Genetically modified babies are close to becoming a reality

Pioneering gene-editing treatments are already in clinical use, saving lives and alleviating suffering from devastating genetic diseases. However, the growing number of patients receiving these treatments still risk passing disease-causing mutations to their children.

Scientific consensus - and legislation in 70 countries - has long recognized that it is very dangerous to use the powerful technique of human germline editing, the process of manipulating the DNA of the human embryo to prevent genetic diseases and prevent them from being passed from one generation to the next.

New research, however, has found that it is now possible to edit the DNA of human embryos with unprecedented precision, suggesting that editing the human germline may be possible in the relatively near future. Scientists, however, have warned that there are still significant hurdles to overcome before it is possible to safely edit viable human embryos.

"Six years ago, I thought the use of gene editing in human embryos was unfeasible," said Amander Clark, professor of molecular, cellular and developmental biology at the University of California, Los Angeles (UCLA), and director of the UCLA Center for Reproductive Science, Health and Education.

"This work renews the possibility that gene editing for therapeutic purposes may be feasible with IVF embryos in the future," Clark, who was not involved in the research, said in an email.

Laboratory research using human embryos, usually donated by patients undergoing in vitro fertilization, remains strictly regulated in most countries and is normally only permitted for a period of 14 days after the embryo is created. It is also unclear the level of public support for genetically modified babies; In addition to medical safety concerns, skepticism is largely driven by ethical concerns surrounding the potential use of this cutting-edge technology in creating so-called "custom babies," whose genes are edited or intentionally selected for desirable traits.

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Sharpening a dull tool

The gene editing technique known as CRISPR-Cas9 is used in laboratories around the world and has revolutionized scientific research, allowing scientists to edit the genes of living organisms for biotechnology and medical research purposes. In 2020, two of the scientists who developed the technology won the Nobel Prize in Chemistry, and in 2023, the U.S. Food and Drug Administration (FDA) approved the first two gene therapies for sickle cell anemia, a debilitating, life-shortening inherited disease that disproportionately affects African Americans.

But in some ways, CRISPR-Cas9 is an imprecise tool. When the technology edits DNA, it creates a double-strand break at the target site of the helix, and when used to modify human embryos, several studies have shown that it results in large, unintended changes - possibly even the loss of an entire chromosome.

The potential for unknown health effects is one of the reasons why the scientific community condemned the work of Chinese researcher He Jiankui when he revealed, in 2018, the existence of two girls who were born from embryos that he said he had modified using CRISPR-Cas9 technology to make them resistant to HIV. He was sentenced to three years in prison in 2019 but has since been released. He did not respond to a request for comment.

Modifying a single letter in DNA
A newer, more precise form of CRISPR, known as base editing, can change a single letter (or base) in DNA at a time.

Base editing was first used in a 2022 clinical trial to modify the immune cells of a UK teenager after doctors exhausted all other treatment options for the type of leukemia she suffered. Eight other children and two adults also received the treatment. Last year, doctors used base editing to treat a baby born with a severe CPS1 deficiency, a rare and dangerous genetic disease.

Now, two new studies have used the technique to edit human embryos in the early stages of development, donated for research purposes by individuals who have undergone in vitro fertilization (IVF) treatment. Both teams found that the precision of the technique reduced the likelihood of unwanted chromosomal abnormalities.

Kathy Niakan, professor of reproductive physiology and director of the Loke Center for Trophoblast Research at the University of Cambridge, and her team used the technique to better understand the functioning of a fundamental gene in human embryonic development. They discovered that a gene called NANOG - named after the mythical Celtic Tír na nÓg, or land of eternal youth - plays a crucial role in the formation of the first embryonic cells that will ultimately become the fetus and placenta. The study was published on June 25 in the scientific journal Nature.

Niakan said base editing represents a significant advance over conventional CRISPR-Cas9, as it poses a much lower risk of causing unintended chromosomal errors. "Base editing can precisely change a single nucleotide pair to another across the entire human genome, which has about 3 billion base pairs - that's an incredible feat," she explained.

