Fertility with frozen eggs: not a sure thing

In case you didn’t see it, the Washington Post has this story about how more women are trying to improve their overall chances of having a baby—particularly in the later reproductive years of their 30’s and 40’s—but success is far from certain.  Human oocytes (eggs) are fragile things, and it was not until recent years that freezing techniques developed to a point that would allow the eggs to survive being frozen and, some time later, thawed (the “freeze-thaw” cycle).  Then, they would be fertilized in the lab, by in vitro fertilization, and implanted into the womb of the would-be mother.

As the article points out, women are born with their entire endowment of eggs, which become less likely to be successfully fertilized and develop into a healthy baby as they, and the woman, age.  Hence a woman’s inexorably declining fertility, particularly from their mid-30’s on.  Freezing eggs for later use is increasingly popular, if one can afford it, or if employers offer it as a perk, as some do, to their female employees.

It’s still expensive, and success appears to depend on the age of the woman (and eggs) at their harvest, and the number harvested and kept in frozen storage.  One must use the qualifier “appears,” because, as the article also points out, reliable statistics are not being kept.  The not-so-subtle implication is that the fertility “industry” wants to sell the process but would rather not know that the ultimate success rate could be as low as, or lower than, the 50-60% rate quoted by New York University.

Clear implications: better data and more transparency are to be desired, and there appear to be at least some remaining biologic limits, strong if not absolute, to reproductive freedom.  Beyond that, as I opined in May of 2013 (fairly bluntly, I do confess) are the radical implications for our concepts of parenthood and begetting children, and for turning said procreation into just plain old, quality-controlled, fully artificial creation.  Things haven’t gotten quite so absolute, yet.  But better quality control of egg freezing and the outcomes, if possible, would be a move in the direction of more artificial reproduction.

It’s a good article from the Post.  Too much to try to do justice to here.  Read the whole thing.

Selection of embryos in IVF to increase birth rates

A recent article in the Daily Mail brought my attention to recent research by the British assisted reproduction scientist Simon Fishel (see abstract) on a technique which can help select which early developing embryos produced by IVF are most likely to result in a live birth when they are implanted. This technique in evolves repeatedly photographing the developing embryos and using a computerized process to assess which embryos are showing the developmental characteristics that are associated with successful live birth. The study indicates that they were able to achieve a 19% increase in the number of live births in women under age 38 and a 37% increase in live births in women over age 37 by using this technique compared to conventional ways of selecting the healthiest appearing embryos.

On the surface the study appears to be about a simple process for making a particular form of biotechnology more effective and more efficient. What caught my eye from an ethical standpoint was the way in which this study demonstrates how biotechnology is so completely focused on the fulfillment of human desires that it tends to ignore any other concerns. The human desire that drives infertility treatment is the desire to give birth to a baby. The study shows how a particular improvement in technique makes it possible to fulfill that desire in a higher percentage of patients. What is interesting is that the focus on fulfilling that desire is so complete that there is no mention of what happens to the embryos that are not selected when their photographs are input into the computer-generated profile for selecting the best embryos. It also says nothing about whether the babies who are born using this process are healthier or less healthy than those using conventional techniques. The sole focus is on whether the desire to give birth to a baby is fulfilled.

Having technology that can help us fulfill our desires can be beneficial, but effective technology tends to be very focused on what it accomplishes. Life and particularly the moral life is more complex than that. We need to evaluate our desires to see if they are worthwhile. We need to consider what effects it may have on others if our desires are fulfilled. Since technology is successful when it fulfills our desires it may lead us to think that we are doing well when we have effective ways to fulfill those desires, without stopping to consider whether our desires and the means that we choose to fulfill them are good.

Christmas and the personhood of the unborn

One of the most interesting details of the account of Jesus’ birth in the gospels is what happened when Mary visited her cousin Elizabeth. Luke tells us in the first chapter of his gospel that Elizabeth and her husband Zechariah were infertile and beyond their childbearing years. The angel Gabriel appeared to Zechariah and told him that he and his wife were going to have a son who would prepare the way for the coming of the Lord. Elizabeth did indeed become pregnant and when she was in her sixth month the same angel appeared to Mary and told her that she was going to conceive a son, Jesus, who would be the Son of God. Immediately after this, Mary went to stay with Elizabeth. When she greeted Elizabeth her fetus, who was later known as John the Baptist, leaped for joy in Elizabeth’s womb.

