Thursday, February 21, 2019

China’s CRISPR twins might have had their brains inadvertently enhanced

The brains of two genetically edited girls born in China last year may have been changed in ways that enhance cognition and memory, scientists say.

The twins, called Lulu and Nana, reportedly had their genes modified before birth by a Chinese scientific team using the new editing tool CRISPR. The goal was to make the girls immune to infection by HIV, the virus that causes AIDS.

Now, new research shows that the same alteration introduced into the girls’ DNA, to a gene called CCR5, not only makes mice smarter but also improves human brain recovery after stroke, and could be linked to greater success in school.

“The answer is likely yes, it did affect their brains,” says Alcino J. Silva, a neurobiologist at the University of California, Los Angeles, whose lab uncovered a major new role for the CCR5 gene in memory and the brain’s ability to form new connections.

“The simplest interpretation is that those mutations will probably have an impact on cognitive function in the twins,” says Silva. He says the exact effect on the girls’ cognition is impossible to predict, and “that is why it should not be done.”

he Chinese team, led by He Jiankui of the Southern University of Science and Technology in Shenzhen, claimed it used CRISPR to delete CCR5 from human embryos, some of which were later used to create pregnancies. HIV requires the CCR5 gene to enter human blood cells.

The experiment has been widely condemned as irresponsible, and He is under investigation in China. News of the first gene-edited babies also inflamed speculation about whether CRISPR technology could one day be used to create super-intelligent humans, perhaps as part of a biotechnology race between the US and China.

There is no evidence that He actually set out to modify the twins’ intelligence. MIT Technology Review contacted scientists studying the effects of CCR5 on cognition, and they say the Chinese scientist never reached out to them, as he did to others from whom he hoped to get scientific advice or support.

“As far as I know, we never heard from him,” says Miou Zhou, a professor at the Western University of Health Sciences in California.

Although He never consulted the brain researchers, the Chinese scientist was certainly aware of link between CCR5 and cognition. It was first shown in 2016 by Zhou and Silva, who found that removing the gene from mice significantly improved their memory. The team had looked at more than 140 different genetic alterations to find which made mice smarter.

Silva says because of his research, he sometimes interacts with figures in Silicon Valley and elsewhere who have, in his opinion, an unhealthy interest in designer babies with better brains. That’s why, when the birth of the twins became public on November 25, Silva says he immediately wondered if it had been an attempt at this kind of alteration. “I suddenly realized—Oh, holy shit, they are really serious about this bullshit,” says Silva. “My reaction was visceral repulsion and sadness.”

Whatever He’s true aims, evidence continues to build that CCR5 plays a major role in the brain. Today, for example, Silva and a large team from the US and Israel say they have new proof that CCR5 acts as a suppressor of memories and synaptic connections.

According to their new report, appearing in the journal Cell, people who naturally lack CCR5 recover more quickly from strokes. What’s more, people missing at least one copy of the gene seem to go further in school, suggesting a possible role in everyday intelligence.

“We are the first to report a function of CCR5 in the human brain, and the first to report a higher level of education,” says UCLA biologist S. Thomas Carmichael, who led the new study. He calls the link to educational success “tantalizing” but says it needs further study.

The discoveries about CCR5 are already being followed up in drug trials on both stroke patients and people with HIV, who sometimes suffer memory problems. In those studies, one of which is under way at UCLA, people are being given an anti-HIV drug, Maraviroc, which chemically blocks CCR5, to see if it improves their cognition.

Silva says there is a big difference between trying to correct deficits in such patients and trying to create enhancement. “Cognitive problems are one of the biggest unmet needs in medicine. We need drugs, but it’s another thing to take normal people and muck with the DNA or chemistry to improve them,” he says. “We simply don’t know enough to do it. Nature has struck a very fine balance.”

Just because we shouldn’t alter normal intelligence doesn’t mean we can’t. Silva says the genetic manipulations used to make “smart mice” show not only that it is possible, but that changing CCR5 has particularly big effects.

