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Rationale for Connecting DNA to Disease Using BLAST

Author: Catherine Quist

The rationale comments are in bold italics below.

Grade Level: 10th

This activity may take roughly 2 hours. It is an activity that was purported to take 1.5 hours, with roughly .5 hours of additional work added to make it more inquiry-based.
Time required: 2 hours

Instructional Sequence:
  • Introducing the Lesson:
Constructivist teaching theory states that the first step in teaching is assessing students prior knowledge of the subject matter. This gives the teacher the teacher an awareness of the background she may need to cover before beginning the activity. The first few questions are basic questions about DNA. The rest of the questions explore the relationship between DNA and disease.
    • Activating Prior Knowledge with Questions:
  • 1. What are the four nucleotides that make up a DNA code? What are their common abbreviation?
  • 2. What does DNA code for?
  • 3. What is a gene? Where/how do we get genes?
  • 4. Where are genes located?
  • 5. Explain how DNA determines the traits of an organism. Use the words nucleotides, gene and protein in your answer.
  • 6. What do you think can cause a genetic disease?
  • 7. What will happen to an organism's homeostasis if a gene for an important protein becomes defective?
  • 8. What would happen if an organism inherited a gene that coded for defective proteins?

Studies have shown that authentic instruction, in which students learn real world methods for solving real world problems, are extremely effective ways of teaching science. Students are motivated by the opportunity to engage in authentic instruction. The activity described below is an example of authentic instruction. The teacher spends time at the beginning of the lecture explaining how the procedures to be learned in the lab are authentic. This establishes the motivation for the lesson. In addition, the National Sceince Education Standards (NSES) point out that investigations should derive from questions and issues that have meaning for students. The question of how to diagnose a disease using DNA is one that is very meaningful to students interested in health care. Any student who is a fan of the show House, in which medical mysteries are solved using biomedical research techniques, will find this activity meaningful.

    • Establish links to the purpose of the lesson:
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*** Give mini-lecture: Over the past decade, through large-scale genome and proteome sequencing efforts, such as the Human Genome Project, nucleotide and protein sequence databases have been filled with publicly available sequence data. Efforts to catalogue these sequences and associate them with functions and diseases have kept pace with sequencing efforts. As a result, today, when a biomedical researcher discovers a DNA or protein sequence in a tissue, he or she can run the program BLAST to compare the sequence to the publicly stored data in order to identify it by matching it to a sequence in the database. Using the database, the researcher will then retrieve its function and the associated disease. Today, we will use BLAST and Google to identify a gene sequence and it's associated disease.

Are all defective proteins inherited?
You do a nice job of tying in the problem, but this may be too technical for some students.
 
You may need to introduce BLAST and Google (Boolean searches) to class, including name, purpose,
 procedure for use.

  • Body of the Lesson:
The authenticity of the activity is established by the introduction of a scenario in which the student is asked to play the role of a biomedical researcher. Introducing an authentic scenario that is meaningful to the students is in keeping with the NSES.
    • The teacher tells the students that using DNA chips you have inferred that a gene sequence is differentially expressed in a patient's tissue. In order to figure out which disease is affecting the patient, you must first figure out which disease is associated with the gene. To do this you will first use the program BLAST to identify the protein associated with the gene. Next, you will perform a Google search to find out the disease associated with that protein.
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Socioconstructivist teaching theory suggests that students learn better when working in groups, since people learn best through discussion.

Do you actually believe this?  Does this match your experience?  Social
constructivism (Vygotsky) says we give our tools for sensemaking 
from our culture, e.g. language, math, etc.  Discussion in a critical setting may help us refine our
understandings, but "group work" 
can also be a waste of time. That
is why, as a teacher, you should 
always think through what value students working in groups is 
adding.

Also, working in a group will allow the students to compensate for each other's weaknesess.

An we know how much students enjoy doing this.  :-)  Especially the stronger 
 students.

    • The teacher forms the students into seven groups, and gives each of the groups a DNA sequence to identify and to associate with a disease.
The requirement that students report their findings adds a degree of accountability. It also, adds to the level of authenticity, since scientists are expected to report their findings. In addition, it gives students practice in communicating scientific ideas, which is a fundamental ability for scientific inquiry according to NSES.
    • Tell the students that each group is expected to report their findings at the end of the activity.
    • The teacher also gives the students a worksheet: The worksheet guides the students through the process of:
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Transcribing and translating the DNA sequence is primarily for practice, since the activity can be done without this step. It also makes it possible for the students to draw connections from DNA to disease, which would not be possible if protein sequences were used.
      • Transcribing their DNA sequence to yield an mRNA sequence
      • Translating the resulting mRNA sequence to yield a protein sequence
This part of the activity is a benchmark lesson, in which students learn how to use a tool for scientific investigation. The NSES list the ability to use technology and mathematics to improve investigations as fundamental for scientific inquiry. Here, students practice this skill with the tool BLAST.
      • Submitting their sequence to the BLAST server to yield a protein identification
      • Using Google to find the disease associated with the protein
This part of the activity is inquiry-based, since students have to figure out the procedure themselves based on what they've learned about how to use BLAST in the benchmark lesson. The NSES indicate that the abilities necessary to do scientific inquiry include the ability to design and conduct a scientific investigation. In the following activity, students engage in inquiry by designing the methodology themselves.
      • Running BLAST and using Google to identify the disease associated with a DNA sequence directly
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  • Concluding the Lesson:
Again, constructivist teaching theory emphasizes the value of groups reporting their findings after group work. It pushes the students to develop their ability to communicate scientific ideas. It also pushes them to understand the ideas well enough to explain them. Finally, the communication of scientific ideas is fundamental to scientific inquiry according to the NSES.

