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✂️Biology8 min read

CRISPR

In 2012, scientists adapted a bacterial immune system into a tool that can find any sequence in a genome of three billion letters, cut it precisely, and rewrite it. It works in any living cell. It costs less than £100. It took the world eleven years to go from discovery to a cure for sickle cell disease.

In plain English

Your genome is a text: three billion letters, written in four-character code (A, T, G, C), encoding every protein your body makes. For decades, reading that text was the challenge. Then came sequencing. Writing it, making precise changes, was the next frontier.

Before CRISPR, gene editing existed but was expensive, slow, and imprecise. The tools available could find a general location in the genome but often cut the wrong place, and engineering them for each new target took months and cost tens of thousands of pounds.

CRISPR-Cas9 changed all of this. The "search" function is a short strand of RNA, cheap to design and synthesise, changed in a day. The "cut" function is a protein called Cas9, a molecular scissors. You attach the guide RNA to the Cas9, introduce them to a cell, and the complex scans the genome at high speed until it finds the exact sequence you specified, one match among three billion letters, and cuts the DNA there.

The cell tries to repair the cut. If you do nothing else, the repair is imperfect and the gene is disabled. If you also introduce a template, the cell can use it to repair the cut with your new sequence: a precise edit, a correction, a replacement.

The whole system came from bacteria. Bacteria use a related mechanism as an immune memory, storing snippets of viral DNA so they can recognise and destroy the virus if it attacks again. Jennifer Doudna and Emmanuelle Charpentier recognised that this mechanism could be repurposed as a universal editing tool. Their 2012 paper describing the system was published in Science. In 2020, they received the Nobel Prize in Chemistry.

Five things to file under "wait, what?"

  • A CRISPR experiment that would have taken years in 2010 now takes weeks and costs under £100. The guide RNA that directs the Cas9 to the target sequence can be designed on a laptop in minutes and synthesised overnight for trivial cost. This has democratised genetic research in a way no other tool has. Labs that could never have afforded gene editing experiments now routinely use CRISPR. The speed and accessibility of the technology have compressed the timeline between discovery and application in a way no earlier tool matched.

  • In 2023, the first CRISPR therapy was approved for sickle cell disease. Sickle cell disease is caused by a single mutation in the haemoglobin gene, one wrong letter out of three billion. For decades it was considered incurable. Casgevy, developed by Vertex Pharmaceuticals and CRISPR Therapeutics, uses CRISPR to reactivate foetal haemoglobin production in patients' stem cells, compensating for the defective adult haemoglobin. In clinical trials, 97% of patients had no severe pain crises for at least twelve months. Eleven years after Doudna and Charpentier's discovery paper, a cure for a previously untreatable genetic disease had reached clinical approval.

  • A rogue scientist used CRISPR to edit human embryos in 2018 and went to prison. He Jiankui, a Chinese biophysicist, secretly used CRISPR to edit the CCR5 gene in human embryos, which were then implanted and resulted in live births. His stated aim was to make the children resistant to HIV infection. He did not have informed consent adequate to the intervention, had not received ethical approval, and the scientific rationale was contested. He was sentenced to three years in prison in China. The children, twin girls and subsequently a third child, carry germline edits that will be inherited by their own children. The scientific community's response was near-universal condemnation. The case crystallised the bioethical stakes of germline editing in a way no theoretical discussion had.

  • CRISPR has already been used to create hornless cattle, disease-resistant pigs, and drought-tolerant crops. In agriculture, CRISPR allows targeted modifications that would previously have required decades of selective breeding or the introduction of foreign DNA (which triggers GMO regulations). Editing within a species' own genome, disabling a gene rather than adding a new one, falls in a regulatory grey zone in many countries. Hornless cattle (eliminating the dangerous and painful process of dehorning) were created using CRISPR in 2016. Pigs resistant to African swine fever are in development. Wheat with resistance to powdery mildew has been produced by editing susceptibility genes.

