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Lourdes Alemán, Ph.D.
Stacie Bumgarner, Ph.D.
April 8-9th, 2010
Howard University STAR Workshop
Office of Educational Innovation and Technology (OEIT)Biology Department
170 liters
Nobel Prize website
Aquaporin structural model
10% of what they hear30% of what they see60% of what they hear & see80% of what they hear, see, & do100% of what they hear, see, do, smell, feel, taste…& purchase on credit
By Ronald A. BerkProfessors are from Mars. Students are from Snickers.
Students learn…
ChallengeBridging the divide between research & the classroom using
interactive technology.
Professor Graham Walker
Professor Graham Walker
Who we are
MIT Biology DepartmentOffice of Educational Innovation & Technology (OEIT)
What we are doing
Designing interactive teaching software toolsto be used IN & OUTSIDE class
Software Tools for Academics & Researchers (STAR) biology tools
1 Educational goals
2 Design process
3 Access & outreach
Educational goals
ChallengeTeaching protein structure in a traditional classroom setting
StarBiochem: protein 3D viewer
ChallengeTeaching experimental design & data interpretation outside of
a genetics lab
StarGenetics: virtual genetics lab
Design process
Collaboration between MIT faculty & OEIT
StarBiochem Professor Graham WalkerIntroductory Biology Series
StarGeneticsProfessor Chris KaiserGeneticsGraduate Student Bridge Program
Access & outreachSoftware & curriculum materials -> freely accessible online
StarBiochem http://web.mit.edu/star/biochem
StarGenetics http://web.mit.edu/star/genetics
Create curriculum modules.
Conduct workshops.
Collaborate with wide range of educational institutions.
Assess how software tools impact different populations of students.
Access & outreach
StarBiochem usage beyond MIT
Visits9881
Countries82
StarBiochem Workshop – Day 1
1 Introduction to StarBiochem
2 StarBiochem hands-on activity
3 StarBiochem educational applications (Part I)Classroom applications
4 StarBiochem educational applications (Part II)Lab applications
5 Designing & writing new StarBiochem curriculum activities
StarBiochem Workshop – Day 1
1 Introduction to StarBiochem
2 StarBiochem hands-on activity
3 StarBiochem educational applications (Part I)Classroom applications
4 StarBiochem educational applications (Part II)Lab applications
5 Designing & writing new StarBiochem curriculum activities
Proteins perform many important biological functions
hemoglobincarry oxygen in the blood
F1 ATPasegenerate energy
antibodyprotect against
infections
aquaporinwater transport
microtubulescell division
Protein Data Bank website
The function of a protein is determined by its structure
structure function
ChallengeTeaching protein structure in a traditional classroom setting.
Traditional methods for teaching about protein structure and function
CartoonsCan introduce misconceptions
2-D representationsLimits student exploration
Protein Structure & Function (2007)
Using 3-D protein viewers for teaching about protein structure & function
Research PyMol, KING, Rasmol, Chimera, First Glance in Jmol, Webmol
Educational Protein Explorer, BioMolecular Explorer, other guided tutorials
Limitations of existing 3-D proteins viewers forteaching about proteins structure & function
Research
Educational
uses crystallography jargon
not user-friendly
ability to scale-up not known
windows functionality only
tutorials with limited views/manipulations
StarBiochem: protein 3-D viewer
StarBiochem is a protein 3-D viewer designed for educational purposes
Website: http://web.mit.edu/star/biochem/
Platform independent.
Interface is designed with students in mind.
Parallels how proteins are taught in introductory biology.
Can upload >54,000 Protein Data Bank structures.
