Controlling gene editing

The title does not mean societal or legal control of gene editing technology.  Rather, it speaks of controlling, or shutting off, a specific gene editing process.  In retrospect, it had to be the case that there is a resistance, or control, mechanism for the CRISPR system, the gene-editing machinery that functions as a way for bacteria to resist invasion by viruses.  An engaging essay in Nature this week discusses this on a level accessible to one who, like me, is not a technical specialist in the field.  Briefly, a few years ago a grad student at UC/San Francisco discovered cases in which the CRISPR system was ineffective in certain bacteria.  Following up led to the discovery of some 50 proteins that can act as “kill switches” for CRISPR.

On a surface level, the implications are clear—learn how to deploy these proteins and one can monitor one’s gene editing efforts for unwanted effects, or for spinning out of control, and if things haven’t gotten too far out of hand, one could turn things off—have an antidote, as it were.

Suppose at some future date that someone were being treated with a gene editing approach for a genetic disease, and things start happening suggesting that other genes than were intended to be the target were being altered.  Presumably one could intervene to treat or prevent the consequences.  Or suppose that genes were being edited to control a certain pest, like malaria-causing mosquitoes.  Presumably there could be an intervention to try to stop the process.

That’s a pretty superficial discussion, but technical experts in the field are trying to learn how to use these “kill switches” to control their gene-editing efforts. 

The also-superficial implication seems clear: these efforts should be understood, and applied in laboratory systems, then perhaps in “somatic” gene editing (treating an existing person for a genetic disease) BEFORE attempts are made to edit human embryos, whether the embryos are intended for gestation or birth or not.  Until things are MUCH more fully understood, there should be no direct work on heritable genome editing.

Chastening and enthusiasm about genome editing

A writer in Nature says that China sent a “strong signal” by punishing He Jiankui and two colleagues with fines, jail times, and bans against working again in human reproductive technology or applying for research funding.  (They lost their jobs as well and may not be able to do research work, presumably in any field, in a Chinese institution again.)  It is encouraging, this writer says, that China took this action demonstrating a commitment to human research ethics.  He and other researchers doing gene-editing work that is not ethically objectionable worry that there may be collateral damage, so to speak, against ANY gene-editing research in China.

Another writer in Nature says cites progress under “appropriate caution” for using gene editing techniques for so-called “somatic” gene editing; that is, editing disease genes in an existing person with that disease, to treat it.  This is, in essence, a form of gene therapy and is ethically permissible under proper research ethical guidelines.  Some clinical trials in progress involve injecting the gene-editing apparatus into a person, while most such trials remove the person’s blood cells, edit them in the laboratory, then re-introduce them into the bloodstream, after which the edited cells are left to mature normally.  The latter approach is particularly attractive to treat genetic blood diseases such as sickle cell anemia.

Both perspectives seem correct, as far as they go—never mind whether Dr. He’s jail sentence fits the crime, as Joy Riley asked on this blog last weekend.  Never mind also whether Dr. He’s research should be published; as Mark McQuain commented, it’s a bit incongruous to want to assess the technical merits of work that should not have been done in the first place.  He linked an opinion in Technology Review that argued, briefly, that because the ethics of editing genes in human embryos is under societal debate, people trying to decide on the ethical merits should be able to assess for themselves whether Dr. He succeeded, technically at what he set out to do.  (The consensus to date seems to be, no, he did not.)   But the role of technical success in assessing the ethical merits of a medical intervention—or, better, an intervention made in the name of medicine—depends on the degree to which the ethical judgment is a matter of making a reasonably reliable of risk and benefit, and the degree to which risk-benefit is a criterion for judging the ethical merits.  And therein, as they say, lies the rub—which I hope to revisit in coming posts.

2020, or 20/20?

Near the end of 2018, He Jiankui was on the world’s stage announcing that he had edited the genome of twin girls, in the hope of making them resistant to HIV. On Tuesday, December 31, 2019, the Wall Street Journal (WSJ) printed a report that Dr. He and two others have been convicted of “illegally practicing medicine related to carrying out human-embryo gene-editing intended for reproduction.” (online version here).

