Better and worse ways to fiddle around with T-cells using CRISPR

By Monika Berezowska 

“Because the first person to put it on paper wins!” – that’s how the committee of the 2018 International Summit on Genome Editing in Hong Kong justified their sharp criticism of a presentation He Jiankui made during the conference. 

As a postdoctoral fellow at Stanford University, He learned the CRISPR/Cas9 genome editing technique. Its emerging potential and the enormous future impact it carries quickly became apparent to him and he planned a series of ground-breaking experiments. As a result, twin girls – nicknamed Nana and Lulu to protect their identity – were born in October 2018 to become the first humans in history whose genome was modified.1   

In his experiment He approached HIV-positive couples planning to have a baby and recruited them to undergo a standard in-vitro feralization treatment with one small modification: Immediately after the egg was fertilized the single cell zygotes were modified using CRISPR to edit the CCR5 gene – a receptor that allows the HIV virus to enter and hijack T-cells. Such mutation was long observed to protect from AIDS2.

CCR5 – Chemokine receptor type 5 in general plays a regulatory role in the human body. It is present on the surface of lymphocytes. These cells use cytokines to communicate between each other and coordinate immune responses. The most widespread HIV strand however uses CCR5 as an entry point to infect human cells. Good news is that if its binding to that receptor is disabled, the virus gets disarmed. This can happen due to a lack of that receptor or a structural change to it. A particularly abundant mutation to that receptor called CCR5-Δ32 (32 base pairs deleted rendering the receptor dysfunctional) arose spontaneously several thousand years ago and may now be present in as many as 1 in 10 Europeans. Studies on people who were born with this variation of that receptor proved they are indeed naturally protected from HIV3. In his experiment the Chinese researcher set out to induce that exact mutation in the twin girls.       

Once announced, the project evoked a storm of mixed feelings within the media and the entire scientific community. Some saw it as pioneering and the Chinese Central Television called He Jiankui “the founding father of genome editing”. Many remained sceptical and there was one person in particular concerned upon hearing that news – Jennifer Doudna, the co-recipient of the 2020 Nobel Prize in Chemistry for the development of the CRISPR/Cas9 method of genome editing. During her numerous press appearances over the past few years, she has been ringing alarm bells calling on fellow scientist to approach the technique with due enthusiasm but also with caution.   

In one of her dreams a colleague asked her to go and meet someone who’d very much like to learn more about CRISPR. She entered a dark room with a single back-turned chair and as the chair slowly rotated, she realized the person was Hitler. She woke up with a sense that she should become more vocal about the possible applications of genome editing. In the future it might be used to cure diseases, but it might also be used to make any other alterations to humans: from changing eye colour, through cognitive enhancements to greater muscle mass. soldiers who don’t feel fear or pain (guess which one the president of Russia seemed interested in). Doudna decided therefore to raise this concern to the public and call for possibly a moratorium and regulations to ensure that any edits to human embryos only happen where and when actually needed.

What’s “actually needed” however, means completely different things to different people. A good standard is however focusing on using genetic editing to cure life threatening or debilitating diseases to which there is no alternative therapy. 4 He Jiankui’s experiment lies somewhere within the grey area. Superficially, he backs his idea up by pointing out the significant social stigma associated with HIV in the Chinese culture. 

What he failed to point out at all in the reports is the role the CCD5 receptor plays in other biological contexts. The same kind of receptor is also present on the surface of cells other than T-lymphocytes. One of the most important areas where they are present are glial cells in the brain. In the central nervous system lower expression of CCR5 increases MAPK pathway signalling leading to increased potential of neurons for plasticity, overall learning and memory. This is also speculated to be caused by lower neuroinflammation after disactivating the CCR5 receptor. In practice, mice in which the expression of this receptor was knocked-out are more successful in remembering their way around a maze.5 It is not perfectly valid to extrapolate these results onto humans, but it won’t come as a surprise if, due to the edit made to their genes, Nana and Lulu will have better memory or cognition than their peers. 