StarBiochem hands-on guided tour
http://web.mit.edu/star/biochem/
StarBiochem Workshop – Day 1
1 Introduction to StarBiochem
2 StarBiochem hands-on activity
3 StarBiochem educational applications (Part I)Classroom applications
4 StarBiochem educational applications (Part II)Lab applications
5 Designing & writing new StarBiochem curriculum activities
How mutations in DNA can result in diseasesickle cell anemia: hemoglobin
Hemoglobin
Highly expressed in red blood cells
Responsible for oxygen transport
Contains four protein subunits -> each one binds to a O2 molecule
Protein Data Bank website
Hemoglobin
heme
heme
Protein Data Bank websiteHighly expressed in red blood cells
Responsible for oxygen transport
Contains four protein subunits -> each one binds to a O2 molecule
severe bone pain & necrosis
stroke
enlarged heart
bloodstream infections and pneumonia
www.commercialappeal.com
Sickle cell anemia
A mutation in hemoglobin causes sickle cell anemia
University of Utah Learn Genetics website
How does a mutation in the hemoglobin gene causes the protein to become sticky?
normal hemoglobin vs. sickle hemoglobin (2HBS)(1A3N)
Structure of sickle hemoglobin:
DNA sequenceA -> T
proteinhemoglobin becomes sticky
amino acid sequence Glu6 -> Val6
diseasesickle cell anemia
StarBiochem Workshop – Day 1
1 Introduction to StarBiochem
2 StarBiochem hands-on activity
3 StarBiochem educational applications (Part I)Classroom applications
4 StarBiochem educational applications (Part II)Lab applications
5 Designing & writing new StarBiochem curriculum activities
GoalTo illustrate how StarBiochem can be implemented into an
existing class curriculum.
StarBiochem educational applications (Part I) Classroom applications
1 Current StarBiochem applications
2 In-class activities
3 Outside-class activities
4 Assessment & testing
StarBiochem educational applications (Part I) Classroom applications
1 Current StarBiochem applications
2 In-class activities
3 Outside-class activities
4 Assessment & testing
Current StarBiochem educational applications
• Undergraduate settingIntroductory Biology (MIT)
Introductory Biology Lab (Brandeis)
• High school settingMIT Museum/Environmental Health Sciences Outreach Program (MIT)
Outreach HS program (Broad Institute)
HS fieldtrips (Biology Department, MIT)
Introductory Biology Courses (7.01 series)
StarBiochem modules core topics
StarBiochem case study: MIT
biochemistry molecular biology
recombinant DNA technology
signalingimmunology
cancer biologyneurobiology genetics
PAH amyloid GFP BCR-Abl Herceptin DNA pol Ras HemoglobinPFKcrystallin
Diviya Sinha
StarBiochem case study: Brandeis University
Introductory Biology Lab Course (Bio118)
crystallin protein cataracts
• explore the structure of crystallin using StarBiochem
• design mutation in crystallin based on structure
• test mutant crystallin for in vitro cataract formation
Melissa Kosinski-Collins
StarBiochem educational applications (Part I) Classroom applications
1 Current StarBiochem applications
2 In-class activities
3 Outside-class activities
4 Assessment & testing
StarBiochem in-class activities
Short (2-5 min)
Intermediate (10-20 min)
Long (40-60 min)
StarBiochem in-class activitiesShort
Example: snapshot of a structure or a concept
use StarBiochem live
create video using StarBiochem
create images of a particular structural snapshot
StarBiochem in-class activitiesShort
Example: snapshot of a structure or a concept
use StarBiochem live
create video using StarBiochem (ex: hemoglobin)
create images of a particular structural snapshot
StarBiochem in-class activitiesIntermediate
Example: interactive building protein activity
Protein 1 Protein 2cell membrane protein cytoplasmic protein
StarBiochem in-class activitiesIntermediate
Example: interactive building protein activity
Protein 1 Protein 2cell membrane protein cytoplasmic protein
1 Students are asked to consider what would be necessary to build proteins: location & function.
2 Students answers are compared with actual protein structures in StarBiochem.
StarBiochem in-class activitiesLong
Example: basics of protein structure lecture using StarBiochem (Dr. Chia-Yung Wu)
Example 1 Example 2Potassium channel GFP
Protein structure lecture using StarBiochem Introductory Biology
The live demos using StarBiochem helped me gain a better understanding of the relationship between a
protein's structure and its function.
