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    Executive Summary for Teachable Unit

    Abstract: Students integrate and apply prior knowledge of biological conceptstoward solving a case study problem involving a real-life ALS mystery.

    Table of Contents:

    I. Title: Integrating Biology: Solving an ALS Mystery p. 2II. Developer: Lori Adams-Phillips p. 2III. Teachable Unit Description p. 2IV. Learning Goals and Intended Outcomes p. 3

    V. Teaching Themes (active learning, assessment, diversity) p. 4VI. Teaching Plan p. 5-6VII. Instructor Materials p. 7-13

    VIII. Student Materials p. 14-23IX. Analysis and Evaluation of Assessment p. 24-28X. Common Misconceptions p. 28XI. References and Resources p. 28-30

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    I. TITLE: Integrating Biology: Solving an ALS Mystery

    II. DEVELOPER: Lori Adams-PhillipsDepartment of Plant PathologyUniversity of Wisconsin-Madison

    III. DESCRIPTION

    This teachable unit provides a platform for students to integrate and apply priorknowledge in plant physiology, animal physiology and ecology towards solving areal-world problem. The goals of this teachable unit are to demonstrate the

    nature of science in its interdisciplinary interactions among researchers, as wellas the active process of constructing and revising hypotheses using the scientificmethod. The concept of biomagnification is simultaneously introduced to thestudents. The targeted audience for this unit consisted of approximately 160sophomore level students enrolled in Introductory Biology 152, a 3-credit lecturecourse required for majors in biological sciences. This unit was presented duringthe ecology portion of the course after students completed both plant and animalphysiology sections. It was implemented over several class periods, however theamount of in-class time spent on this case was approximately 40 minutes.

    Additional work outside of class on the part of the students is required forcompletion of this unit. This unit utilizes active learning approaches to teaching,

    designed to target a diverse range of student abilities. The primary activity of thisteachable unit is a case study entitled Integrating Biology: Solving an ALSMystery. This case study requires both individual and group participation. Thestudents are asked to perform outside research, interpret data given to them thatis relevant to the ALS mystery, explain this data to fellow students, and formulatea hypothesis based on the evidence they have accumulated. After completingthis case, the students will be able to recognize the value of collaboration amongscientific researchers and will have actively experienced the process of thescientific method.

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    IV. LEARNING GOALS AND INTENDED OUTCOMES

    Learning Goal Learning OutcomeStudents will be able to criticallyanalyze experimental evidence inorder to answer a scientific question.(Essential)

    Students will be able to complete aworksheet that requires them tointerpret experimental data andexplain whether the data support orrefute a hypothesis.

    Students will be able to apply andintegrate biological concepts in orderto solve a real-world problem.(Essential)

    Students will be able to generate aplausible hypothesis for why theChamorro people of Guam experiencedhigh incidence levels of ALS in the1960s, based on prior knowledge ofplant and animal physiology and

    ecology.Students will understand the utility ofmulti-disciplinary interaction inanswering a scientific question.(Essential)

    Students will be able to describe thecontributions that researchers frommultiple disciplines made towardssolving the ALS problem.

    Students will be able to collaboratewith other groups by sharing data andformulating a consensus hypothesis.

    Students will be able to extend theirprior knowledge of how changes in

    chemical signaling affect neuronfunction. (Important)

    Students will be able to explain howBMAA impacts neuron function.

    Students will be able extend theirprior knowledge of plant-microbesymbiotic interactions. (Important)

    Students will be able to explain thenature of the cycad/cyanobacteriainteraction and explain theconsequences from this type ofinteraction.

    Students will be able to identify therole of biomagnification in anecological system. (Important)

    Students will be able to explain howbiomagnification plays an importantrole in the incidence levels of ALSamong the Chamorro people of Guam.

    Students will understand howinformation from the ALS case studycould be related to a potentiallyserious human health problem.(Important)

    Students will be able to apply theknowledge and information gainedfrom the case study to predict effectsof BMAA on the US population.

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    V. SCIENTIFIC TEACHING THEMES

    Scientific teaching

    This unit uses active learning approaches intended to give students experience

    in data interpretation and explanation, hypothesis construction/revision, andcollaboration with group members. The exercises are designed to teachstudents about the utility of interdisciplinary interaction across multiple fieldsof biology.

