“The power to control our species’ genetic future is awesome and terrifying. Deciding how to handle it may be the biggest challenge we have ever faced.”
Jennifer A. Doudna
A year ago, He Jiankui announced that he had used CRISPR to create two gene engineered baby girls. Since the initial announcement, there has been little new information released. The government terminated Dr. Jiankui’s lab and research activities. “China’s Vice-Minister of Science and Technology Xu Nanping quickly shut down Dr He’s lab, ordering a full investigation and flagging some form of punishment for the researchers.” It is also not clear where Dr. Jiankui is located “Hong Kong media reported that the university president, Chen Shiyi, personally flew to Hong Kong to collect and escort Dr He back to Shenzhen, where he was put “under house arrest”. The university denied Dr He was detained, telling the South China Morning Post “nobody’s information is accurate” on Dr He’s whereabouts, but refused to provide any details.”
For about a year, this was the state of the information about the first two genetically engineered human beings. Then early this month (Dec 2019), MIT Technology Review published a series of articles about Dr. Jiankui’s research. It seems that He Jiankui wrote a 4699-word article titled “Birth of Twins After Genome Editing for HIV Resistance,” while the paper remains unpublished Dr. Jiankui submitted it to Nature and JAMA the Journal of the American Medical Association (China’s CRISPR babies: Read exclusive excerpts from the unseen original research.) Dr. Jiankui’s unpublished work answer several questions that were left unanswered last year. However, the answers are perhaps more troubling than the speculation.
To understand what Dr. Jiankui was trying to accomplish, we need a little bit of history. Dr. Jiankui calms that he was trying to engineer humans to be resistant to HIV. The HIV-1 virus infects CD4 immune cells. Over time an individual infected with HIV reaches a point where they cannot produce enough CD4 cells to mount a viable immune response. Leading to the collapse of the immune system and often death by disease. Around 1996 a naturally occurring mutation in the CCR5 gene was discovered that rendered individuals resistant or possibly immune to infection by the HIV-1 virus. The CCD5 mutation is a deletion of 32 base pairs (called Δ32) in the coding sequence of the CCR5 gene. (Homozygous defect in HIV-1 coreceptor accounts for resistance of some multiply-exposed individuals to HIV-1 infection.)
The Δ32 mutation makes it so that the HIV-1 virus can’t bind to the CCR5 protein. Since the HIV-1 virus uses the CCR5 receptor to enter cells, this mutation renders cells resistant or immune to infection by HIV-1. According to his paper, Dr. Jiankui used the CRISPR technology to engineer the CCR5-Δ32 mutation into the in-vitro fertilized embryos of a couple where the husband was HIV positive, and the wife was HIV negative. The genetic change, in turn, would confer immunity to the children born from these embryos.
In the abstract, Dr. Jiankui says they were successful in editing the CCR5 gene. “Genomic sequencing during pre-implantation genetic testing and after birth confirmed that the twins’ CCR5 genes were edited successfully and are thus expected to confer either complete or partial HIV resistance.” (China’s CRISPR babies: Read exclusive excerpts from the unseen original research) However, the actual data in the paper shows that one of the embryos has a frameshift mutation in the CCR5 gene, while the second embryo has a 15 bp delegation. While both mutations cause changes in the CCR5 protein, they do not create the same disruption as the CCR5-Δ32 mutation. It is not clear that these mutations will confer immunity to HIV since not every single mutation in CCR5 confers HIV immunity. Beyond the question of the effectiveness of the created mutations, new research suggests that being homozygous for the CCR5-Δ32 mutation leads to a decrees in life expectancy (CCR5-∆32 is deleterious in the homozygous state in humans.) Additionally, it appears that the cells in the embryos may not have all changed to the same extent leading to mosaics.
In addition to the potentially harmful nature of CCR5 mutations, there is a question about the type of genetic engineering. If you are going to induce a mutation in a gene because of an observed effect, you need to create the same mutation that caused the original effect, not a similar mutation. The reason is twofold one if you create a new mutation, you don’t know that the new mutation will have the same effect as the old one. Two of the new mutation could cause a new and unintended consequence that the original mutation did not have.
Now at a first pass, Dr. Jiankui’s motives sound reasonable and altruistic. He is trying to help a couple that is HIV positive have children. Dr. Jiankui even states in his abstract, “Millions of children are born annually with inherited genetic diseases or infectious diseases acquired from parents.” (China’s CRISPR babies: Read exclusive excerpts from the unseen original research) As stated by Rita Vassena, scientific director of the Eugin Group, there are well-established techniques to prevent transmission of HIV from parent to offspring.
“It is worth remembering that HIV infection is not passed on through generations like a genetic disease; the embryo needs to “catch” the infection. For this reason, preventive measures such as controlling the viral load of the patient with appropriate drugs, and careful handling of the gametes during IVF, can avoid contagion very efficiently.” (China’s CRISPR babies: Read exclusive excerpts from the unseen original research)
From a medical point of view, it is rarely if ever considered acceptable to use an experimental and potentially dangers technique when effective options already exist.
Beyond the question of whether the technology was ready, Dr. Jianjui’s foray into genetic engineering brings into sharp focus a question about the utilization of genetic engineering. Dr. Jianhui attempted to create a new biological function in the twins. He tried to engineer viral resistance. What makes this especially troubling is that while we know that CCR5-Δ32 confers resistance to HIV-1 research into the normal biological functions of CCR5 is still ongoing. The work showing that being homozygous for the CCR5-Δ32 can be harmful to the life span was published this year (2019). Instead of trying to create something “new,” why didn’t Dr. Jianjui try and fix a “broken” gene.
If Dr. Jianjui had at least tried to use genetic engineering to reverse a disease-causing mutation to the normal function, he would not have had to deal with the potential conquests of changing a gene function he would have restored it to normal function. While this article should make it clear that gene-editing technology is not yet specific enough for reproductive genetic engineering, at the rate the technology is improving, it will not be long before we the technology can make specific changes in an embryo without producing additional defects.
A companion article also from the MIT Technology Review Opinion: We need to know what happened to CRISPR twins Lulu and Nana States that Dr. Jianjui’s papers need to be made public. Specifically, Dr. Kiran Musunuru says, “Why must the information be public? It’s because He’s work reveals serious, unresolved safety concerns. It’s not clear that any effort to directly edit human embryos, even if done ethically and with full social approval, can reliably avoid these problems.” While I think Dr. Musunuru’s interpretation is a little extreme. I don’t believe Dr. Jianjui had a good enough grasp of what he was trying to do to use his research as a cornerstone of the technology limits. After all, most of the information uncovered in his unpublished work is in aliment with the concerns and beliefs put forward by the scientist when human engineering was first made public. I do agree that we need to discuss the uses and potentials of genetic engineering.
However, for people to have discussions about the ethics of genetic engineering, people need to understand the basics of genetics and genetic engineering. Humans have been using genetic engineering since we planted our first crops and domesticated the first animals. Our faithful companion, the dog, is the product of thousands of years of genetic engineering. We are entering a point when we can change our ecosystem and ourselves at a rate faster than ever before. However, how much does the general public know about genetics? Can we make a legitimate decision about genetic engineering if we don’t even understand the basics of what is going on?
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