Addressing gene editing with “thin” bioethics

Yesterday’s post on this blog, by Steve Phillips, warned that a narrow, “rules limited” approach to bioethics reduces ethics in science and medicine to matters of regulatory compliance and risks making thoroughly logical conclusions based on faulty premises that are adopted without regarding “deeper ethical thinking” for which scientists’ thinking must be brought under the discipline of broader humanitarian reflection if correct basic notions of what it is to be human, and what humans should be up to, are to be arrived at.

A different but closely related way to look at this was suggested by John Evans of the University of California, San Diego in his contribution to Human Flourishing in an Age of Gene Editing, a new collection of essays, edited by Erik Parens and Josephine Johnson.  In brief, Prof. Evans commented that too much of bioethics is “thin,” reduced to the Belmont principalism (respect for persons/autonomy; beneficence/nonmalificence; justice) governs human subject research.  This “thin” bioethics is convenient for regulators to use to derive a manageable set of rules, and for scientists to, if you will, hide behind (my expression, not Prof. Evans’s).  Rather, he writes, we must be willing to criticize the assumption that all we need to ask about technology is how to use it, and seek a deeper wisdom about what is a good or worthy human life, for individuals or communities.  In making this argument, he appeals to “critics of technology,” both politically conservative (Leon Kass) and politically liberal (Jacques Ellul).  Jacques Ellul!  How often does anyone hear him mentioned anymore?  How many of us have read him?  (I venture fewer than should!) 

This criticism of worshipping at the Belmont altar, if you will, is hardly new, but it’s critical, especially when something as profound as heritable human gene editing is being considered.  You see, Belmont principalism is quite robust when asking how to deal with clinical trials.  But it really most closely applies to things like regulated drug development, and germline gene editing goes far beyond drug development.  It isn’t drug development at all, and cramming it into the conceptual framework of drug development is fundamentally misguided.

Nonetheless, the International Commission on the Clinical Use of Human Germline Genome Editing appears to be proceeding merrily along the drug development path. The second meeting, in London, is next month; one can sign up for a webcast. Just check out the agenda, especially day 2’s planned sessions on risk-benefit analysis and defining “a translational pathway.”  That language applies to new therapy development, not fundamental alterations of human inheritance.

One should keep in mind also that the assumption one can assess risks and benefits is only as good as one’s data.  This week it is reported that scientists have retracted an analysis suggesting that babies edited for an HIV-susceptibility gene might be at risk of relatively short life spans, something this blog poster readily jumped on in his June 6, 2019 post.   But, then again, so did the prestigious journal Nature Medicine, so I guess I shouldn’t beat myself up too much.  Seems the researchers didn’t define matters carefully enough.  Even if this particular analysis, from a large database of human genetic data, was flawed, similar analyses in the future might be helpful, it is argued.  Until more is known, it is further argued, one should not seize on a retracted analysis to infer a full “green light” to edit unborn babies’ genes.  But that may take “thicker” bioethics than whatever risk-benefit analysis we think we can muster now.

The importance of premises

In an interesting article in the Hastings Center Bioethics Forum, titled “Hannah Arendt in St. Peter’s Square,” Joseph Fins and Jenny Reardon write about the importance of deep ethical reflection in dealing with the ethical challenges of biomedical research. They point out that when ethics becomes a matter of simply following a set of rules we can end up in the wrong place. Even such fundamentally good concepts as informed consent and the need to have research proposals reviewed to be sure that they are ethically sound can lead to a mindset of regulatory compliance, essentially following the letter of the law, while leading to poor conclusions about what we ought to do. In the end they suggest that in order to facilitate deeper ethical thinking regarding new areas of biomedical research we need more interdisciplinary conversation between the sciences and engineering on one hand and the humanities and social sciences on the other. I think this is quite true and is a strong argument for a liberal education in its classic sense.