  • CRISPR is already being used to try to revive the woolly mammoth. Colossal Biosciences, founded in 2021, has raised over $220 million to develop the technology to introduce mammoth traits, cold resistance, fat storage, thick fur, into Asian elephant cells using CRISPR, eventually producing an "elephant-mammoth hybrid" suited to Arctic conditions. The scientific and ecological rationale (restoring grassland ecosystems that sequester carbon) is supported by some ecologists; the timeline (first calves within years, not decades) is disputed by others. Whether or not it succeeds, it illustrates that the technology has moved beyond medicine and agriculture into territory that was previously science fiction.

The full story

How it actually works

The Cas9 protein is a large molecular machine with two cutting domains, each capable of cleaving one strand of the DNA double helix. Alone, it is inactive. Paired with a guide RNA, a roughly 20-nucleotide sequence designed to match the target, it becomes a precision instrument.

The guide RNA has two parts: a scaffold sequence that attaches to the Cas9, and a variable spacer sequence, the part you design, that matches the target DNA. The Cas9-guide RNA complex unwinds DNA and reads it as it goes, checking whether the spacer matches what it finds. When it finds a match, it makes a double-strand break: both strands of the DNA helix are cut.

The cell responds to a double-strand break immediately. There are two main repair pathways. Non-homologous end joining (NHEJ) is fast and error-prone: it reconnects the cut ends but often introduces small insertions or deletions that disrupt the gene's function. Homology-directed repair (HDR) uses a template to repair the break precisely, but requires a template to be present and is less efficient. CRISPR can exploit either pathway depending on whether gene disruption or precise replacement is the goal.

The base editors and prime editors

Since 2012, the toolkit has expanded substantially. Base editors, developed by David Liu's lab at Harvard, do not cut the DNA at all. Instead, they chemically convert one DNA letter to another (A to G, C to T) without making a double-strand break. This is safer in many applications and enables correction of the large class of genetic diseases caused by single-letter mutations.

Prime editing, also from Liu's lab (2019), uses a modified Cas9 and a specially designed guide RNA to write new genetic information directly into a specific genomic location, a "search and replace" rather than "cut and patch." Prime editing can make all 12 types of point mutation as well as small insertions and deletions, with fewer off-target effects than standard CRISPR. It is the most versatile editing approach currently available.

The ethics

The He Jiankui case exposed the inadequacy of existing ethical frameworks for a technology that was moving faster than regulation. The scientific community's response, condemnation, investigation, and calls for a global moratorium on germline editing, reflected genuine alarm.

The core distinction in the ethics is between somatic editing (changing cells in a living person, affecting only that person) and germline editing (changing an embryo or reproductive cells, so the changes are inherited by all subsequent generations). Somatic editing, which is what the sickle cell therapy does, is broadly accepted, subject to the same ethical framework as other medical interventions. Germline editing is categorically different: it affects people who have not consented, including people not yet born.

Beyond the germline question, CRISPR raises issues of access and equity. If gene therapies can eliminate certain genetic diseases, who will have access to them? The first approved CRISPR therapy for sickle cell disease was priced at $2.2 million per patient in the US. Sickle cell disease disproportionately affects people of African, South Asian, and Middle Eastern descent, populations with, on average, less access to high-cost medical care. The technology that could eliminate the disease may be available only to the wealthy.

What comes next

The pipeline of CRISPR therapies in clinical trials is long: Huntington's disease, several forms of cancer, transthyretin amyloidosis (a fatal heart condition), high cholesterol, HIV. In vivo editing, delivering CRISPR directly to cells inside the body rather than editing cells extracted in a lab, is in early trials for liver diseases and beginning to be tested for other organs.

Beyond medicine, CRISPR-based diagnostics, using the Cas proteins' ability to detect specific DNA sequences to create cheap, rapid tests for infectious diseases, saw rapid development during the COVID-19 pandemic.

The technology is eleven years old. The pace of development makes it difficult to project what a further eleven years will look like. The ability to read, write, and edit the genome at arbitrary positions in any living organism has changed biology permanently.

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