1237: "Cryo-Electron Microscopy"

Interesting Things with JC #1237: "Cryo-Electron Microscopy" – Discover the breakthrough that allows scientists to image molecules as they truly are hydrated, moving, and intact. By freezing samples at -150°C and using electrons instead of light, cryo-EM delivers near-atomic resolution that’s transforming medicine and molecular biology.

• Episode Anchor

  Title: Cryo-Electron Microscopy
  Episode #: 1237
  Molecular imaging, scientific innovation, electron microscopy
  Subject Area(s): Biology, Chemistry, Physics, Technology, Science Communication
  Recommended Grade Level:
  US: Grades 9–12
  UK: Key Stage 4–5
  IB: MYP Level 4–5 / DP Year 1
  Estimated Lesson Time: 30–45 minutes
  Standards Tags: NGSS, CCSS.ELA, UK-KS4-Sci, IB MYP Science

• Lesson Overview

  Lesson Title: Cryo-Electron Microscopy

  Learning Objectives:

  • Define cryo-electron microscopy and explain its scientific purpose

  • Analyze how vitrified ice preserves biological samples for imaging

  • Compare cryo-EM to other molecular imaging techniques

  • Evaluate real-world applications in medicine and biology

  • Interpret the scientific and technological impact of cryo-EM on society

  Big Question:
  How has cryo-electron microscopy changed our ability to see and understand life at the molecular level?

• Key Vocabulary

  1. Cryo-electron microscopy (cry-oh ee-LEK-tron my-KROSS-kuh-pee) – A technique that uses frozen samples and electron beams to visualize biological structures in their natural state

  2. Vitrified ice (VIH-truh-fide) – Water that has been flash-frozen into a smooth, non-crystalline glass-like state

  3. Electron microscope (ee-LEK-tron MY-kro-skope) – A powerful microscope that uses electrons instead of light to image very small structures

  4. Angstrom (ANG-struhm) – A unit of length equal to 0.1 nanometers, used to measure atomic-scale distances

  5. Crystallography (KRISS-tuhl-AH-gruh-fee) – A method of imaging structures by analyzing X-ray diffraction patterns from crystallized samples

  6. Fixative (FIK-suh-tiv) – A chemical used to preserve biological material, often altering its natural state

  7. Molecular complex – A group of molecules that function together in a biological process

  8. Nanometer (NAN-oh-mee-ter) – A unit of measure equal to one-billionth of a meter

  9. 3D reconstruction – Creating a three-dimensional model from multiple two-dimensional image angles

  10. Near-atomic resolution – Imaging detail so fine that individual atoms or molecular structures can be distinguished

• Narrative Core

  Open
  For centuries, scientists described what life was made of—but not what it looked like. Molecules were imagined through math, drawn in textbooks, but never truly seen. That changed when a method emerged that could freeze life in motion and capture its details—without altering a single bond.

  Info
  Cryo-electron microscopy, or cryo-EM, uses flash freezing and beams of electrons to observe the true shape and structure of biological molecules. Samples are dropped into liquid ethane at -150°C, forming a thin layer of vitrified ice. This process preserves biological samples in their natural, hydrated state without crystal damage.

  Details
  Placed in an electron microscope, the frozen samples are scanned by electron beams, which pass through them to create two-dimensional images. Thousands of these projections are used to compute a precise three-dimensional model, often at resolutions finer than 3 angstroms—about 0.3 nanometers. That’s the width of a single hydrogen atom.

  Unlike X-ray crystallography or NMR, cryo-EM doesn’t require crystallization, staining, or chemical alteration. It allows scientists to view unstable, complex molecules exactly as they exist in living systems. This has led to breakthroughs in understanding COVID-19, Alzheimer’s disease, antibiotic resistance, and more.

  Reflection
  When Jacques Dubochet, Joachim Frank, and Richard Henderson received the Nobel Prize in Chemistry in 2017, it wasn’t just for creating a new machine—it was for giving science a new way to see. Cryo-EM isn’t just imaging. It’s a window into the machinery of life.

  Closing
  These are interesting things, with JC.