However, I find it particularly interesting how the thinking of Hannah Arendt enters into their discussion. Arendt was a German Jew who fled from Europe to the US in the Nazi era. She wrote about the kind of thinking that allowed the totalitarian regimes of Hitler and Stalin to gain control. Fins and Reardon focus on her idea that logical thinking can lead from a seemingly self-evident statement to a replacement of common sense with thinking that leads in a direction that is very wrong. They see a culture in medicine and science that considers ethics as a matter of regulatory compliance rather than deep reflection an example of this.

What I find most interesting in Arendt’s thinking is the idea that logic will lead to faulty conclusions if the premise is not true. The problem that she saw in the thinking leading to totalitarian regimes was not that the thinking was illogical. The problem was that the seemingly self-evident statements which were used as the premises were false. When we apply that to ethics it means that we will only reach sound ethical conclusions when we begin with moral premises that are true. A liberal education with interplay between the humanities and the sciences is one way to seek true premises for our ethical thinking in the wisdom that can be found in the interplay of academic disciplines. Another is to recognize that the existence of common sense morality suggests a source of moral wisdom that is beyond human wisdom. Christian ethics finds its premises in that higher source of moral wisdom. A Christian liberal education integrates them both.

Humanoid Mass Production

Henry Ford would be proud.

We now have the ability to mass produce humanoids, embryonic cells derived from human embryonic stem cells or induced pluripotent stem cells (the latter can be made from adult cells). These cells are specifically designed by researchers to have some but not all of the necessary elements to be fully human. The goal is to grow these humanoids beyond the current 14-day limitation imposed on research studies on human embryos that ARE fully human.  In theory, these humanoids are physiologically similar enough to humans that by observing their growth and development, scientists hope to learn about human development. By design, the claim is that humanoids are different enough from humans that they would not/could not /should not live outside the Petri Dish. The original report in Nature may be found here.

I use the Henry Ford analogy on purpose. He revolutionized the automobile industry by standardizing the manufacturing process such that less skilled laborers could sequentially assemble an automobile. This allowed the cars to be built faster, at higher volume and far less expensively. Previously, higher skilled craftsmen machined each unique part for each unique car. Though the cars looked the same, their parts were not interchangeable. The process was painstakingly slow, resulting in a very low production volume at a very high price. With mass production, cars became far more common,  much less expensive and, to some extent, disposable.

Moving toward a standardized “mass production” process will have the same effects for humanoid production. Standardizing the manufacturing process will reduce the variance of a given humanoid, making the scientific study of its growth more reliable, reproducible and less expensive, all good things from a scientific standpoint. Will it also cause us to view the humanoids as more disposable?

I continue to want more discussion on the moral status of humanoids before more experimentation is permitted, particularly as we extend their lifespans. Whatever they are, at minimum, they are living entities.  Humanoids must be more than the sum total of their individual cells otherwise we humans would not have so much interest in their development. How human-like does a humanoid have to be before we should consider additional human-like moral/ethical protection in humanoid experimentation?

Or their mass production?

Fewer U.S. Twins and the Development of IVF

Readers of this blog may have seen the report in the general press that, after three decades of increases, the rate of twin births in the U.S. has declined by 4% from 2014 to 2018.

Those three decades correspond to the era of IVF, since the birth of Louise Brown in England in 1978.  It seems likely that changes in IVF practice contributes at least in part, if not substantially, to the trend in twin births.

Specifically, doctors at IVF clinics are more commonly implanting only one, rather than more than one, embryo back into a prospective mother’s womb with each attempt at a live birth.  Multiple pregnancies—even twins, not just “Octomom” scenarios—carry increased risk for mother and babies.  Previously, two or more embryos were implanted in an effort to increase the chance that at least one would make it to live birth.  Sometimes, “selective abortion” was practiced to reduce the number of initially multiple pregnancies to one.  Now, it appears that gradually increasing success rates of IVF are supporting single-embryo transfer as a standard practice.

