Gene Edited Humans: The (sort of) good, the bad and the 'weird'

this stuff ain't going away, best we can do is understand what they are doing

Joel Walbert

Apr 06, 2024

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The (sort of) good:

Source: Genetic Engineering & Biotechnology News

Warnings to Avoid Using CRISPR-Cas9 on Human Embryos Reinforced by New Findings

June 27, 2023

As far back as 2015, scientists have been warning against using CRISPR-Cas9 technology to modify germline genomes. Indeed, a perspective published that year in Science suggested that otherwise unexceptionable disease-curing applications could place human genome engineering on a “slippery slope” toward germline gene modification, with unpredictable consequences.

When the warning against germline editing was ignored by Chinese scientist He Jiankui, PhD, at least some of the consequences were predictable. The scientific community was shocked, even aghast. And Chinese authorities launched an investigation. Ultimately, He Jiankui was fired by his university, the Southern University of Science and Technology in Shenzhen. He also received a hefty fine, a three-year prison sentence, and a ban from further research in assisted reproductive technologies.

If the “CRISPR Babies” revelation led to clear professional and legal outcomes, the scientific outcomes, to say nothing of the individual health consequences, remained murky. However, a degree of scientific clarity became evident this week, at the 39th annual meeting of the European Society of Human Reproduction and Embryology (ESHRE). At this meeting, one of the presenters, the University of Oxford’s Nada Kubikova, DPhil, reported that the cells of early human embryos are often unable to repair damage to their DNA.

During her presentation, which was titled, “Deficiency of DNA double-strand break repair in human preimplantation embryos revealed by CRISPR-Cas9,” Kubikova suggested that insufficient DNA repair in embryos has important implications. “Gene editing has the potential to correct defective genes, a process that usually involves first breaking and then repairing the DNA strand,” Kubikova said. “Our new findings provide a warning that commonly used gene editing technologies may have unwanted and potentially dangerous consequences if they are applied to human embryos.”

She described how she evaluated the gene editing tool, CRISPR-Cas9, to cut out and replace sections of DNA in early embryo cells.

“Our results show that the use of CRISPR-Cas9 in early human embryos carries significant risks,” she said. “We have found that the DNA of embryo cells can be targeted with high efficiency, but unfortunately this rarely leads to the sort of changes needed to correct a defective gene. More often, the strand of DNA is permanently broken, which could potentially lead to additional genetic abnormalities in the embryo.”

Gene editing has begun to be used in children and adults with diseases caused by gene mutations such as cystic fibrosis, cancer, and sickle-cell disease. Many more inherited disorders could be avoided if gene editing could be carried out on embryos before they implant in the womb, since this is the only stage of development when CRISPR-Cas9 technology can be guaranteed to reach every cell of the embryo. However, because it has the potential to create changes in the human genome that would be passed down through generations, and because of uncertainty about its safety, its use in embryos is currently banned in most countries worldwide.

“Significant gaps in our knowledge still remain,” Kubikova noted. “We wanted to evaluate whether CRISPR-Cas9 could be an effective method for correcting genetic mistakes in human embryos and to shed light on whether such methods would be safe to use.”

In an ethically approved study, Kubikova and her colleagues fertilized donated eggs with donated sperm using intracytoplasmic sperm injection to create 84 embryos. In 33 of the embryos, they used CRISPR-Cas9 to create breaks in the two strands that make up the DNA molecule.

“We used CRISPR to target areas of the DNA that don’t contain any genes,” Kubikova pointed out. “This is because we wanted to learn what is always true about how CRISPR affects embryo cells and their DNA, and not be distracted by changes caused by disrupting a particular gene.”

The remaining 51 embryos were kept as controls.

“All the cells of the body have highly efficient mechanisms for repairing damage affecting their DNA,” Kubikova continued. “In most cases, the ends of broken DNA strands are quickly reconnected. This is very important, as the persistence of unrepaired DNA damage stops cells working properly and can be lethal. The most common way that cells repair DNA is by reconnecting the two ends of the DNA strand, although when this happens it is common for a few letters of genetic code to be deleted or duplicated at the site where the strands are reattached. This can disrupt genes and does not allow mutations to be corrected. This is known as nonhomologous end joining.

