A debate: Should we edit the human germline?

Last week in First Opinion, six experts explored the use of gene editing to fix a defective gene in a sperm or egg cell, or in an embryo that’s only a few days old. This technique, called germline editing, raises ethical questions because the edited gene would be passed to future generations.

George Church, professor of genetics at Harvard Medical School, and Francis Collins, director of the National Institutes of Health, put forth opposing points of view. Eager to continue the conversation, Church later wrote a point-by-point response to Collins’ essay.

We’re presenting the back and forth here as a dialogue. Collins declined to respond to Church’s critique, so his passages are taken from his original essay. Those marked “Church” are new.

We’d love to continue the conversation. Please share your thoughts on germline editing. We may use some of them in a future story.

Collins: The ethical arguments against human germline engineering are significant. A most compelling one is that medical research should always seek to balance benefits and risks, with individuals who are participating in research giving fully informed consent. But the individuals whose lives are potentially affected by germline manipulation could extend many generations into the future. They can’t give consent to having their genomes altered from what nature would have made possible.

Church: Parents do not get consent from future generations to make mutations in gametes via excessive time at high altitude, or to alter young minds with rules, tools, and schools. Each of these can be transmitted to multiple generations (some without changing DNA, some harder to reverse than DNA changes).

Collins: There’s also a concern about human hubris. Who gets to decide what’s an improvement on the genome?

Church: This is similar to asking, “Who currently gets to decide about many interventions during child development?” such as fetal surgery, genetic counseling, vaccines and education. The answer is physicians, parents, and society. The term “hubris” seems dismissive rather than encouraging deep exploration of exemplary cases.

Collins: Many of the scenarios being discussed aren’t about correcting a disorder caused by misspelling of a single gene. For that, preimplantation genetic diagnosis already offers a practical and much less ethically challenging option for most couples seeking to avoid the birth of a child with a serious genetic disorder. Instead, futurists dream about changing traits that someone decides could be improved, such as intelligence, height, or risk of some common chronic illness. All of those are complex multigene situations in which the environment plays critical roles, and no single genetic change would be expected to have much benefit.

Church: “Multigene situations” do not prevent single-gene changes from being very significant. For example, alterations in growth hormone genes have large impacts on height in humans. Changes in other specific genes can positively affect learning, memory, anxiety, and problem solving in mice. In humans, single gene variants can protect against chronic Alzheimer’s disease, AIDS, and coronary artery disease. Safety and efficacy, case by case, should determine FDA acceptance, not unproven a priori biases about single vs. multiple gene impacts.

Collins: Evolution has been working toward optimizing the human genome for 3.85 billion years. Do we really think that some small group of human genome tinkerers could do better without all sorts of unintended consequences?

Church: Those billions of years were spent optimizing the human genome for environments and goals very different from those found in modern times. Humans are not optimally adapted for desk work, high-rise megacities, or space travel. A small group of human tinkerers did indeed optimize, for modern needs, IR8 rice, border collies, and many other forms of life. We will eventually address unintended consequences, if any, not via prejudicial bans lacking end points, but by encouraging experiments — as was done with in vitro fertilization, medications from recombinant DNA, and genetically modified crops.

Collins: There are also issues of equity and justice. Who would have access to this kind of human germline engineering? Do we want to accept the scenario that only those with financial resources get to “improve” the genomes of their children?

Church: We do not need to accept a scenario in which costs stay fixed. Cellphones have dropped in price such that even remote, poor villages can afford them — and services such as GPS and computer searches are free. The cost of DNA sequencing has dropped over 3 million fold and seems to be continuing downward. If we encourage creativity in genome engineering, then the huge drop in cost that accompanied CRISPR is likely just a start.

Collins: A more subtle but significant concern is whether the application of germline manipulation would change our view of the value of human life. If genomes are being altered to suit parents’ preferences, do children become more like commodities than precious gifts?

Church: The trend away from children as commodities can be compatible with germline alterations. Past expectations of needing large numbers of children to replace those lost to infection and genetic disease is giving way to expectations of long, high-value lives. The old “one size fits all” medicine is giving way to personalized medicine in which each child is precious and unique. “Parents’ preferences” have, for ages, influenced their descendants’ genetics (via mate choice), their initial religion, language, hometown, and occupation. But increasingly, parents accept that their children are not “gifts” to be owned. The better the launch, the further the child may go from the parent.

Collins: If there was a truly compelling argument that only human germline engineering could alleviate the suffering of many people, then I would say we might consider trying it under closely controlled circumstances. But the fact that there is a profound paucity of compelling cases, and that the ethical counterarguments are so significant, makes me conclude that the balance of the debate leans overwhelmingly against human germline engineering.

Church: The historical paucity of compelling cases articulated for human flight, personal computers, stem cells, etc., reflect the lack of imagination of the opinion leaders of the day. We need only one compelling argument to initiate a new social norm — even when the market is small (as for orphan drugs). For germline modification, we have at least three compelling cases: 1) mitochondrial diseases; 2) families in which post-natal remedies are inadequate and both parents are fully afflicted (20 percent of the world’s marriages involve close relatives); and 3) scenarios in which treating (and possibly pre-screening) single germ cells is safer than treating millions of somatic cells, since each cell adds to the collective risk of developing cancer.