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Genetic Engineering / Beyond CRISPR

From cutting DNA to rewriting it. A field-tour of base editors, prime editors, epigenetic switches, gene drives, and the engineered organisms that will...

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From cutting DNA to rewriting it. A field-tour of base editors, prime editors, epigenetic switches, gene drives, and the engineered organisms that will define the next decade of biology. Key sections include: GENETIC ENGINEERING Beyond CRISPR; CRISPR-Cas9, 2012; Base editing — change one letter, never break the strand; Prime editing, 2019; Epigenetic editing — turn genes on or off, no scissors; Delivery is the bottleneck; Approved therapies, today; Heritable editing — He Jiankui, 2018; Gene drives — edits that copy themselves; Xenotransplantation, edited.

Key sections

  • 01GENETIC ENGINEERING Beyond CRISPR
  • 02CRISPR-Cas9, 2012
  • 03Base editing — change one letter, never break the strand
  • 04Prime editing, 2019
  • 05Epigenetic editing — turn genes on or off, no scissors
  • 06Delivery is the bottleneck
  • 07Approved therapies, today
  • 08Heritable editing — He Jiankui, 2018
  • 09Gene drives — edits that copy themselves
  • 10Xenotransplantation, edited
  • 11De-extinction
  • 12The honest assessment
  • 13References & further viewing

Topics covered

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Slide outline
  1. 01GENETIC ENGINEERING Beyond CRISPR
  2. 02CRISPR-Cas9, 2012
  3. 03Base editing — change one letter, never break the strand
  4. 04Prime editing, 2019
  5. 05Epigenetic editing — turn genes on or off, no scissors
  6. 06Delivery is the bottleneck
  7. 07Approved therapies, today
  8. 08Heritable editing — He Jiankui, 2018
  9. 09Gene drives — edits that copy themselves
  10. 10Xenotransplantation, edited
  11. 11De-extinction
  12. 12The honest assessment
  13. 13References & further viewing
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Slide 01

GENETIC ENGINEERING Beyond CRISPR

  • A 13-Slide Briefing · 2026
  • From cutting DNA to rewriting it. A field-tour of base editors, prime editors, epigenetic switches, gene drives, and the engineered organisms that will define the next decade of biology.
  • K. Ning
  • ·
  • Catalog Series
  • ·
  • 13 Slides
Slide 02

CRISPR-Cas9, 2012

  • Slide 02 · The Base Layer
  • A bacterial immune system, repurposed by Doudna and Charpentier into a programmable molecular scalpel. Give it a 20-letter RNA guide and it cuts that exact spot in any genome — bacteria, plant, mouse, human.
  • Programmable: swap the guide RNA, change the target.
  • Cheap: reagents cost a graduate student less than lunch.
  • Blunt: double-strand breaks heal messily; the cell improvises.
  • Foundational: every editor on the next slides is built on Cas9.
Slide 03

Base editing — change one letter, never break the strand

  • Slide 03 · Single-Letter Surgery
  • David Liu's lab, 2016. Take a deactivated Cas9 (it can find but not cut), bolt on a deaminase enzyme, and you can flip a single C to T or A to G. Most known disease mutations are point mutations — this addresses them directly.
  • CBE
  • Cytosine Base Editor
  • Converts C·G to T·A. The first base editor; useful for installing stop codons or disrupting splice sites.
  • ABE
  • Adenine Base Editor
  • Converts A·T to G·C. Engineered from a tRNA deaminase — nature didn't have a DNA version, so the lab built one.
  • Why it matters
  • No double-strand breaks
  • Far fewer indels, translocations, large deletions. The cell's repair machinery never gets to improvise.
  • Verve Therapeutics, 2022: first in-human base editing trial. One injection, lifelong cholesterol reduction by editing PCSK9 in liver cells.
Slide 04

Prime editing, 2019

  • Slide 04 · Search and Replace
  • Liu lab again. Cas9 nickase (cuts only one strand) fused to a reverse transcriptase, guided by an extended pegRNA that encodes the new sequence. The cell rewrites itself to match the template.
  • Can install any single-letter swap, plus small insertions and deletions.
  • Estimated to address ~89% of known pathogenic human variants.
  • Twin Prime, PASTE, and other variants now insert whole genes.
  • First clinical trials began 2024 (Prime Medicine, chronic granulomatous disease).
  • BEFORE
  • 5'... A T G C A G T A C ...3'
  • 3'... T A C G T C A T G ...5'
  • ↓ pegRNA template
  • AFTER
  • 5'... A T G G G T T A C ...3'
  • 3'... T A C C C A A T G ...5'
  • A precise three-letter substitution — no double-strand break, no donor template required.
Slide 05