The Centers for Disease Control and Prevention (CDC), which provides a substantial amount of information on the current status of IVF on its website, summarizes the changes in the percentage of single-embryo transfers in recent years—increasing from 11.6% of non-donor-egg transfers in 2007 to 39.9% in 2016.

To the extent that this reduces the practice of selective abortion and, one hopes, decreases the number of embryos created but kept frozen, never to be born, at IVF clinics, this is a welcome development.  The Christian Medical Dental Association takes the position that, in IVF, the number of embryos should be kept to a minimum, and all embryos created should be so created with the intent of having the genetic mother carry all of them in pregnancy, to live birth one hopes.

IVF remains a transformative enabling technology that facilitates contractual arrangements for reproduction, profound changes in the structure of families, and the use of pre-implantation genetic diagnosis to control what sort of people are allowed to be born.  One might view these developments as non-physical harms, that alter our overall experience of being human in ways that may properly be subject to question.

And: the rate of twin birth is still twice what it was in 1980.  If one sees a mom or dad pushing a stroller with fraternal twins, chances are they are IVF kids.

Screening that benefits the screener

I teach it course on human diseases for students in a public health program. One of the things that we talk about is asymptomatic disease. If a disease has no symptoms the only way that we can detect it is by screening. For screening to be beneficial it needs to be able to detect asymptomatic diseases accurately and there needs to be something which can be done that will help those in whom the asymptomatic disease is diagnosed. Many times, a screening test will only be accurate if the test is used to screen a selected population which is at risk. Sometimes there are asymptomatic diseases which we can detect accurately, but the people diagnosed do not benefit because there is not something we can do to make their life better than it would be if the asymptomatic disease had not been diagnosed. Since the purpose of screening is to help people, there is no reason to do it if the people being screened will not be helped. That idea is based on the principle of beneficence. Everything that we do in medicine should be done for the benefit of the person being treated.

Some people do not follow that moral principle. There have always been some who have used the practice of medicine to benefit themselves more than those they were treating. That is why the Hippocratic physicians had to put a statement about beneficence in their oath. One of the ways that the principle of beneficence can be violated is for some people to encourage other people to do screening that will not benefit those being screened but will benefit the one doing the screening. One of the examples I see most often is supposedly low cost ultrasound screening for such things as carotid stenosis. Those doing the screening can make a significant amount of money by screening everyone who will accept their pitch but the people being screened do not benefit. It is currently not recommended to screen for asymptomatic carotid stenosis because there is no evidence that intervention is beneficial for those who are diagnosed and some evidence that intervention may cause more harm than good.

As new technology is developed it is subject to being used in a way that violates the principle of beneficence. One of the new ways to do that is with genetic screening. A recent article in the health news section of Reuters.com describes the fraudulent promotion of genetic screening to older adults in the US. Again, this is screening being done to benefit screeners who have collected huge sums from Medicare while providing no benefit to those being screened.

These abuses do not mean that we should not do screening. It simply means that screening should be done the right way. We should choose which screening tests we use and which people we screen with those tests based on how the screening will benefit those who are being screened. We should not do it to benefit those who are doing the screening.

Why do we do this?

Many of the posts on this blog involve cautions that there are things in medicine which we are capable of doing and which some want to do that we should not do. Much of the time those cautions go unheeded by our society. For fifty years we have been saying that we should not perform abortions, but many unborn human beings continue to lose their lives. We give reasons why we should not do euthanasia, but PAS becomes legal in state after state. We write about why we should not alter the genes of human embryos, but the research continues. Is it just that we are anti-medical science and like telling people what they should do?

No. We do it out of love. Sometimes it is love and concern for people who are powerless and cannot speak for themselves. It is because of our love for the person who is aborted as a fetus or comes into being as the result of a genetic manufacturing project rather than being accepted unconditionally as a gift. It is out of love for the Canadian man who chooses euthanasia because he cannot obtain the 24 hour a day care he needs to live life with ALS.