    Diversity

    Diversity is addressed in this unit by incorporating a variety of teachingmethods, resources, and abilities. Teaching methods utilized in this case studyinclude: mini-lectures and active learning at the individual and group level.Students are encouraged to utilize multiple resources in order to solve the case

    study: reliable websites, scientific publications, and other group members.Students become aware of the utility of different biological fields of study andthe importance of the social sciences as well (understanding cultural practices)in solving a real world problem. The questions in the case study are designedto encompass diverse student abilities. For example, some questions requireoutside research, others require mathematical reasoning. In addition, the casestudy takes place in Guam and incorporates an international appeal to auniversal human health issue: ALS.

    Active Learning

    The core activity is a case study. The case study is designed to guide studentsthrough a complex real-life mystery based on basic concepts that they havealready learned regarding plant and animal physiology and ecology. Studentswill be involved in brainstorming activities as well as individual and groupproblem solving. These activities are designed to stimulate their ability/desireto develop hypotheses and answer scientific questions.

    Assessment

    Learning is assessed through a pre/post survey, case study questions, and afinal exam question. The pre-survey questions measure student bias regarding

    the relevance of certain biological disciplines. A series of case study questions(Handout #2A or 2B) assess student comprehension of concepts they havealready learned and the students ability to interpret data. Handout #3 assessesability of the students to explain data to other group members and formulate ahypothesis. A post-survey is conducted to see if attitudes expressed in the pre-assessment survey have changed following completion of the case. A finalexam question assesses a students ability to apply their new knowledge inorder to predict potential health consequences facing the US population.

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    VI. TEACHING PLAN

    Time Learning Goal Activity/AssessmentPre-unit Students will understand the utility of

    multi-disciplinary interaction in answeringa scientific question.

    Assess student biases and misconceptions.

    Handout #1

    (p.14-15)

    Engage/Elicit/Explore: Students are responsible for reading and individuallycompleting Handout #1. This handout contains an introduction to the casestudy and several questions designed to engage the students in the case.Day 1

    (0-10)

    Students will understand the utility of

    multi-disciplinary interaction in answeringa scientific question.

    Students will be able to apply andintegrate biological concepts in order tosolve a real-world problem.

    Mini lecture-

    (Power Point A)

    Explore: Students listen to a short lecture (Power Point A) introducing thegoals of the case study. It is explained that the case study provides anopportunity for the students to integrate their prior knowledge of biological

    concepts to solving a real world problem. Results from the EnGaugementquestions from Handout #1 (Question #1 and #2) are presented as segue toHandout #2.Day 1 Students will be able to critically analyze

    experimental evidence in order to answera scientific question.

    Students will be able to apply andintegrate biological concepts in order tosolve a real-world problem.

    Handout #2A or #2B(p. 16-19)

    Elicit/Explore/Explain: Students complete either Handout #2A or #2B (seeInstructor notes). Students are required to analyze and explainexperimental data and recall biological concepts taught in previous lecturesin order to answer the questions in this handout. Additional outsideresearch is required in order to answer the questions.

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    Time Learning Goal Activity/AssessmentDay 2(0-30)

    Students will be able to identify the roleof biomagnification in an ecologicalsystem.

    Mini-lecture

    Explore: Students are introduced to the concepts of a food web andbiomagnification using familiar examples other than the ALS study.

    Day 2(30-60)

    Students will understand the utility ofmulti-disciplinary interaction in answeringa scientific question.

    Students will be able to identify the role

    of biomagnification in an ecologicalsystem.

    Assess student learning.

    Mini-lecture(Power Point B)

    Handout#3 (p. 20-21)

    Post-survey (p. 22)

    Explain/Explore: The instructor sets the stage for this in-class exercise byexplaining the importance of interaction among scientists when it comes tosolving real-world problems. The exercise is introduced as a Meeting of theMinds (see Power Point B). The scenario for this group activity is anInternational ALS Conference. To begin the exercise, students assigned

    Handout #2A explain their data to a group with Handout #2B and vice versa.Once the data have been explained, the groups formulate a hypothesis forwhy the Chamorro people are getting ALS and complete the questions onHandout #3. Each individual is asked to complete a post-survey.

