Monday Article #53: The World's First Genetically-Edited Babies: A Leap of Faith in Science
Genetic engineering has existed for quite a while now. Almost every argument and argument against it has already been made, and national and international laws have attempted to address it in a legal and ethical manner. In November 2018, news outlets from all over the world reported on the birth of two twin girls who had had their genes altered to make them immune to the Human Immunodeficiency Virus (HIV) (Raposo, 2019). They were born as a result of He Jiankui's "experiment" (for the time being, that is all it can be called), which involved couples with HIV-positive male partners. Jiankui was able to disable the CCR5 gene, which is responsible for the HIV infection, by using CRISPR technology to immunize the infants against the HIV virus (although he still did not present complete evidence of this achievement) (Raposo, 2019).
Figure 1: Dr. He Jiankui's "experiment" which involved the birth of 2 genetically-edited twins (9news, n.d.)
Research on human in vitro embryos after the 14th day of existence and its subsequent implantation into a human uterus are expressly prohibited by the 2003 "Ethical Guiding Principles for Research on Embryonic Stem Cell" published by China's Ministry of Science and Technology and then Ministry of Health (now National Health Commission) (Raposo, 2019). In addition, the scientific community is aware that the CCR5 gene is associated with important brain functions despite the claim that the genetic intervention was done to prevent HIV. He Jiankui may have enhanced two people by giving them a higher IQ and better memory as a form of human enhancement (Raposo, 2019). This incident sparked discussion about CRISPR-Cas9, the most recent gene editing method.
A naturally occurring genome editing system that bacteria use as an immune defence is the basis for CRISPR-Cas9 (MedlinePlus, 2020). Bacteria that are virus-infected seize tiny bits of the viruses' DNA and splice it into their own DNA in a specific pattern to form sections known as CRISPR arrays. The bacteria can "remember" the viruses thanks to the CRISPR arrays (or closely related ones). In the event of a subsequent virus attack, the bacteria create RNA segments from CRISPR arrays that can recognise and bind to particular regions of the viral DNA (MedlinePlus, 2020). The virus is then rendered inoperable by the bacteria's use of Cas9 or a related enzyme to split the DNA. This immune system's defence was modified by researchers to edit DNA. Similar to the RNA segments bacteria produce from the CRISPR array, they produce a tiny piece of RNA with a short "guide" sequence that attaches (binds) to a particular target sequence in a cell's DNA. Additionally, this guide RNA also binds to the Cas9 enzyme. Similar to how the Cas9 enzyme works in bacteria, when the guide RNA is introduced into cells, it recognises the desired DNA sequence and causes the DNA to be cut at the desired location (MedlinePlus, 2020). Other enzymes, like Cpf1, can also be used, though Cas9 is the one that is most frequently used (MedlinePlus, 2020). In comparison to earlier techniques to modify genes, CRISPR-Cas9 is much easier, less expensive and more accurate (Raposo, 2019). CRISPR-Cas9 allows for the addition, deletion or replacement of genes, whereas earlier techniques could only add new components to the human genome. This allows for new kinds of genetic interventions not previously possible. The ability to undo the effects of flawed procedures in order to deal with potential errors may be one of its most promising accomplishments (Raposo, 2019).
Figure 2: An Illustration of the CRISPR-Cas9 System (Redman et al., 2016)
Dr. He Jiankui wanted to develop embryos that were immune to the majority of HIV strains. The majority of HIV strains use a protein coded by the CCR5 gene to enter cells (Rose and Brown, 2019). His goal was to stop this protein from being produced in order to prevent these HIV strains from entering cells. He first chose eight couples where the fathers had HIV and the couple wanted to take action to protect their child from ever getting HIV. The method used by Dr. He involved deleting a specific 32 base pair segment of the CCR5 gene. The CCR5 gene's delta 32 mutation is referred to as this particular targeted deletion (Rose and Brown, 2019). 10% of Europeans naturally possess it (Rose and Brown, 2019). It would be reassuring to create a delta 32 mutation as opposed to another mutation because the planned genetic alteration occurs naturally and is thus unlikely to have unexpectedly negative health effects in the offspring (Rose and Brown, 2019). However, the delta 32 mutation is not entirely benign. A person is more vulnerable to Japanese encephalitis and West Nile virus if they have a dysfunctional CCR5 gene. It might also increase the chances of a person dying from influenza (Rose and Brown, 2019).