Epigenetic editing — turn genes on or off, no scissors

  • Slide 05 · The Volume Knob
  • Fuse dead Cas9 to a transcription activator (VPR), repressor (KRAB), or methyltransferase (DNMT3A). The DNA sequence is preserved; only the chemical marks around it change. The cell keeps the new setting through divisions.
  • CRISPRa activate
  • dCas9-VPR recruits the transcription machinery; turn a gene up 10x to 1000x without touching its sequence.
  • CRISPRi interfere
  • dCas9-KRAB blocks transcription — reversibly silence a gene. Tunable, and you can switch it back.
  • CRISPRoff durable
  • A 2021 fusion that writes methyl marks — one transient hit, silencing that propagates through cell divisions.
  • The pitch: for many diseases (pain, cardiovascular risk, addiction) you don't want to permanently rewrite the genome — you want to dial the volume. Tune Therapeutics is in trials silencing PCSK9 and Hep B this way.
Slide 06

Delivery is the bottleneck

  • Slide 06 · The Hard Part
  • Editing the genome in a dish is now routine. Editing it inside a living person, in the right tissue, without breaking everything else — that is the actual frontier.
  • Lipid nanoparticles (LNPs): the mRNA-vaccine envelope. Goes naturally to liver. One dose, transient editor expression.
  • AAV vectors: stripped-down viruses. Tissue-specific tropism, but small payload (~4.7 kb) and pre-existing immunity.
  • Electroporation: for ex vivo — pull cells out, zap them, put them back. The Casgevy approach.
  • Engineered virus-like particles: deliver protein-RNA complexes directly, no DNA cargo.
  • Where edits go today
  • Liver
  • Eye
  • Muscle
  • CNS
  • Lung
  • Kidney
  • Approximate clinical viability of in vivo delivery, 2025. Liver is solved. Most other tissues are not.
Slide 07

Approved therapies, today

  • Slide 07 · In the Clinic
  • For most of the 2010s, gene therapy was a promise. By 2025 it is a billing code. Three landmarks:
  • 2023 · FDA & MHRA
  • Casgevy
  • Vertex / CRISPR Therapeutics
  • First CRISPR therapy ever approved. Edits patient's own stem cells ex vivo to reactivate fetal hemoglobin. Cures sickle cell disease and beta-thalassemia. ~$2.2M per patient.
  • 2017 · FDA
  • Luxturna
  • Spark Therapeutics
  • First FDA-approved gene therapy for an inherited disease. Subretinal AAV2 injection delivers a working copy of RPE65 — restores vision in a form of Leber congenital amaurosis.
  • 2019 · FDA
  • Zolgensma
  • Novartis
  • One-time IV infusion for spinal muscular atrophy in infants. Delivers a working SMN1 via AAV9. $2.1M list price — for years the most expensive drug in history.
  • ~20
  • Approved gene/cell therapies (US, 2025)
  • ~3,000
  • Active clinical trials worldwide
  • 7,000+
  • Known monogenic diseases — potential targets
  • $1-3M
  • Typical price tag — the next bottleneck
Slide 08

Heritable editing — He Jiankui, 2018

  • Slide 08 · The Line That Was Crossed
  • A Chinese researcher announced he had edited CCR5 in human embryos and brought twin girls (and later a third child) to term. Aim: HIV resistance. Outcome: global condemnation, three years in prison, an indefinite scientific moratorium.
  • The edits were imprecise — not the published natural variant; novel mutations whose effects are unknown.
  • Changes affect every cell, including sperm and eggs — passed to descendants forever.
  • WHO, NAS, and the UK Royal Society called for a global moratorium on clinical germline editing.
  • The technical barrier is gone. The barrier now is governance, consent, and political will.
  • Why this stays hard
  • Mosaicism. Editing reaches different cells at different rates — an embryo can carry multiple genotypes.
  • Off-targets. A mistake in the germline propagates through every future generation.
  • Pleiotropy. A "disease" gene often does many things. CCR5 disruption may raise West Nile risk.
  • Consent. The edited person never agreed; neither did their descendants.
  • For now: PGT (embryo selection) handles most heritable disease ethically. Germline editing's case is narrow.
Slide 09

