not having a child by means of sperm donation. There is an underlying assumption of reproductive freedom, the idea that people should be free to fulfill their desire to have a child by any means that they choose. The author properly advocates for the position that potential parents considering this option should be fully informed about the emotional risks as well as any physical risks and should consider preventive counseling, but never mentions the possibility of deciding not to create a child in this way because of the risks.

When we discuss the risks of reproductive technologies, whether those be physical risks or emotional risks, we need to remember that imposing risks on a child to fulfill the desires of an adult individual or an adult couple is a serious moral concern. Despite our society’s focus on autonomy, there are some things we should not do to meet our own desires when doing so puts another person at risk, particularly if the person being put at risk is a child that we are creating.