Gene editing and gene therapy

The first principle

A cell does not tolerate a broken chromosome: when both strands of its DNA are cut, it rushes to repair the break, and the repair is where change enters. Gene editing exploits this. The tool only has to cut, or chemically nick, the right place among billions of letters, and the cell's own repair machinery writes the edit; gene therapy, the older idea, adds a working gene rather than fixing the faulty one. Everything in this note, from the cure for sickle cell disease to the ban on edited babies, follows from how precisely the place is found and how the repair is steered.

The core

CRISPR, the programmable cutter

• CRISPR began as a bacterial immune system. Bacteria store short pieces of viral DNA between Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR) in their own genome, copy them into RNA, and use that RNA to guide a CRISPR associated (Cas) enzyme to cut the same virus if it returns. Emmanuelle Charpentier and Jennifer Doudna showed in 2012 that this system could be reprogrammed to cut any chosen DNA, and they received the 2020 Nobel Prize in Chemistry.
• Two parts do the work. A guide RNA of about 20 bases is designed to match the target, and the Cas9 enzyme binds the guide, scans the genome and cuts both strands where the guide pairs, provided a short motif called the protospacer adjacent motif (PAM) sits next to the target. Changing the guide is enough to aim at a new gene, which made CRISPR far cheaper than the earlier zinc finger nucleases and TALENs, which needed a new protein for every target.
• The repair decides the edit. Non homologous end joining glues the ends back quickly and often adds or loses a few letters, which usually switches the gene off; homology directed repair copies a template the scientist supplies, so a precise change or a new sequence can be written in, though it works mainly in dividing cells and less often.

Editing without the break

• Base editing, reported by David Liu's laboratory in 2016, joins a disabled Cas9 that cannot cut both strands to an enzyme that chemically converts one base into another, C to T or A to G, so a single point mutation can be corrected without a double strand break.
• Prime editing, reported in 2019, adds a reverse transcriptase and a longer guide that carries the new sequence, so small insertions, deletions and all twelve kinds of single letter change can be written directly.
• The trade off is reach against risk. Fewer breaks mean fewer unwanted large deletions and rearrangements, but the newer editors are larger and harder to deliver into cells.

Gene therapy

• Gene therapy treats disease by adding, silencing or correcting genes in a patient's cells. Somatic therapy changes only the patient's body cells and is not inherited, while germline editing changes eggs, sperm or embryos so that the change passes to every later generation.
• Delivery is the hard part. Adeno associated viruses (AAV) carry a gene into cells without joining the chromosome and are used for therapy inside the body (in vivo); lentiviruses, derived from HIV but disabled, insert the gene into the chromosome and are used to modify cells outside the body (ex vivo), which are then returned; lipid nanoparticles, the same carriers used for mRNA vaccines, deliver editors to the liver.
• CAR T cell therapy is ex vivo gene therapy against cancer. A patient's T cells are taken out, given a gene for a chimeric antigen receptor (CAR) that recognises a protein on cancer cells, multiplied and infused back, where they hunt the cancer; the stem cells note covers India's own CAR T product.

Dimensions

• Medical. About 7,000 rare diseases are known, most of them genetic and many caused by a single faulty gene, and gene therapy is the first approach that treats the cause rather than the symptoms; the first CRISPR medicine, Casgevy for sickle cell disease and beta thalassaemia, was approved in the United Kingdom in November 2023 and in the United States in December 2023.
• Agricultural. Editing a crop's own genes gives the traits breeders want without adding foreign DNA, and India took such plants out of the genetically modified approval process in 2022, which the GM crops note covers.
• Ethical. Germline editing affects people who cannot consent and changes the human gene pool, and the line between treating disease and enhancing traits such as height or intelligence is hard to hold once the tools exist.
• Economic and equity. Approved gene therapies cost from about one to over three million United States dollars per patient abroad, so the question for India is whether they can be made at a price its patients and public schemes can pay.
• Ecological. A gene drive is an edit built to copy itself onto the partner chromosome, so it spreads to nearly all offspring instead of half; it could collapse populations of malaria mosquitoes, but a release into the wild cannot be called back.