It is also out of love for those who do things that are wrong. Love for the physician who performs abortions or euthanasia. Love for the researcher who uses human embryos as research subjects destined to die. We do it for the sake of the gospel which tells us that we have all done wrong and are destined for judgment unless someone intervenes. The gospel that tells us Jesus did intervene by his death and resurrection and has made forgiveness and restoration available to all who confess their wrongdoing and put our trust in him. We do it for those who will miss out on the amazing grace of the God who died for us if they listen to a culture that says that anything you desire to do is right and there is no need to ask for forgiveness for anything.

“Velvet Eugenics”

Human Flourishing in an Age of Gene Editing is a new collection of essays, edited by Erik Parens and Josephine Johnson.  In the introduction, the editors explain they are concerned with “nonphysical harms” of human gene editing.  That is, these harms would not affect bodily systems, but harm “people’s psyches…[their] experiences of being persons,” and could impair human flourishing.  These harms could be incurred not only by gene editing but also by use of other “reprogenic” technologies such as preimplantation genetic diagnosis (PGD) and prenatal diagnosis.

Your correspondent has just begun to read this collection.  In the first entry, “Welcoming the Unexpected,” bioethicist Rosemarie Garland-Thomson of Emory University, takes the view that flourishing is not a matter of proximity to some ideal of health or human excellence, but is, for each person, a growing into expression of that person’s unique capabilities.  Accordingly, rather than embrace a project of eliminating disabilities, society should work to make the environment more welcoming to people with those conditions—many of which, after all, need not impair a person’s ability to live a life of happiness and contribution to others.  Communities have an obligation, she says, “to support the distinctiveness of its members according to the egalitarian principles of justice, liberty, and equality,” and “build environments that…support the widest spectrum of embodiments…in which human embodied existence can successfully thrive as it is.”  Put another way, we should not be building a regime in which we are deciding what sort of people we will allow to be born, but we should be ready to welcome and embrace the ones who are.  In this, Professor Garland-Thomson sounds a “caution against an aggressive normalization imperative…an outlook of humility about the human capacity to control future circumstances through present action…against the arrogance of [what one writer called] ‘the danger of a single story.'”

We should, she writes, adopt a stance of “growing” rather than “making” human beings, and “reconsider the logic of a velvet eugenics that would standardize human variation in the interest of individual, market-driven liberty and at the expense of social justice and the common good.”  In this, she embraces the argument of contemporary German philosopher Jurgen Habermas that rejects “a liberal eugenics regulated by supply and demand.”  One can be forgiven for hearing in this an echo of C.S. Lewis’s worries about “conditioners” in The Abolition of Man.

This is set in the author’s description of her ongoing friendship with three other women, all, like her, married PhD’s who like good wine, good food, and are amply supported by technology and community.  One of her friends is congenitally deaf, another has hereditary blindness, the third has a genetic muscular condition, and the author herself was born with what is now called “complicated ectodactyly,” with “asymmetric unusual hands and forearms.”  The sort of thing your correspondent understands the Chinese to be trying to eliminate through the use of PGD.

A remarkable essay to lead off a collection that appears worthy of careful consideration.

Stem Cell Rx No Longer For Sale on Google

Perhaps once a week, I will be asked by a patient about the potential benefits of stem cells for reversing the normal affects of age, particularly with respect to arthritis of the knee joints, hip joints or the degenerative discs in the lumbar spine. I believe one of the reasons for this interest has come from increasing advertisements by various clinics in my region of East Tennessee claiming stem cells are the answer for these problems. My region is not unique. A simple Google search on “stem cells for knee pain” yields ads for clinics offering such treatment.

Stem cells are cells that have potential to become any type of cell in the human body such as a new blood cell, nerve cell or bone/cartilage cell. Scientists are rapidly learning how to find or create stem cells, as well as how to safely use them to replace old or missing cells, thus restoring function in worn out, damaged or diseased areas of the body. In fact, stem cells are presently used to replace the bone marrow for some individuals with certain cancers and disorders of the blood and immune system, and in many of these cases, the results are lifesaving.

