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Biotechnology and health

US scientist who edited human embryos with CRISPR responds to critics

Can we safely fix the DNA of human embryos in a lab dish?

Facing criticism from fellow scientists, the researcher behind the world’s largest effort to edit human embryos with CRISPR is vowing to continue his efforts to develop what he calls “IVF gene therapy.”

Shoukhrat Mitalipov, of Oregon Health Sciences University in Portland, drew global headlines last August when he reported successfully repairing a genetic mutation in dozens of human embryos, which were later destroyed as part of the experiment.  

The laboratory findings on early-stage embryos, he said, had brought the eventual birth of the first genetically modified humans “much closer” to reality.

The breakthrough drew wide attention, including from critics who quickly pounced, calling it biologically implausible and potentially the result of careless errors and artifacts.

Today, those critics are getting an unusual hearing in the journal Nature, which is publishing two critiques of the Oregon research as well as a lengthy reply from Mitalipov and 31 of his coworkers in South Korea, China, and the Salk Institute in La Jolla, California.

The scientific sparring centers on CRISPR’s well-known tendency to introduce unseen damage into a cell’s DNA.

Such damage is always difficult to detect and even more so when dealing with days-old human embryos, made up of a dozen cells and so small as to be invisible to the naked eye. 

Paul Thomas, a mouse geneticist at the University of Adelaide, and author of one of the reports taking aim at Mitalipov’s results, raised the specter of children born with terrible birth defects should CRISPR errors, such as deleted genes, go undetected.

“Failure to detect large deletions could lead to disastrous outcomes in potential clinical applications,” Thomas wrote, adding that the need for better ways to measure what CRISPR really does to embryos “cannot be overstated.”

Germline medicine

Mitalipov remains intent on proving that CRISPR can work safely on embryos. In an interview, Mitalipov said he believes it will take five to 10 years before the process is ready to attempt in an IVF center.

Image of Shoukhrat Mitalipov looking into a microscope
Embryologist Shoukhrat Mitalipov leads an effort to alter the DNA of embryos using CRISPR.

The revolutionary medical technology being pursued is a way to adjust an embryo’s DNA to remove disease risks. It is sometimes called germline gene editing because any DNA fixes a baby is born with would then be passed down to future generations through that person’s germ cells, the egg or sperm.

For its initial research, the Oregon team recruited women around Portland and paid them $5,000 each to undergo an egg retrieval. With those eggs the team created more than 160 embryos for CRISPR experiments.

Mitalipov said his Oregon center continues to obtain eggs in an ongoing effort to confirm his results and extend them in new directions.

Mitalipov declined to say how many embryos the center has made over the last year, but suggested his center is the only one in the world pursuing gene therapy for IVF embryos at a large scale.

Teams in China and the UK have also tried editing embryos with CRISPR. But those efforts are limited in scope and in many other countries embryo editing is restricted by law.

That has made it difficult for anyone to independently confirm Mitalipov’s findings in human embryos, Thomas says.

Gene conversion

Normally, to edit a cell, scientists use CRISPR to slash open its DNA at a precise spot. If they also inject a correct copy of a gene, a cell can use this template to guide a successful replacement of faulty DNA.

Mitalipov’s surprise finding was that newly fertilized eggs ignored the templates he’d added to repair a gene mutation that causes hypertrophic cardiomyopathy, a heart ailment. Instead, he claimed, mutated DNA from the father’s sperm was corrected using the mother’s healthy version of the same gene.

Some skeptics, including Maria Jasin at Memorial Sloan Kettering Cancer Center, author of the second critique appearing in Nature, considered that a near biological impossibility. That is because immediately after fertilization the father’s DNA and that of the mother are each temporarily ensconced in separate nuclei.

If they aren’t physically touching, how could the repair possibly get made?

Doubts over the research gained purchase because there was a possibility Mitalipov’s initial report hadn’t fully ruled out. If CRISPR had accidentally deleted the father’s gene, instead of repairing it, it could have wrongly appeared that the procedure had been successful.

New support

Mitalipov thinks his conclusions will stand up. He says his group reanalyzed DNA from hundreds of cells taken from the edited embryos and didn’t find evidence of major CRISPR mistakes.

What’s more, there’s new evidence emerging from other labs that the unexpected repair phenomenon is real. A group at MIT experimenting with CRISPR on mouse embryos, for instance, claimed earlier this year it had “conclusive” evidence that it happens in that species, too.

Guoping Feng, leader of that study, said in an email that his research “supports” Mitalipov’s conclusions.

The use of gene-editing to correct disease mutations in IVF embryos remains widely debated. A recent poll found that Americans support the idea of preventing disease but remain uneasy about actually testing gene-editing technology on human embryos.

Mitalipov says trying out CRISPR on embryos is the only way to make progress and determine how to make germline gene editing safe and effective.

“If we don’t do it, it will never come closer,” he says.

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