Analysis: a Chinese scientist's claims that he created the world's first genetically engineered babies has highlighted the ethics of gene editing
In November 2018, the genetics community was rocked by the announcement from a little known Chinese scientist who claimed to have altered the genomes of twin girls to make them resistant to AIDS. While his claims have yet to be independently verified, Professor He Jiankui has said that he used a powerful gene editing technique called CRISPR to inactivate a gene that allows the HIV virus to enter white blood cells. CRISPR, pronounced "crisper" and an abbreviation for Clustered Regularly Interspaced Short Palindromic Repeats, is a new and very powerful technique for precisely editing DNA.
Professor He Jiankui talks about his work
During the height of the AIDS epidemic, doctors noticed that a small proportion of gay men were never infected by the HIV virus, despite taking no precautions against it. The cause of this resistance was eventually tracked down to a small deletion in a gene called CCR5. This gene contains the instructions to build a protein that sits on the surface of white blood cells. The HIV virus can bind to the CCR5 protein and use it as a "doorway" to gain entry into the cell, where it replicates itself and eventually destroys the cell. The deletion in the CCR5 gene prevents the protein from reaching the cell surface, essentially shutting the door.
This mutant version of CCR5 is found in about 10 to 15 percent of people with northern European ancestry. Such a high frequency suggests that it must have been selected for by evolution, i.e. there must have been an advantage to having it. Providing resistance to HIV infection cannot be the selecting agent, as the AIDS outbreak occurred too recently to bring the frequency to such a high level. The bubonic plague was suggested to be the selecting agent as the timing of plague epidemics seemed to coincide with the increase in frequency of mutant CCR5.
Scientists use CRISPR to modify genes in lung cells in people with cystic fibrosis or blood cells in people with leukaemia or sickle-cell disease
But a likelier cause is smallpox. Smallpox is a deadly infectious disease that is estimated to have killed 300 to 500 million people in the 20th century alone and was only declared eradicated in 1980. The smallpox virus uses a similar mechanism to HIV to infect white blood cells so people with the mutant gene are less likely to get infected and therefore more likely to survive and pass their genes on to the next generation. It is the CCR5 gene that Professor He claims to have edited in Lulu and Nana, the twin girls.
From RTÉ Radio 1's Drivetime, Myles Dungan on the history and impact in Ireland of smallpox, one of the most dreaded diseases of the 18th and 19th centuries.
The CRISPR system can be programmed to permanently modify any gene in living cells and organisms. It offers great potential and it is likely that it will soon be possible to correct mutations that cause genetic diseases. It is faster, simpler to use and cheaper than other gene editing techniques. In the vast majority of cases, scientists use CRISPR to modify genes in somatic cells (any cell type that is not sperm or eggs), such as lung cells in people with cystic fibrosis or blood cells in people with leukaemia or sickle-cell disease. In August 2018, it was reported that CRISPR had been used to partially restore the expression of a critical protein in dogs with Duchenne muscular dystrophy (DMD)
Any changes that CRISPR makes to the DNA of these cells will be passed on to their daughter cells when they divide, and the daughter cells will pass them on to their progeny, and so on. Importantly, these DNA changes are restricted to the cell type that has been treated with CRISPR. For example, the modifications that are introduced to the genome of muscle cells in a boy with DMD will not be found in the genome of the neurons in his brain, and if the boy goes on to have children, these changes will not be passed on to them.
From RTÉ Radio 1's Drivetime, Dr Oliver Feeney from NUI Galway on the bioethics of gene editing and CRISPR
There are three shocking aspects to the announcement made by Professor He Jiankui. Number one, if his claims are true, he has made changes to the germline (the sperm or egg). He introduced the CRISPR during the IVF procedure to fertilise the mother’s egg with the father’s sperm. Embryos which had an altered CCR5 gene were chosen and, for the first time, gene-edited embryos were implanted back into the mother.
Because Professor He edited the germline of the twins, the changes he has made to their genome will be found in all their cells in the body, and not just in their white blood cells. Any harmful mutations that he has inadvertently introduced will not be restricted to just a single cell type or tissue (it should be noted that Professor He claims that there were no "off-target" effects). Furthermore, because these gene edits will be found in the girls’ eggs, they will be passed on to their children and their children’s children.
One of the shocking aspects to Professor He’s announcement is that he altered the genomes of healthy children in the hope of making them resistant to HIV infection
The first report of gene-edited embryos appeared in 2015, but these were never implanted into a mother. Nevertheless, this study raised serious ethical concerns at the time. The research group attempted to correct mutations in the human beta-globin gene which cause the inherited blood disorder b-thalassemia. Only a fraction of the 86 embryos used in the study had the mutation repaired. For germline editing to be used in clinical practice this needs to be close to 100 percent.
More worryingly, there were a large number of "off-target" effects, unintended mutations introduced to other parts of the genome. Many geneticists say that the germline should never be edited, and that people who want to have children but are concerned about passing on mutant genes for genetic disorders such as Huntington’s disease or Tay-Sachs disease, are better served by in vitro fertilisation followed by preimplantation genetic diagnosis. This ensures that only embryos carrying normal copies of the gene are implanted.
From RTÉ Six One News, a report on new concerns about gene-editing technology
The second shocking aspect to Professor He’s announcement is that he altered the genomes of healthy children in the hope of making them resistant to HIV infection. This is unnecessary, as AIDS is an entirely preventable disease and there are very effective treatments for people who are infected with HIV, for controlling it. If his claims are true, Professor He acted recklessly by risking the health of two girls for very little gain.
Third, the experiment seemed to have been performed without raising any alarm bells. The university that employs He say he took a leave of absence in February 2018, and that it was unaware of the experiments he was conducting. Furthermore, they have raised questions over the authenticity of ethical approval forms have been produced by He. A committee to investigate the claims is to be established.
He’s work has been widely condemned in China, and there is growing pressure from the research community there for an overhaul of the country’s bioethics laws. These types of experiments are already banned or outlawed in most countries, but it is believed that the most relevant legislation in China dates back to 2003, before CRISPR technology became available. CRISPR is a very powerful technology which has the potential to cure a great many diseases, however the backlash to one man’s ego may possibly set the field back for years.
The views expressed here are those of the author and do not represent or reflect the views of RTÉ