The problem is that stem cell treatment remains yet unproven in all other medical conditions, including the age-related arthritis conditions which I treat. This lack of efficacy has not stopped clinics from offering and patients from receiving stem cell injections with the hope of achieving improved function or cure. I am willing to grant that many offer these treatments with the sincere hope and belief that they are acting in their patient’s best interest, though I suspect not all have the patient’s best interest in mind. Unfortunately, there have been severe adverse events. Examples include blindness following an injection of stem cells into the eye, and loss of function with development of a spinal cord tumor following stem cell injection into the spine.

The FDA is trying to educate the public and prevent stem cells from being offered for unproven treatments. The FDA has the authority in the US to stop these unproven treatments and take punitive action if needed. This is not to suggest that the FDA is in the business of preventing legitimate investigation into the potential benefits of stem cells, such as this Mayo Clinic Phase 1 study looking at the risks of injecting stem cells in to the cerebrospinal fluid of patients following a spinal cord injury to see if this particular stem cell technique causes harm (with future studies needed to determine benefit).

The FDA is recently getting some help from Google. On September 6th, Google announced it would stop accepting ads for unproven medical treatments, including stem cell therapies. It is early in the effort and the initial link above still has four ads for non-bone marrow stem cell treatments returned with the Google search. Maybe by the time you read this blog entry, the stem cell ads for unproven treatments will be gone.

I am hopeful that stem cells will eventually provide patients with safe therapies that repair injury and return patients to normal health. Offering that promise without the studies that prove such benefit is unethical and potentially harmful. It is good to see Google favoring human welfare over financial profit.

Two developments

A new effort at “somatic” gene editing in China is reported this week.  The key summary:

“As the researchers report in the New England Journal of Medicine,

[note to reader: subscription required]

they transplanted [blood stem] cells that had undergone CRISPR-based editing [of a gene that encodes for a receptor, or “docking station”] into a patient with HIV and acute lymphoblastic leukemia. While [the edited cells lasted for a long time in the bloodstream of the HIV-infected recipient], they only made up between 5 percent and 8 percent of blood cells. A higher percentage is needed for this to be an HIV cure…”

In “somatic” gene editing, mature cells, such as “adult stem cells” or diseased tissues, are gene edited for the purples of treating a fully-formed individual with a disease.  That is what appears to be in view here.  Similar efforts are in progress to treat sickle cell anemia and other genetic diseases.  The ethical issues are relatively well-understood, and fit within the regime of regulating cells-as-medicines in clinical trials of humans, under the ethical and regulatory regime that governs the latter.

That’s in contrast to “heritable” gene editing, which attempts to edit genes in embryos, fertilized eggs (zygotes), or gametes (sperm or eggs) with changes that would be passed on through the generations, as recent entries on this blog have been addressing.  The Chinese twin girls who were reported to have undergone gene editing late in 2018 are examples of an attempt at “heritable” gene editing.

A second report from Nature describes efforts to use human “reprogrammed” stem cells, aka pluripotent stem cells, to make human “embryo-like structures.”  This is distinct from making a human embryo, for example in IVF, then removing cells, likely destroying it, for use in research or to develop medical treatments.  In conservative commentaries in recent years, these “reprogrammed” stem cells are considered the “ethical embryonic stem cells,” because they can’t form a full individual and they don’t require creation and destruction of an embryo, that would under normal circumstances form a full individual.

Thing is, these “embryo-like structures” can still form something called a “primitive streak,” which, in normal embryos, is the first sign of formation of a nervous system.  The primitive streak usually forms 14 days after fertilization, so, to try to avoid concerns about research on embryos, scientists who think such research is ethical in limited circumstances have operated under a “14-day rule”–voluntary in the US, mandated by law in the UK–after which embryos would not be destroyed for research.  These “embryo-like structures” may form a primitive streak, it appears.  The situation is similar to “synthetic human entities with embryo-like features,” or “SHEEFs,” which may bypass the primitive streak but raise similar issues of whether something too like a natural human being is being engineered by this work for it to be ethical.

