September 16, 2023: Gene Editing

Good afternoon. Today we will look at human gene editing: where we are with gene therapy, what might happen in the future, and some of the relevant ethical issues.

Gene Therapy

All human gene editing that takes place today outside of limited research settings is for therapeutic purposes. The basic goal of gene therapy is to alter genetic code to allow proteins to function properly. Therapy is performed by using a vector (e.g. a modified virus or bacterium) to deliver a modified genome to cells in the body, thereby restoring a desired function.

The first successful nuclear gene transfer in humans occurred in 1989, discussed in a 1990 paper, and the first therapeutic transfer occurred in 1990. The first gene therapy approved nationally for clinical use was Gendicine in 2003, approved in China, and the first approval in the European Union occurred in 2012. As of 2019, about 4000 gene therapies were administered worldwide per year, and that number was projected to grow to 50,000/year by 2030. Thus we observe/project a 40 year trajectory from the first successful demonstration to what will still be niche clinical uses. For all the talk about rapid advancement in biotechnology, gene therapy has moved slowly.

There are a handful of commercial gene therapies available. One is for Leber congenital amaurosis, a vision condition that typically leads to blindness and for which there is no other cure; a cancer treatment using chimeric antigen receptor (CAR) T cell therapy; and for spinal muscular atrophy, a neurodegenerative condition that usually leads to death. There is a treatment for sickle cell disease, using CRISPR-Cas9, under clinical trial. These medications can cost hundreds of thousands of dollars per dose.

Beyond the high cost and limited applicability, gene therapies come with significant risk of harmful unintended modifications, particularly in the clinical trial phase (though it is often unclear when the therapies are responsible for the deaths; patients in clinical trials obviously can die from the underlying disease). These risks are part of the reason that development has been so slow. Nevertheless, participation in a clinical trial is for now the best hope of getting access to a gene therapy.

Germline Gene Editing

It is worth clarifying some terminology. Gene editing can be divided into somatic and germline editing (GGE), which mean, respectively, edits that cannot be passed to future generations, and edits that can. No country explicitly allows GGE for an embryo that is used to initiate pregnancy, and most explicitly prohibit it. In the United States, the National Institutes of Health regards the risk to be sufficiently great that they will not fund any research involving GGE. A few years ago, Chinese researcher He Jiankui claimed to have used CRISPR to modify the genes of twin girls; he was placed under house arrest for this. There are disputes about how relevant the somatic/germline distinction is from an ethical perspective.

The most immediate concern about GGE is the risk of unintended, unwanted mutations that could be passed to future generations. Finding ways to reduce this risk is an active area of research. Just a few days ago, a Japanese research team announced a new editing method that they claim is as effective as CRISPR but has a lower chance of off-target mutations. We will see.

It is also worth distinguishing between therapeutic uses, which are intended to cure a disease, and enhancement. GGE for enhancement is the image that for most of us is conjured when we think about genetic engineering. But the kind of images seen in the movie Gattaca are, for the foreseeable future, fantasy. All gene therapies that exist today or are under active development target an expressed trait caused by a single gene or a very small number of genes. The most commonly discussed trait in the context of enhancement is intelligence. There are over 1000 genes that affect intelligence, and the complexity of the interaction make it infeasible that GGE for intelligence will occur in the foreseeable future, even if political conditions were amenable to this, which they certainly are not. For now, some medical researchers have called for moratorium on all GGE research.

In 2018, public opinion research from the Pew Research Center found that a majority of American adults support GGE for therapeutic purposes but not for enhancement.

Recognizing that the issue is largely hypothetical at this point, let’s look at some of the ethical issues around GGE. This is not an attempt to be comprehensive, as that would be infeasible, but it is an attempt to discuss the most important issues.

Ethical Considerations for GGE

The most compelling ethical consideration is the potential health benefit of GGE. Article 15(1)(b) of the International Covenant on Economic, Social and Cultural Rights states that everyone has the right

To enjoy the benefits of scientific progress and its applications.

Article 12(1) of the same convention states,

The States Parties to the present Covenant recognize the right of everyone to the enjoyment of the highest attainable standard of physical and mental health.

And so, beyond the ethical hazard of impeding the development of potentially life-saving medical care, this could be legally problematic as well. I know of no compelling potential medical applications of GGE that have been posited at present and are ready for serious research. But it may be the case that legal restrictions against GGE deter such applications from emerging.

Powell and Buchanan argue that evolution through natural selection is a cruel process that has genetic propagation, not human well-being, as its end. Intentional modification would be a much more humane approach to change. Similar reasoning can be seen in Richard Dawkins’ The Selfish Gene.

Baylis and Robert see GGE as a way for humanity to take control of its own evolutionary future, which they regard as a moral positive.

Michael Huemer discusses “dysgenic entropy”, the tendency for human genetics (or genetics within any population) to decay away from desired expressions absent selective pressures. Huemer focuses on medical care: modern medicine allows people with hereditary genetic conditions to survive and pass their genes to the next generation. Since withholding medical care from people with genetic conditions or forcibly sterilizing them is not ethical, GGE is the most ethical alternative to allowing dysgenic entropy to accumulate. Here we are getting into the realm of eugenics, which for good reason is a taboo subject. While Huemer’s argument sounds superficially plausible, I don’t see compelling evidence to back it up, and given the subject matter, very compelling evidence indeed would be needed.

