These Scientists Deserved A Nobel Prize, But Didn’t Discover Crispr

Jennifer Doudna and Emmanuelle Charpentier have won the 2020 Nobel Prize in Chemistry "for the development of a method for genome editing."

The method, often simply called 'Crispr', has revolutionized molecular biology. For example, it lets scientists target DNA to make genetically-modified organisms that serve as more realistic animal models for studying diseases like cancer. Crispr also has potential applications in improving human health through gene therapy, to correct mutations that cause inherited conditions like muscular dystrophy.

In the press release, the Royal Swedish Academy of Sciences claims that Doudna and Charpentier "discovered the Crispr/Cas9 genetic scissors." Besides being a clumsy phrase, that statement isn't strictly true. No, the pair did not "discover" Crispr.

So why do the two female scientists deserve the Nobel Prize?

What is Crispr exactly?

Crispr itself is technically a sequence of chemical letters in DNA. The acronym ‘CRISPR’ stands for 'Clustered Regularly Interspaced Short Palindromic Repeats'.

In nature, Crispr is half of a defence system that enables bacteria and archaea to remember and adapt to invading viruses. That adaptive immune system will cut-up the genetic material a virus injects into a microbial cell, which then pastes bits of material into its own DNA, like a memory or 'Wanted poster' that allows the microbe to rapidly recognize and destroy similar viral invaders.

The ofter half of the system are the enzymes that do the cutting and pasting. One of the most important is 'Crispr-associated protein 9' or 'Cas9' — which, together with the Crispr sequences saved in DNA, forms the Crispr-Cas9 system.

How does gene editing work?

Scientists modified the natural system to create an artificial tool that can harness Crispr-Cas9's power to recognize, cut and edit DNA.

In the lab, a Crispr system is used to target and cut a specific sequence of DNA letters then delete or insert genetic material — even an entire gene — into that exact location, which results in precise genome editing.

The cutting process is key as it prompts repair machinery to fix the break in DNA. Like photos used in reconstructive surgery, the cell's machinery needs a template to repair what's missing. That template is provided by a short piece of genetic material carried by the Cas9 protein, a 'guide RNA'.

Why did the two scientists win?

Two men can be credited with discovering of Crispr: Yoshizumi Ishino detected "unusual DNA" inside bacteria in 1987 and in 1993 Francisco Mojica described it as "repetitive". Researchers only realized it was an immune system in the mid-2000s.

Structural biologist Jennifer Doudna and microbiologist Emmanuelle Charpentier were instrumental in turning Crispr into a tool. In 2012, biochemist Virginijus Šikšnys had shown that 'crRNA' — an RNA copy of a Crispr DNA sequence — could be customized to direct Cas9 to cut new DNA targets. The guide RNA that cells use as a template to fix DNA consists of 'crRNA' and another component: 'tracrRNA'.

After Charpentier uncovered tracrRNA in the bacterium Streptococcus pyogenes (Yes, here you could say "discovered") in 2011, she and Doudna fused crRNA with tracrRNA to create a single guide RNA, or 'sgRNA'. That 2012 breakthrough meant that researchers only need to redesign one component — sgRNA — to create molecular scissors that can be programmed to target a specific DNA sequence, leading to a simple yet powerful gene-editing tool.

Who deserved the Prize?

Two other men are often mentioned as 'inventors' of Crispr, partly due to an ongoing patent battle over the technology. In 2013, bioengineer Feng Zhang and geneticist George Church independently showed that a system can be used to edit DNA in mammals, arguably the most challenging technical hurdle.

Like many recent discoveries, however, the history of Crispr research is biased toward senior scientists and (as Church pointed out) it ignores the contribution of junior researchers who conceive and carry out experiments, the unsung heroes.

Almost every Nobel Prize comes with controversy. This year's award marks the first time two women have shared a prize without a male recipient, but you could argue that Šikšnys deserved to share the glory. Relative to past awards, however, the 2020 Chemistry prize is one of the least controversial.

Making it easy to design an RNA guide so Crispr can target specific DNA means that, compared to rival genome editors, unintended 'off-target' effects will be relatively rare. For their role in developing programmable molecular scissors, and because prizes are only awarded to individuals, Doudna and Charpentier are worthy winners.