The Era of Genome Editing: experimentation with human embryos
Since I posted my previous article I have been encouraged by many of my readers to write about the usage of CRISPR technology in human beings. Little after my article was published, ethically controversial news was coming from China, where a researcher at the Southern University of Science and Technology, in Shenzhen, claimed to have performed CRISPR genome editing in two newborn girls. This news was followed by a great amount of positive/negative critiques. Now, what do you think? Would you subject your future kids to genome engineering under the promise of a “healthy” future?
How did everything start?
The first CRISPR was detected 30 years ago by Y. Ishino (1987, Japan) in the bacteria Escherichia coli. However, little he knew about his biological function. We had to wait until the early 2000s when F. Mojica and others shed light into the function of CRISPR as an adaptative immune system in bacteria. In brief, the CRISPR’s mechanism of action is based on DNA reading. Once external viral DNA (coming from a viral infection) is detected, the system will target it and cut such DNA sequence with the aim of avoiding viral replication and further infection.
Why is CRISPR so revolutionary?
The use of CRISPR technology was not very revolutionary in bacteria. However, it became an incredibly practical tool for genome editing in eukaryotic cells (including human cells). However, eukaryotic cells count with an error-prone mechanism — non-homologous end joining (NHEJ) — that in its attempt to fix the CRISPR-generated DNA break generates deletions at the repaired genomic region interrupting the targeted gene.
Alternatively, the CRISPR approach can be used to introduce specific genomic changes using homology-directed repair (HDR) approach. Here, a DNA repair template needs to be delivered for the cell to repair the DNA break by “copying” and, therefore, inserting into the genome the template sequence.
“Genetic engineering by CRISPR and homology-directed repair (HDR) is utilized to introduce precise genetic modifications in a controlled way.”
Experimentation in human embryos: a step too far?
The novel CRISPR approach promised the ultimate eradication of devastating genetic disorders by just “correcting” the altered genes, and more importantly before the baby is even born!. At this point, many feared the beginning of experimentation on human embryos, but many others did not lose the chance to implement the CRISPR tool.
Chinese researches were the first worldwide in editing genes of human embryos in 2015, suggesting the birth of genetically modified humans by in vitro fertilization (IVF) a theoretical possibility. Here, the team aimed to modify the gene responsible for beta-thalassemia, a blood disorder; however, their results claimed severe obstacles to using CRISPR in medical applications, starting by the surprising amount of “off-target” mutations generated by CRISPR/Cas9 complex acting in other parts of the genome.
“If you want to do [CRISPR] in normal embryos, you need efficiency to be close to 100%,” Junjiu Huang.
This work sparked a global debate about the ethical implications and pleas from the scientific community not to employ the technology on making babies, at least not for the moment. Nonetheless, there are differing opinions regarding how far we should take genetic engineering, given both its merits but also its dangers when using the technology beyond disease treatment and prevention.
Controversial birth of the world’s first CRISPR twins
As I mentioned before, it was China who started experimentation in human embryos; therefore, it was not very surprising to read about He Jiankui, a Chinese scientist based at the Southern University of Science and Technology in Shenzhen (China), who claims to have engineered the first CRISPR babies on the world.
Dr. He was born in 1984 while the one-child policy was in effect in China. Although it officially ended in 2015, many restrictions continue. China’s government established the one-child policy to especially restraint population growth reducing the quantity and improving the quality. This became explicit in 1994 with the Eugenics and Health Protection Law, which forbid people with mental or physical disorders from reproducing.
He was concerned about this policy uses and, as he declared in a YouTube video, he felt morally compelled to modify the CCR5 gene, which in theory would give the twins, Lulu and Nana, resistance to HIV. Nonetheless, the reaction was a massive rejection of He’s research which ended up with He being fired from his university on the past 21st January.
“He had avoided supervision, raised funds and organized researchers on his own to carry out the human embryo gene-editing research intended for reproduction, which is banned by Chinese law.”
Such extreme reaction is reasonable, given the many uncertain and worrying details about the He’s experiment. Bellow, I summarize the technical errors and ethical concerns from his research.
- Deactivating CCR5 doesn’t confer complete immunity to HIV. He focused on the CCR5 gene, which the HIV virus uses to infiltrate human cells; however, some other strains of the virus can enter the cell via different membrane proteins. Moreover, people with CCR5 deficiencies are more susceptible to the West Nile virus and more likely to die from influenza.
- The editing was not well executed. Based on some slides He presented in a meeting in Hong Kong, both Lulu and Nana are carrying modified and non-modified copies of CCR5 gene. That could either be because every cell in their body has one normal copy of CCR5 and one edited one (heterozygous) or because half of their cells carry two edited genes and half carry two normal ones (mosaic).
Moreover, He tried mimicking a naturally occurring mutation named “delta_32”; however, none of the girls carry such mutation. He made new variations/mutations, and there’s no reason to think that they’d be protective, or even that they’d be safe.
- It is not clear what the effect of the new mutations is. He disrupted the CCR5 gene, which could potentially silence its function. However, prior characterization of these mutations in mice or other lab models is missing. Therefore, the girls are test-subjects for CCR5 allelic variants, which is not ethic.
- Changes might have consequences in further generations. It is unknown what might have happened in the germ cells of the girls. There is a possibility that the Cas9 enzyme would have made cuts elsewhere in the genome, what we usually call unintended off-targets. Although He sequenced their whole genome, the sequenced samples did not come from the germ cells.
Conclusion
Although promising, it appears to me that heritable germline editing is still in very early stages of its development. The technique is far from accurate and efficient, at least when modifying multicellular organisms, since 100% efficiency is hardly achieved. Therefore, in my opinion, heritable germline should be kept off limits until the refinement of the technique. Instead, we should focus on improving gene therapy delivery methods or editing genes in targeted cell types in diseased individuals (e.g. leukemia).
Nonetheless, researchers should continue using CRISPR as a tool in the plants and laboratory animals and observe its effects through many generations. At the moment, we understand very little about genetic interactions, half-life or the Cas9 (or any other CRISPR-associated) nuclease or genetic compensation in complex systems. Therefore, research in this field is important and, in my opinion, a must before proceeding with human gene editing.
It is true that genome editing has an extraordinary potential for improving our future lives, where every human can live longer, healthier and even with enhanced abilities. However, rushing into that will only bring adverse outcomes and fear from the public. That future could be ours, but we need to be wise and patient to wield genome editing technology in a way that would benefit us all.
