Gene Editing in Human Embryos Could Lead to an Unexpected Hazard

The Context: CRISPR gene editing holds a great deal of promise for correcting disease-causing mutations in humans, potentially as early as during embryonic development. However, before this intervention can reach the clinic, it must be proven safe and effective.

The Study: CRISPR gene editing in human embryos may result in unintentional deletions of entire chromosomes finds a new study in Cell by former NYSCF scientist and NYSCF – Robertson Stem Cell Investigator Alumnus Dieter Egli, PhD, of Columbia University.

The Importance: This study builds on Dr. Egli’s work at the NYSCF Research Institute, which was made possible through private philanthropy, and identifies a pitfall in CRISPR gene editing in human embryos that must be addressed to ensure safety before the practice enters clinical use. 

Dr. Egli’s team is interested in understanding whether disease-causing mutations could be safely removed from a human embryo before they cause damage. CRISPR, the revolutionary gene editing tool whose pioneers earned this year’s Nobel Prize in Chemistry, has emerged as a promising tool for gene correction, but little is known about its effects in the human embryo. Before this practice reaches patients, scientists must mitigate its risks and prove that the process is safe.

Dr. Egli’s study suggests that right now, it isn’t.

“Our study shows that CRISPR/Cas9 is not yet ready for clinical use to correct mutations at this stage of human development,” noted Dr. Egli, an Assistant Professor of Developmental Cell Biology in the Department of Pediatrics at Columbia University Vagelos College of Physicians and Surgeons, in a press release from Columbia.  

CRISPR and Human Embryos: Promise and Perils

The first use of CRISPR in human embryos came in 2015. In 2018, the biomedical field was shocked by a claim from former researcher He Jiankui, of Southern University of Science and Technology in China, that he had applied the process to twins in an attempt to prevent transmission of HIV from parent to child. The experiment was widely condemned as unethical.

Bad practices like this demonstrate why Dr. Egli’s work is so critical. While CRISPR gene editing in embryos could one day transform the way we prevent disease, we must understand more about the tool’s effects and how to address them before it is carried out in patients. 

“If our results had been known two years ago, I doubt that anyone would have gone ahead with an attempt to use CRISPR to edit a gene in a human embryo in the clinic,” said Dr. Egli.  

Dr. Egli’s study builds upon work he began during his time at the NYSCF Research Institute. Restrictions on federal funding can make studies of gene editing in human embryos difficult to carry out, but NYSCF’s model of private philanthropy allowed Dr. Egli to get his research off the ground, and his work was later supported by funding from the NYSCF – Robertson Investigator program.

“I owe a great deal to NYSCF and their unique model of accelerating the most cutting-edge science toward the clinic, with patients as the first priority. This work simply would not have been possible without private philanthropy,” said Dr. Egli.

Discovering the Deletion

Dr. Egli’s team discovered the pitfall while studying CRISPR’s genome editing ability in human embryos carrying a mutation in a gene called EYS known to cause hereditary blindness.

“We know from previous studies in differentiated human cells and in mice that a break in the DNA results in mostly two outcomes: precise repair or small local changes. At the EYS gene, these changes can yield a functional gene, though it is not a perfect repair,” explained Michael Zuccaro, a research scientist at Columbia University Vagelos College of Physicians and Surgeons and co-lead author of the paper. 

The team then examined the entire genome of the edited embryos, where they found a profound issue.

“We learned that in human embryonic cells, a single break in the DNA can result in a third outcome, the loss of an entire chromosome or sometimes a large segment of that chromosome, and this loss of the chromosome is very frequent,” said Zuccaro. 

The results raise several questions about what scientists have already observed from gene editing human embryos in the lab. For example, a study in 2017 reported that CRISPR successfully corrected a heart-disease-causing mutation in human embryos. Dr. Egli’s study suggests that perhaps instead of fixing the mutation, the chromosome carrying it was deleted.

“Our hope is that these cautionary findings should discourage premature clinical application of this important technology, but can also guide responsible research to achieve its ultimate safe and effective use,” remarked Dr. Egli.

Repurposing an Unexpected Ability

However, now that scientists know CRISPR is capable of deleting entire chromosomes, they may be able to leverage this ability to prevent problems brought on by extra chromosomes, such as miscarriage or developmental syndromes.

“Now that we know more about what Cas9 does in the human embryo, we can begin to understand how it might be helpful in previously unanticipated ways,” said Dr. Egli.

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