Ethical Considerations Against GGE

The greatest objection marshaled against GGE is the risk of unwanted mutations propagating into the germline and thus into the gene pool. In the face of unquantified but potentially catastrophic risks, the precautionary principle is often posited to forbid a risky activity. In the case of GGE, the precautionary principle is enshrined into law in the Oviedo Convention in the European Union.

In the past, I have been critical of the precautionary principle in other contexts on two grounds. First, there is seldom a risk-free alternative. GGE research does pose a risk of harmful mutations spreading into the gene pool, but banning GGE research poses a risk of what might have been curable medical conditions being uncured, which could potentially kill thousands. Second, the precautionary principle offers a shield for those who would ban an activity for reasons other than a genuine concern about risk. Both of those concerns apply here.

But it does appear to me that the risk is sufficiently great, and the potential benefits are sufficiently weak, so as to justify a ban on GGE for the time being. This does not imply that a ban should exist for all time. See also this paper for a view of what a more balanced approach to risk might look like.

Bostrom and Sandberg argue that human genetics are highly optimized and thus any intentional change is likely to cause damage. Their paper is entitled “The Wisdom of Nature”, though the argument is more sophisticated than a naturalistic fallacy. Their argument is also compatible with both an intelligent design and a strictly naturalistic view of human development. Nevertheless, Bostrom and Sandberg do demonstrate some flaws in their understanding of genetics and evolution, as shown by the aforementioned paper by Powell and Buchanan, who term their argument the “master engineer analogy”.

There are concerns that GGE could fuel genetic discrimination. These are reasonable concerns, but some commentators, such as this piece by Darnovsky, Lowthorp, and Hasson, start with reasonable concerns and let their imaginations run wild.

In 1997, UNESCO approved the Universal Declaration on the Human Genome and Human Rights, which declares the genome to be the “heritage of humanity”. This might not necessarily proscribe GGE for therapeutic purposes. I’m not really sure what this means, though aside from promoting a preservationist ethic on genetics, it was also meant to address patenting of genes, which was a major concern at the time of the Human Genome Project. This language is reminiscent of the “common heritage of mankind” language in the Moon Agreement. There is also concern that GGE could inhibit the autonomy of future, modified persons, though here too I’m not sure what this really means.

Finally, the aforementioned Pew Research Center survey found that religious people tend to be less positively disposed to GGE than non-religious people. This statement by Marylin Coors for the U.S. Council of Catholic Bishops outlines the reasoning. There are several concerns raised here, some more plausible than others, but a central concern is that gene editing can reflect a commoditization and cheapening of human life. She argues,

Catholic teaching, as explained by John Paul II, thus defends a human essence that possesses inherent dignity and deserves respect and protection. John Paul expressed concern that genetic enhancement could result in changes that “provoke fresh marginalization” in the world by altering human traits so as to compromise the integrity of humans. He warned that genetic intervention must not “derive from a racist, materialist mentality aimed at human happiness which is really reductive. Man’s dignity transcends his biological condition.” That which is transcendent in the human being, our dignity and freedom, must be protected from technological assault.3 These comments reveal John Paul II’s concern that the power of genetics could reduce the human person to his or her genes, a kind of Genes-R-Us mentality that claims we are our genes and nothing more. Even at the purely biological/social levels, there is ample evidence to refute this mindset when we consider the astonishing accomplishments of persons with disabilities, who overcome life-limiting genetic conditions to perform well beyond what their DNA would seem to dictate.

Note the use of the word “can” rather than “does”. The Catholic Church is not strictly anti-biotech, and it would be fair to characterize their concerns as more about the ends to which biotechnologies such as gene editing are deployed, rather than the technologies themselves.

Conclusions

There are quite a few parallels between the ethical issues around GGE and those around other technologies, such as geoengineering. Some critics of GGE see unacceptable risks in modification of a complex genetic system, whereas some critics of stratospheric atmosphere injection see unacceptable risks in modification of a complex climate system. But the reader may observe that I am more sympathetic with a restrictive approach to GGE than I was to a restrictive approach to SAI last month. We can read abstract principles into these debates, such as principles around risk, progress, human agency, and so forth, but at the end of the day, each issue should be considered separately and evaluated on its own terms.

And although this post was long, and the issues around gene enhancement have been extensively discussed, it must be said that this whole subject is much less important than the attention given to it would suggest. The mainstream use of GGE is not politically plausible in the foreseeable future, and the use of GGE for enhancement is not technically plausible in the foreseeable future either. How to design effective health care systems, and how to conduct medical research in a way that is effective and safe, are of far greater importance, and I don’t know if the debate around gene enhancement is anything more than a distraction.

Quick Hits

Marco den Ouden, discussing Andrew Kopplemna’s book, illustrates what can go wrong when libertarianism is taken in too doctrinaire a manner, or when principles become divorced from reality.

If you have six hours to burn, this documentary on the history of video games is most fascinating.

Richard Coffin (The Plain Bagel) discusses the Vanguard/Blackrock situation and associated controversies.

Captain Michael P. Ferguson is critical of the new Replicator initiative from the Department of Defense, which envisions a heavy use of drones in a possible war with China. He analogizes to past failed ventures, such as the Eisenhower-era Pentomic Army and bad assumptions behind the wars in Iraq and Afghanistan.