A developmental biologist at Caltech says, the California Institute of Technology in Pasadena. “We will have to confront ourselves with the question of what is a human embryo, and whether these models really have the potential to develop into one.”  The researchers making these synthetic embryos argue that they lack a placenta and other cells needed for development, so could not develop into a person.

At least for now.

Heritable genome editing: a too-short list of 12 questions

Last week, I discussed efforts by a US/UK commission formed to recommend a framework for regulating and monitoring heritable human gene editing.  This commission has called for “expert evidence” to assist them in the task “to develop a framework for considering technical, scientific, medical, regulatory, and ethical requirements for human germline genome editing, should society conclude such applications are acceptable.”  The deadline is September 27, 2019 to make recommendations.  The website to do so appears open to the public. 

Now, I suppose the commission will ultimately decide who qualifies as an “expert,” and several of the questions are decidedly technical.  But I submit that many who read this blog qualify as experts in bioethics or in some aspect of biomedicine, and will be able to offer considered responses to at least some of the questions.  So I encourage readers of this blog to access the link and weigh in.

I have yet to complete my effort.  I started last week, then pulled back in the middle.  Responses to each question appear to be submitted in real time, and the possibility to save work (there are ‘”back” and “next” buttons) for future editing seemed unclear.  And these questions merit careful responses.  So I decided to wait for another day—before the September 27 deadline!

If you would like to mull over possible responses in advance of trying to offer them online, I have copied them here, for advance thinking before submitting at the online portal, or to inform reflection and discussion otherwise:

  1. Which diseases and conditions, if any, do you see as appropriate for human germline genome editing?
  2. If there were to be an appropriate use case for human germline genome editing, what evidence would be needed to proceed to first in human use?
  3. What is the status of editing mechanisms for early stage human embryos (e.g., using different editing techniques, improving homology directed repair, etc.)? What are the factors that predict whether single nucleotide changes or other intended modifications in human embryos will be correct? To what extent will genome editing affect the viability of embryos?
  4. What is the status of the technology for validating that a correct edit (on target characterization) has been made and that unintended edits (e.g., off target effects, mosaicism, etc.) have not occurred in a range of cell and tissue types? If possible, please provide evidence drawn from work on induced pluripotent stem cells, embryonic stem cells, and/or early stage human embryos.
  5. What is the status of generating cell lines from human and non-human germline stem cells?
  6. How might animal models inform the editing in human embryos (inclusive of analysis of phenotypic correction)?
  7. To what extent do different genetic backgrounds affect success and phenotypic outcomes after genome editing?
  8. What is the success rate of full-term pregnancies following pre-implantation genetic diagnosis? What affects this (e.g., age, number of oocytes harvested, technique used, etc.)?
  9. What are the appropriate mechanisms for obtaining informed consent, long-term monitoring of the future children, assessing potential effects in subsequent generations, and addressing untoward effects? Are there best practices from: a) assisted reproductive technologies; b) pre-implantation genetic diagnosis; c) gene transfer research for children; d) mitochondrial replacement therapy; and e) somatic genome editing?
  10. How should we think about the inter-generational medical (e.g., genetic changes to the genome) and ethical implications of human germline genome editing (e.g., potential harms and benefits)? How should the rights of future generations and the wider human population be taken into account?
  11. What international oversight structures would need to be in place to facilitate, in a responsible way, a path forward for germline genome editing?
  12. Are there any topics or issues that are not covered by the above questions that you think the Commission should attend to during its deliberations?

This last question, of course, is the most pregnant of all.  The list of questions is so technical, so question-begging about whether heritable gene editing should be done at all, that the commission should receive carefully-considered reflections on the meaning of the potential enterprise, how the future practice of heritable genome editing should not be a foregone conclusion, and how and why the right answer to “when should we edit human genes heritably” might well be “never.”

By all means, reader of this blog, go online and offer what you reasonably can to this important discussion!