Howard university presentation ver3

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

Nobel Prize website
Aquaporin structural model

10% of what they hear
30% of what they see
60% of what they hear & see
80% of what they hear, see, & do
100% of what they hear, see, do, smell, feel, taste…& purchase on credit
By Ronald A. Berk
Professors are from Mars. Students are from Snickers.
Students learn…

Challenge
Bridging the divide between research & the classroom using
interactive technology.

Who we are
MIT Biology Department
Office of Educational Innovation & Technology (OEIT)
What we are doing
Designing interactive teaching software tools
to be used IN & OUTSIDE class

Software Tools for Academics &
Researchers (STAR) biology tools
1 Educational goals
2 Design process
3 Access & outreach

Educational goals
Challenge
Teaching protein structure in a traditional classroom setting
StarBiochem: protein 3D viewer
Challenge
Teaching experimental design & data interpretation outside of
a genetics lab
StarGenetics: virtual genetics lab

Design process
Collaboration between MIT faculty & OEIT
StarBiochem Professor Graham Walker
Introductory Biology Series
StarGenetics Professor Chris Kaiser
Genetics
Graduate Student Bridge Program

Access & outreach
Software & 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
Visits
9881
Countries
82

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
hemoglobin
carry oxygen
in the blood
F1 ATPase
generate energy
antibody
protect against
infections
aquaporin
water transport
microtubules
cell division
Protein Data Bank website

The function of a protein is
determined by its structure
structure function

Challenge
Teaching protein structure in a traditional classroom setting.

Traditional methods for teaching
about protein structure and function
Cartoons
Can introduce misconceptions
2-D representations
Limits 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 for
teaching 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/

How mutations in DNA can result in disease
sickle 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

Hemoglobin
heme
heme
Highly 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 sequence
A -> T
protein
hemoglobin becomes sticky
amino acid sequence
Glu6 -> Val6
disease
sickle cell anemia

Goal
To 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

Current StarBiochem educational
applications
• Undergraduate setting
Introductory Biology (MIT)
Introductory Biology Lab (Brandeis)
• High school setting
MIT 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 biology
neurobiology genetics
PAH amyloid GFP BCR-Abl Herceptin DNA pol Ras Hemoglobin
PFK
crystallin
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 in-class activities
Short (2-5 min)
Intermediate (10-20 min)
Long (40-60 min)

Short
Example: snapshot of a structure or a concept
use StarBiochem live
create video using StarBiochem
create images of a particular structural snapshot

Short
Example: snapshot of a structure or a concept
use StarBiochem live
create video using StarBiochem (ex: hemoglobin)
create images of a particular structural snapshot

Intermediate
Example: interactive building protein activity
Protein 1 Protein 2
cell membrane protein cytoplasmic protein

Intermediate
Example: interactive building protein activity
Protein 1 Protein 2
cell 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.

Long
Example: basics of protein structure lecture using
StarBiochem (Dr. Chia-Yung Wu)
Example 1 Example 2
Potassium 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)

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 for
students to use software.
Outside-class activities

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
implementation
Use 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

Goal
To illustrate how to implement StarBiochem lab activity.

DNA mutations
neutral
positive -> evolution
negative -> disease
Effects
Consequences of DNA mutations

Consequences of DNA mutations
DNA mutations
neutral
positive -> evolution
negative -> disease
Effects

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
DNA
glycosylase

How our cells try to fix DNA mutations
DNA glycosylase

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. Barker
Scientific 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.

Oxidation can cause mutations in DNA

1
2

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:
structure
human DNA glycosylase &
DNA substrate
mechanism
rotating DNA bases outside of
double helix to check for mutations

Personalized medicine for treating cancer
Rebecca Henretta (2007)

Non-responders
Responders

Non-responders
Responders
alternative
treatment
conventional
treatment

Personalized medicine for treating cancer:
hOGG1 levels & lung cancer
low
cancer risk
high
low
high
hOGG1 levels
Cleveland Clinic website

Lab activity: post-assignment
Goal
Synthesis 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.

Goal
Empower 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

What is the goal of the activity?
structure -> function
structure -> function -> disease
structure -> medical therapies
protein regulation
evolution of protein structure

1 Course
• Introductory Biology
• Biochemistry
• Cell/Molecular Biology
• Pharmacology
• Etc.
2 Course curriculum
• format
• duration of activity

Example 1
Structure -> function
Course Introductory Biology
Curriculum central concept of the course
Activity
StarBiochem protein structure lecture + StarBiochem exercise
(homework/lab activity)

Example 2
Structure -> medical therapies
Course Cell Biology
Curriculum minor point within a lecture
Activity
StarBiochem video or in class-demo illustrating structure –>
targeted therapies

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

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

Researching & finding the appropriate structure
Hemoglobin: exercise with a well defined activity
structure -> function -> disease
Glu6 -> Val6 in hemoglobin leads to sickle cell anemia
DNA glycosylase: exercise with less well defined activity
illustrate how DNA glycosylase repairs DNA

1 Format/duration
Short activity straight to the the point
ex: DNA glycosylase video
Long activity framework for building complexity
ex: DNA glycosylase exercise

References
Structure: 1EBM
Bruner, S. et al. (2000) Structural basis for recognition and repair of the
endogenous mutagen 8-oxoguanine in DNA. Nature 403: 859-866.
Structures: 1YQK, 1YQR
Banerjee, A. et al. (2005) Structure of a repair enzyme interrogating
undamaged DNA elucidates recognition of damaged DNA. Nature
434: 612-618.

Structure: 1EBM
Bruner, 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

“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 - its
8-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.”

Structures: 1YQK, 1YQR
Banerjee, 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

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.”

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.”

Long activity: framework for building complexity
Begin with: simple questions
Allow students to become familiar with protein structure basics
End with: complex questions
Allow students to understand the goal of the activity

Long activity: framework for building complexity
Begin with: simple questions
Allow students to become familiar with protein structure basics
DNA Glycosylase Exercise: questions 1-5
End with: goal of the exercise
DNA Glycosylase Exercise: questions 6-8

DNA Glycosylase Exercise: simple questions
Question 1: overall structure
explore different 3-D models for representing atoms
Question 2: amino acid structure
explore difference between amino acid backbone and side chain
Question 3,4: secondary structure
explore how individual amino acids fold to form secondary structures
Question 5: tertiary structure
explore 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 helix
location of oxoG with respect to the double helix
Question 7: hOGG1 recognizes oxidized bases by contacting the
damaged base directly and recognizing a specific modification
comparison 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 hOGG1
comparison of the oxoG:hOGG1 interaction with that of the G:hOGG1
interaction

Interactive exercise: creating a
StarBiochem activity
- Goal of the activity you would like to implement
- Type of activity (length, structure, specifics)
1. Work alone
2. Discuss with a partner
3. Share ideas with the group

Acknowledgements
Star Team
Sara Bonner
Rocklyn Clarke
Ivan Ceraj
Justin Riley
Chuck Shubert
Biology Department
Chris Kaiser
Graham Walker
Diviya Sinha
OEIT
Vikay Kumar
Molly Ruggles
Collaborators
Stacie Bumgarner
Melissa Kosinski-Collins
Megan Rokop
Kathy Vandiver
Lourdes Aleman laleman@mit.edu
Collaborating Institutions
Brandeis University
Broad Institute Outreach Program
Howard University
MIT Museum
Suffolk University
Tufts University
Outside Funding
Davis Educational Foundation
HHMI 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
Visits
14,963

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