Random cell surface markers are often associated with contagious diseases as they serve as a docking point for a virus from which it can carry on with its invasion. For Covid-19, that role happens to be assigned to the ACE2 – an enzyme attached to the surface of cells that serves mainly to lower blood pressure. The exact way in which that causes the extensive cardiovascular and respiratory symptoms associated with SARS-CoV-2 hasn’t been described yet. What is known, however, is that people who naturally have lower levels of that protein are less susceptible to infection6. Remembering that the enzyme serves its own purpose within the body, should we just go ahead and remove any fragment of the intricate puzzle that our metabolism is in an attempt to reduce the risk of transmission?

The bottom line is that editing even a single gene can have multiple effects, some of which are impossible to predict because of the complex interactions between different systems, pathways, and molecules in our body. The idea to modify T-cells using CRISPR in general is not an intrinsically bad one. Another cell surface marker CD95 promotes cell death in T-cells. A group of scientists from Connecticut is working on removing that gene in tumour fighting T-cells. This could hopefully enhance an organism’s own ability to fight cancer by creating a more durable and efficient immune response to tumors.7 The technology they are developing is looking at targeting only the specific subset of white blood cells dedicated to fighting tumours. This approach is more prudent than editing every cell in an organism like He Jiankui did. It is more responsible in the sense that by making edits to only a particular area of our physiology it minimizes the risk that the same edit could cause an unwanted effect in a different part of the body.   

Gene editing is inevitable. It’s been going on for a long time in history for agricultural purposes and now thanks to the discovery of the CRISPR/Cas9 method it can be studied for clinical applications. It is going to become a part of our reality and that’s not up to discussion. What is up to discussion however is when and why any edits are made and how much premeditation and preparation is done beforehand.   

References:

  1. Greely, Henry T. “CRISPR’d babies: human germline genome editing in the ‘He Jiankui affair’.” Journal of law and the biosciences vol. 6,1 111-183. 13 Aug. 2019, doi:10.1093/jlb/lsz010
  2. Lopalco, Lucia. “CCR5: From Natural Resistance to a New Anti-HIV Strategy.” Viruses vol. 2,2 (2010): 574-600. doi:10.3390/v2020574
  3. Ni, Jun et al. “The CCR5-Delta32 Genetic Polymorphism and HIV-1 Infection Susceptibility: a Meta-analysis.” Open medicine (Warsaw, Poland) vol. 13 467-474. 16 Oct. 2018, doi:10.1515/med-2018-0062
  4. Krimsky S. “Ten ways in which He Jiankui violated ethics.” Nat Biotechnol. 2019 Jan 3;37(1):19-20. doi: 10.1038/nbt.4337. PMID: 30605150.
  5. Zhou, Miou et al. “CCR5 is a suppressor for cortical plasticity and hippocampal learning and memory.” eLife vol. 5 e20985. 20 Dec. 2016, doi:10.7554/eLife.20985
  6. Ravaioli, Sara et al. “ACE2 and TMPRSS2 Potential Involvement in Genetic Susceptibility to SARS-COV-2 in Cancer Patients.” Cell transplantation vol. 29 (2020): 963689720968749. doi:10.1177/0963689720968749
  7. Chen, Xin et al. “Functional Interrogation of Primary Human T Cells via CRISPR Genetic Editing.” Journal of immunology (Baltimore, Md. : 1950) vol. 201,5 (2018): 1586-1598. doi:10.4049/jimmunol.1701616

Leave a Reply

Fill in your details below or click an icon to log in:

WordPress.com Logo

You are commenting using your WordPress.com account. Log Out /  Change )

Google photo

You are commenting using your Google account. Log Out /  Change )

Twitter picture

You are commenting using your Twitter account. Log Out /  Change )

Facebook photo

You are commenting using your Facebook account. Log Out /  Change )

Connecting to %s