This account raises some interesting thoughts about the personhood of the unborn. Luke is clearly saying that John, who was at this time a 6-month fetus, had the spiritual insight to recognize Mary as the mother of Jesus. That would indicate the Holy Spirit was already working in the life of John before he was born and it would be hard to say that he was not a person when this occurred. He was already beginning to fulfill his role as the one who would announce the Messiah when he was 3 months from being born.

Less clear, but even more interesting, is the unstated possibility that what John was responding to was the presence of Jesus himself. If Jesus was conceived shortly after the angel appeared to Mary, and she went immediately to stay with Elizabeth, Jesus would have been an embryo at the time of John’s leaping for joy. If John as a fetus was responding to the presence of Jesus as an embryo, we have reason to confirm the personhood of a human embryo.

Whether John was responding to the presence of Mary or the presence of Jesus, it is the incarnation of Jesus that provides one of the strongest reasons for us to understand that every human being has great worth. Every human being has great value because each one is made in the image of God, but the incarnation tells even more. That fact that Jesus became a human being elevates human beings to a value above other created beings. Since we have been told that he was conceived in Mary’s womb, he grew as an embryo and fetus before being born in Bethlehem and has elevated the value of the unborn as well as those who have been born.

God bless us every one, including those who are not yet born.

Seeing having children as a harm

A recent Breakpoint article led me to read an opinion piece on nbcnews.com by Travis Rieder, a research scholar with the Berman Institute of Bioethics at Johns Hopkins, titled “Science proves kids are bad for Earth. Morality suggests we stop having them.” Rieder references several articles that indicate that the most effective way that individuals, particularly those in affluent societies, can reduce their impact on climate change is by having fewer children. The articles that he references suggest that having fewer children would have a much bigger impact than any conservation measures that we might take.

It is important to be clear that in spite of the title of the article Rieder is not advocating that we have no children or that there should be a specific limit on how many children people have. However, he is saying that each child that we bring into the world represents a negative impact on our environment and that we have a moral obligation to consider that harm in our moral decision-making about having children. He deals with some possible objections to his position in which include concerns about whether a child’s environmental impact is the responsibility of the child or the parent, and the idea that individual actions place such a small role in global issues such as climate change that they are insignificant.

However, I think that he fails to consider the most significant objection to his position. By suggesting that the net effect of having a child can be considered a moral harm, he is failing to consider the immense value of an individual human life in his reasoning. This is primarily because he is seeing moral decisions consequentially. One of the failings of consequential or utilitarian moral thinking is to look only at measurable consequences and to neglect the more difficult to measure value of individual human lives. The immeasurable value of a human life makes it difficult to see the act of bringing a child into the world as something that involves more harm than good. There may be some situations in which it is morally proper to decide not to conceive a child with a high likelihood of intense suffering. Beyond that the value of a human life is greater than presumed consequences.

Uterine Transplantation – for Men?

Susan Haack began exploring the topic of uterine transplantation in women on this blog back in February 2014. In just under 4 short years, the technology has not only successfully resulted in live births in several women who received the uterine transplants, but outgoing president of the American Society of Reproductive Medicine, Dr. Richard Paulson, is suggesting we consider exploring the technique in men. While there are certainly hurdles to overcome (need for cesarean section for the actual birth, hormone supplementation, complicated nature of the transplant even for cisgender women), Dr. Paulson does not consider these barriers insurmountable for transgender women.