“Could it be conceivable that at one point in the future we could increase the average IQ of the population? I would not be a scientist if I said no. The work in mice demonstrates the answer may be yes,” he says. “But mice are not people. We simply don’t know what the consequences will be in mucking around. We are not ready for it yet.”

CCR5 Is a Therapeutic Target for Recovery after Stroke and Traumatic Brain Injury
Mary T. Joy, Einor Ben Assayag, Dalia Shabashov-Stone, Alcino J. Silva, Esther Shohami, S. Thomas Carmichael.  CCR5 Is a Therapeutic Target for Recovery after Stroke and Traumatic Brain Injury.  Cell. 2019 Feb 21; 176(5):1143-1157.E13.
CCR5 is differentially upregulated in neurons after stroke
Knockdown of CCR5 induces motor recovery after stroke and improves cognition after TBI
Treatment with an FDA-approved drug, maraviroc induces recovery after stroke and TBI
Human carriers for CCR5delta32 have better outcomes after stroke

We tested a newly described molecular memory system, CCR5 signaling, for its role in recovery after stroke and traumatic brain injury (TBI). CCR5 is uniquely expressed in cortical neurons after stroke. Post-stroke neuronal knockdown of CCR5 in pre-motor cortex leads to early recovery of motor control. Recovery is associated with preservation of dendritic spines, new patterns of cortical projections to contralateral pre-motor cortex, and upregulation of CREB and DLK signaling. Administration of a clinically utilized FDA-approved CCR5 antagonist, devised for HIV treatment, produces similar effects on motor recovery post stroke and cognitive decline post TBI. Finally, in a large clinical cohort of stroke patients, carriers for a naturally occurring loss-of-function mutation in CCR5 (CCR5-Δ32) exhibited greater recovery of neurological impairments and cognitive function. In summary, CCR5 is a translational target for neural repair in stroke and TBI and the first reported gene associated with enhanced recovery in human stroke.


1 comment:

  1. A preliminary investigation has concluded that rogue geneticist He Jiankui broke regulations to create the world’s first gene-edited babies. China has said that He will be punished for his actions. The Southern University of Science and Technology in Shenzhen where He worked has now fired him.

    A team of investigators told the official state Xinhua news agency that its investigation found that He intentionally dodged research oversight and used potentially unsafe techniques to edit human embryos. Investigators said He forged ethical approvals to recruit eight couples to his research project, resulting in two pregnancies. One of the mothers gave birth to twins. Another woman is carrying a gene-edited foetus.

    Details of He’s human gene-editing experiments emerged last November at the Second International Summit on Human Genome Editing, following a media frenzy after the geneticist announced what he had done through the press. He described editing the CCR5 gene of embryos to give them resistance to HIV. Geneticists at the meeting and around the world were highly critical, fearing a regulatory backlash against gene-editing.

    Chinese authorities said that He, his staff and organisations involved in this project would be punished. The investigators noted that editing of human embryos is banned in China. China’s ministry of science and technology has reportedly ordered research institutes to halt any of He’s projects they’re involved in. He has not been seen in public since he announced the birth of the twins in November, leading to speculation that he has been detained.

    ‘The latest report about the investigation by Guangdong authorities revealed something new, that Dr He had forged ethical documents,’ comments Kiran Musunuru, a molecular biologist at the University of Pennsylvania, US. ‘Details are so far lacking, but that’s an egregious ethical violation.’

    His actions were quite secretive, says Helen O’Neill, a geneticist at University College London. ‘He had presented data at conferences with animals models, but never made his intentions for human clinical practice known. He had made it clear that his hero was Bob Edwards, who created the first IVF baby.’

    The initial local reaction in Hong Kong was ‘quite positive’, with China viewed as leading the world in gene-editing, but the horror and disgust that met the announcement changed matters, recalls O’Neill. ‘His own personal website disappeared and many of those regional stories also disappeared, because they realised that the public and global perception of his “achievement” was not the same.’

    She says He should have known better. ‘There is an impression that China is the wild west in terms of research ethics, but it is an advanced research environment and [the controversy] has done a disservice to Chinese scientists.’