This sounds reasonable, i.e. it says specifically how you think students
will benefit from sharing their group's results.

    • Reporting Findings: Each group will report the name of their protein, along with the name of its associated disease. The group will also explain the relationship between the protein and the disease.

Will you ask your students to justify their results and inferences at some 
point?  How does what you're asking them to do compare/constrast with
the actions of scientists in the field?

This quick discussion is an opportunity for students to assess themselves. It gives them practice in being meta-cognitive that is in thinking about their own thinking.

    • Discussion: The teacher asks the students what they learned during the lab that they didn't already know, using the question to initiate a brief discussion.

Constructivist teaching theory argues that students learn knowledge best if it is used and if it is connected to other knowledge. The following homework questions push the students to extend the knowledge they've learned in the activity. While I don't expect them to be able to answer all of these questions, I will be able to assess their understanding based on their answers.

Assessing Student Understanding:
Included in the worksheet for the activity are a series of questions, which should be assigned as homework, that are designed to assess the students understanding of the connection between DNA sequence changes and disease, as well as their understanding of BLAST. In addition, the questions assess the student's understanding of the variety of contexts in which BLAST can be used by researchers:

This question asks the students to recall what they've learned about the relationship between genetic mutations and disease.
    • 1. Explain how changes in DNA coding sequence can lead to disease.
This question asks the students to explore the social implications of insurance companies knowing DNA sequence information. To answer this question students need to first assert that the knowledge of the DNA sequence can predict certain diseases, which may lead to insurance companies not providing health insurance or life insurance for people with certain DNA sequences.
    • 2. What do you think the ramifications are for insurance companies knowing DNA sequences of individuals?
This question asks students to make a connection between the relationship between DNA and disease and an imporant issue in the news today, the ethics of gene patenting. The answer to this question is that pharmaceutical companies are patenting gene sequences, such as BRCA1, because they can be used to treat diseases, such as breast cancer.
    • 3. Why do you think pharmaceutical companies are patenting gene sequences?
This question asks students to extend their knowledge of the BLAST procedure to a new situation. The answer is that you'd BLAST the gene against the human nucleotide database.
    • 4. If you were a scientist working with mice and discovered a gene that had something to do with obesity in mice, describe how you might find out if there is a similar gene that is known to exist in humans?
This question asks students to contemplate the relationship between BLAST specificity and the length of a sequence. The answer is that a longer sequence would find more specific matches. To demonstrate this, you could generate results for varying sequence lengths.
    • 5. If you had more nucleotides in your sequence to enter into BLAST (say 1000 instead of 100), do you think it would find more specific or less specific matches? Explain your answer. How would you conduct an experiment using the the BLAST server to provide evidence for your answer.
This question asks students to generalize their knowledge of the applicability of BLAST. The answer is that the scientist should BLAST the sequence against the database of all known nucleotide sequences.
    • 6. How would scientists all over the world check to see what a newly sequenced region of DNA is similar to? What do you think they do with the new DNA sequence if it is unknown? Explain
This question asks the student to understand that BLAST does not look for perfect matches. BLAST can still be used in the event of single letter mutations, in fact, this is it's real utility. To demonstrate this, you'd mutate a sequence before BLASTing it and demonstrate that it gets the same hits. This is important because scientists need to be able to find the identity of mutated sequences.
    • 7. Describe how mutations affect BLAST results. How would you conduct an experiment using the sequences you’ve been given and the BLAST server to answer. Why is this important? Explain.
This question pushes the student to understand how BLAST can be used to study evolution. The answer is that a scientist can compare the number of matches between the genes from both organisms. More matches means the organisms are more closely related.
    • 8. How could a scientist use BLAST to get a rough estimate of how closely related two organisms are?
This question asks the student to infer whether it is better to use BLAST with protein or DNA sequences. The protein sequences are more informative and are less likely to yield random matches.
    • 9. Does running BLAST using nucleotides or amino acids yield more specific matches? Explain.

These questions are good enough  to merit spendingg a day in class 
refining and formulating answers.  Maybe you should use homework for 
initial attempts and then first half of next class for groups to compare
 their answers and present one answer to the rest of the class.

Quist - Connecting DNA to Disease Using BLAST

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