Dr. Julian Savulescu, professor of practical ethics at Oxford, has cautioned that initiating a pregnancy in a transgender woman may be unethical if it poses significant risk to the fetus. The above-linked article misquotes his concern as a concern over “any psychological harm to the child born in this atypical way”. The following is his actual quote from his own blog:

Therefore, although technically possible to perform the procedure, you would need to be very confident the uterus would function normally during pregnancy. The first US transplant had to be removed because of infection. There are concerns about insufficient blood flow in pregnancy and pre-eclampsia. A lot of research would need to be done not just on the transplant procedure but on the effect in pregnancy in non-human animals before it was trialled in humans. Immunosuppressives would be necessary which are risky. A surrogate uterus would be preferable from the future child’s perspective to a transplanted uterus. Uterine transplantation represents a real risk to the fetus, and therefore the future child. We ought to (other things being equal) avoid exposing future children to unnecessary significant risks of harm.

One putative benefit might be the psychological benefit to the future mother of carrying her own pregnancy. This would have to be weighed against any harm to the child of being born in this atypical way.

His concerns are the baseline medical risks involved in using a transplanted uterus to conceive a child regardless of the sex of the recipient. None of his concerns relate to the psychological harm to the child potentially caused by a uterine transplantation in a transgender woman as opposed to a cisgender woman. Savulescu is explicit in the beginning of his blog that “[t]he ethical issues of performing a womb transplant for a [sic] transgender women are substantially the same as the issues facing ciswomen.” Is the only risk to the child “born this atypical way” just the additional need for hormone supplementation in the transgender woman compared to the cisgender woman? Can we really know, a priori, what all of the attendant risks to the child really are with uterine transplantation in a transgender woman?

Regardless, let’s assume Savulescu is correct, that there is indeed no ethical difference between carrying a child to term via uterine transplantation between a cisgender woman and a transgender woman. There certainly can be no ethical difference between carrying a child to term via uterine transplantation between a transgender woman and a cisgender man. If the foregoing is true, can there be any ethical barrier preventing a man via uterine transplantation to use his sperm to fertilize a donor egg and carry his baby to term? After all, per Savulescu, all we need be concerned about from a bioethical standpoint are the technical issues/risks of uterine transplantation regardless of the recipient’s biological sex or self-identified gender.

In Genesis, God created two complimentary sexes and stated this difference was good. We are moving toward eliminating differences between the sexes and arguing that this is good. Both of us cannot be correct.

I wonder if Dr Haack thought that we would get this far down this particular bioethical slippery slope in four short years?

Is Your Polygenic Risk Score a Good Thing?

Back in October, Jon Holmlund wrote a blog entry regarding the popular company 23andMe and their collection of your health-related information along with your genetic material. I missed the significance of that relationship at the time. It took a recent article in Technology Review by my favorite technology writer Antonio Regalado to raise my ethical antennae. In his article, he explains the nexus of big data mining of genetic data and health information (such as is collected by 23andMe) and its future potential use to select embryos for IVF, selecting not only against polygenic diseases such as type 1 diabetes but potentially for non-diseases such as height, weight or even IQ.

Yikes.

Pre-implantation genetic diagnosis (PGD) already is used to select for particular embryos for IVF implantation that do not have genetic patterns such as cystic fibrosis or Down syndrome. Diseases that result from multiple genes (polygenic disorders) presently defy current PGD methods used to detect future diseases. Using Big Data analysis of health information compared against linked genetic data, scientists are getting better at accurate polygenic risk scores, statistical models which may more accurately ‘guess’ at an embryo’s future risk for not only juvenile diabetes but also later-in-life diseases (such as heart disease, ALS or glaucoma) or other less threatening inheritable traits (such as eye color, height or IQ) that result from multiple genes (and perhaps even environmental factors). There is confidence (hubris?) that with enough data and enough computing power, we can indeed accurately predict an embryo’s future health status and all of his or her inheritable traits. Combine that further with all of the marketing data available from Madison Avenue, and we can predict what type and color of car that embryo will buy when he or she is 35.

Ok, maybe not the color…

Seriously, companies such as Genomic Prediction would like to see IVF clinics eventually use their expanded statistical models to assist in PGD, using a proprietary technique they are calling Expanded Pre-implantation Genomic Testing (EPGT). Consider the following two quotes from Regalado’s article:

I remind my partners, “You know, if my parents had this test, I wouldn’t be here,” says [founding Genomic Prediction partner and type 1 diabetic Nathan] Treff, a prize-winning expert on diagnostic technology who is the author of more than 90 scientific papers.

