We need to talk about CRISPR

Editing embryos

CRISPR has dominated the news these past few weeks and months, after a scientist in China edited human embryos that led to live births.

"Clustered regularly interspaced short palindromic repeats" — aka CRISPR — is new, but what's not new is how it's being implemented. Over and over again, reproductive technologies are hustled into use without standard human research protocols being observed. This was true for IVF (Louise Brown's parents were not even told they were the first-ever to have a baby this way), and it was true for ICSI, assisted hatching, egg freezing, and Augment.

Here we go again. 

Below, for those of you not up to speed on what has happened with CRISPR and why it matters, please find my simple walk-through, using links to some of the best journalism on the topic. 

Birth announcement

News of the world's first gene-edited babies broke last November, just as a summit on human genome editing was getting under way in Hong Kong. On November 25, 2018, Antonio Regalado reported in Technology Review that Chinese scientists were using CRISPR to eliminate a gene in the hope of providing disease resistance. 

The gene was known as CCR5 and the alteration was being made in embryos. A big concern was the risk of unintended "off-target" edits. "The technology is ethically charged because changes to an embryo would be inherited by future generations and could eventually affect the entire gene pool," wrote Regalado.

Using CRISPR in this way was illegal in much of the world. 

But there was support for it too — if the kinks could be worked out. "Behind the Chinese trial also lies some bold thinking about how evolution can be shaped by science," wrote Regalado. "While the natural mutation that disables CCR5 is relatively common in parts of Northern Europe, it is not found in China. The distribution of the genetic trait around the world — in some populations but not in others — highlights how genetic engineering might be used to pick the most useful inventions discovered by evolution over the eons in different locations and bring them together in tomorrow’s children."

Read the whole article: 

https://www.technologyreview.com/s/612458/exclusive-chinese-scientists-are-creating-crispr-babies/

Antonio Regalado. "Chinese scientists are creating CRISPR babies." MIT Technology Review. November 25, 2019. 

That same day, the scientist at the centre of the controversy, Jiankui He, posted a promotional video on YouTube about the babies. In the video, He claims the children have already been born and are perfectly healthy. He refers to his use of CRISPR as "gene surgery" and draws a direct parallel between this work and the early days of IVF. 

Watch the promotional video: 

https://www.youtube.com/watch?v=th0vnOmFltc

The backstory

Sharon Begley chronicles how other scientists in the field reacted to the news. Here's an excerpt about when Jennifer Doudna, CRISPR's inventor, found out: 

"Doudna, who co-led a 2012 study showing that a weird bacterial immune system called CRISPR could edit DNA as niftily as Word edits documents, and hundreds of other experts were in Hong Kong for the International Human Genome Editing Summit. He Jiankui, who was scheduled to speak at the summit on Wednesday, had asked to meet privately with Doudna, one of the summit’s organizers. In his presentation, He had planned to talk about the ethics of embryo editing and his experiments on mouse, monkey, and human embryos, with nary a hint that two of those embryos were now living, breathing, baby girls whom He, in an astonishing YouTube birth announcement, called Nana and Lulu. Was that okay?, he asked Doudna as they sat in the lobby. Um, Doudna replied, you’ve dropped this shocking news on the world, right before our summit, and you’re not planning to mention it?"

And there was reason for concern: 

"It would later emerge... that he and his colleagues had enrolled eight couples in which the man is HIV-positive and the woman is not. After injecting a single sperm into an egg, the scientists injected their CRISPR molecules: a guide RNA that bloodhounded its way to CCR5 plus an enzyme that slashed the gene. In all, they injected 31 embryos, succeeding with 21. Analyses of cells when the embryos were 3 to 5 days old revealed a mishmash of edits. None replicated the CCR5 mutation known to protect against HIV. With the parents’ permission (He said they understood the genetic niceties), He implanted 11 of them anyway."

Read the entire excellent piece: 

https://www.statnews.com/2018/12/17/crispr-shocker-genome-editing-scientist-he-jiankui/

Sharon Begley. "The CRISPR shocker: How genome-editing scientist He Jiankui rose from obscurity to stun the world." STAT. December 17, 2018.

Under the radar?