The live demos on the potassium channel protein in StarBiochem helped me understand how this channel
allows for the passage of potassium ions ONLY.
The live demos using StarBiochem helped me understand the four levels of protein structure:
primary, secondary, tertiary & quaternary.
The live demos using StarBiochem helped me understand what protein structures look like in 3D.
I enjoyed today’s lecture on protein structure. Howard University (2009)
StarBiochem educational applications (Part I) Classroom applications
1 Current StarBiochem applications
2 In-class activities
3 Outside-class activities
4 Assessment & testing
http://web.mit.edu/star/biochem/problemsets
Review available curriculum modules online (exercises).
Modify current modules or develop your own.
Students download software from web.
Each module contains full step-by-step instructions forstudents to use software.
Outside-class activities
StarBiochem educational applications (Part I) Classroom applications
1 Current StarBiochem applications
2 In-class activities
3 Outside-class activities
4 Assessment & testing
Goal
Assess effectiveness of the software in illustrating a concept
Assess implementation of StarBiochem activity
Assessment & testing
Example: open-ended exam question
Introductory Biology (MIT)
Aquaporin exercise (homework)•basics of protein structure•aquaporin specificity for passage of water only
Aquaporin question (exam)•assess both protein structure basics and aquaporin structure -> function relationships•could not be completed without doing the aquaporin exercise
Assessment of software’s ability to illustrate concept
Assessment of software’s curriculum implementationUse simple sample survey provided
1 Survey Monkey (http://www.surveymonkey.com/)• best for remote assessment• data is automatically analyzed• basic membership (free), Pro membership ($300/year)
2 Paper survey• best for direct assessment• manual data manipulation• free
2 Quality of exercise
3 Technical difficulties
StarBiochem educational applications (Part I) Classroom applications
1 Current StarBiochem applications
2 In-class activities
3 Outside-class activities
4 Assessment & testing
StarBiochem Workshop – Day 1
1 Introduction to StarBiochem
2 StarBiochem hands-on activity
3 StarBiochem educational applications (Part I)Classroom applications
4 StarBiochem educational applications (Part II)Lab applications
5 Designing & writing new StarBiochem curriculum activities
GoalTo illustrate how to implement StarBiochem lab activity.
10, 000
DNA mutations
neutral
positive -> evolution
negative -> disease
Effects
Consequences of DNA mutations
Consequences of DNA mutations
DNA mutations
neutral
positive -> evolution
negative -> disease
Effects
What causes DNA mutations?
DNA mutations can be caused by various agents
DNA mutations can be caused by various agents
man-made agents(X-rays, smoking, toxic chemicals)
environmental agents(UV rays, toxic chemicals)
foreign biological agents(viruses, transposons)
cellular processes(DNA replication, cell division, respiration)
respiration
radiation
smoking
Each agent is associated with a particular type of DNA mutations
oxidation
agent mutation type
respiration
radiation
smoking
Each mutation type is fixed by a different cellular mechanism
oxidation
agent mutation type
DNAglycosylase
How our cells try to fix DNA mutationsDNA glycosylase
StarBiochem educational applications (Part II) Lab activity
1 Pre-assignment
2 Hands-on activity: DNA glycosylase exercise
3 Post-assignment
StarBiochem educational applications (Part II) Lab activity
1 Pre-assignment
2 Hands-on activity: DNA glycosylase exercise
3 Post-assignment
Lab activity: pre-assignment
Goal
1 Illustrate basic science research -> medical applications
2 Understand relevance of lab activity
Lab activity: pre-assignment
Reading“Mapping the Cancer Genome”
by Francis S. Collins and Anna D. BarkerScientific American Magazine, March 2007: 50-5
Questions• usefulness of the genomic cancer atlas for studying & treating cancer.
• hallmarks of cancer cells such as abnormalities in self-control and repair mechanisms.
• complexity of assembly a genomic cancer atlas.