For adults, risk scores [such as calculated by 23andMe] are little more than a novelty or a source of health advice they can ignore. But if the same information is generated about an embryo, it could lead to existential consequences: who will be born, and who stays in a laboratory freezer.

Regalado’s last comment is dead-on – literally. Who will be born and who stays in the freezer is another way of saying “who lives and who dies”.

Technologies such as EPGT are poised to take us further down the bioethical slope of choosing which of our children we want to live and which we choose to die. For the sake of driving this point home, let’s assume that the technology becomes essentially 100% accurate with regard to polygenic risk scoring and we can indeed determine which embryo will have any disease or trait. Since we already permit the use of single gene PGD to prevent certain genetic outcomes, should there be any limit to polygenic PGD? For instance:

(A) Should this technology be used to select against immediate life threatening illnesses only or also against immediate mentally or physically permanently crippling diseases that don’t cause death directly?

(B) Should this technology be used to select against later-in-life diseases that are life threatening at the time or also against mentally or physically crippling diseases that don’t cause death directly? (Would it make a difference if the disease occurred as a child, teenager or adult?)

(C) Should this technology be used to select against non-disease inheritable traits that society finds disadvantageous (use your imagination here)?

(D) Should this technology be used to select for inheritable traits that society finds advantageous (a slightly different question)?

Depending upon your worldview, until recently, answering Questions A through D used to be the purview of God or the random result of chance. Are we ready (and capable) to assume that responsibility? Make your decision as to where you would draw the line then review this short list of famous scientists and see how many on that short list your criteria would permit to be born.

Are you happy with that result? Would you call it good?

It would be nice to get this right since it now appears to be our call to make…

More about gene therapy and human gene editing

To my post of last week, add the case of a 44 year-old man who has received gene therapy for an inherited metabolic disease called Hunter’s syndrome. This is another example of a form of gene editing as true therapy.  That is, an existing individual is given a construct intended to edit his genes to introduce a gene that makes an enzyme that is lacking in the disease, and that causes terrible problems.  In this case, as part of a clinical trial, the construct, using a so-called “zinc finger” technique, is intended to introduce the gene into only about 1% of the patient’s liver cells.   If successful, the damage already done by the disease won’t be affected, but it’s progress may be arrested, with the potential to avoid having to have repeated, costly treatment with the missing enzyme protein itself.

Cool idea–and well within the current regulatory ethical regime.  The edit would not be inherited, and unborn humans don’t have to be sacrificed to develop the technique.  The adult patients are capable of giving informed consent.  Trials in children would come later, controlled by accepted ethical experimentation on children in clinical trials.

In a separate note, on a separate topic, Nature Biotechnology is editorializing that inherited gene editing is way behind mitochondrial replacement therapy (MRT), the “3-parent baby” approach to treating genetic problems, and will likely have limited use in the future.  Why?  Because it is likely that preimplantation genetic diagnosis (PGD) after in vitro fertilization (IVF) will be preferred to identify and give birth to babies unaffected by serious genetic disorders.  The journal editors argue that gene editing would be preferred only in those few cases where PGD cannot avoid passing on a disease–for example, in cases where it is known that all embryos from a fertilizing couple would be affected. Otherwise, the gene editing would not be worth the trouble.

MRT, on the other hand, has been studied more and is closer to being used to treat unborn humans who have diseases that MRT could treat.  Thing is, those diseases are also rare, on the order of 1000 cases per year in the US, and technically, gene editing would probably not be too useful for those.

There is a lot of talk about using a mix of gene editing and PGD to eliminate certain genetic disease from the human prospect.  I recently wrote about the Chinese government working on this.  To achieve the goal absolutely, every born human would have to be a product of IVF.

And the risk of some of the disorders is low enough that the absolute risk in any one “natural” pregnancy would be low.  So why go to the trouble of trying to eliminate the risks utterly?  (I think that’s a rhetorical question.)