• Transcript

  For centuries, scientists could describe what life was made of, but not what it looked like. Molecules—the real workers of biology—were imagined in sketches and models. We could theorize their shapes, estimate their behaviors, but we couldn’t actually see them. They were too small, too fragile, too fast. And yet, one method now allows us to observe them in their natural state—alive in function, frozen in time.

  Cryo-electron microscopy (cry-oh ee-LEK-tron my-KROSS-kuh-pee), or cryo-EM, has become one of the most powerful tools in structural biology. The process starts not with a lens, but with a plunge—literally. Scientists take a solution of biomolecules, like proteins or viruses, and rapidly freeze it by plunging it into liquid ethane (EE-thayn) chilled below minus 150 degrees Celsius—or minus 238 degrees Fahrenheit. This rapid cooling forms a smooth, glass-like layer of vitrified ice (VIH-truh-fide), not crystalline—which would distort the sample—but amorphous (uh-MOR-fuss) and clear.

  Once preserved, these molecules—now locked in place—are placed inside a transmission electron microscope (MY-kro-skope). Instead of light, it uses electrons to generate images. Electrons have much shorter wavelengths, allowing them to detect details at a resolution smaller than a single nanometer. But electrons also damage organic material. That’s why the freezing step is critical—it stabilizes the sample against destruction.

  Thousands of 2D images are captured from different angles. Using advanced computational reconstruction, those projections are combined to create a 3D model. Not just a visual approximation—but a structure with near-atomic resolution. In some cases, researchers can detect features smaller than 3 angstroms (ANG-struhms), or 0.3 nanometers—the diameter of a hydrogen atom.

  What sets cryo-EM apart isn’t just its clarity—it’s the conditions. Unlike X-ray crystallography (KRISS-tuhl-AH-gruh-fee), cryo-EM doesn’t require altering the molecule. No staining. No crystallization. No chemical fixatives. You’re looking at the molecule as it naturally exists in a hydrated, near-biological state. This means unstable proteins, large complexes, even molecular machinery in motion can be captured mid-function.

  It’s how researchers mapped the spike protein of SARS-CoV-2, revealing its receptor-binding domain. It’s how they visualized amyloid-beta (AM-uh-loyd BAY-tuh) plaques in Alzheimer’s disease. It’s helped in antibiotic resistance studies, cancer therapy design, and even vaccine development. The implications reach every corner of medicine and molecular science.

  In 2017, the Nobel Prize in Chemistry was awarded to Jacques Dubochet (ZHAHK Doo-boh-SHAY), Joachim Frank (YO-ah-keem FRANK), and Richard Henderson—not for inventing cryo-EM in a vacuum, but for refining it into a tool that changed how we see life itself.

  Because for the first time in human history, we aren’t just studying the molecules of life—we’re watching them at work.

  These are interesting things, with JC.

• Student Worksheet (Format A)

  Listening Questions:

  1. What temperature is used to vitrify biological samples in cryo-EM?

  2. What type of particle is used in place of light in cryo-EM imaging?

  3. What are some limitations of older imaging methods like crystallography?

  Short Answer Prompts:

  1. Why is vitrified ice critical in cryo-EM?

  2. Describe one major advantage cryo-EM offers over traditional molecular imaging.

  Vocabulary Matching:

  • Cryo-EM –

  • Vitrified Ice –

  • Angstrom –

  • Electron Microscope –

  • 3D Reconstruction –

  Reflection Writing Space:
  In 3–5 sentences, explain how cryo-EM helps scientists understand disease at the molecular level. Include one specific example.

• Teacher Guide

  Estimated Time and Setup:
  30–45 minutes; audio playback device, worksheet copies, optional internet access for extensions.

  Pre-teaching Vocabulary Strategy:
  Introduce key terms with visuals or models (e.g., a hydrogen atom, microscope image samples).

  Anticipated Misconceptions:

  • Belief that all microscopes use light

  • Confusion between freezing and crystallizing

  • Assuming cryo-EM produces color images

  Discussion Questions:

  • How does cryo-EM allow us to see molecules in motion?

  • What limitations still exist with this method?

  • How does this technology impact drug development?

