Biologist Denis Rebrikov has high hopes for the future of genetically edited human embryos. Last week, Rebrikov announced his plans to seek approval from three Russian regulatory bodies to move forward with his plans to modify babies. In short, Rebrikov wants to use a gene-editing tool called CRISPR (pronounced “crisper”) to prevent HIV-positive mothers from passing the virus to their unborn children. His announcement comes on the heels of last year’s scientific shocker: Chinese scientist He Jiankui created the world’s first germline genetically modified human babies. The twins, codenamed Lulu and Nana, were born in October 2018.
Scientists have been experimenting with genetic modification for many years, but ethical concerns have guided progress in the field. Editing human genetics is a lot more complex than mixing together some sperm and egg cells and hoping for the best! These are the basics you need to know to understand Rebrikov’s research and its ethical implications.
CRISPR-cas9 is a gene-editing tool developed by two badass female scientists, Jennifer Doudna and Emmanuelle Charpentier in 2012. Imagine CRISPR as a set of very tiny signal-guided scissors; these scissors can remove a section of DNA by finding the corresponding RNA signal and altering it. This genetic editing has been used “ex vivo” (in adult humans) to create the cutting edge field of personalized medicine. The Smithsonian reports that CRISPR is our best hope at curing cancer. DNA technologists remove a cancer patient’s T-cells, use CRISPR to tweak them into more effective cancer-fighters, and reintroduce the modified T-cells into the bloodstream.
The major difference between this type of genetic modification and the kind used to create Lulu and Nana is heritability. Changes to a cancer patient’s T-cells can’t be passed down to their offspring and only impact one type of cell in the human body. In comparison, He Jiankui performed what’s known as “germline editing”. That is, he made a change to human embryos that is now replicated in every single cell in the twins’ bodies. What’s more, the twins will pass these genetic edits down to their offspring if they choose to procreate. Jiankui effectively tinkered with the genetic history of all mankind – with no way to know if this edit would be more harmful than it is beneficial.
It remains to be seen if Jiankui’s efforts actually provided the twin girls with the intended immunity to HIV.
When He Jiankui began the clinical trial that created Lulu and Nana, his goal was to help prevent the inheritance of HIV. Lulu and Nana’s biological father is HIV-positive. Scientists lambasted Jiankui for this experiment for several reasons. First, men are far less likely than women to pass HIV to their offspring. In addition, modern HIV treatments are extremely effective at giving those who are HIV-positive an otherwise healthy and long lifespan. Finally, Jiankui’s edits to the human germline could have serious unintended consequences – consequences that will impact future generations if Lulu and Nana decide to become mothers themselves.
Scientist Xinzhu Wei from UC-Berkeley contrasts germline editing and ex-vivo editing in laymen’s terms.
“The difference is as big as modifying the entire operating system of a computer, as opposed to modifying one single [piece of] software installed for a particular task.”
Rebrikov’s research differs from Jiankui’s findings because his target group are would-be mothers – not fathers. The Russian biologist acknowledges the highly effective HIV therapies that benefit most patients, which is why he specifically wants to work with women who are resistant to these antiretroviral treatments. He intends to target the same gene edited by Jiankui, but claims his ability to edit is more refined and prevents “off-target” mutations from occurring.
Rebrikov will target the same gene, CCR5, with the intent of disabling it. CCR5 encodes a protein that allows HIV to enter cells. Turning the CCR5 gene off will, in theory, make it impossible for HIV-positive mothers to pass the virus to their babies in utero. Because human reproduction introduces “natural” changes to our germline, some people have a variant of CCR5 dubbed CCR5-𝚫32 (CCR5-Delta32).
Delta32 is the genetic variation that creates immunity to HIV. However, that’s not the only effect of the natural permutation. One 2015 study showed that people who have one or two copies of CCR5-𝚫32 nearly quadrupled a person’s odds of dying from influenza. Earlier this month, scientists revealed a new discovery. People who have two copies of CCR5-𝚫32 are 21% more likely to die before the age of 76 than those with at least one working (non-variant) copy of the gene. Rasmus Nielsen, a biologist at the University of California, Berkeley and coauthor of that study, warns against the CRISPR-driven editing of the human germline.
“There might be a perception that when you have one mutation, you have one effect. But in fact, one mutation might have many different effects.”
The germline changes to CCR5 in Lulu and Nana were meant to replicate CCR5-𝚫32. However, biologists who have studied He Nianjuki’s work explain that the alteration to CCR5 is not identical to Delta32. This means no one knows what effects Lulu and Nana’s mutations will have on their lives. Although Rebrikov claims to be able to use CRISPR more precisely to make his alterations, few believe it’s an advisable pursuit.
If Rebrikov has his way, he’ll be transplanting genetically-edited embryos into HIV-positive mothers within the next two years.