StarBiochem educational applications (Part II) Lab activity
1 Pre-assignment
2 Hands-on activity: DNA glycosylase exercise
3 Post-assignment
Oxidation can cause mutations in DNA
Oxidation can cause mutations in DNA
1
2
Oxidation can cause mutations in DNA
1
2
1a
1b
2a
2b
DNA glycosylase proteins help repair DNA damage caused by oxidation
DNA glycosylases
1
2
1a
1b
2a
2b
How does DNA glycosylase fix DNA oxidation damage?
DNA glycosylase: human 8-oxoguanine glycosylase (hOGG1)
Structure of DNA glycosylase:
structurehuman DNA glycosylase &
DNA substrate
mechanismrotating DNA bases outside of
double helix to check for mutations
Personalized medicine for treating cancer
Rebecca Henretta (2007)
Personalized medicine for treating cancer
Non-responders
Responders
Rebecca Henretta (2007)
Personalized medicine for treating cancer
Non-responders
Responders
alternative treatment
conventional treatment
Rebecca Henretta (2007)
Personalized medicine for treating cancer: hOGG1 levels & lung cancer
low cancer risk
high
low
high
hOGG1 levelsCleveland Clinic website
StarBiochem educational applications (Part II) Lab activity
1 Pre-assignment
2 Hands-on activity: DNA glycosylase exercise
3 Post-assignment
Lab activity: post-assignment
GoalSynthesis of pre-assignment & DNA glycosylase exercise
Lab activity: post-assignment
Questions
• understand how the genomic cancer atlas can be used to uncover potential new roles of hOGG1 in cancer.
• understand how new cancer treatments can be design based on hOGG1.
StarBiochem educational applications (Part II) Lab activity
1 Pre-assignment
2 Hands-on activity: DNA glycosylase exercise
3 Post-assignment
StarBiochem Workshop – Day 1
1 Introduction to StarBiochem
2 StarBiochem hands-on activity
3 StarBiochem educational applications (Part I)Classroom applications
4 StarBiochem educational applications (Part II)Lab applications
5 Designing & writing new StarBiochem curriculum activities
GoalEmpower you to build your own StarBiochem exercises by
illustrating the design and building process.
Designing & writing StarBiochem curriculum activities
1 Design & building process
What is the goal of the activity?
What type of activity accomplishes goal?
How to select a structure that accomplishes goal?
How to structure the activity?
2 Interactive exercise creating a StarBiochem activity
Designing & writing StarBiochem curriculum activities
1 Design & building process
What is the goal of the activity?
What type of activity accomplishes goal?
How to select a structure that accomplishes goal?
How to structure the activity?
2 Interactive exercise creating a StarBiochem activity
What is the goal of the activity?
structure -> function
structure -> function -> disease
structure -> medical therapies
protein regulation
evolution of protein structure
What type of activity accomplishes goal?
1 Course
• Introductory Biology• Biochemistry• Cell/Molecular Biology• Pharmacology• Etc.
2 Course curriculum
• format• duration of activity
What type of activity accomplishes goal?
Example 1
Structure -> function
Course Introductory BiologyCurriculum central concept of the course
Activity
StarBiochem protein structure lecture + StarBiochem exercise (homework/lab activity)
What type of activity accomplishes goal?
Example 2
Structure -> medical therapies
Course Cell BiologyCurriculum minor point within a lecture
Activity
StarBiochem video or in class-demo illustrating structure –> targeted therapies
How to select a structure that accomplishes goal?
1 Goal
Is the structure suitable for illustrating goal?
2 Course/format of activity
Is the structure accessible to your students?
Is the activity format suitable for explaining the structure?
Schneider, T.L. and Linton, B. (2008) Introduction to Protein Structure through Genetics Diseases. Journal of Chemical Education 85: 663-665
How to select a structure that accomplishes goal?
Schneider, T.L. and Linton, B. (2008) Introduction to Protein Structure through Genetics Diseases. Journal of Chemical Education 85: 663-665
How to select a structure that accomplishes goal?
Researching & finding the appropriate structure
Protein Data Bank http://www.pdb.org/pdb/home/home.do
Search:• keyword• four digit PDB ID• title of paper
How to select a structure that accomplishes goal?
