Experimental Subjects for Life?

More than a year after the birth announcement of genome-edited babies in China, we are only slightly more informed of He Jiankui’s experimentation, the results of which are named “Lulu” and “Nana.” Although apparently approached, neither Nature nor the Journal of the American Medical Association (JAMA) chose to publish He’s work. Antonio Regalado reported on an unpublished manuscript in “China’s CRISPR babies: Read exclusive excerpts from the unseen original research” in Technology Review on 3 December 2019. The Technology Review article includes not only excerpts of the manuscript from He, but also reactions from Stanford law professor Hank Greely; University of California—Berkeley’s gene-editing scientist Fyodor Urnov; the scientific director of Eugin assisted reproduction clinics, Rita Vassena; and reproductive endocrinologist Jeanne O’Brien, from Shady Grove Fertility.

Regalado summarizes some of the problems with Chinese experiment as follows:

 . . . key claims that He and his team made are not supported by the data; the      babies’ parents may have been under pressure to agree to join the experiment; the supposed medical benefits are dubious at best; and the researchers moved forward with creating living human beings before they fully understood the effects of the edits they had made.

Greely points out the lack of “independent evidence” of the claims made in the paper. Urnov labels the paper’s claim of reproducing the usual CCR5 variant “a deliberate falsehood,” and calls the statement about the possibility of millions being helped through embryo editing “equal parts delusional and outrageous.” O’Brien’s concerns include the possibility of coercion of the couples involved, and, noting the social stigma of HIV-positivity in China, she poses the question of whether this was a genetic fix for a social problem. Certainly, the Chinese experiment raises many questions, including how a culture views children. Are children gifts to be received or projects to be completed? Is it appropriate to subject children to experimental research because we can? One of the quotes from the paper reads, “we have made a follow-on plan to monitor the health of the twins for 18 years and hope to then reconsent for continued monitoring through adulthood.”

We would be remiss if we thought that China alone plans to remake humanity. Vassena is quoted regarding He’s study:

Unfortunately, it reads more like an experiment in search of a purpose, an    attempt to find a defensible reason to use CRISPR/Cas9 technology in human embryos at all costs, rather than a conscientious, carefully thought through, stepwise approach to editing the human genome for generations to come.  As the current scientific consensus indicates, the use of CRISPR/Cas9 in human embryos destined to give rise to a pregnancy is, at this stage, unjustified and unnecessary, and should not be pursued.

Vassena, who directs a fertility enterprise, it should be noted, appears comfortable with impacting the human genome for generations to come:  It just needs to be a “reflective” and “mindful” approach. That is chilling. Would she, or the study’s authors, or Greely, or Urnov, or O’Brien sign up to be a science experiment for the rest of their lives? I would not consent—not for myself nor for my children—no matter how “reflective” or “mindful” the researcher happened to be.

Finally, “Lulu” and “Nana” should be known as more than the results of someone’s laboratory experiment. They are human beings, not laboratory rats or cells under a microscope to be studied at the will and convenience of the experimenters.

Giving thanks for life

The “bio” in bioethics means life. Although it includes other types of life the focus of bioethics is on human life. The announcement a year ago of human infants born in China after their genes had been edited has caused us to think this year about how human life should come into being.

The story in Genesis of the creation of humans tells us some things about who we are. We learn that we are created beings made from the material substance of creation with the breath of life breathed into us by God. We are made to be male and female and complement each other. When we come together in marriage, we have been given the ability to bring new human beings into the world as a result of our union as one flesh. Each new child is given to us as a gift from God. We also learn that God made us in his image so that we are intended to reflect his glory in the world we have been given to steward. That sets us apart from other created life and puts great value on every human being.

How does all this impact how we think about how we bring new human lives into the world? It means we should remember that each new child is a gift from God who should be accepted unconditionally. Children are not intended to be something we make to fulfill our own desires. Each new human being from the very beginning of his or her life has great value. It means we should hesitate to modify the genetics of a new human being to give that child the genes that we think are best. It also means that we should show great respect to any human being who is a subject of research. Human subject research can be very important, but the subjects should enter in voluntarily giving of themselves as a gift to others. When we do research on human beings who are not able to volunteer, the research should cause no more than minimal harm. We should not see human embryos as a disposable resource for research.

As our family travels to our home to celebrate Thanksgiving together this year, I am thankful for each of their lives. I am thankful for my parents who brought me into this world and nurtured me both physically and spiritually. I am thankful for my wife whom God has given to me as a faithful partner and the children God gave to us. I am thankful for the spouses God gave to them and the children they have been given. Above all I am thankful to the God who gives us life.

Skepticism about polygene scores to select for IQ and height

One caution when objecting to the prospect of heritable human gene editing is to take care not to overestimate what it technically possible.  That is, an all-too-easy argument is that attempts to edit a disease gene will lead, by momentum if nothing else, to “designer babies,” with children not just being genetically selected but in fact engineered in great detail for traits like attractiveness, athletic prowess, height, and intelligence.  This contributor to this blog has repeatedly taken the position that heritable human gene editing is a project that fundamentally alters the way we see ourselves and each other; that divides the human race into “actors” and “acted upons;” that has no prospect of prospectively assessing long-term, unintended consequences, to an individual subject, subsequent generations, or society at large; and that fortifies a perspective of admitting to the human race only those members we want to admit.