In practice

• The global markers. The first approved gene therapy trial, in 1990 in the United States, treated a girl with an inherited immune deficiency; the death of Jesse Gelsinger in a trial in 1999 slowed the field for a decade; and in November 2018 the Chinese scientist He Jiankui announced twin girls whose embryos he had edited, an act condemned worldwide for which a Chinese court jailed him in 2019. The World Health Organization (WHO) issued recommendations on governing human genome editing in 2021, including a global registry of trials.
• India's rules. The National Guidelines for Gene Therapy Product Development and Clinical Trials, issued in 2019 by the Indian Council of Medical Research (ICMR), the Department of Biotechnology (DBT) and the Central Drugs Standard Control Organisation (CDSCO), treat every gene therapy as a new drug needing CDSCO approval, set up a Gene Therapy Advisory and Evaluation Committee, and forbid germline therapy; the National Guidelines for Stem Cell Research of 2017 also list germline gene therapy and human reproductive cloning as prohibited.
• Sickle cell disease. It is caused by a single letter change in the beta globin gene and is common in tribal communities of central, western and southern India, which is why the National Sickle Cell Anaemia Elimination Mission, launched in July 2023, aims to end it as a public health problem by 2047. The Council of Scientific and Industrial Research's Institute of Genomics and Integrative Biology (CSIR-IGIB) engineered a more precise Cas9 from the bacterium Francisella novicida, called enFnCas9, and in November 2025 the government launched BIRSA 101, a CRISPR therapy for sickle cell disease built on it, with the Serum Institute of India as the partner for manufacture; it had been tested in three patients in a first phase trial at that point, so it is not yet a licensed treatment.
• Haemophilia A. The Centre for Stem Cell Research at Christian Medical College, Vellore, with DBT support, treated five patients with severe haemophilia A using their own blood stem cells given a working clotting factor VIII gene by a lentiviral vector, and reported in December 2024 that none had a bleeding episode during follow up.
• Crops. The Ministry of Environment, Forest and Climate Change exempted genome edited plants without foreign DNA from the biosafety rules for genetically engineered organisms in March 2022, and in May 2025 the Indian Council of Agricultural Research released India's first two genome edited rice varieties.

Issues and way forward

• Off target edits and mosaicism. A guide can bind a similar sequence elsewhere and cut it, and in an embryo not every cell may take the edit, so long term follow up and whole genome checks of edited cells are required; high fidelity enzymes such as enFnCas9 and the base and prime editors reduce, but do not remove, the risk.
• Delivery and immunity. Many people already carry antibodies to AAV or to Cas9, which comes from bacteria that commonly infect humans, so a therapy may fail or provoke reactions; better non viral carriers and editing cells outside the body are the current answers.
• Cost and manufacture. Ex vivo therapy needs a stem cell transplant, chemotherapy to clear the marrow and a sterile facility for each patient; the way forward is Indian manufacture, as NexCAR19 showed for CAR T, and bringing approved therapies under schemes for rare diseases.
• Regulation by guideline. India's gene therapy rules are guidelines, not a statute, and the line between research and treatment is enforced through drug law; a clear legal ban on clinical germline editing and a public registry of trials, as WHO recommended in 2021, would close gaps.
• Equity and consent. Sickle cell research draws on tribal patients, so consent in their own language and access to the therapy once approved must be planned from the start.

Common confusions

• Gene therapy and gene editing. Gene therapy is any treatment that works by changing genes, often by adding a working copy, while gene editing is one way of doing it, by changing the patient's own sequence at a chosen place.
• Somatic and germline. Somatic changes stay in the patient, while germline changes are inherited; the first is allowed in approved trials in India and the second is prohibited.
• Genome editing and genetic modification. A genetically modified organism carries foreign DNA, while an edited organism may differ from the original by a few letters that could also arise naturally, which is why India's rules treat them differently.
• Ex vivo and in vivo. Ex vivo therapy edits cells in a laboratory and returns them, as in Casgevy and CAR T, while in vivo therapy sends the vector or editor into the body, as with AAV therapies for the eye or the liver.
• Base editing and prime editing. Base editing changes one letter chemically, while prime editing writes a short new sequence from a template; neither cuts both strands.

For the exam

• Keyword bank: CRISPR-Cas9, guide RNA, PAM, double strand break, non homologous end joining, homology directed repair, base editing, prime editing, off target effect, AAV and lentiviral vectors, ex vivo therapy, CAR T cells, germline editing, gene drive, enFnCas9.
• Previous year questions: Practise the previous year questions on this topic →
• Use in an answer:
  • Introduction with data: Sickle cell disease is caused by a change in a single letter of the beta globin gene, and its burden in India's tribal districts is why the country launched its first indigenous CRISPR therapy, BIRSA 101, in November 2025.
  • Introduction with a source: The National Guidelines for Gene Therapy Product Development and Clinical Trials of 2019 treat every gene therapy as a new drug and prohibit germline therapy, drawing India's line between healing a patient and changing the species.
  • Conclusion: Gene editing has moved from a bacterial curiosity to an approved cure in a decade; India's task is to make it affordable for the patients who need it most, under rules with the force of law.
  • Conclusion: The same precision that lets CRISPR cure a disease lets it change heredity, so the science needs to advance alongside a clear prohibition on clinical germline editing.