CUT & PASTE

THE STORY OF CRISPR-CAS9 AND WHY GENE EDITING WILL CHANGE EVERYTHING

In the 1997 science fiction film Gattaca, normal human beings are deemed as inferior to an upper class of genetically engineered “valid” humans, all with 20/20 vision, perfect skin and teeth, superior athleticism and intelligence and no genetic predisposition to genetic disease.

Fast-forward about 20 years: Chinese scientists have just announced (in November) that they were the first to use a revolutionary gene-editing technique called CRISPR-CAS9 to inject gene-altered cells into a living person, a patient with aggressive lung cancer. This, according to Nature, is part of a groundbreaking clinical trial at the West China Hospital in Chengdu that will likely kick off “Sputnik 2.0”, a biomedical space race between China and the US to see who can get gene-edited cells into the clinic first. Gene editing, and soon genetic enhancement in humans, has suddenly become a reality.

Genetic modification has been with us for a while, but the CRISPR-CAS9 technique has made gene editing vastly cheaper, quicker,

extremely precise and – crucially – quite easy. As the narrator of an eyeopening video on the subject by the Kurzgesagt Youtube channel said: “Anyone with a lab can do it.” The implications are staggering. With CRISPR-CAS9, scientists will be able to prevent a myriad genetic diseases, quite possibly cure HIV and several types of cancer within a couple of decades, create drought-resistant crops and animals and, yes, eventually also create designer babies.

This raises important moral and ethical questions that scientists have only just begun to address. Is it ethical to change the genetics of a human embryo before birth? If such gene editing can prevent suffering later in life, is it ethical not to do it? These are questions that humans will, thanks to CRISPR-CAS9, have to face sooner than most people expected. molecule called RNA, an exact replica of the viral DNA sequence. RNA is a chemical cousin of DNA, and it allows interaction with DNA molecules that have a matching sequence.

So those little bits of RNA bind to the Cas9 protein to form a complex that functions like a sentinel in the cell. It searches through all the DNA in the cell, to find sites that match the exact target sequence in the bound RNA. When those sites are found, confirming the presence of a virus, CRISPR lets loose the Cas9 protein, which is equipped with little cleaver-like arms, to cut up the viral DNA to make a very precise double-stranded break in the DNA helix to effectively deal with the virus.

This complex is programmable, so it can be preconfigured to recognise particular DNA sequences, thanks to the so-called “guide RNA” (the copy of the target DNA sequence), and make a break in the DNA at the appropriate site. Doudna and Charpentier recognised that this activity could be harnessed for genome engineering, to allow cells to make very precise changes to DNA at the site where these breaks are introduced.

“The reason we envisaged using the CRISPR system for genome engineering is because cells have the ability to detect broken DNA and repair it,” said Doudna in a 2015 TED talk. “So, if we were able to program the CRISPR technology to make a break in DNA at the position at or near a mutation causing cystic fibrosis, for example, we could trigger cells to repair that mutation.

“We can think of older genome engineering technologies as similar to having to rewire your computer each time you want to run a new piece of software, whereas the CRISPR technology is like software for the genome – we can program it easily, using these little bits of RNA. So once a double-stranded break is made in DNA, we can induce repair, and thereby potentially achieve astounding things, like being able to correct mutations that cause sickle cell anaemia or Huntington’s Disease.”