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    VII. INSTRUCTOR MATERIALS

    The entire case consists of three components. The following is a suggestedbreakdown of points if a grade is to be formally assigned:

    Handout #1 0.5

    Handout #2A or #2B 8.0Handout #3 1.5TOTAL 10.0 points

    HANDOUT #1 (Pre/Post Survey)Instructor notes: Handout #1 of the case study can be e-mailed to the entireclass prior to the start of the case. These questions are not formally graded.Rather, completion of them will count toward the final case grade. Theyshould be turned in prior to the mini-lecture on Day 1 so that the instructor candiscuss the students responses in class.

    Alignment with goals: The first question is designed to engage the students inthe ALS case through brainstorming. The second question is designed for thestudents to explore the interdisciplinary nature of science by having them thinkabout assembling a research team to approach the ALS problem. Questionsthree and four are designed to measure students biases towards the utility ofthe three disciplines studied in the Bio 152 course: plant physiology, animalphysiology and ecology. The last question is designed to measure theconfidence level of the students in their ability to solve real-world problems.The last three questions are presented again to the students as part of a post-survey.

    HANDOUT #2A or #2BInstructor notes: Students are assigned to groups of 3 or 4 people. In thecourse for which this exercise was designed, students are assigned seats in thelecture hall based on their assigned group number so that they are alwaysseated in the same place with their group (see diagram below). Based on theseating chart, student groups receive either Handout #2A or #2B. Groupsreceiving Handout #2A need to be in close proximity to a group that hasreceived Handout #2B and vice versa so that the in-class exercise on Day 2 canproceed smoothly. Each member of the group will be responsible foranswering the questions on the handout, but they should be encouraged towork with their group for help. Students will have one week to complete the

    questions. As an alternative to group-to-group interaction, Handout #2A and2B can be assigned randomly to individuals within a group.

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    Diagram of the seating chart. Each group of 3-4 students is assigned a

    number (1-49). This number is also assigned to a permanent location in thelecture hall so that the students are always seated with their group. Basedon this seating chart, groups receive either Handout #2A or #2B. Eachgroup is assigned a folder with the corresponding group number labeled onit, enabling the instructor to disseminate materials to specific groups.

    Alignment with goals: The questions on Handouts #2A and #2B are designed tomeasure student comprehension of concepts learned in prior plant physiologyand animal physiology lectures. Regarding plant physiology, students extendtheir prior knowledge of symbiotic interactions between plants and bacteria.Regarding animal physiology, students extend their prior knowledge of how

    changes in chemical signaling affect neuron function. Students are required toapply their knowledge of these concepts to a new situation and exploreresources such as the Internet and scientific publications in order to answer thequestions. The questions also measure the students ability to formulate ahypothesis based on their evaluation of data.

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    Handout#2A Assessment (8 points)Data Set #1. (2 points) One of your collaborators sent you data regardingcalcium levels in motor neuron cell cultures (Figure 1). A) Based on what youknow about chemical synaptic signaling, explain the role of calcium during thisprocess. B) Predict how chemical synaptic transmission would change in a pre-

    synaptic neuron from a patient with high levels of BMAA in their brain, basedon the results of Figure 1.A) When an action potential reaches a synaptic terminal, it depolarizes theterminal membrane and opens voltage-gated Ca2+ channels in the membrane,triggering an influx of Ca2+. Synaptic vesicles fuse with the terminal membrane,releasing neurotransmitter into the synaptic cleft via exocytosis.

    B) Increasing calcium in the pre-synaptic motor neurons due to BMAA wouldresult in an increase in the amount of neurotransmitter that would be releasedinto the synaptic cleft.

    Data Set #2.(3 points) Your collaborators also reported that BMAA can induceneuron cell death and activate a neurotransmitter receptor (Rao et al., 2006).A) Based on this information, predict whether BMAA would trigger an excitatoryor inhibitory postsynaptic potential. Explain your answer. B) BMAA shareschemical similarities with certain types of neurotransmitters. Considering thechemical structure of BMAA, predict which type of neurotransmitter receptorBMAA would likely activate.A) BMAA would trigger an excitatory post-synaptic potential because an influxof Ca2+ would depolarize the membrane bringing the membrane closer to thethreshold voltage, which would explain how BMAA could activate aneurotransmitter receptor.

    B) BMAA would most likely activate the neurotransmitter receptor forglutamate. BMAA is an amino acid and is most similar in chemical structure toglutamate. Glutamate is an excitatory amino acid neurotransmitter thataffects neuromuscular junctions. (In addition, patients with ALS haveincreased levels of glutamate in their blood).