Researching & finding the appropriate structure
Hemoglobin: exercise with a well defined activity
structure -> function -> diseaseGlu6 -> Val6 in hemoglobin leads to sickle cell anemia
DNA glycosylase: exercise with less well defined activity
structure -> functionillustrate how DNA glycosylase repairs DNA
How to select a structure that accomplishes goal?
How to structure the activity?
1 Format/duration
Short activity straight to the the point
ex: DNA glycosylase video
Long activity framework for building complexity
ex: DNA glycosylase exercise
How to structure the activity?
1 Format/duration
Short activity straight to the the point
ex: DNA glycosylase video
Long activity framework for building complexity
ex: DNA glycosylase exercise
How to structure the activity?
1 Format/duration
Short activity straight to the the point
ex: DNA glycosylase video
Long activity framework for building complexity
ex: DNA glycosylase exercise
How to structure the activity?
References
Structure: 1EBMBruner, S. et al. (2000) Structural basis for recognition and repair of the endogenous mutagen 8-oxoguanine in DNA. Nature 403:
859-866.
Structures: 1YQK, 1YQRBanerjee, A. et al. (2005) Structure of a repair enzyme interrogating undamaged DNA elucidates recognition of damaged DNA.
Nature 434: 612-618.
How to structure the activity?Structure: 1EBMBruner, S. et al. (2000) Structural basis for recognition and repair of the endogenous mutagen 8-oxoguanine in DNA. Nature 403: 859-866.
How hOGG1 repairs oxidized guanines:
1.Extrusion of oxoG from the double helix
1.Recognition of oxoG by Gly 42
How hOGG1 repairs oxidized guanines:
1.Extrusion of oxoG from the double helix
1.Recognition of oxoG by Gly 42
“The structure of the hOGG1-DNA complex provides a clear solution to the long-standing puzzle of how the cellular repair machinery recognizes oxoG in DNA amidst the vast excess of guanine, a close structural relative. The oxoG residue is fully extruded from the DNA helix and inserted into an extrahelical active-site pocket on the enzyme, consistent with structure-based predictions made for other members of the HhH-GPD superfamily.”
“The most characteristic feature of oxoG - its8-oxo-carbonyl function - is completely devoid of any interacting partner. Instead, the enzyme recognizes the urea system in oxoG by virtue of its N7-H, which donates a hydrogen bond to the main chain carbonyl of Gly 42… Indeed, of all the contacts made to the oxoG base, that involving Gly 42 is the only one that would clearly be different with oxoG versus guanine; thus, the responsibility for discriminating oxoG from guanine appears to be borne by a single hydrogen bond.”
How hOGG1 repairs oxidized guanines:
1.Extrusion of oxoG from the double helix
1.Recognition of oxoG by Gly 42
How to structure the activity?Structures: 1YQK, 1YQRBanerjee, A. et al. (2005) Structure of a repair enzyme interrogating undamaged DNA elucidates recognition of damaged DNA. Nature 434: 612-618.
How hOGG1 distinguishes oxidized guanines from undamaged guanines:
1.oxoG:hOGG1 interaction differs from the G:hOGG1 interaction
How hOGG1 distinguishes oxidized guanines from undamaged guanines:
1.oxoG:hOGG1 interaction differs from the G:hOGG1 interaction
“Whereas the oxoG nucleobase inserts itself deeply into the lesion recognition pocket on the enzyme (Figs 2, left, and 3a), G is rejected by the lesion recognition pocket and instead lies against the protein surface at an exo-site some 5A ° outside the pocket (Figs 2, right panel, and 3b). The G base does interact with two active-site residues, Phe 319 and His 270, but the contacts are completely different from those made with oxoG.”
How hOGG1 distinguishes oxidized guanines from undamaged guanines:
1.oxoG:hOGG1 interaction differs from the G:hOGG1 interaction
“…a hydrogen bond is apparent between the carbonyl oxygen of Gly 42 and N7 H of oxoG. This attractive interaction would be replaced in the case of G by a strongly repulsive interaction with the N7 lone pair, if G and Gly 42 assumed the same positions as in the oxoG complex.”
