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NOVA scienceNOW: Deadly Letters

Classroom Activity

Activity Summary
Student teams investigate a fictional anthrax case by modeling DNA sequencing and tracking down the "guilty" lab.

Learning Objectives
Students will be able to:

  • Define the term DNA sequencing

  • Describe the steps of one well-known DNA sequencing method (the Sanger method)

  • Demonstrate how scientists use DNA sequencing to make distinctions between different strains of anthrax

  • Discuss the role mutations play in the identification of DNA samples from different labs

Suggested Time
One class period


Multimedia Resources

  • Anthrax QuickTime or Windows Media Video
  • How DNA Replicates QuickTime Animation
    This 48-second narrated QuickTime animation shows how DNA normally replicates.
  • The Nuts and Bolts of DNA Replication QuickTime or RealPlayer animation
    This 2-minute silent animation shows both normal DNA replication and DNA replication that creates a mutation.
  • Sanger Method of DNA Sequencing QuickTime or Windows Media Video (scroll down to find it)
    This 51-second narrated animation illustrates the Sanger method.

Additional Materials


To solve the mystery of the anthrax-laced letters, as presented in the Anthrax segment, investigators turned to technology to identify the research lab where the harmful bacteria originated. First, they determined which strain of Bacillus anthracis, the bacterium that causes anthrax in humans, was in the letters. Yet even after pinpointing the specific type, they realized that many research laboratories around the world have that particular strain. So investigators needed to analyze the anthrax in a more detailed way.

A. How mutations occur during cellular replication
The investigators suspected that the bacteria's DNA might be slightly different in some laboratories. Why? As the Bacillus anthracis was distributed to different labs over the years, the cells grew and reproduced, replicating their own DNA with each division. During normal DNA replication, the DNA's double helix unzips into two strands. At that point, each strand can act as a template. Nucleotides arrange themselves one by one, in complementary pairs corresponding to the sequence on the templates, with adenine (abbreviated A) matching thymine (T), and cytosine (C) matching guanine (G). Sometimes, however, a small error occurs, and the wrong nucleotide inserts itself in the sequence. The result is called a mutation . While some mutations can change how a cell's DNA functions, most have no effect. Cells with such benign mutations can function just as well as cells without the mutation. However, if the mistake is not reversed by the cell's repair mechanisms, the resulting copy of DNA (and all subsequent copies) will be different from the original. Mutations are useful because they can help scientists identify differences within a single strain of anthrax.

B. The science behind identifying the suspected lab
In the anthrax case, the scientists used DNA sequencing technology to determine the exact sequence of the DNA obtained from each suspected lab. The result was a string of approximately five million nucleotides, represented by A's, T's, G's, and C's, from each lab. After comparing these sequences, scientists found a handful of differences among the suspected labs. And when they compared the labs' results to the sequence contained in the letters, they struck gold”the Bacillus anthracis DNA in the letters matched the DNA sequence from a lab at the US Army Medical Research Institute for Infectious Disease (USAMRIID) in Fort Detrick, Maryland.

C. Summary of a common DNA sequencing technique
The Sanger method is a well-known DNA sequencing technique whose main steps are:

  1. Mix the components ” In a test tube, scientists combine template DNA, nucleotides (A, T, G, and C), helper proteins, and special fluorescent versions of A, T, G, and C.
  2. Build DNA strands ” The helper proteins bind to the template DNA and pull nucleotides out of the solution to build a new DNA molecule, nucleotide by nucleotide.
  3. Incorporate a fluorescent nucleotide ” Eventually a fluorescent A, T, G, or C will attach to the end of the strand. The fluorescent versions interrupt and stop the copying process. Because the process is interrupted at random places, before long the test tube contains many incomplete copies of the DNA strand, each one of a varying length and each one ending with a fluorescent A, T, G, or C.
  4. Sort the strands ” A sequencing machine sorts the copies by length and "reads" which fluorescent nucleotide is at the end of the strand.
  5. Determine the sequence ” By knowing the length of the strand and which nucleotide is at the end of the DNA strand, scientists can determine the sequence. For example, if a strand is five nucleotides long and the one at the end is a "T", then the fifth position must be a "T." Similarly, if a DNA strand has 20 nucleotides, and the one on the end is a "G," then position 20 must be "G."