The title of the editorial in question is “Humans 2.0.”  Indeed.

There’s gene therapy and there’s gene therapy

I’ve seen a number of different things described in the general press as “gene therapy.” But they are indeed different.  It’s important to be specific.

For one, there’s the situation where a set of mature human cells are obtained from the person to be treated and genetically altered outside the body to make them into a potentially useful treatment, then re-administered (by vein) to the patient.  Such is the case with so-called “CAR-T” therapy, which is well handled by current regulatory structures.  Main ethical issues: common human subject research concerns, regulation of the quality of the cells, and whether the treatment, which can be dramatically effective, is worth the high price.

Then there are situations where a diseased tissue is altered to make it normal, like the recent report of how a mutation in the skin of a boy was altered, and the repaired skin grafted back on, to spread over most of his body and replace the defective skin.  Again, way cool, well dealt with by current ethical and regulatory structures.

Or, similarly, Spark Therapeutics’ LUXTERNA, which is a gene injected into the eye to repair a defective gene causing blindness, literally restoring some sight, recently recommended for approval by an advisory committee to FDA.   Truly a gene made into a therapy.

Where the ethical issues get thorny is when one speaks of possibly editing a gene in a person–likely an unborn person very early in development; i.e., and embryo–in a way that can be inherited over generations.  I and others have discussed this recently on this blog.  See for example my post of last month (October 5).  Adherents say that there are serious diseases demanding cures, and that those who would counsel caution are obstructionists who fret too much about enhanced Olympic athletes.  (Example here, but subscription required.)  But the ethical issues are several: How safe and reliable will the technique be, and how much testing should be required before trying to birth “edited” babies?  How many embryos will have to be destroyed to perfect the approach?  How can we know whether there will be unforeseen long-term effects, after several generations?  How much should we care about that?  How will discrimination be avoided?  What are the implications for control of human reproduction–no more babies from sex? And who will decide and control that?

And–where, short of the Olympics, will it all end?  Should we try to edit genes that are known to increase cancer risk, to eliminate them from the human race?

The Hastings Center recently convened journalists to discuss some of the ethical issues with gene editing.  But even then, they are more concerned about whether there is a parental duty to “edit” the next generation.  Precautionary deliberations appeared to be limited to environmental concerns from the use of “gene drive” to spread genetic modifications rapidly through entire plant or animal species.  (Fair enough, but I’d extend the precautions to humans, where “gene drive” is not an issue.)  And, helpfully, the Hastings symposium did ask, will general press coverage necessarily be biased because reporters’ sources are the very scientists who tend to be enthusiasts?  In any event, the Center should not only do more public education events, but should make much more of the detailed content from such symposia available to the public for free, online, much as the Presidential bioethics commissions do.  As it is, we are left with their brief press releases, usually.  Thin gruel, IMHO.

Selective data collection – what do we know about the risks of IVF?

A recent article in Newsweek reports on a physician, Dr. Jennifer Snyder, who is calling for the formation of a registry of egg donors to help determine the risks to women who “donate” eggs to other women undergoing IVF for monetary compensation. Her motivation in calling for this registry was the death of her daughter at age 31 from cancer after donated eggs on three occasions. She points out that egg donors are commonly told that there are no known long-term risks of egg donation, but that the reason that there are no known long-term risks is that the risks of egg donation have never been studied.

The article reports that Alan Penzias, chair of the practice committee at the American Society of Reproductive Medicine, agrees that such a registry is needed, and states that “national reporting on IVF, including data on both mothers and babies, is required by law.” It is good that this representative of those who practice reproductive medicine is in favor of a registry to assess the risks of egg donation, but there is a problem with his statement about the current reporting that is done on IVF in the United States.

That reporting on IVF is done under the authority of the CDC by the National Assisted Reproductive Technology Surveillance System. According to their National ART Surveillance website what they measure to comply with the Fertility Clinic Success Rate and Certification Act is data about patient demographics, patient stature: medical history, parental infertility diagnosis, clinical parameters of the ART procedure, and information regarding resultant pregnancies and births. The outcomes data is limited to information about the percentage of IVF cycles that achieve pregnancy and achieve live birth and information on how many of those pregnancies are single or multiple gestations and how many are delivered prematurely or at term. No data is collected on the complications or ill effects that women who undergo IVF may experience, and no data is collected on either birth defects or any other adverse consequences other than prematurity, birth weight, and plurality for the infants born by way of IVF.