    Data Set #3.(2 points) Your graduate student performed the experimentdescribed in Figure 2. Based on those results, determine if cycad flour is alikely source of dietary BMAA for the Chamorro people. Support your argumentfor or against using reasoning based on body weight and include your

    mathematical work. Assume that the average Chamorro person weighsapproximately 70 kilograms and consumes around 28 grams of cycad flour a day(equivalent to 2 tortillas per day).There are several different ways to set up the ratio to answer this question andthey all result in the same answer:Cycad flour is not a likely source of dietary BMAA for the Chamorro people.Mice weighing 50 grams eating 0.2 grams of flour per day showed a significantreduction in viable motor neurons. This is equal to eating 0.004% of their body

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    weight in cycad flour per day. However, Chamorro people weighapproximately 70 kilograms and eat 2 tortillas a day (28 grams of flour), whichis only 0.0004% of their body weight in flour. Mice that eat 0.0004% of theirbody weight in flour (0.02 grams per day) do not show significant reduction inviable neurons. A Chamorro person would have to each 10 times as many

    tortillas (280 grams) a day (0.004% of their body weight) in order to see asignificant reduction in viable neurons.

    Conclusion #1.(0.5 point) Do the results so far support your original hypothesisthat BMAA compound is responsible for the symptoms of ALS in the Chamorropeople? Explain.My conclusions support the hypothesis that the BMAA compound is responsiblefor symptoms of ALS due to the fact that BMAA is able to increase intracellularcalcium levels in neurons and is associated with neuron death.

    Conclusion #2.(0.5 point) Do the results so far support your original hypothesis

    that the cycad flour is the likely source of the BMAA? Explain.The hypothesis that cycad flour is the source of the BMAA is not supported dueto the fact that the Chamorro people do not consume enough of the flour to bephysiologically relevant.

    Handout #2B Assessment (8 points)Data Set #1.(4 points) You made a trip to Guam, collected samples from the

    sources shown in Table 1, and measured the concentration of BMAA in eachsource. A) Provide a simple interpretation of the results in Table 1. B) Is theecological interaction between the cyanobacteria and cycad plant an exampleof predation, mutualism, commensalism or competition? Include in youranswer the result of the interaction from the perspective of both species. C)List three other classes of organisms that form similar associations withcyanobacteria.A) Roots from the cycad plant do not produce BMAA unless they are associatedwith cyanobacteria. The BMAA may be transferred to the cycad roots through asymbiotic interaction.

    B) The association between the cyanobacteria and the cycad is an example ofmutualism. The cycad plant receives fixed nitrogen from the cyanobacteria forgrowth while the cyanobacteria receive a direct supply of carbon and nutrientsfrom the cycad.

    C) Cyanobacteria form similar associations with fungi, gymnosperms, algae,angiosperms, bryophytes and pteridophytes, protists, sponges, lichens, sloths.

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    Data Set #2.(1 point) Your group is interested in the Marianas flying fox batbecause it is known to be a major seed-disperser for cycad trees on Guam,evidenced by the fact that BMAA is found in bat skin (4 mg/gram). Yourcollaborator has been studying the population density of this bat, and sent youdata regarding the population levels of this bat over the last 100 years (Figure

    1). Explain how the results from Figure 1 are relevant to the mysterysurrounding ALS and the Chamorro people.The decreasing bat population correlates with ALS incidence among theChamorro people. As the bat population dropped to near extinction in the1980s, ALS incidence levels among the Chamorro people returned to normallevels.

    Data Set #3. (1 point) The results from data set #2 are very intriguing. Youwant to know what the nature of the interaction is between the Chamorropeople and the fruit bat. Consult the scientific literature to answer thisquestion and provide a citation for your source.

    The Chamorro people eat the fruit bats. This interaction is an example ofpredation. There are numerous acceptable references to this in the literature(see references and resources).

    Conclusion #1.(1 point) Based upon the data you have obtained, draw thepossible flow chart(s) depicting the movement of BMAA through the Guamecosystem where the final endpoint could result in human interaction. Do yourresults support your original hypothesis that there may be multiple points forhuman interaction with the BMAA compound?Yes, my conclusions support the current hypothesis that there are multiplesources of BMAA.

