Gene-edited Babies Immune to HIV: A Discussion about “CRISPR-Cas9” and “CCR5”

The news "World’s First Gene-edited Babies Immune to HIV Born in China" flooded WeChat moments on Nov. 26, 2018, which said, "A pair of gene-edited babies named Lulu and Nana was born healthily in China in November. A gene (CCR5) of them was edited with CRISPR-Cas9, enabling them to naturally resist to HIV after birth. This is the world’s first case of gene-edited babies immune to HIV, and shows a historic breakthrough of China in the field of genome editing technique for disease prevention."

This news immediately created a big stir after its release, and caused the boycott of many industry scientists. The "CRISPR-Cas9", "genome editing", and "ethical arguments" have invoked again the reflection of scientists and the public.

Here, I will skip the ethical arguments behind the event, and focus on the two keywords: "CRISPR-Cas9" and "CCR5", to discuss the rationality and safety of the scientific theory behind the news event.

I. Hot technique for Nobel Prize | CRISPR-Cas9 genome editing

Keyword I: CRISPR-Cas9

CRISPR-Cas9 genome editing has developed by leaps and bounds since 2012, and it was listed as one of the top 10 scientific breakthroughs by Science separately in 2013 and 2015!

Cores of CRISPR-Cas9 genome editing technique:

1. Cas9 endonuclease conducts site-specific cleavage of specific nucleotide sites

2. gRNA sequence can be understood as the GPS navigation system of the technique, which guides Cas9 targeted modification

3. The gene sequence after modification can be normal gene including ideal mutation, which is inserted or knocked out the nucleotide sequence of certain segment.

In the above figure, a segment of normal hemoglobin gene is introduced using CRISPR-Cas9 genome editing technique, to cure the sickle cell disease patient. In the above news, CCR5 gene went through directed mutation using the CRISPR-Cas9 genome editing technique, to simulate "Berlin patient".

CRISPR-Cas9 genome editing technique can easily and quickly mutate, insert, or knock out certain segment of gene, and has become a high-profile genome editing technique.

Certainly, there have been human clinical trials relating to CRISPR-Cas9 genome editing conducted worldwide, with indications mostly of rare diseases and being at early stages. Relevant information can be found on CRISPR Therapeutics.

However, the technique is far from mature, with the biggest safety hazard being the off-target effect, therefore, efforts have been put therein in recent years.

II. CCR5 and HIV

Another keyword in the above news is "CCR5" gene

CCR5, i.e., C-C chemokine receptor type 5, is also called CD195, which is widely expressed on the white blood cell surfaces, and is closely linked with body immunity. (Also refer to https://zh.wikipedia.org/wiki/白血球)

CCR5 and HIV

HIV mainly attacks CD4+ T cell, and CCR5 protein can be understood as an important accomplice of HIV: HIV’s success in invading T cell can’t do without the important co-receptor: CCR5 protein.

Scientific rationality: CCR5 gene is closely linked with HIV infection

The rationality of the scientific theory of CCR5 gene lies in:

1. CCR5 gene mediates the key process of HIV’s entry into T cell, being a key receptor;

2. The anti-HIV drug: CCR5 inhibitor Selzentry (Maraviroc) developed by Pfizer has been marketed successfully, proving the rationality of the target;

3. The breakthrough medical miracle brought by CCR5- delta 32 mutation to "Berlin patient" is also an irrefutable fact;

However, there are still many problems with treating HIV through CCR5 target:

1. CCR5 gene is not the only receptor mediating HIV’s entry into T cell: CXCR4 can also do that; mutating CCR5 gene cannot guarantee the complete cure of HIV;

2. CCR5 gene is widely expressed in white blood cells and is closely linked with the immune system; CCR5 does not only relate to HIV, which is why CCR5 receptor is being developed for autoimmune diseases (such as rheumatoid arthritis);

3. The marketed drug Selzentry (Maraviroc) can only be used in patients with drug tolerant and CCR5-positive HIV, and has serious hepatotoxicity, and skin and allergic reactions, which closely relates to the characteristics of the target. There is a black box warning on the drug package.

4. The existing therapeutic regimens can well control the HIV of infants. Why take such big risk?

CCR5 gene | gene mutation safety still inconclusive

Put aside the ethical arguments. CCR5 gene mutation is still not mature in terms of its safety. CCR5 gene does not only relate to HIV, but also closely relates to the immune system; the safety of CCR5 gene mutation is still not clear, and its risk/benefit cannot be certain.

Besides the ethical aspect, the rationality of the scientific theory of CCR5 gene still cannot be justified!

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