How to structure the activity?
Long activity: framework for building complexity
Begin with: simple questionsAllow students to become familiar with protein structure basics
End with: complex questionsAllow students to understand the goal of the activity
How to structure the activity?
Long activity: framework for building complexity
Begin with: simple questionsAllow students to become familiar with protein structure basicsDNA Glycosylase Exercise: questions 1-5
End with: goal of the exercisestructure -> functionDNA Glycosylase Exercise: questions 6-8
DNA Glycosylase Exercise: simple questions
Question 1: overall structureexplore different 3-D models for representing atoms
Question 2: amino acid structureexplore difference between amino acid backbone and side chain
Question 3,4: secondary structureexplore how individual amino acids fold to form secondary structures
Question 5: tertiary structureexplore relationship between a protein’s environment & its tertiary structure
DNA Glycosylase Exercise: complex questions
Question 6: hOGG1 repairs DNA by extruding oxidized bases from double helixlocation of oxoG with respect to the double helix
Question 7: hOGG1 recognizes oxidized bases by contacting the damaged base directly and recognizing a specific modificationcomparison of secondary structures where amino acids that interact with oxoG are likely to be located
Question 8: hOGG1’s specificity for oxidized guanines lies in the inability of guanine to bind to the active site of hOGG1comparison of the oxoG:hOGG1 interaction with that of the G:hOGG1 interaction
Designing & writing StarBiochem curriculum activities
1 Design & building process
What is the goal of the activity?
What type of activity accomplishes goal?
How to select a structure that accomplishes goal?
How to structure the activity?
2 Interactive exercise creating a StarBiochem activity
Designing & writing StarBiochem curriculum activities
1 Design & building process
What is the goal of the activity?
What type of activity accomplishes goal?
How to select a structure that accomplishes goal?
How to structure the activity?
2 Interactive exercise creating a StarBiochem activity
Interactive exercise: creating a StarBiochem activity
- Goal of the activity you would like to implement
- Type of activity (length, structure, specifics)
1. Work alone2. Discuss with a partner3. Share ideas with the group
StarBiochem Workshop – Day 1
1 Introduction to StarBiochem
2 StarBiochem hands-on activity
3 StarBiochem educational applications (Part I)Classroom applications
4 StarBiochem educational applications (Part II)Lab applications
5 Designing & writing new StarBiochem curriculum activities
Acknowledgements
Star TeamSara Bonner
Rocklyn ClarkeIvan Ceraj
Justin RileyChuck Shubert
Biology DepartmentChris Kaiser
Graham WalkerDiviya Sinha
OEITVikay Kumar
Molly Ruggles
CollaboratorsStacie Bumgarner
Melissa Kosinski-CollinsMegan Rokop
Kathy Vandiver
Lourdes Aleman [email protected]
Collaborating InstitutionsBrandeis UniversityBroad Institute Outreach ProgramHoward UniversityMIT MuseumSuffolk UniversityTufts University
Outside FundingDavis Educational FoundationHHMI MIT’s Institutional Grant
“The ‘trip’ through the potassium channel protein was AMAZING. I'll explain to Grandma. Refreshing! :)”
“I'm not a bio major but found the interphase fun, easy, and educational. I plan to recommend it to my high school bio teacher.”
“I have found an appreciation for biochemistry almost entirely due to this program.”
“Great Job! Thank you! The StarBiochem program is truly innovative and gives a new perspective on the 2-D images provided by books and overheads.”
StarBiochem feedback
StarGenetics
•test new version (Yeast)
•add visualizers-C. elegans-bacteria
•curriculum modules
•tutorials
•videos: -illustrate use cases
•assessment
•human pedigrees
•association studies
•population genetics
Other genetic tools StarCellBio
•test new version
•curriculum modules
•videos: -illustrate use cases
StarBiochem
Future directions for STAR biology software
StarBiochem & StarGenetics usage beyond MIT
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