D. Tying the anthrax story to your curriculum
In this activity, your students will investigate a fictional anthrax case using paper to model the Sanger method of DNA sequencing. Modeling Step 4 above, each student group will receive an envelope containing strips of paper that represent the incomplete copies of anthrax DNA from a suspected lab. Then, modeling Step 5 above, students will sort these strips to determine the DNA sequence from that lab. Finally, as a class, students will compare their sequences to the one found in the fictional anthrax-laced letter to determine which lab is guilty.


Consider providing these terms to students:

  • Anthrax : a very rare but deadly disease caused by the bacterium Bacillus anthracis
  • Bacillus anthracis : the scientific name of the bacterium that causes anthrax
  • DNA : a molecule, known as deoxyribonucleic acid, that contains the genetic instructions for the development and functioning of organisms
  • Nucleotides : the four building blocks of DNA: adenine, guanine, cytosine, and thymine
  • Mutation : a change to the DNA sequence of an organism
  • DNA sequencing : a process used to determine the order of nucleotides in DNA

Procedure Before the Lesson The Lesson
  1. As a class, watch the NOVA scienceNOW segment Anthrax. You can stream it from the NOVA scienceNOW Web site at
  2. Discuss students' questions about the segment. Explain that they will conduct their own investigation of a fictional anthrax case. Tell students that the Bacillus anthracis from different labs may have slightly different DNA, and this feature could be useful in the investigation. Ask: What would have caused the DNA differences, from lab to lab, in the first place? (Mutations)
  3. To refresh students' understanding of DNA replication, show them the animations below (in the order suggested). Students may benefit from seeing the animations more than once.
    As a class,
    • review what mutations are and how they can cause differences among populations of bacteria in different labs.
    • relate the information in the animations to the NOVA segment.

    (Emphasize that, in a population, mutations arise over time and that they are the source of variation among the lab populations. This variation ultimately enables investigators to compare the anthrax DNA from different labs and find a match between the DNA from a lab and the DNA found in the letter.)
  4. Tell students that to find a match, investigators first had to establish the DNA sequence of the Bacillus anthracis in the letter and also the sequences from the suspected labs. This activity employs a well-known type of DNA sequencing called the Sanger method. Show students the Sanger Method of DNA Sequencing animation ( (Scroll down to find it.) Show the animation multiple times, if necessary.
    As a class:
    • summarize the animation.
    • relate the information in the animation to the NOVA segment.

    (Define DNA sequencing as a technology used to determine the order of nucleotides in DNA.)
  5. Divide the class into pairs. Give each student the Deadly Letters: The Anthrax Mystery handout, and distribute envelopes containing DNA samples (one envelope per pair). Explain that the envelopes contain "anthrax" DNA samples from suspected labs, and that the samples have already undergone the first part of the Sanger sequencing process. Envelope contents represent many incomplete copies of the DNA strand, each one of a varying length and each one ending on the left with a "fluorescent" A, T, G, or C. Students will need to sort the copies by length and determine the sequence. For example, the sequence would be TCGG for strips aligned like this:

    Position 4Position 3Position 2Position 1

  6. When student pairs have determined their anthrax DNA sequence, check their answers (#2 in the Procedure on the Student Handout). Every sequence should have ten nucleotides. At this point, do not tell students whether or not they have the "guilty" sequence; simply check for accuracy. Answers should read either TGACAATCGG (innocent) or TGACAATCAG (guilty).
  7. Have groups write their anthrax DNA sequences on the board. Make a chart to organize their responses. For example:

    Maria and Alex T G A C A A T C G G

  8. Ask the class to review the sequences and see if they can spot any differences.
  9. On the board, write the anthrax DNA sequence found with the fictional "guilty" letter: TGACAATCAG. Ask if any group's sequence matches the one found in the "guilty" envelope. What is the significance of the match? (Answer: the match identifies the source of the fictional DNA found with the letter.)
  10. Ask students how the activity compares to the real investigation shown in the Anthrax program (e.g., investigators compared five million nucleotides, class only compared ten). Point out how important it is to have samples from every lab. Otherwise, the guilty lab might be missed.

A) Have students research other types of DNA sequencing (such as Shotgun sequencing or High Throughput sequencing) and report their findings to the class.