  Differentiation Strategies:

  • ESL: Use labeled diagrams and phonetic cues

  • IEP: Provide sentence starters and scaffolded questions

  • Advanced: Assign journal reading on 2017 Nobel Prize citation

  Extension Activities:

  • Research task: Compare cryo-EM with atomic force microscopy

  • Create a diagram showing the cryo-EM process

  • Watch Jacques Dubochet’s Nobel Lecture and summarize

  Cross-Curricular Links:
  STEM (physics, chemistry), Health Sciences, Ethics in Technology, History of Science

• Quiz

  Multiple Choice (choose one):

  1. What is the main purpose of cryo-EM?
     A. Colorize biological samples
     B. Burn molecular samples for analysis
     C. Preserve and visualize molecules in their natural state
     D. Stain proteins to measure weight

  • Correct answer: C

  2. What temperature is used in cryo-EM freezing?
     A. 0°C
     B. –20°F
     C. –150°C
     D. 100°F

  • Correct answer: C

  3. Which substance is commonly used to vitrify samples in cryo-EM?
     A. Liquid nitrogen
     B. Water
     C. Liquid ethane
     D. Dry ice

  • Correct answer: C

  4. Which method does cryo-EM outperform in molecular imaging?
     A. X-ray crystallography
     B. Fluorescent tagging
     C. Thermal scanning
     D. Magnetic fields

  • Correct answer: A

  5. What award recognized cryo-EM as a major scientific breakthrough?
     A. Fields Medal
     B. Pulitzer Prize
     C. Nobel Prize in Chemistry
     D. Lasker Award

  • Correct answer: C

  Short Answer:

  1. Describe how electrons are used in cryo-EM to form an image.

  2. What makes cryo-EM useful for imaging unstable proteins?

  Critical Thinking Prompt (optional):
  Cryo-EM preserves life at the molecular level for viewing. What ethical considerations might arise when technology allows us to manipulate or alter these same molecules?

• Assessment

  Prompt 1:
  Explain the cryo-EM process from sample preparation to image creation. Include technical terms like vitrified ice and 3D reconstruction.

  Prompt 2:
  Evaluate the scientific and medical importance of cryo-EM by giving at least two real-world examples where it has been used to advance understanding.

  Scoring Rubric (for each):
  3 = Full understanding, detailed, accurate
  2 = Partial understanding, some detail or minor errors
  1 = Needs support, major misconceptions

• Standards Alignment

  NGSS:

  • HS-LS1-1: Structure and function of cells—Cryo-EM reveals detailed structure of cell components

  • HS-ETS1-2: Engineering & design—Application of electron optics in real-world solutions

  • HS-PS4-5: Electromagnetic radiation—Electron behavior in imaging

  CCSS – ELA/Literacy in Science:

  • CCSS.ELA-LITERACY.RST.9-10.2: Determine central ideas in a scientific text

  • CCSS.ELA-LITERACY.RST.11-12.3: Follow complex scientific procedure

  • CCSS.ELA-LITERACY.RST.9-10.7: Translate visual information into understanding

  UK National Curriculum:

  • KS4 Science: Use of scientific ideas and theories to explain phenomena

  • KS4 Physics: Understanding particle behavior and waves in technology

  • KS5 Biology: Advanced molecular techniques and research applications

  IB MYP/DP:

  • MYP Sciences Criterion B: Inquiring and designing (use of imaging tools)

  • MYP Sciences Criterion D: Reflecting on the impacts of science

  • DP Biology: Topic 2.2 & 7.1 – Molecular biology and structural visualization

• Show Notes

  Topics covered:

  • How cryo-electron microscopy (cryo-EM) works

  • The flash-freezing process and vitrified ice

  • Use of electron beams instead of light to visualize molecules

  • 3D reconstruction from 2D projections at near-atomic resolution

  • Cryo-EM’s advantages over X-ray crystallography and NMR

  • Applications in drug discovery, Alzheimer’s research, and COVID-19

  • Recognition by the 2017 Nobel Prize in Chemistry

  Thanks:

  • Special thanks to Charlotte, a homeschooler in Northern Virginia, and her mom Kris, whose curiosity and question inspired this episode.

  Citation:

  • Frank J. Single-particle reconstruction of biological macromolecules in electron microscopy – 30 years. Quarterly Reviews of Biophysics. 2009;42(3):139-158. doi:10.1017/S0033583509990059

  Contact:

  • Have an idea for a future episode? Reach out at https://jimconnors.net/home