Gene drives — edits that copy themselves

  • Slide 09 · CRISPR For Ecosystems
  • Normal inheritance: a trait passes to ~50% of offspring. A gene drive carries the editing machinery itself, so it converts the second chromosome too — spreading to ~100% of offspring, generation after generation, until the trait saturates a population.
  • The dilemma: a successful drive could end malaria (600,000 deaths/year). It could also unintentionally drive a species extinct, or jump to a non-target species. Daisy-chain and split drives are designed to self-limit — but no one has yet released one in the wild.
Slide 10

Xenotransplantation, edited

  • Slide 10 · Pigs As Organ Donors
  • ~17 people die every day in the US waiting for a transplant. eGenesis and Revivicor have engineered pigs with dozens of CRISPR edits — knocking out the antigens that trigger human rejection, inactivating endogenous pig retroviruses, adding human immune-regulator genes.
  • Sept 2021: NYU surgeons attach an edited pig kidney to a brain-dead recipient — it functions for 54 hours.
  • Jan 2022: University of Maryland transplants a 10-edit pig heart into David Bennett. Survives 60 days.
  • Mar 2024: Mass General performs the first edited pig kidney into a living patient. Survives ~2 months.
  • 2025: First formal Phase 1 clinical trials begin (United Therapeutics, eGenesis).
  • CRISPR edits in eGenesis donor pigs
  • pig glycan antigens knocked out (alpha-Gal, Neu5Gc, Sda)
  • PERV (porcine retrovirus) sites inactivated
  • human transgenes added (CD46, CD55, thrombomodulin, …)
  • ~100k
  • people on US transplant waitlist
Slide 11

De-extinction

  • Slide 11 · Reverse Gear
  • Colossal Biosciences (and others) are trying to bring back lost species — not by cloning ancient DNA (it's too degraded) but by editing the closest living relative's genome to express extinct traits.
  • Woolly Mammoth
  • Target: 2028
  • Edit Asian elephant cells with mammoth-derived alleles for cold tolerance, hair, fat. In 2024 Colossal announced elephant-derived iPSCs — a major prerequisite. Many edits still ahead.
  • Thylacine
  • Tasmanian tiger
  • Closest living relative is the fat-tailed dunnart, a mouse-sized marsupial. The genome gap is enormous. Colossal sequenced a 110-year-old specimen in 2024.
  • Dodo
  • Extinct ~1681
  • Edit Nicobar pigeon (closest relative) cells. In 2025 Colossal achieved primordial germ cell culture in pigeons — the bird-genetics equivalent of iPSCs.
  • The honest framing: what's actually being made is an elephant with mammoth-like traits, not a mammoth. The technology spinning out (large-scale editing, exotic IVF, cell reprogramming) may matter more than any resurrected animal — particularly for endangered-species rescue.
Slide 12

The honest assessment

  • Slide 12 · Where We Actually Are
  • Real and growing
  • Somatic editing for monogenic disease: working, approved, scaling.
  • Liver-targeted in vivo editing: a platform with dozens of programs.
  • Engineered T-cells for cancer: a new pillar of oncology.
  • Pig organs in human bodies: now a clinical reality, not a thought experiment.
  • Crops with bespoke traits: deregulated edits in wheat, tomato, soy.
  • Fraught and unresolved
  • Heritable editing: technically near, ethically and politically nowhere near consensus.
  • Gene drives: reversibility uncertain; first wild release will set precedent for all biology.
  • Polygenic enhancement: marketing outpaces science; modest selection effects only.
  • Cost and access: $2M therapies don't scale to global disease burden as built.
  • Off-targets: the long tail of "we won't know for 30 years."
  • The next decade is less about new editors and more about delivery, durability, and decisions — technical, regulatory, and moral.
Slide 13

References & further viewing

  • Slide 13 · Going Deeper
  • Reading
  • Doudna & Sternberg, A Crack in Creation (2017)
  • Walter Isaacson, The Code Breaker (2021)
  • Kevin Davies, Editing Humanity (2020)
  • Liu lab papers: Nature 2017 (ABE), Nature 2019 (prime editing)
  • Innovative Genomics Institute — innovativegenomics.org
  • Broad Institute editing primer — broadinstitute.org
  • Watch
  • YOUTUBE · SEARCH
  • CRISPR gene editing — the future
  • Talks from Doudna, Liu, Zhang; documentary primers
  • YOUTUBE · SEARCH
  • He Jiankui — the CRISPR babies
  • News reporting, ethics panels, interviews after release
  • GENETIC ENGINEERING / Beyond CRISPR
  • Catalog Series · 2026
  • End of deck — press ← to revisit.
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