    There are at least two routes:1. cyanobacteria cycad seed human consumption2. cyanobacteria cycad seed fruit bat human consumption

    Conclusion #2. (1 point)Do your conclusions prove that BMAA is the compoundthat is responsible for causing ALS? Explain your answer.My conclusions reveal an association between BMAA and ALS incidence, butfurther testing would be required in order to prove that BMAA is the compoundthat is responsible for causing ALS.

    HANDOUT #3

    Instructor notes: Take a few minutes to set the stage for this exercise byexplaining the importance of interaction between scientists when solving ascientific question (see Power Point B). The setting for this exercise will be asimulation of the International Meeting on ALS Research. Students should besituated so that two members of a group with Handout #2A will be able to meetwith 2 members of a group with Handout #2B without having to move aroundthe classroom to find a partner. This exercise takes approximately 30 minutesto complete in class.

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    Alignment with goals: Question #1 is designed to assess the ability of thestudents to communicate their data to one another. In order for the correctflow chart to be assembled, both parties must have correctly explained theirdata to one another. Part C of Question #1 is designed to reiterate the

    important contribution that each type of researcher made to the case study.The second question is designed to prepare the students to think aboutextending the information from this case regarding people in Guam, to anothersituation in preparation for the final exam question.

    Handout #3 Assessment (1.5 points)Question #1. (1 point)After assimilating all of the data, propose the mostlikely reason for the increased incidence of ALS among the Chamorro peoplefollowing WWII and why it subsequently returned to normal levels. Include thefollowing information in your explanation:

    A) Evidence that supports your hypothesis.

    B) A flow chart depicting the concentration of BMAA as it moves throughthe Guam ecosystem. State the ecological phenomenon that isrepresented by the flow chart.

    C) A list of the critical contributions each type of researcher (neurologist,plant biologist, ecologist) made towards your hypothesis.

    A) The most likely reason for the increased incidence of ALS among theChamorro people following WWII was due to an increase in consumption ofthe flying fox bat, which contained dangerously high levels of BMAA. TheChamorro population had access to more guns and ammunition after the USmilitary occupation in the 1960s, which enabled them to hunt the fruit batto near extinction in the 1980s. It was at this time that the incidence of

    ALS started to level off. The evidence that support this hypothesis includesa correlation between ALS incidence and the bat population and thepresence of high levels the BMAA compound in bat skin tissue. In addition,neurobiological studies demonstrated the ability of BMAA to mimic theaction of the excitatory neurotransmitter glutamate, increase intracellularcalcium levels, and induce neuron death causing symptoms similar to ALS.

    B) Cyanobacteriacycadfox bat peopleBiomagnification is the ecological phenomenon represented by this chart.BMAA increases in concentration from left to right.

    C) Neurologist-discovered how BMAA could cause symptoms of ALSPlant biologist-discovered an association between cyanobacteria and cycadEcologist-recognized biomagnification, familiar with food chain andpredator-prey relationships

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    Question #2. (0.5 points) Based on what you now know about ALS and theChamorro people, could this information impact ALS incidence in the USpopulation in the present day? Explain.The information from this case study could certainly impact ALS and the US

    population in the present day. Cyanobacteria (blue-green algae) are aubiquitous organism and are known to form similar associations with a widerange of organisms found in the US. It is possible that a similar pathwayinvolving biomagnification of BMAA through ecosystems in the US could result inan increase in ALS incidence in the US. The biochemical information pertainingto the BMAA compound is also useful in terms of understanding more about theincurable ALS disease.

    Final Exam Question Assessment:You discovered that when the herbicide Diquat is used in combination withanother herbicide, Fluridone, the growth of cyanobacteria (blue-green algae)

    strains found in freshwater is stimulated. As you may recall, cyanobacteriahave been shown to produce BMAA, a neurotoxin. Explain the human healthconsequences of drinking water or consuming fish from these waters due to theincreased growth of BMAA-producing cyanobacteria. How might the process ofbiomagnification be involved?BMAA is excitotoxic and activates action potentials by mimicking theneurotransmitter, glutamate. Thus, humans who become exposed to highlevels of BMAA can develop neurological disorders such as ALS. Drinking thewater containing BMAA producing cyanobacteria may not be that harmful, asconcentrations are likely to be low enough to not cause symptoms. This issimilar to the situation regarding cycad flour consumption and neuron cell

    death in mice. However, the small amount of BMAA being produced by thecyanobacteria in the water can have profound impacts on human health due tobiomagnification. Through biomagnification, BMAA can accumulate to higherlevels as it moves up through higher trophic levels. For example,cyanobacteria can be consumed by small fish, which are in turn consumed bylarger predatory fish, and finally consumed by humans. As the concentration ofBMAA increases as it moves up the trophic cascade, it could eventually becomeconcentrated enough to produce symptoms of ALS in humans.

