Gene editing holds great promise for treating — and even curing — a variety of genetic diseases. In a medical first, the technique was used recently to treat a young girl’s cancer. When done in a child or an adult, the edited gene dies with its bearer; it isn’t passed to any offspring.
But the technology can also be used to repair a defective gene in a sperm or egg cell, or in an embryo that’s only a few days old. In these cases, called germline editing, the new gene would be passed to future generations. This could change the genetic makeup of humans, in possibly unpredictable ways.
In April, an influential group of scientists recommended that scientists hold off germline editing until the implications are better known.
We asked experts for their take. Here’s what they said.
Francis S. Collins: Future generations can’t give consent
Gang Bao: Beware off-target effects
Debra Mathews: Germline editing will be done somewhere around the world
George Church: We need a moratorium now to evaluate benefits, risks
Josephine Johnston: Embrace uncertainty
Steven Pinker: A droplet in the maelstrom of churning genomes
Eleonore Pauwels: Don’t let the story get ahead of the facts
Francis S. 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.
There’s also a concern about human hubris. Who gets to decide what’s an improvement on the genome?
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.
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?
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?
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?
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.
Francis S. Collins, MD, is the director of the National Institutes of Health. (The opinion expressed is the author’s, and should not be taken as the official position of the US government.)
Gene editing potentially holds great promise, and equally great peril. Today, there are too many unknowns about this technique to apply it to the germline of humans and other species.
Think of the CRISPR-Cas9 gene editing technique as a nanoscissors. Put some of these nanoscissors into a cell and they will make cuts near the gene defects you want to alter, which can then be replaced by a properly functioning gene segment. But the nanoscissors can also cut other genes in a somewhat unpredictable fashion. This could change the function of a gene responsible for keeping a cell from becoming cancerous, for example, or causing other diseases.
CRISPR studies by year and country
These unwanted edits are called off-target effects. Even if on-target gene editing is accurate, the off-target effects could influence the function of many genes, possibly posing serious health problems. In the germline, off-target effects might persist for generations and could lead to long-term changes in the genome.
Until we know the full consequences of gene editing, it would be a huge mistake to use it to modify the germline.
Gang Bao, PhD, is professor of bioengineering at Rice University in Houston, where he directs the Nanomedicine Center for Nucleoprotein Machines. Bao’s work focuses on gene-editing treatments for sickle cell disease.
Fantastic and unrealistic fears inspired by science fiction often get all the attention in popular culture, while the very real potential benefits or risks of genetic research go unexplored and undiscussed. That is ethically problematic.
Research on germline editing to gain fundamental knowledge about the nature of the human genome and early embryonic development is important and ethically permissible. We can learn much from this kind of research even if it isn’t applied to human reproduction. If we later want to consider genome editing for reproductive use, then this initial basic research will be essential.
That said, concerns over modifying the human germline are justified and deserve careful attention. I am part of the Hinxton Group, a collaborative of international, interdisciplinary scholars, policymakers, journals, and funders focused on stem cells, ethics, and the law. In a September statement on human germline genetic modification, we said that there may be morally acceptable uses of this technology in human reproduction “given all safety, efficacy and governance needs are met.” Before that happens, however, substantial societal discussion and debate will be needed.
Regardless of what we decide to do in the United States, germline gene editing for reproductive purposes will be done somewhere around the world. We can have this difficult but deeply important conversation now and make proactive decisions about how to harness this science to achieve the benefits we care most about, or we can wait until the decisions are made for us by others and we are forced to react. I believe that we need to engage the public, policymakers, and broader scientific community to weigh the potential benefits and harms of human genome editing for research and human health instead of stopping all discussion, debate, and research.
Debra Mathews, PhD, is assistant director for science programs at the Johns Hopkins Berman Institute of Bioethics.
Many of the two thousand or so gene therapies, including precise gene editing, being tested in clinical trials around the world today are already curing patients, and some are being approved for general use. As with all new therapies, we need to pay great attention to the effectiveness, safety, reversibility, and cost of gene editing. In some cases, genetic counseling is more effective than gene therapy, but in other cases, both parents carry only the high risk genetic types, or do not want to harm embryos, and so they might choose gene therapy of somatic or germ cells.
The effectiveness of gene editing can depend on age. To cure some types of blindness, it may need to be performed in a young child. Other disorders might require gene editing even earlier, just as some surgeries need to be performed on children in the womb. Doing gene editing in sperm or egg cells can greatly improve both the safety and effectiveness of the procedure. One potential problem with gene editing is the occurrence of “off-target” mutations that can affect the treated cell in possibly unpredictable ways. Correcting a problem in liver or retinal cells may require gene editing in millions of cells. Even if the risk of off-target mutations is low, with so many cells involved the chance of it happening is not insubstantial. Gene editing in a single sperm or egg cell, could lower the risk of off-target mutations by a million-fold.
Although I believe that germline gene editing may soon be of great value, we need to better understand and manage the risks that could arise before moving forward with it, as we do with all new medical technologies. That is why I joined 17 other investigators calling for a moratorium on the clinical use of germline gene editing while diverse groups of citizens examine emerging data on this technology and evaluate its risks and rewards.
