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Lesson Plan

The Bullet

1907 to 1910, Frankfurt and Wiesbaden • KRAS, first identified as a human oncogene in 1982, is mutated in more than 90 percent of pancreatic cancers (among the deadliest of cancers) and large fractions of lung and colorectal cancers. For roughly forty years it was considered the archetypal 'undruggable' target, because the RAS protein is structurally smooth and lacks the deep binding pockets that small-molecule drugs normally exploit; company after company tried and failed. In 2026 that changed. The Phase 3 RASolute 302 trial of daraxonrasib, a RAS(ON) inhibitor from Revolution Medicines, was presented at the ASCO Annual Meeting in late May 2026 and published in the New England Journal of Medicine: in previously treated metastatic pancreatic cancer it nearly doubled median overall survival, about 13.2 months versus roughly 6.7 months for chemotherapy. The drug works not by forcing a fit into a pocket that does not exist, but by binding the cellular helper protein cyclophilin A, which then clamps onto the active (ON-state) RAS protein and shuts down its signalling: a 'molecular glue' that reaches an unreachable target. It is Paul Ehrlich's magic-bullet logic, designing one molecule to find and stop one target, applied a hundred and sixteen years later to a target everyone had declared impossible. •
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Key Concepts and Vocabulary 5. Discussion / writing (15-30 min) Extensions

The Bullet: Lesson Plan

Overview

This lesson uses two breakthroughs against targets that experts had declared impossible, Paul Ehrlich and Sahachiro Hata's 1909 discovery of Salvarsan (compound 606), the first synthetic cure for an infectious disease, and the 2026 success of daraxonrasib against the "undruggable" cancer gene KRAS, to explore how drugs are discovered, what "selective toxicity" and "targeted therapy" really mean, and why persistence through systematic failure is itself a scientific method.

Subject areas: Biology, Chemistry, History of Science, Health Science Grade levels: 9-12, AP Biology, AP Chemistry Duration: 1-2 class periods (45-90 minutes)

Essential Questions

  1. What did Paul Ehrlich mean by a "magic bullet," and why was it a radical idea in 1909?
  1. How does a drug kill a microbe or stop a cancer without killing the patient (selective toxicity)?
  1. What made KRAS "undruggable" for forty years, and how did daraxonrasib get around it?
  1. Why is systematic screening of hundreds of compounds a legitimate scientific method, not just luck?
  1. What does it tell us that compound 606 was abandoned as useless before it became a cure?

Learning Objectives

Students will be able to:

  • Define selective toxicity and explain Ehrlich's "magic bullet" concept
  • Describe how Salvarsan was discovered through numbered, systematic compound screening
  • Explain why a protein with no binding pocket resists conventional drug design
  • Describe the "molecular glue" mechanism: recruiting cyclophilin A to clamp onto active KRAS
  • Interpret an overall-survival result (13.2 vs 6.7 months; hazard ratio) and discuss its significance
  • Connect 1909 and 2026 as instances of the same discovery logic

Key Concepts and Vocabulary

  • Magic bullet (Zauberkugel): Ehrlich's idea of a chemical that seeks one target in the body and spares the rest.
  • Selective toxicity: harming the pathogen or cancer cell far more than the host's own cells.
  • Chemotherapy: the use of chemicals to treat disease; a term Ehrlich coined.
  • Spirochete: a corkscrew-shaped bacterium; Treponema pallidum causes syphilis.
  • Compound screening: systematically synthesizing and testing many related molecules.
  • Oncogene: a gene that, when mutated, drives cancerous growth; KRAS is one.
  • Undruggable target: a protein lacking the deep pockets that small-molecule drugs usually bind.
  • Molecular glue: a drug that recruits a second protein to act on a target it could not bind alone.
  • Overall survival / hazard ratio: clinical-trial measures of how long patients live and the relative risk between treatment arms.

Lesson Activities

1. Hook (10 min)

Pose the question: "If a disease is caused by something living inside you, how do you poison it without poisoning yourself?" List student ideas, then reveal that this is exactly the problem Ehrlich set out to solve in 1909, and the same problem cancer biologists faced with KRAS.

2. The 1909 story (15 min)

Walk through Ehrlich's "factory" approach: synthesize, number, test, repeat. Emphasize that compound 606 was made in 1907, judged useless, and shelved, and that Hata revived it in 1909. Discuss why screening hundreds of compounds is a deliberate strategy, not a failure of imagination.

3. The 2026 story (15 min)

Introduce KRAS: discovered 1982, mutated in over 90% of pancreatic cancers, "undruggable" because the protein is smooth. Explain daraxonrasib's molecular-glue trick (cyclophilin A clamps onto active RAS). Show the survival numbers and discuss what "nearly doubled survival" means and does not mean for a still-lethal disease.

4. Compare and contrast (10 min)

Students fill a two-column table: Salvarsan vs daraxonrasib (target, mechanism, what made it hard, how it was cracked, who said it was impossible). Identify the shared logic.

5. Discussion / writing (15-30 min)

Prompt: "Ehrlich's bullet was number 606, so 605 failed first. Is persistence through failure a scientific skill? Who decides when a target is 'impossible,' and what is the cost of believing them too soon?"

Assessment Ideas

  • Short answer: Explain selective toxicity using either Salvarsan or daraxonrasib as an example.
  • Diagram: Draw and label how a molecular glue lets a drug act on a target with no binding pocket.
  • Data literacy: Given a survival curve, identify median survival for each arm and explain the hazard ratio in plain language.
  • Essay: "The bullet was never magic." Argue what actually drove both discoveries.

Extensions

  • Research another "undruggable" target now being pursued (e.g., MYC, p53).
  • Investigate antibiotic resistance as the modern echo of Ehrlich's selective-toxicity problem.
  • Debate the ethics and economics of pricing breakthrough cancer drugs.

Standards Alignment (examples)

  • NGSS HS-LS1: Structure and function at the molecular and cellular level.
  • NGSS HS-PS1: Structure and properties of matter; chemical reactions.
  • AP Biology: Cell communication and signaling; the cell cycle and its regulation.
  • CCSS literacy in science: Citing evidence, interpreting quantitative data.

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