“Another way cells can repair a break in the DNA is by using an intact copy of the affected area as a template, copying it, and replacing the damaged area as it does so. It is possible to supply the cells with pieces of DNA containing slightly altered DNA sequences, such as having a normal sequence rather than a mutation. The cell may then use these templates when it repairs the break produced by CRISPR, removing the broken piece of DNA and copying the rest of the supplied sequence at the same time. This is known as homology-directed repair and is the process required for correcting a mutation.”

The researchers detected alterations at the targeted DNA sites in 24 out of 25 embryos, indicating that CRISPR is highly efficient in the cells of human embryos. However, only 9% of targeted sites were repaired using the clinically useful process of homology-directed repair, and 51% of broken DNA strands underwent nonhomologous end joining, producing mutations where the strands were reconnected. The remaining 40% of broken DNA strands failed to be repaired. The unrepaired breaks in the DNA strands eventually led to large pieces of chromosome, which extend from the site of the break to the end of the chromosome, being lost or duplicated. Abnormalities of this type affect the viability of embryos and if affected embryos were transferred to the uterus and produced a baby, they would carry a risk of serious congenital abnormalities.

“Our study shows that homology-directed repair is infrequent in early human embryos and that, in the first few days of life, the cells of human embryos struggle to repair broken DNA strands,” Kubikova emphasized. “CRISPR-Cas9 was remarkably efficient in targeting the DNA site. However, the majority of cells repaired the DNA break induced by CRISPR using nonhomologous end joining, a process that introduces additional mutations rather than correcting existing ones. This would be a challenge if there were attempts to use CRISPR-Cas9 to correct inherited disorders in human embryos, as it suggests that most times when it is attempted, it will not be successful.

“While the results caution against the use of genome editing in human embryos, there were some positive findings, suggesting that risks can be lowered and the ability to successfully remove mutations can be increased by modifying the way in which genome editing is undertaken. This offers hope for future improvements to the technology.

“On average, only about a quarter of the embryos created using in vitro fertilization (IVF) succeed in producing a baby. Half of them stop developing in the laboratory before they can be transferred to the womb. The inability of embryos to efficiently repair DNA damage, revealed by this study, may explain why some IVF embryos fail to develop. This understanding may lead to improved IVF treatments.”

Now, the researchers will look for new ways to protect early embryos from DNA damage, which could lead to potential improvements in fertility treatments. They also plan to explore more gentle methods of gene editing that avoid breakage of the DNA strands, which embryos might find easier to cope with.

“In the future, such methods may offer the possibility of reversing mutations that have blighted families for generations, preventing the inheritance of catastrophic disorders,” Kubikova concluded.

The research was commented on by Karen Sermon, PhD, professor in genetics and embryology at the Vrije Universiteit Brussel, and the chair-elect of ESHRE. “This is an excellent study by Dr. Kubikova and her colleagues,” Sermon said. “It underlines the importance of why gene editing needs to be thoroughly researched and understood before any attempt is made to gene edit human embryos.

“I think it’s likely that gene editing will become a useful tool at some point in the future for preventing babies from being born with serious genetic diseases in a restricted number of cases where preimplantation genetic testing would not apply. However, this research shows one of the ways that it can go wrong. It will be some time before we can be confident that we really understand how to use it successfully without any unwanted and unexpected surprises. It will require stringent regulation. In the meantime, careful research such as this brings us one step closer, and it may also help with understanding how to improve fertility treatments.”

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The bad:

Source: Futurism

Scientist Who Gene-Edited Human Babies Back in the Lab Again After Prison Release

He's working on ways to fight Alzheimer's disease by gene-editing human embryos.

Chinese scientist He Jiankui shocked the world in 2018, when news emerged that he had used the powerful gene-editing technique CRISPR to tinker with the genetic code of several human embryos that were later born as babies.

The experiments led to a massive uproar, with scientists, ethicists, and regulators balking at the "egregious scientific and ethical lapses."

In 2019, He was sentenced to three years in prison for violating medical regulations.

Now, roughly a year and a half after being released from prison, the scientist has resumed his research on human embryo gene editing — and only has a few regrets about his past work.

In a new interview with Japanese newspaper the Mainichi Shimbun, He reflected on his belief that we'll soon be facing a demand for "designer babies."

"We will use discarded human embryos and comply with both domestic and international rules," he said, shutting down rumors that he was working on a follow-up to the twin sisters, who were born back in 2018 after modifying their genes before birth in a bid to make them immune to HIV.