George Church, PhD, is professor of genetics at Harvard Medical School and is also affiliated with the Wyss Institute, Broad Institute, and MIT Media Lab.
Germline gene editing is ethically defensible to prevent serious diseases like Huntington’s disease — provided such conditions can’t be avoided in a less expensive and less medically complex way. I don’t believe there will be many such cases. As Eric Lander of the Broad Institute argued recently in the New England Journal of Medicine, for single-gene diseases like Huntington’s, it will often be cheaper and safer to perform in vitro fertilization followed by preimplantation genetic analysis of the embryos, and then to transfer only embryos without the problematic gene, than it would be to edit an embryo’s genes.
In the rare cases when all of a couple’s embryos are affected, gene editing would be defensible to avoid significant suffering and premature death. This argument has already been used to allow mitochondrial replacement therapy, which swaps damaged mitochondria (the powerhouses of a cell) with healthy ones. This procedure can also lead to changes in the human genome.
A more problematic use of germline gene editing would be to shape a child so she will have more advantages in life or will better fit the preferences of her parents. The argument here is that prospective parents should be the ones to decide whether and how to create a child that best fits their desires. It will be difficult to ban the use of gene editing for this purpose, because doing so would restrict both parental rights and reproductive freedom.
I hope that prospective parents thinking about using this technology will recognize the downsides of trying to control even more tightly who their children will become. Parenting already involves a significant amount of choice and responsibility. But it also involves learning how to relinquish control and accept the person the child is becoming. Prospective parents who go to great lengths to shape their children risk disappointment, because no one can completely control who a child will become. But they also risk missing out on the personal growth that comes with embracing uncertainty and being open to the gift of their child’s unpredictable nature.
Josephine Johnston is director of research and a research scholar at The Hastings Center, a bioethics research institute in Garrison, N.Y.
Germline editing should be treated like any other medical procedure, weighing benefits against harms. It should not be banned out of a nebulous terror about tampering with a sacrosanct entity called “the human germline” — a concept which is biological nonsense. We affect the genetic makeup of our offspring, and the species, every time we choose one sex partner over another. And each of us introduces dozens of mutations into our own germlines by exposing ourselves to everyday radiation and chemical mutagens. Genetic editing would be a droplet in the maelstrom of naturally churning genomes.
What are the potential benefits? There are several scenarios in which germline editing could benefit parents who carry disease genes. It could be used when both parents are homozygous for the disease, when in vitro fertilization doesn’t produce enough viable and unaffected embryos for preimplantation genetic diagnosis, or if future data shows that babies who undergo the procedure have compromised longevity or health.
The principal harm of germline editing is the risk of producing a sick or deformed child. Frankly, I suspect that this risk will always be unacceptable, so most of this discussion is moot. But suppose safety could be ensured. Should we fear the prospect of parents genetically enhancing their babies, the outcome the prohibitionists dread? This is highly unlikely — a relic of the early 1990s, when people thought there was “a gene for” this or that talent.
We now know that heritable psychological traits, such as intelligence and personality, are the product of hundreds or thousands of genes, each with a tiny effect. And many genes have multiple effects, some of them harmful, such as an increased risk of neurological disease or cancer.
With each enhancement providing a trifling benefit and a non-negligible risk, and with the editing process itself imposing risks, it’s unlikely that today’s morbidly risk-averse helicopter parents will take a chance at enhancing a child. They won’t even feed their babies genetically modified applesauce!
Add these risks to the expense and tribulation of IVF compared to good old-fashioned sex, and one can conclude that widespread genetic enhancement is too unlikely a possibility to worry about.
Steven Pinker is professor of psychology at Harvard University and the author of 10 books, most recently “The Sense of Style: The Thinking Person’s Guide to Writing in the 21st Century.”
For the public to fully understand the potential of germline gene editing — and the risks it poses — scientists, writers, and policymakers must change how they talk about this new technology.
Metaphors saturate scientific conversations. They can simplify or confuse new technologies like gene editing. Gene editing opponents offer up dystopian nightmare scenarios, such as wealthy parents choosing attributes for their “designer” babies. Some turn a complex biological procedure into a sci-fi story, as seen in references about “editing humanity.”
Those who support gene editing often describe it as molecular scissors that cut out harmful DNA sequences on a chromosome and thus “edit out” disease. They sometimes use the image of a red pen, or the “undo” function on a computer, only applied to the book of life. These images make the gene editing process seem easier and cleaner than it really is, and assume a control over our germline we have not yet mastered. This reinforces the hype and glosses over the potential for off-target edits, which can create unintended mutations in the genome.
Talk of designer babies draws attention away from the more realistic risks associated with gene editing applications in non-humans. Scientists can already modify the genome of disease-carrying insects. But few calls have been made for research into what genetically modified mosquitos released into a Florida swamp might do to the ecosystem.
If we are lucky, gene editing may someday contribute to treating certain cancers and inherited diseases. Until then, we must not let the story get ahead of the facts.
Eleonore Pauwels is a scholar with the Science and Technology Innovation Program at the Wilson Center in Washington, D.C., where she conducts research and writes about the governance of genomics technologies.