Along the way, we must keep in mind that “designer babies” are not likely to be feasible in the foreseeable future.  One recently-reported case in point is a study by scientists at the Hebrew University of Jerusalem.  A preprint (in advance of publication in a peer-reviewed journal, it is said) is publicly available here.  I daresay the details will be inaccessible to all but specialists in genetics, but a summary of key points is provided by a technical writer at a website called GenomeWeb.  In brief, some of those points:

  • A score based on assessment of multiple genes has previously been suggested to explain only about 5% of the difference between individuals in IQ (300,000 people genetically tested) or 25% in height (700,000 people tested).
  • These researchers tested about 1000 people, and considered about 15,000 genetic variations.
  • They looked at offspring of actual couples and also “simulated” matches for about 500 would-be couples made from individuals for whom they had genomic data.
  • Of note, they appear to have looked at “SNPs,” or “single nucleotide polymorphisms,” which are relatively easy to catalog across the 30,000 or so human genes, and which themselves run into the hundreds of thousands across those genes, but SNPs are far from the whole genetic story.  Larger differences in genes, or how those genes are translated into biological traits, is much more complex to assess.
  • They surmised that, if their score were used to try to predict height, the average gain would be about 2.5 cm (about one inch), with a range of 1-6 cm.  If used to predict IQ, the average gain would be about 2.5 points, with a range of 1-7 points.
  • Then they also looked at 28 actual families with lots of kids, from 3 to 20 (!).
  • For the actual families, the score predicted to cause the tallest child did so for only 7 of the 28 families, and the highest scoring child was actually shorter than average in the family in 5 of the 28 families.  No attempt to assess IQ for these real families, apparently.
  • They point out other reasons why trying to select for IQ might be problematic—potential association with autism and anorexia, for example, as well as just general complexity.
  • They suggest that for most people undergoing IVF, and creating fewer than 10 embryos in the process with less than 100% success after implantation in the womb, the odds are not good for making a reliable forecast of an offspring’s height or IQ.
  • They make these points without commenting more broadly on the ethics or policy wisdom of allowing or encouraging heritable genome editing to proceed.

A complex story, and a developing one, to be sure, but one should not be too quick to accept grandiose promises for predicting complex traits based on genetics.  At least for now, those appear to be rather “ahead of the puck,” shall we say.

Future new CRISPR baby in Russia?

Nature reports that Russian scientist Denis Rebrikov has started experiments intended to lead to editing a gene, in human oocytes (egg cells) associated with human deafness.  Prior reports had claimed that he was working on eggs from deaf women in an attempt to repair the defect and, presumably, provide a normal egg for IVF.  This apparently is not the case—yet.  At the moment, he is using eggs donated by women who can hear, to do experiments on editing the gene in question and ferret out what might go wrong in the process—that is, is the right gene edited, is only the right gene edited, and related questions.   

He says he has had discussions with deaf women, but has not yet sought approval from the Russian regulators to try IVF with a gene-edited egg.  The regulators appear reluctant, and Rebrikov says he will not proceed without prior approval.  He had previously said he wants to edit the same HIV-susceptibility gene that was edited in twin babies born in China last year, but it looks like there aren’t too many candidates for that approaching him, and that attempt has not gone forward—yet.

He’s clearly impatient.  Other scientists working in the gene editing field—which has broad applications short of making “gene-edited babies”—are urging patience, and saying that it is at a minimum rashly irresponsible to rush ahead with the effort, particularly for non-fatal conditions like deafness.  And they are right—too little is known to justify the effort—yet—even if one thinks there are conditions for which it ethically could or even should be attempted.

But “the field” is working hard to define a path forward.  The second meeting of an international panel discussing how to move ahead meets in London November 14-15.

Nature includes a brief Q+A with Dr. Rebrikov.  Forgive me, but some of it is chilling, reflecting blindness to the deeper issues.  Paraphrasing selected questions, quoting the answers, offering italicized commentary:

  • Question:  don’t the risks of trying this outweigh the benefits, for a non-life-threatening condition like deafness?  Answer: “Any new drug carries certain risks. The deafness model is the most appropriate for applying genomic editing at the zygote [newly fertilized egg] stage. And it is only for deaf parents to decide whether … deafness is enough to not expect the same for their child.”  Beg pardon:  heritable gene editing is NOT A DRUG, and the risk-benefit decision is NOT solely the province of private decisions about reproductive-related risks.
  • Question:  the regulators point out that editing people is currently not permitted.  Answer: “Laws are written to change them. As soon as we demonstrate the safety of technology, the rule will change.”  Ahem: some laws are enduring, even eternal—cf. divine law. Recognizing that the regulators’ judgment is not divine, eternal law, reverent attention to the latter should be a paramount concern.  And ‘safety’ appears to be narrowly defined here, blissfully ignoring the deeper human questions posed by modifying people’s genes permanently.
  • Question: people trying to build a regulatory framework for human genome editing think researchers should slow down until the framework is agreed upon. What do you say?  Answer: “Are you serious? Where did you see the researcher willing to slow down?”  Hello!  McFly!  We are not ASKING you to slow down.
  • Question: Russian regulators and the World Health Organization say it is too soon to create edited children.  What do you say?  Answer:  “What does it mean, too soon? Lenin said ‘yesterday was too early, tomorrow it will be too late.”.

Lenin?? LENIN?!  For real??

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.

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?

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.

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.