22 oocytes were obtained from the in vitro fertilization of five women. Each father's sperm was prepared in a way that would reduce or completely remove HIV contamination. According to reports, 18 of the unfertilized oocytes received injections of a sperm and the CRISPR-Cas9/Cas9 enzymes (Rose and Brown, 2019). The five women received 13 edited embryos transferred back to them. One couple produced four embryos, and two of them had the CCR5 gene modified. One of those transferred embryos was known to still have one copy of a healthy CCR5 gene, per Yong's reporting for The Atlantic. The result of this embryo transfer was Lulu and Nina (Rose and Brown, 2019).
Figure 3: An Illustration of the CCR5 Receptor in HIV Infection (Moon, n.d.)
Dr. He was able to successfully alter the genes of embryos that later managed to become fully developed newborns (Rose and Brown, 2019). The fact that he fell short of his goals, though, is troubling. The genome of each child had been sequenced, and aside from the CCR5 genes, it revealed no changes. Dr. He reported this at the Hong Kong conference where the births were announced (and in the YouTube video he made, dated November 25, 2018) (Rose and Brown, 2019). This suggests that the genome of the embryo was not altered unintendedly by the use of CRISPR-Cas9. Lulu won't be immune to HIV infection, though, as she still possesses one normal CCR5 gene, which will continue to produce the normal protein. The fact that the slides displayed did not depict a delta 32 mutation in any of the CCR5 genes, according to an unnamed expert who attended the conference where the births were announced, is even more concerning (Rose and Brown, 2019). It was also mentioned that Nina's CCR5 genes underwent mutations that may or may not result in the production of functional proteins. According to this report, Nina's gene modifications may not have prevented her from contracting HIV and may or may not have had other negative effects on her health. Lulu and Nina may never be exposed to HIV, so even monitoring their health over their lifetimes won't guarantee that the goal of preventing HIV infection was achieved (Rose and Brown, 2019).
Figure 4: Dr. he Jiankui presenting his work at the Hong Kong Genetics Conference (Wee, 2019)
References
1. MedlinePlus (2020). What are genome editing and CRISPR-Cas9? Retrieved from https://medlineplus.gov/genetics/understanding/genomicresearch/genomeediting/.
2. Moon, D. (n.d.). Mutation that blocks you from getting AIDS or HIV. Retrieved from https://www.geneticlifehacks.com/mutation-that-blocks-you-from-getting-aids-or-hiv/.
3. Raposo, V.L. (2019). ‘The First Chinese Edited Babies: A Leap of Faith in Science’, JBRA Assisted Reproduction, 23(3). [Online] DOI: https://doi.org/10.5935/1518-0557.20190042. (Accessed: 13 March 2023)
4. Redman, M., King, A., Watson, C. and King, D. (2016). ‘What is CRISPR/Cas9?’ Archives of Disease in Childhood - Education & Practice edition, 101(4), pp.213–215. [Online] DOI: https://doi.org/10.1136/archdischild-2016-310459. (Accessed: 13 March 2023)
5. Rose, B.I. and Brown, S. (2019). ‘Genetically Modified Babies and a First Application of Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR-Cas9)’, Obstetrics & Gynecology, 134(1). [Online] DOI: https://doi.org/10.1097/aog.0000000000003327. (Accessed: 13 March 2023)
6. Wee, S.-L. (2019). Chinese Scientist Who Genetically Edited Babies Gets 3 Years in Prison. The New York Times. Retrieved from https://www.nytimes.com/2019/12/30/business/china-scientist-genetic-baby-prison.html.
7. 9news (n.d.). China halts work on gene-edited ‘designer babies’. Retrieved from https://www.9news.com.au/world/he-jiankui-xu-nanping-gene-editing-crispr-designer-baby-aids-virus/ee0aaaff-bf51-4dca-8c5c-84f39cc88d5a [Accessed 13 Mar. 2023].
This Article was prepared by Thiiben A/L Krishnan Sami
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