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L03 — Rewriting the Edit

Module: M06 — Rewriting Life
Periods: 1
NGSS: HS-LS3-1, HS-LS3-2
Lesson Type: Explore / Elaborate

Learning Objective

  • By the end of this lesson, students will be able to simulate a CRISPR gene edit on a target DNA sequence by designing a guide RNA, making a cut, and modeling DNA repair to correct a mutation.

Phenomenon / Hook

“In L02, we found the typo that causes sickle cell disease. Today, you’re the scientists. Your job: design the tool that finds and fixes the typo. You have a paper DNA strand and a blank guide RNA strip — can you fix the mutation before time runs out?”

Materials

  • Paper DNA strips (one per pair, with intentional mutation marked)
  • Blank guide RNA strips (students must write the complementary sequence)
  • Scissors (Cas9)
  • Tape (DNA repair)
  • “Correct” DNA replacement strips (HDR template)
  • Handout: [[resources/handouts/gene-editing-simulation]]
  • Timer for challenge rounds

Agenda

Opening (5 min)

  • Review: How does CRISPR-Cas9 work? (30-second recap from L01)
  • Introduce the challenge: “You have a mutated DNA strand. Design a guide RNA, cut the DNA, and repair it with the correct sequence. You have 12 minutes.”

Explore (15 min)

  • Gene Editing Simulation (Pairs)
    • Round 1: Students design a guide RNA complementary to the mutated region
    • Round 2: They cut the DNA at the target site (simulate Cas9)
    • Round 3: They choose a repair method:
      • NHEJ (Non-Homologous End Joining): Tape the cut ends together — quick but error-prone (may insert/delete bases)
      • HDR (Homology-Directed Repair): Use the correct template strip to replace the mutated section — precise but harder
    • Students record their results: Did the edit work? What went wrong?
    • Challenge: Introduce “off-target” sequences that partially match the guide RNA. What happens?

Explain (10 min)

  • Debrief the simulation:
    • Which repair method gave better results? (HDR = precise, NHEJ = error-prone)
    • What happened with off-target sites? (Real-world problem with CRISPR)
  • Connect to real science:
    • Scientists use HDR when possible but NHEJ is more common
    • Off-target effects are a major safety concern in clinical trials
    • Victoria Gray’s treatment used CRISPR on somatic cells (non-heritable)

Elaborate (8 min)

  • Design Challenge: Each pair must design a guide RNA for a DIFFERENT mutated sequence (not their original). They write the complementary guide RNA and predict whether NHEJ or HDR would be better for that specific edit.
  • Pairs swap designs and test each other’s guide RNAs

Closing (5 min)

  • Exit Ticket: [[exit-tickets/L03-exit-ticket]]
    1. Why is HDR preferred over NHEJ for fixing a mutation? When might NHEJ be useful instead?
    2. What is an “off-target” effect and why is it dangerous?

Differentiation

SupportExtension
Provide a partially completed guide RNA with 2–3 bases filled inAsk students: If you could only do somatic edits OR germline edits, which would you choose? Why? (Preview L04–L05)
Allow use of the codon chart from L02 as referenceResearch: What are “prime editors” and how do they improve on standard CRISPR?

Assessment

  • Formative: Observe simulation — are guide RNAs complementary? Are repair steps logical?
  • Exit Ticket: NHEJ vs. HDR reasoning and off-target understanding

Teacher Notes

  • Prep is critical: Pre-cut DNA strips, cut guide RNA blanks to size, have tape and replacement strips ready.
  • The simulation gets noisy — that’s good. Circulate and ask guiding questions.
  • Common error: Students write the guide RNA as the SAME sequence as the DNA target (instead of complementary). Catch this early.
  • If a pair finishes early, give them a second mutation to fix with a different repair method.
  • This is the engagement peak of the module — let students struggle productively.