A court in Shenzhen concluded that the defendants had acted for “fame and profit,” when they “deliberately violated the relevant national regulations, and crossed the bottom lines of scientific and medical ethics.” For the crime committed, He received the most severe sentence. In addition to the three-year prison sentence, He is banned for life from “working in the field of reproductive life sciences and from applying for related research grants, “ according to the WSJ.

The Xinhua News Agency also noted that a third genome-edited baby had been born, and that this child, along with the previously born twins, “would be monitored by government health departments.” The WSJ did not state for how long the monitoring would continue. Not only were the children experimental subjects as embryos, but they continue to be subjects as well. Further, these genome effects will affect their progeny, potentially into perpetuity. Additionally, the Smithsonian Magazine reports that in the summer of 2019, He met with “investors to discuss a potential commercial genetic modification clinic in Hainan, which aims to become a ‘world-class medical tourism hub’.”  One might reasonably call this “a crime against humanity,” even if it does not include genocide of humans already born. (For further reading, see David Luban, “A Theory of Crimes Against Humanity”)

In the print edition of the WSJ, alongside the article on He is an article about Pastor Wang Yi of the Early Rain Covenant Church. Pastor Wang was sentenced on 30 December to nine years in prison. His crime was “incitement of subversion of state power and illegal business operations” (online article here).

Consider that a pastor receives a nine-year sentence for an offense against the State; and a scientist, a sentence of three years for a crime against multiple generations, and indeed, humanity. In the year 2020, we could use a check of our understanding of what is important in the life of the world. Would that our vision were 20/20 also.

Can we hop the gene-editing train?

As Joy Riley pointed out on this blog on December 7, the world and the scientific community recently marked, with almost no fanfare, the one-year birthday of “Lulu” and “Nana,” the first (we think) and still only (we think) humans to have had their genes edited heritably—in a way that will be passed on to future generations.  Joy commented these children are “experimental subjects for life,” or, to use the phrase I found and discussed some time ago on this blog, “the babies are the experiment.”  To wit: it is not possible fully to assess and limit the risks of heritable genome editing before actually editing humans.  One must forge ahead.  Even if one were to edit a series of embryos, and abort them at different times during gestation to get a full assessment of their prenatal development, the questions about lifelong effects and effects on future generations would persist. 

And, as mentioned in other posts on this blog earlier this year, there is the issue of “nonphysical” harms to how we understand ourselves and our human existence.

A number of world scientific bodies are assessing, independently of each other, what regulatory safeguards should be instituted, on the assumption that heritable genome editing is something that should be pursued.  Last month, the journal Nature editorialized that efforts by the World Health Organization, US and UK scientific bodies, and a third international commission should not proceed separately (they are all due to report their findings in 2020), but should work together.  The editors apparently think that it would be straightforward, obvious, and right to adopt a moratorium on clinical applications of heritable genome editing, establish an enforced registry for all experimentation in this area, and expand the conversations to include representatives of people with disabilities.  If I read that correctly, it’s hard to disagree.

In the laboratory, things are moving fast and it is well-nigh impossible to keep up with the science or the conversations about it without that work being one’s main occupation.  A recent contribution linked by the Nature editors is called “prime editing” that appears to increase substantially the efficiency of gene editing, raising the prospect of correcting abnormalities associated with the vast majority of genetic diseases.  The relatively naïve, like your present correspondent, might wonder whether this approach could be limited to already-born people with genetic diseases, as treatment, rather than engineer the genomes of the unborn in an apparent attempt to eliminate these abnormalities from the human prospect.

Even thinking about the general public trying to influence where this work leads feels like assuming the role of an old-style hobo, trying to hitch a free ride by jumping onto a moving freight train.  One is liable to fall under the wheels.  But in the case of heritable genome editing, you’re likely to get run over anyway.

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?