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    VIII. STUDENT MATERIALSHandout #1This case study provides you with an opportunity to recall biological conceptsyou have learned so far and apply them to solving a real-life mystery. Thefollowing story is true and most of the data you will analyze come from

    published papers. Note that aspects of this case will appear as one of the finalexam questions. Plan to become familiar with all parts of this case.

    Integrating Biology: Whodunit? Solving an ALS Mystery

    The native people of Guam, the Chamorro, are believed to have arrivedon the island of Guam around the year 3000 B.C. and evolved as a culture inrelative isolation. Beginning in the early twentieth century, Guam's importanceas a trading center and military outpost increased. A cash economy, includingfunds for guns and ammunition, became more prominent within the indigenousChamorro community. After World War II, the US military took over the island

    of Guam. US military physicians observed an increasing number of nativeChamorro patients presenting with symptoms of a debilitating brain disease,which was eventually identified as ALS.

    Amyotrophic lateral sclerosis (ALS), also known as Lou Gehrigsdisease, is named for the great New York Yankee, Hall of Fame first basemanof the 1920-1930s, Lou Gehrig. ALS is a rapidly progressive, fatal neurologicaldisease that attacks and kills the nerve cells responsible for controllingvoluntary muscles (www.ninds.nih.gov/disorders/amyotrophiclateralsclerosis).The average life expectancy for a patient diagnosed with ALS is approximately2-5 years. ALS occurs throughout the world with no racial, ethnic, orsocioeconomic boundaries (www.alsa.org). There is no known cure.

    By the 1960s, the incidence of ALS among the Chamorro people of Guamwas at a rate 50100 times that any other country in the world. The disease hadbecome the number one killer of Chamorro adults. Then surprisingly, in the1980s, cases of the disease fell to normal levels (approximately 5/100,000). Tothis day scientists are intrigued by this phenomenon and seek answers as towhy the incidence of ALS was so alarmingly high among the Chamorro peopleand why it has now returned to normal levels.

    Directions: Design a strategy for how you would approach solving this mysteryon the next page. Save this page for future reference. This handout will not be

    formally graded. However, you will receive credit for the completion of thesequestions, which will count towards your final case study grade.

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    Handout #1Name:_________________ Group Number:__________

    1. You are the leader of a research team charged with the task ofunderstanding why the incidence of ALS was so high among the Chamorro

    people and how returned to normal levels. Propose at least two questions thatyou feel are important to answer in order to solve this mystery.

    2. Assemble a research team (2 or more members) to answer those questions.

    List the types of professionals you would put on your team. In one or twosentences, explain why you chose those particular professionals for your team.

    3. Rank the importance of the following Bio 152 fields of study to solving

    particular case study (1-most important, 3-least important).

    Plant Physiology ______Animal Physiology ______Ecology ______

    4. Rate the contribution that the following professionals will likely maketowards solving this case (0-no contribution, 10-large contribution).

    Plant Physiologist ______Animal Physiologist ______

    Ecologist ______

    5. How confident are you in your ability to identify and analyze real worldproblems that require integration of knowledge from plant/animal physiologyand ecology to solve?

    A. Not confident C. ConfidentB. Somewhat confident D. Very Confident

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    Handout #2AName:_________________ Group Number:__________

    The reason for the dramatically high incidence of ALS among the Chamorropeople of Guam during the 1960s and subsequent return to normal levels

    during the 1980s still remains a mystery. Genetic transmission of ALS in theChamorro people was ruled out and scientists have become certain that thecause for the increased cases of ALS must have been due to environmental/cultural factors. Recently, one research group reported high levels of the rareamino acid 2-Amino-3-(methylamino)-propanoic acid (BMAA) in brain tissuefrom Chamorro people that died of ALS. The cycad plant, an ancientgymnosperm that inhabits Guam, is one of the only known organisms toproduce BMAA. The seeds attract some animals, which serve as dispersalagents. The cycad seeds have also been a dietary staple for the Chamorropeople for centuries. The seeds are washed several times in order to reducethe amount of toxin and are used to make tortillas.