B) As a class, discuss differences between human genome sequencing and bacterial sequencing. (For example, the amount of DNA is different and chromosomes are different.)

C) Show students the DNA sequence from the Bacillus anthracis AMES strain, described in the segment. ( It is from the National Center for Biotechnology Information, a free resource with genetic information about many different organisms. Mention that scientists share DNA information to promote research and understanding.

D) Remind students that genes are segments of DNA that are transcribed to mRNA and then translated into amino acids, the building blocks of proteins. Ask students to imagine that the DNA from this activity represents a small section of a gene. Ask them to transcribe and translate the DNA sequence. A table of the genetic code, usually found in biology textbooks, is required for this extension.

"Innocent" DNA:TGA-CAA-TCG-G
Transcribed to mRNA codons:ACU-GUU-AGG-C
Translated to amino acids:threonine-valine-arginine-
Transcribed to mRNA codons:ACU-GUU-AGU-C
Translated to amino acids:threonine-valine-serine-


Student Handout Questions
Procedure Step 1: Sample description of the main steps of the Sanger method of DNA sequencing. Student answers will vary, but they should include:

  • Scientists combine template DNA, nucleotides (A, T, G, and C), and fluorescent nucleotides.
  • Nucleotides line up to complement the DNA template.
  • Eventually, a fluorescent nucleotide gets added, stopping replication and creating many incomplete copies of DNA.
  • A machine sorts fragments by size and reads the fluorescent nucleotides.

Procedure Step 2: Depending on the sequence students received, they will have one of the following:
  • TGACAATCGG (the "innocent" sequence, determined by all the groups but one)
  • TGACAATCAG (the "guilty" sequence, determined by only one pair of students)

Answers to Questions

  1. In a sentence or two, briefly describe the purpose of DNA sequencing.
    DNA sequencing is a process used to determine the order of nucleotides that make up a DNA sample.
  2. What role did mutations play in the solution to the anthrax case featured in the segment?
    Mutations in the anthrax DNA created variation among the anthrax from different labs. Investigators used those differences to trace the anthrax from the letters back to a particular lab.
  3. Just knowing the lab where the anthrax originated is not enough to solve this crime. What additional information would you like to have in order to find out exactly who sent the letter?
    Finding the source of the anthrax did not reveal who sent the letters. Investigators have to consider lots of additional information, such as who had access to the anthrax, who had a motive to send the letters, and where the letters were mailed.
  4. Summarize how your class solved the anthrax mystery.
    First, each pair of students modeled the Sanger method to determine the DNA sequence from a suspected lab. Then, the class compared the sequences. Only one sequence from the class matched the deadly sample from the envelope with the letter. That sequence represented the "guilty" lab.

Use the following rubric to assess each team's work.

Excellent Satisfactory Needs improvement
Modeling DNA sequencing and answering the questions on the Anthrax Student Handout.
  • Students use Web resources effectively from more than one resource to answer questions, model DNA sequencing, and solve the Anthrax mystery.
  • Students sequence the DNA fragments, solve the Anthrax mystery, and can discuss information from multiple Web sites.
  • Students are familiar with the terms related to the activity and use them, along with other relevant terms, to discuss bacteria, DNA replication, mutation, and sequencing techniques.
  • Students use resources and integrate information from one source.
  • Students sequence the DNA fragments and solve the Anthrax mystery.
  • Students are familiar with the terms related to the activity and use them correctly.
  • Students have difficulty connecting the Web resources to the modeling activity or make little effort to build models and answer follow-up questions.
  • Students cannot integrate information from multiple sources.
  • Students are unfamiliar with the terms used in the activity.


The Anthrax activity aligns with the following National Science Education Standards (see

Grades 9-12
Content Standard A: Science As Inquiry

  • Understandings about scientific inquiry

Content Standard C: Life Science

  • Molecular basis of heredity

Content Standard E: Science and Technology

  • Abilities of technological design
  • Understandings about science and technology

Classroom Activity Author

Alison Fromme

Teacher's Guide
NOVA scienceNOW: Bird Brains

WebsiteAnthrax QuickTime or Windows Media Video
WebsiteHow DNA Replicates QuickTime Animation
WebsiteThe Nuts and Bolts of DNA Replication QuickTime or RealPlayer Animation
WebsiteSanger Method of DNA Sequencing QuickTime or Windows Media Video


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