What’s New, and What’s Not, in the Reported Birth of the CRISPR Babies

Editing human DNA, either in embryos or in cells that are reintroduced to the body, had come a long way before Lulu and Nana were born

CRISPR-Cas9 is a gene editing tool that has allowed scientists to alter the genomes of living organisms with unprecedented accuracy and ease. (Ernesto del Aguila III/National Human Genome Research Institute/NIH)
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The announcement from Chinese researcher He Jiankui claiming to have created the world’s first gene-edited babies—twins whose genomes were altered, as embryos, using CRISPR technology—shook the scientific world and prompted a maelstrom of ethical controversy. The experiment, if its outcome is verified by peer review, would certainly take CRISPR use in humans further than it’s gone before. But where, exactly, do the CRISPR babies stand in the swiftly-moving field of genetic editing?

He’s work (which has not yet been published in a peer-reviewed journal or independently verified) involved creating embryos from a healthy mother and HIV-positive father and applying the gene-editing tool CRISPR-Cas9 to those embryos to remove the CCR5 gene, which allows HIV to enter cells. Those CRISPR-modified embryos led to a pregnancy and eventually, the birth of twin girls named Lulu and Nana. One of the children is said to lack both functional copies of the CCR5 gene, which would prevent her from ever contracting HIV, while the other has one functional copy, meaning she could still possibly contract the virus.

Lulu and Nana’s birth would certainly represent a first in the budding field of gene editing. But Kiran Musunuru, a cardiologist and geneticist at University of Pennsylvania’s Perelman School of Medicine who reviewed a preliminary manuscript by He’s team for the Associated Press, says He’s announcement “does not represent in any way a scientific advance” because “there was nothing preventing previous researchers who edited human embryos from doing the same, except their own ethics and morals.”

CRISPR (which stands for clustered regularly interspaced short palindromic repeats) is a genetic material found in bacteria and other prokaryotes that can be used to target specific stands of DNA. The technology works by introducing a carefully programmed strand of RNA into a cell. The RNA can locate a target sequence of DNA and, with the help of an enzyme (most commonly Cas9), cut the DNA at the designated spot. The cell’s native DNA repair mechanisms will repair the break, removing part of the genetic sequence, and researchers can also add a desired DNA strand into the cell that will be swapped in for the just-snipped gene.

In 2012, a team of scientists led by Jennifer Doudna of the University of California, Berkeley, and Emmanuelle Charpentier, now of the Max Planck Institute, (and almost at the same time, Lithuanian researcher Virginijus Siksnys) harnessed CRISPR sequences to snip and edit prokaryotic, or single-celled, DNA. Half a year later, several scientists, beginning with the Broad Institute’s Feng Zhang and Harvard’s George Church, pioneered a way to use CRISPR to edit multicellular DNA, including in humans.

The studies revolutionized gene editing. CRISPR’s simplicity and efficiency blew earlier techniques out of the water.

The first CRISPR breakthrough in human embryos came in 2015, when Chinese scientists Canquan Zhou and Junjiu Huang used CRISPR to remove a gene that, when mutated, causes the blood disorder beta thalassemia. However, none of the resulting embryos were considered successful; they showed unintended genetic edits as well as mosaicism, meaning the cells did not uniformly adopt the CRISPR-induced changes. In a crucial distinction from He’s work, Zhou and Huang used tripronuclear zygotes (one egg, two sperm) in their research, which could not have developed into grown humans if implanted in a womb.

Last year, a team led by Shoukhrat Mitalipov of Oregon Health & Science University built upon Zhou and Huang’s work and successfully used CRISPR to remove a genetic variant from embryos that causes hypertrophic cardiomyopathy, a deadly heart condition. Mitalipov’s embryos were viable and lacked the unintended edits and mosaicism of previous experiments, but the researchers did not let them develop for more than three days, at which point they were separated and genetically analyzed. In a statement, Mitalipov wrote that unlike his own research, He’s work “involves mutating a normal gene and then transferring the embryos to establish a pregnancy, apparently with little scientific oversight. The outcome of this work is unpredictable and lacks the rigor of a well-planned clinical trial.”

Several of the scientists who helped developed CRISPR technology have censured He, with Zhang calling for a “moratorium on implantation of edited embryos” until the technology advances further. Church, however, took a more moderate stance, questioning some of He’s choices but telling Science, “At some point, we have to say we’ve done hundreds of animal studies and we’ve done quite a few human embryo studies.”

CRISPR technology has a wide range of potential applications, notably in the agriculture and pharmaceutical industries. In recent years, however, CRISPR has also made its way into clinical research with a focus on human disease prevention.

In 2016, Chinese scientists broke ground as the first to inject CRISPR-edited cells into a human. The first similar study in the United States is currently recruiting. It aims to help cancer patients by removing their T-cells, tweaking them to make them more effective at fighting cancer cells, and reintroducing the modified immune cells into the patients’ bloodstreams. One crucial difference between this line of work and embryo editing, according to lead researcher Edward Stadtmauer, is that “ex vivo” work involves making genetic alterations outside of the patient’s body and only to a specific type of cell. In contrast, a change to embryonic cells has the potential to impact every single cell in the resulting person’s body, and these “germline” changes would be passed down to any future descendants as well.

He appears to have anticipated the furor over the twins’ births. In a video posted on YouTube the day the news broke, he says, in English, “I understand my work will be controversial, but I believe families need this technology, and I’m willing to take the criticism for them.”

He Jiankui speaking at the Second International Summit on Human Genome Editing, November 28, 2018. (Public Domain)

As predicted, He’s work has been decried by scientists and ethicists alike. A National Academy of Sciences panel recently concluded that germline changes to humans might be permissible, “but only after much more research to meet appropriate risk/benefit standards,” “under strict oversight,” and only for “compelling reasons” like allowing couples with heritable, untreatable diseases to have healthy children. Chinese guidance, while prohibiting clinical research that breaches “ethical or moral principles,” is ambiguous. However, China’s vice-minister for science and technology did characterize He’s research as “blatantly” breaching the law on state-owned television.

He’s work, which was conducted in secrecy and identified as research for “AIDS vaccine development” in participant consent forms, is now under joint investigation by local health and ethics authorities. Additionally, Shenzen HarMoniCare Hospital, which was listed as having approved the project’s ethics, released a statement denying its involvement.

Because He’s work, while submitted to a journal, has not yet been peer reviewed and published, it’s impossible to judge whether or not his genetic editing was successful. Musunuru says that the data he saw indicated mosaicism in at least one placenta and an off-target edit in one embryo (but not in placenta samples). He’s presentation at this week’s Hong Kong-based gene-editing summit left some colleagues convinced of his results, but others still have lingering questions, according to Nature.

Beyond the accuracy of He’s claims, scientists have expressed broader concern because people without the CCR5 gene can be more vulnerable to other illness like influenza. He has also drawn rancor for using CRISPR when other effective methods exist that allow HIV-positive couples to have healthy children, such as “washing” sperm before in vitro fertilization without making any genetic modifications. He's method, however, which involves washing sperm as well as editing the embryos' genes, has the potential to produce children who are immune from ever contracting HIV. But of course, any germline editing raises a quagmire of ethical questions down the road, as Lulu and Nana could pass on any unintended mutations in their genomes should they choose to have children.

Given the international uproar, experts also worry that He’s cavalier approach could have a chilling effect on future research, potentially leading to similar protocol-skirting experiments.

“I would not call this a historic achievement,” Musunuru says. “I would call this a historical ethical violation.”

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