Dr. Snyder’s call for a registry for data on adverse effects experienced by women who donate eggs is absolutely necessary to be able to give women the information needed to be able to make an informed decision about being an egg donor. There is an urgent need for the same type of registry of adverse outcomes for women who undergo IVF and the children produced by IVF. It is inexcusable to expect women to consent to these procedures without knowing the risks because those who perform the procedures have failed to collect data about those risks.

Human gene editing marches on

Nature has recently carried two new reports of human gene editing.  In one, embryos donated from an IVF clinic had a gene critical to very early development altered, to study what happens when you do that, and try to understand early human development more than we now do.  In the other, scientists studied editing of an abnormal recessive gene, specifically the one causing a type of blood disorder called thalassemia, by using cloning to create a new embryonic version of an adult with the disease.  (This made it technically easier to start in the laboratory with an embryo that has the disease, because it is genetically recessive, meaning that both copies of the gene are abnormal.)  This follows earlier publication of similar work to edit dominant mutation-causing genes, in which the embryos arose because of new IVF, done in the lab, by the scientists, using donated eggs fertilized with sperm from a male donor who carried the abnormal gene.

In all three cases, the main biologic approach, and the main ethical issues, are the same.  The main differences were which genes were being edited, and how the embryos were obtained.

This prompted Nature to run an editorial to say that it is “time to take stock” of the ethics of this research.  Read the editorial here.  The key points:  This is important work that should be undertaken thoughtfully.  Accordingly, donors of any embryos or cells should be fully informed of the planned research.  Only as many embryos should be created as are necessary to do the research.  Work on embryos should be preceded by work on pluripotent, or “reprogrammed,” stem cells, and if questions can be fully answered by work with those cells, then it may not be necessary to repeat the studies on whole, intact human embryos, and if that is not necessary, perhaps it should not be done.  Finally, everything should be peer reviewed.

I agree that editing work in non-totipotent cells should be at all times favored over work on intact embryos, but if one holds that an embryo is a human being that should have the benefits of protections afforded human research subjects, then Nature’s ethical principles are rather thin, little more than an extension of animal use provisions for studies in which early humans are the raw materials for the development of new medical treatments.

Included was a link to the journal’s policies for considering for publication any reports of experimentation on living organisms.  Those policies include this paragraph regarding modification of the human germline:

“In deciding whether to publish papers describing modifications of the human germline, we will be guided by safety considerations, compliance with applicable regulations, as well as the status of the societal debate on the implications of such modifications for future generations. We have established an editorial monitoring group to oversee the consideration of these concerns. (The monitoring group includes the Editor-in-Chief of Nature publications, the Nature Editorial Director, the Head of Editorial Policy, Nature Journals and the Executive Editor, Life Sciences.) This group will also seek advice from regulatory experts to ensure that the study was conducted according to the relevant local and national regulations. In this evaluation, we will be strongly guided by the guidance issued by the International Society for Stem Cell Research: Guidelines for the Conduct of Human Embryonic Stem Cell Research (http://www.isscr.org/home/publications/guide-clintrans ).”

I want to be reassured by their invoking “the status of the societal debate on the implications of such modifications for future generations,” but the weaknesses are first, that debate is just not very robust, and “society” is generally in a position of accepting, more or less uncritically, the ongoing technical push; and second, that the ones considering the status of the issues will more or less naturally view them through the relatively narrow researchers’ scope I describe above.  To be sure, the goals at a minimum appear to be to ensure that the research is not reckless, that it meets technical standards, that obtaining and creation of embryos is relatively limited in scope, and that nobody, for now, is trying to bring gene-edited embryos to human pregnancy, much less birth.  At least, not until the scientists and regulators tell us they think it’s time to try that.