Many people wondered how this could have happened without anyone else knowing. Turns out, people did know, but weren't sure what to do. According to this article by Pam Belluck, one ethicist didn’t notify anyone because "'I decided it wasn’t like I knew somebody was going to murder somebody; it was a fait accompli. I didn’t feel like there was either any moral obligation or practical benefit to my raising it.' ”

Read the whole piece:

https://www.nytimes.com/2019/01/23/health/gene-editing-babies-crispr.html

Pam Belluck. "How to stop rogue gene-editing of human embryos?" New York Times. January 23, 2019.

What now? 

David Cyranoski pointed out that He "neglected to do adequate safety testing and failed to follow standard procedures in procuring participants." He was later fired from his university. The scientist could also face criminal charges — there are questions about whether participants may have been coerced, there was swapping of blood samples, and some documents may have been forged, Cyranoski reported.  

Cyranoski also raised questions about unintended consequences. "He claims to have disabled a gene called CCR5, which encodes a protein that allows HIV to enter cells. He was aiming to mimic a mutation that exists in about 10% of Europeans, and helps protect them from HIV infection. But He might have inadvertently caused mutations in other parts of the genome, which would have unpredictable health consequences." 

Read the full story: 

https://www.nature.com/articles/d41586-019-00673-1

David Cyranoski. "The CRISPR baby scandal: what's next for human gene-editing." Nature. February 28, 2019.

A moratorium?

Two weeks ago, a group of eighteen scientists and ethicists from seven countries called for a halt to any gene-editing that will be passed down through the generations. They urge this moratorium while discussions take place about the technical, scientific, medical, societal, ethical and moral issues that such gene-editing raises. They propose that thereafter, countries voluntarily pledge to adhere to certain agreed standards, such as that a CRISPR intervention is medically and scientifically justified. 

Read the full document:

https://www.nature.com/articles/d41586-019-00726-5

Eric Lander, Francoise Baylis, Feng Zhang, Emmanuelle Charpentier, Paul Berg, et al. "Adopt a moratorium on heritable genome editing." Nature. March 13, 2019. 

A registry? 

Then, just last week, a World Health Organization panel recommended setting up "a WHO-directed database where journal publishers and funders of gene editing research would require scientists to sign up" but they "acknowledged they had not yet worked out how to reprimand any scientists who refused to register."   

https://www.apnews.com/32d57608d19a48caa68c182b64c6edab

Jamey Keaten and Maria Cheng. "UN: Gene editing for human reproduction is 'irresponsible'." Associated Press. March 19, 2019. 

More background on CRISPR

From The New Yorker:

"CRISPR has two components. The first is essentially a cellular scalpel that cuts DNA. The other consists of RNA, the molecule most often used to transmit biological information throughout the genome. It serves as a guide, leading the scalpel on a search past thousands of genes until it finds and fixes itself to the precise string of nucleotides it needs to cut. It has been clear at least since Louis Pasteur did some of his earliest experiments into the germ theory of disease, in the nineteenth century, that the immune systems of humans and other vertebrates are capable of adapting to new threats. But few scientists had considered the possibility that single bacterial cells could defend themselves in the same way.

"It didn’t take ... long to realize that, if nature could turn these molecules into the genetic equivalent of a global positioning system, so could we. Researchers soon learned how to create synthetic versions of the RNA guides and program them to deliver their cargo to virtually any cell. Once the enzyme locks onto the matching DNA sequence, it can cut and paste nucleotides with the precision we have come to expect from the search-and-replace function of a word processor... With CRISPR, scientists can change, delete, and replace genes in any animal, including us."

https://www.newyorker.com/magazine/2015/11/16/the-gene-hackers

Michael Specter. "The Gene Hackers." The New Yorker. November 16, 2015. 

Also:

A great CRISPR primer from CBC radio (30:53): 

https://www.cbc.ca/radio/quirks/quirks-quarks-for-jan-2-2016-1.3378142/crispr-the-genetic-engineering-revolution-1.3378171

Jim Lebans. "CRISPR - The genetic engineering revolution." Quirks and Quarks. January 2, 2016. 

The original scientific paper: 

http://science.sciencemag.org/content/337/6096/816

Martin Jinek et al. "A programmable dual-RNA-guided DNA endonuclease in adaptive bacterial immunity." Science. August 17, 2012.

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Get in touch: alison.motluk@gmail.com