However, He said that he's working on ways to treat genetic diseases including Duchenne muscular dystrophy and familial Alzheimer's disease with gene-editing techniques in human embryos.

Since being released from prison, the researcher has kept busy, making in-person appearances last year in Cambridge, Massachusetts to discuss his motivations and actions.

The topic of his research, however, has remained controversial. In March 2023, He was set to speak at Oxford University, but mysteriously canceled the appearance, tweeting that "I feel that I am not ready to talk about my experience in past three years."

During a virtual and in-person bioethics event last year, He also refused to answer any questions, a decision that was later criticized by other experts in his field as a "publicity stunt."

Given his latest interview with the Mainichi Shimbun, He is now starting to open up. His comments, however, aren't exactly giving away anything particularly new, and his research remains shrouded in mystery.

The scientist told the Japanese newspaper that the twin girls, as well as a third child that was born in 2019, are all "perfectly healthy and have no problems with their growth."

He claimed that the results of the experiments were looking promising and that an analysis had shown that "there were no modifications to the genes other than for the medical objective, providing evidence that genome editing was safe."

"I'm proud to have helped families who wanted healthy children," he added.

When asked about the criticism that was triggered by his research, He appeared largely unshaken.

"I regret that it was too hasty," he told the Mainichi Shimbun, refusing to elaborate further.

More on He Jiankui: Scientist Who Gene Edited Human Babies Had Plan to Transform Humankind

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The ‘weird’:

Source: Futurism

Gene Editing Experiment Halted as Patient Gets Weird Side Effects

This is a setback.

The experimental biotech startup Verve Therapeutics has paused the first phase of a buzzy human gene-editing trial due to strange side effects in a patient, according to a report from Bloomberg.

The trial in question — dubbed the "Heart-1" trial — is the company's attempt to use gene editing to reduce heart-attack-causing cholesterol in patients with familial hypercholesterolemia, a passed-down genetic disorder that causes buildups of LDL cholesterol in individuals. LDL is the bad kind of cholesterol, and familial hypercholesterolemia drastically heightens patients' risk of early heart attack and can lower life expectancy overall. Verve's proposed solution: inject "VERVE-101," a serum designed to lower fatty LDL molecules by genetically altering the cholesterol-managing PCSK9 gene, into trial participants' livers.

While promising tests on monkeys paved the way for Verve's much-anticipated human trial, however, Heart-1 has now hit another speed bump.

Late last year, it was revealed that a patient enrolled in Heart-1 had passed away from a heart attack. A panel of experts concurred that VERVE-101 wasn't responsible — according to Nature, experts concluded that the patient's death was the result of their already-advanced heart disease — but coupled with some gnarly reported side effects, the tragic incident did raise some alarm bells. And now, some particularly bad side effects experienced by another Heart-1 participant have raised enough safety concerns to pause the trial altogether.

Of the first six patients enrolled in the Heart-1 trial, according to Bloomberg, five saw their cholesterol levels decrease. Meanwhile, though, a sixth patient developed "abnormal liver enzymes" as well as thrombocytopenia, which is the medical term for a low blood platelet count in a patient. Thrombocytopenia is a serious condition that, in the worst cases, can lead to deadly internal bleeding.

Thankfully, the patient's troubling symptoms reportedly disappeared after a few days off the drug. And per Bloomberg, Verve says it believes the abnormalities were caused by the fatty lipids found in the serum used to deliver VERVE-101 into patients' livers. So, in other words, the researchers think it's a problem with the delivery method, rather than the gene-editing process itself.

According to Verve's website, 13 patients in total were treated with VERVE-101. But now, due to the abnormal side effects, the biotech startup is turning its focus to VERVE-102, a version of the gene-editing drug suspended in a different lipid serum. Per Verve, this delivery system was "well tolerated" by patients in a third-party clinical trial. This new trial, expectedly dubbed Heart-2, is set to start in the second quarter of this year.

Genetic heart conditions are an elusive and widespread problem, and if Verve can make a successful, one-and-done gene-editing treatment that alleviates some of these ailments, the company could change — and save — a lot of lives. While the Heart-1 trials did show some promise, though, it seems that Verve still has a way to go.

More on Heart-1: Patient Dies after Being Gene-Edited to Have Lower Cholesterol