历史
基因编辑的历史
从DNA结构的发现到首个获批的CRISPR药物——带领这一领域走到今天的种种发现、争论与决策。
23 条事件，每条均附来源。日期为发布日期或官方决定日期，而非实际工作完成的日期。
时代
Foundations
The structure of DNA is described
Watson and Crick publish the double helix, using X-ray diffraction data produced by Rosalind Franklin and Maurice Wilkins. The complementary base pairing they describe immediately suggests how genetic information is copied — and is the reason a short RNA guide can find one sequence among three billion letters.
来源: Nature ↗
Recombinant DNA is created
Paul Berg combines DNA from different sources, opening genetic engineering and prompting the scientific community to convene the 1975 Asilomar conference on self-governance — the template every later biotechnology governance debate has referred back to.
来源: PNAS ↗
Strange repeats are noticed in bacterial DNA
Yoshizumi Ishino's group in Osaka reports unusual repeated sequences in E. coli while studying an unrelated gene. Nobody knows what they are for, and it will be nearly twenty years before anyone finds out.
The Human Genome Project is completed
After thirteen years and roughly $2.7 billion, the human genome sequence is declared complete. Editing without a reference sequence would be nearly impossible; the cost of sequencing has since fallen by about six orders of magnitude.
CRISPR spacers are recognised as viral in origin
Francisco Mojica reports that the sequences between CRISPR repeats match bacteriophage DNA, proposing that the arrays are an adaptive immune memory. The paper was rejected by several journals before publication.
CRISPR is proved to be a bacterial immune system
Working at a company producing yogurt cultures, Barrangou and Horvath show experimentally that bacteria acquire phage resistance by capturing viral sequence into their CRISPR arrays.
来源: Science ↗
时代
Early engineering
Zinc finger nucleases are invented
Chandrasegaran's group fuses zinc finger DNA-binding domains to the FokI cutting domain, creating the first programmable gene-editing tool — the beginning of targeted genome editing as a discipline.
来源: PNAS ↗
The first human gene-editing clinical trial begins
Sangamo's zinc finger nuclease programme disrupts CCR5 in the T cells of people with HIV — the first time a targeted, permanent genetic edit is made in a patient's cells. Three years before CRISPR is shown to be programmable.
TALENs make targeted editing routine
Modular TALE proteins, each repeat recognising one DNA letter, make custom nucleases far easier to design than zinc fingers. They remain in clinical use and are still the route to editing mitochondrial DNA.
时代
CRISPR era
Cas9 is shown to be programmable
Jinek, Charpentier, Doudna and colleagues demonstrate that Cas9 can be directed to cut chosen DNA by a guide RNA, and engineer the single guide RNA that makes the system practical. Šikšnys publishes closely related work at almost the same time.
来源: Science ↗
CRISPR is shown to work in human cells
Feng Zhang's and George Church's laboratories independently publish CRISPR editing in human cells in the same issue of Science. Within a year the technique is in use in laboratories worldwide.
来源: Science ↗
The first patient is treated with gene-edited cells
Clinicians at Great Ormond Street Hospital treat an infant with relapsed leukaemia using TALEN-edited donor T cells under compassionate use, after conventional treatment fails. She goes into remission.
Base editing is invented
David Liu's laboratory publishes cytosine base editing — changing a single DNA letter chemically, without cutting both strands. Adenine base editors follow in 2017, requiring the directed evolution of an enzyme that does not exist in nature for DNA.
来源: Nature ↗
Gene-edited children are born, to global condemnation
He Jiankui announces the birth of twins from embryos in which CCR5 was edited. There was no unmet medical need, consent was found to be deficient, the editing was mosaic, and the changes are heritable. He is convicted in China and imprisoned. The episode reshapes global governance of the field.
Prime editing is invented
Anzalone and Liu publish search-and-replace editing: writing chosen new sequence directly into a site without cutting both strands, in principle covering the large majority of known pathogenic variants.
来源: Nature ↗
时代
Clinical era
The Nobel Prize in Chemistry is awarded for CRISPR
Emmanuelle Charpentier and Jennifer Doudna share the prize for the development of a method for genome editing — eight years after the paper, an unusually short interval for the Nobel committee.
CRISPR is delivered into a human bloodstream for the first time
Intellia and Regeneron report that NTLA-2001, infused into patients with ATTR amyloidosis, reduced the target protein substantially — the first systemic in vivo administration of CRISPR in humans.
The first CRISPR medicine is approved
The UK MHRA authorises Casgevy in November 2023 for sickle cell disease and beta thalassemia; the FDA follows in December for sickle cell disease and in January 2024 for thalassemia. Eleven years after the founding paper, gene editing becomes medicine.
A gene-editing medicine is made for a single patient
An infant with severe CPS1 deficiency receives a base editor designed, manufactured and authorised specifically for his own mutation, roughly six months after diagnosis. He improves and is discharged.
Prime editing works in patients
Results from PM359 in chronic granulomatous disease are published: prime-edited stem cells engraft and restore the immune function the patients lacked. The first clinical evidence for the technique.
A death in an in vivo editing trial leads to a clinical hold
A participant in the Phase 3 MAGNITUDE trial develops severe liver injury after dosing and dies. Intellia pauses dosing voluntarily and the FDA imposes a clinical hold on both MAGNITUDE studies; the hold on MAGNITUDE is later lifted. The field's clearest reminder that a permanent treatment cannot be withdrawn.
Regulators open a path for one-patient therapies
The FDA reduces the default requirement from two adequate and well-controlled trials to one, and issues draft guidance on individualised therapies for ultra-rare diseases under which improvement in a single participant could, in defined circumstances, support approval.
来源: Fierce Biotech ↗
In vivo gene editing succeeds in a Phase 3 trial
Intellia reports positive Phase 3 results for lonvoguran ziclumeran in hereditary angioedema — described as the first successful registrational trial of gene editing performed inside the body — with a licence application signalled for the second half of the year.