Even in times as grim as the current global scenario, a few science stories offer hope and optimism. One such story is that of CRISPR-Cas9—a gene-editing system that can influence the genes that get expressed in plants, animals and even humans.

One can think of CRISPR-Cas9—where CRISPR stands for Clustered Regularly Interspaced Short Palindromic Repeats and Cas9 denotes CRISPR-associated protein 9—as a pair of molecular scissors that can snip away the faulty genes and replace them with desirable ones. Generally speaking, CRISPRs (pronounced crispers) are DNA sequences that are part of the defence mechanism of bacteria and other microorganisms.

In the past five years or so, researchers have discovered how bacteria use the CRISPR-Cas9 system to protect themselves from viruses. Through this system, bacteria are able to unarm the virus by editing and influencing the genes that get expressed. Although CRISPR-Cas9 is primarily known for its use in treating diseases like AIDS, amyotrophic lateral sclerosis (or ALS, the one that afflicted the late Stephen Hawking) and Huntington’s disease, researchers are now looking at furthering its use to tackle famine, lending a hand in creating antibiotics, and even wiping out an entire species such as the malaria-spreading mosquitoes.

In 2016, Yinong Yang, a researcher at Penn State University used CRISPR-Cas9 to edit a particular gene in a white button mushroom so that it does not brown easily.

We later learnt that even blood diseases can benefit from the use of CRISPR-Cas9, specifically sickle-cell anaemia. Such is the popularity of the DNA editing system that cancer-related trials are being planned in the US and China.

The glaring issue with CRISPR-Cas9

Perhaps the one characteristic that renders CRISPR-Cas9 problematic is its “state of permanency". What happens when it permanently edits out an unintended gene target, thus pushing those very edits to future generations as well?

Such is the popularity of the DNA editing system that cancer-related trials are being planned in the US and China-

This very nature of the system has researchers worrying as CRISPR-Cas9 has faced problems where it modified unintended DNA targets. Think about possible implications of this phenomenon if it were to take place with human embryos. CRISPR-Cas9 could very well be a loaded gun that keeps missing crucial targets and, instead, inflicts grave harm where it shouldn’t.

In one such study where an entire genome of mice that had undergone CRISPR-Cas9 gene-editing was sequenced and analysed to check for mutations, a problem was detected.

Even though the system had correctly altered a blindness causing gene, it had left behind 1,500 single-nucleotide mutations and more than 100 deletions or insertions. This was detected by Kellie Schaefer, a PhD student at Stanford University. The most startling discovery was that the most widely used computer algorithms never predicted these DNA mutations. However, steps are being taken to modify and update this system to make it safer to use.

Shiny new tools

To overcome these worrisome problems with CRISPR-Cas9, there are two new tools that propose a solution. One is called REPAIR and it comes straight from researchers at the Massachusetts Institute of Technology and Harvard University. REPAIR turns its focus on modifying RNA instead of DNA and uses the enzyme Cas13 to edit RNA. What you need to understand about RNA is that it’s imperative in the transformation of a gene into protein. Without RNA, DNA cannot carry out the instructions encoded in cells. The reason researchers are heaving a sigh of relief with REPAIR is because the changes made to RNA are reversible due to its ephemeral nature, thus overcoming the safety concerns.

The second tool, known as Adenine Base Editor (ABE), involves the use of individual DNA “base-pairs". DNA contains information for forming proteins and they are expressed in four letters: cytosine (C), guanine (G), thymine (T) and adenine (A). These base pairs involve the formation of bonds—C with G and T with A.

Diseases like sickle-cell anaemia are caused due to a single mutation in either of these base pairs. The new tool can help fix that single point mutation—without the need for snipping—and is far more effective than its predecessor.

Ethical issues

The debate around CRISPR-Cas9 has been rife with questions about the future possibility of engineering human beings and the ethical ramifications of it, not to mention the possibility of designer babies.

Another problem: unintended consequences of gene-editing in human beings, including the fear of passing down the changes to future generations unknowingly.

However, these are still far off in the future and researchers are currently focused on constantly improving the existing CRISPR-Cas9 systems to tackle diseases and environmental issues that could do with a helping hand.

Pranav Anam is co-founder of the Gene Box, a genetics-based healthcare platform.

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