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Scientists Have Genetically Engineered Two Babies with the CCR5 Delta32 Mutation, Providing Complete Immunity Against HIV/AIDS

An explanation of the mechanisms behind how the CCR5 delta32 mutation confers immunity to HIV/AIDS and why scientists are so interested in it

Photo by Kateryna Kon on gettyimages.com

In 2018, two twin girls were born to the world, Lulu and Nana. The pregnancy had been normal, except for one important detail. This was a world first in performing gene surgery, manually changing the twins’ DNA such that they would have a specific “delta32” mutation within the CCR5 gene. This meant that the twins were now completely immune from HIV.

This is how they gained complete immunity.

Every second of your life, you are under attack by billions of bacteria, viruses and fungi, all competing to use you as their new home.

Fortunately, your immune system is capable of acting as a miniature army, patrolling your body and fending off incoming attackers. You have macrophages that engulf the invaders via a process called phagocytosis. You have B-cells which are capable of producing antibodies that neutralise the attacking pathogens.

And you have T-cells, which are capable of activating the immune defences and retain immunological memory, so that if you ever are re-infected, your body will be better prepared.

Macrophage engulfing bacteria. Photo by Kateryna Kon on gettyimages.com

What is HIV/AIDS?

Among the viruses that can attack the body is the human immunodeficiency virus (HIV). This virus is particularly dangerous as it is capable of causing critical failure of the immune system.

The T-cells that faithfully defend your body are targeted by the virus. HIV enters the T-cells via a special surface receptor called the CCR5 receptor. This receptor acts as a gate, allowing chemical signalling molecules to travel between the cell membrane. However, this receptor cannot distinguish between friend or foe, so the HIV virus tricks the receptor into letting it into the cell.

Upon entering, the virus hijacks the cellular machinery by integrating itself into the DNA of the cell. While this cellular machinery would otherwise be allowing the cell to duplicate, the virus uses it to create more copies of itself.

Figure made using BioRender

Once enough copies have been made, the viruses burst through out of the cell, rupturing the cellular membrane and causing its death. These viruses go on to infiltrate other T-cells, replicating exponentially as more cells are infected and die.

If enough of these T-cells are killed, then the patient suffers from acquired immunodeficiency syndrome (AIDS). The T-cells that are responsible for activating the immune defences and retaining immunological memory are killed off, leaving the body susceptible to any attacker looking to infect the body.

Additionally, HIV is particularly dangerous as it is a chronic condition — you can never completely cure yourself of it. The reason for why it is chronic goes back to how HIV infects your body — it integrates itself into your DNA of your T-cells. The virus can lay dormant for years, and while it may not be present in the bloodstream, you will have T-cells that are compromised and unknowingly carry the information required to mass-produce viruses. The virus can re-activate itself at any moment, and renew its attack on your immune cells. The only solutions are having the delta32 mutation or taking antiviral medication for life.

What is the delta32 mutation?

Fortunately, a mutation in the genetic sequence that encodes the CCR5 receptor is capable of conferring complete resistance to HIV. Otherwise known as the CCR5 delta32 mutation, individuals who inherit this mutation from both their parents do not have the CCR5 receptor expressed on the surface of their T-cells meaning HIV cannot use it to gain entry.

Additionally, while the CCR5 receptor is responsible for responding to chemical signalling during an immune reaction, the loss of this receptor is well tolerated and doesn’t detrimentally affect the body as there are many other receptors that perform similar functions.

Understanding more precisely how this mutation affects the receptor expression and HIV infection requires an understanding of the central dogma of molecular biology.

Figure made using BioRender

The central dogma describes how DNA is eventually converted into amino acids, the building blocks of proteins and in this case, the CCR5 receptor.

Through a process called transcription, a gene is transcribed by special enzymes into messenger RNA (mRNA). This mRNA is single stranded and can be read by protein-producing machinery called ribosomes. Each triplet of nucleotides (the letters) is a codon, with each codon corresponding to an amino acid. Thus, a unique sequence of codons corresponds to a unique chain of amino acids, thereby resulting in a specific protein being produced.

This ribosome needs to know where to start and where to stop. Thus, each mRNA sequence starts with a START (AUG) codon and ends with a STOP (UAG) codon, designating where the translation process can occur.

The delta 32 mutation results in a premature STOP codon, meaning the amino acid chain stops prematurely, resulting in a non functioning protein. This means that the receptor protein isn’t expressed on the surface of the cell. Without the receptor, where is no gate for the virus to enter.

Figure made using BioRender

No receptor, no entry, no HIV

Figure made using BioRender

Who is immune to HIV/AIDS and why?

A paper published in 2005 analysed the global distribution of the CCR5 delta32 mutation. The paper found that the mutation was most common in Europe and Western Asia, with 10% of Europeans having at least one parent with the mutation.

The reason for this distribution was hypothesised to be linked with the bubonic plague, which has been discovered to also use the same CCR5 receptor to gain entry into cells. This plague had an extremely high case mortality rate, decimating the populations in Europe. However, individuals with the mutation were more resistant to the disease, and survived more on average. The survivors were able to have children and pass on their beneficial genetic mutation.

This hypothesis was corroborated by computer simulations, which found that prior to the bubonic plague, the frequency of the delta32 mutation was 1/20,000 people whereas after the plague, the frequency rose to 1/10.

Photo by traffic_analyzer on gettyimages.com

Can we harness this mutation and make more people immune?

“Two beautiful little Chinese girls, named Lulu and Nana, came crying into this world as healthy as any other baby.” — He Jiankui

In 2018, Grace [their mum] started her pregnancy with regular IVF, but with one difference. He Jiankui, a Biophysics Researcher, performed a world-first gene surgery, artificially inducing the delta32 mutation into the children’s CCR5 gene to confer complete resistance to HIV.

He Jiankui then released a controversial video explaining why he followed through with the procedure. He had previously worked in HIV-related fertility problems and argued that because their father was HIV-positive, he was worried that the father could pass on the disease to his children.

This event sparked worldwide controversy. He was labelled him as a “rogue scientist” and “Dr Frankenstein”, with most scientists condemning him for his rash act. The World Health Organisation, in response to He’s acts, called for a halting in all human genome editing work and called for the creation of a registry that would track any and all research in the field.

To which He Jiankui replied

“[We] don’t want a designer baby. Just a child who won’t suffer from a disease that medicine can now prevent”

Is it right to halt progress in this field where so many lives could be saved? How can we ensure that there is equal access to this technology and that we do not violate any ethical codes?

What do you think?

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