In a separate study, Dietrich Egli, associate professor of developmental cell biology at Columbia University, used base editing to insert one of two genetic mutations into newly fertilized eggs. One targeted a gene known as PCSK9, which regulates cholesterol, and the other targeted HBG, which codes for the fetal form of hemoglobin, a protein that transports oxygen. He chose these two genes because they are well-studied targets in non-heritable gene editing. Egli said a peer-reviewed scientific journal conditionally accepted the study.

While both studies represent a step toward heritable gene editing, Egli said there is still a long way to go before use in a clinical context. Even though base editing does not appear to cause significant chromosomal damage, at least two important drawbacks remain.

Egli, Niakan and their teams found that some of the embryos they edited exhibited what they described as "mosaicism," when the intended edit does not have an effect on all cells. Furthermore, both found some "off-target" effects, in which unintended genes were changed. This poses a risk when editing human embryos, as this embryo will give rise to all the cells in the body.

"This is a long staircase with many different steps and maybe some plateaus in the middle," said Egli. "We started at the bottom and took some steps in that direction, but I think we can look at the progress that has been made and discuss the pros and cons of going further."

Genome editing in human embryos has value in allowing scientists to understand the rules that govern the early stages of human life, said Helen O'Neill, associate professor of reproductive and molecular genetics at the Institute of Women's Health at University College London. She did not participate in any of the studies.

"This may help us understand why so many IVF embryos fail to develop, stop implanting, or progress despite appearing morphologically acceptable," O'Neill said in a statement.

"In the long term, this may help us think more clearly and compassionately about a very small group of patients with serious inherited diseases for whom preimplantation genetic testing is not sufficient."

O'Neill added that the debate around embryo editing is often framed as if the only possible goal is to create genetically modified babies. "This approach ignores true scientific and clinical value," she noted.

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Concerns surrounding genetically modified babies
Laurie Zoloth, professor of religion and ethics at the University of Chicago, said the research has reignited the ethical debate over altering human embryos, noting that editing embryos is risky and, except for use in scientific research, should therefore remain banned for now, just for safety reasons. She noted that there are already ways to prevent babies with genetic abnormalities - through genetic screening before conception and during pregnancy, and pre-implantation embryo testing during in vitro fertilization (IVF).

"The problem of mosaicism is not solved; they don't really understand the long-term effects of the intervention; and there is no way to do a clinical trial of a pregnancy without, well, an actual pregnancy and a child," she said in an email.

She added that there are also long-term theological and philosophical questions related to "designing" babies to have desirable characteristics.

"These problems are even more profound when it appears that they are designing babies who, in the distant future, would have a lower risk of cardiovascular problems, which could be solved with lifestyle choices and, in fact, could be completely treatable with medication in that hypothetical future."

While it may be defensible to edit embryos to prevent diseases such as Tay-Sachs, a fatal neurological disorder that manifests itself in the first few months of life, she said there would likely be a "discrepancy between treatment and enhancement," a situation that could lead to what Zoloth called the "Gattaca problem," in reference to the 1997 film, which imagines a society obsessed with and dictated by genetic perfection.

"Will this path lead us to an even more unfair and unequal future, where the children of the richest will be privileged and the children of the poor, without resources, will be unable to compete in a democracy?", she asked.

"It's amazing that, on the one hand, we have the ability to invest so much resources and attention into altering an embryo's genetic code so that it conforms precisely to what we consider normal or ideal, while, on the other, we can't figure out how to provide clean, safe, and stimulating elementary schools for children, with well-paid teachers, after they are born," Zoloth added, noting that knowledge about how human genetics affects physical characteristics and behavior is still very limited.

A recent survey of public opinion regarding human embryo research in four countries indicated that the majority of respondents in the United Kingdom, the Netherlands and Spain supported the use of genome editing in embryos to enable a pregnancy by eliminating a serious or potentially fatal condition. However, in Italy, this number was 46%.

Zoloth noted that while bioethicists have a duty to reflect and raise questions, banning science also presents risks.

"We don't want to prohibit the investigation," she said. "This is why setting limits on new science is important and protects both research and society."

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Source: CNN