    You are part of a team of neurobiology researchers interested in identifyingpotential causes of ALS. Your hypotheses are that the BMAA compound isresponsible for the symptoms of ALS in the Chamorro people and that the cycadflour is the likely source of the BMAA. Your funding agency requires a progressreport of the results from your research. You will present this report at theupcoming International Meeting on ALS and Motor Neuron Diseases.

    Directions: Interpret the following data sets sent to you by your researchcollaborators and graduate student (Data sets 1 through 3). Determine ifthese data support your hypotheses (Conclusions). Turn in your individualreports containing your answers to Data Sets 1-3 and the Conclusions section ona separate sheet of paper by the start of the next class period.

    Data Set #1. One of your collaborators sent you data regarding calcium levelsin motor neuron cell cultures (Figure 1). A) Based on what you know aboutchemical synaptic signaling, explain the role of calcium during this process. B)Predict how chemical synaptic transmission would change in a pre-synapticneuron from a patient with high levels of BMAA in their brain, based on theresults of Figure 1.

    Figure 1. Calcium levels inmotor neuron cell cultures.Calcium levels were recorded 10minutes prior to and 30 minutes aftertreatment with BMAA (Rao et al.,

    2006).

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    Data Set #2. Your collaborators also reported that BMAA can induce neuroncell death and activate a neurotransmitter receptor (Rao et al., 2006). A)Based on this information, predict whether BMAA would trigger an excitatory orinhibitory postsynaptic potential. Explain your answer. B) BMAA has chemical

    similarities to certain types of neurotransmitters. Considering the chemicalstructure of BMAA, predict which type of neurotransmitter receptor BMAAwould likely activate.

    Data Set #3. Your graduate student performed the experiment described inFigure 2. Based on those results, determine if cycad flour is a likely source ofdietary BMAA for the Chamorro people. Support your argument for or againstusing reasoning based on body weight and include your mathematical work.Assume that the average Chamorro person weighs approximately 70 kilograms

    and consumes around 28 grams of cycad flour a day (equivalent to 2 tortillasper day).

    Conclusion #1. Do the results so far support your original hypothesis that BMAAcompound is responsible for the symptoms of ALS in the Chamorro people?Explain.

    Conclusion #2. Do the results so far support your original hypothesis that thecycad flour is the likely source of the BMAA? Explain.

    References:Rao et al., (2006) Experimental Neurology 201:244-252.

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    cycad flour Figure 2. Neuron cell death inresponse to flour consumption inmice. Samples of cycad flour wereobtained from Guam containingapproximately 0.1 milligram of BMAA pergram of flour. Mice weighing approximately0.05 kilograms each were fed various

    amounts of cycad flour or wheat flour(containing no BMAA) ranging from 20 to 200milligrams of flour per day. Viable neuronswere counted and recorded for eachtreatment group.

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    Handout #2BName:_________________ Group Number:__________

    The reason for the dramatically high incidence of ALS among the Chamorropeople of Guam during the 1960s and subsequent return to normal levels

    during the 1980s still remains a mystery. Genetic transmission of ALS in theChamorro people was ruled out and scientists have become certain that thecause for the increased cases of ALS must have been due to environmental/cultural factors. Recently, one research group reported high levels of the rareamino acid 2-Amino-3-(methylamino)-propanoic acid (BMAA) in brain tissuefrom Chamorro people that died of ALS. The cycad plant, an ancientgymnosperm that inhabits Guam, is one of the only known organisms toproduce BMAA. The seeds attract some animals, which serve as dispersalagents. The cycad seeds have also been a dietary staple for the Chamorropeople for centuries. The seeds are washed several times in order to reducethe amount of toxin and are used to make tortillas.

    Your group represents a team of plant physiologists and ecologistsinterested in cycad plant biology and cycad-associated organisms. For example,specialized roots (coralloid roots) of the cycad plant are oftentimes inhabitedby cyanobacteria. Your hypothesis is that there may be multiple sources ofBMAA via association with the cycad and therefore multiple points for humaninteraction with BMAA. Your funding agency requires a progress report of theresults from your research. You will present this report at the upcomingInternational Meeting on ALS and Motor Neuron Diseases.

    Directions: Interpret the following data sets sent to you by your researchcollaborators and graduate student (Data sets 1 through 3). Determine ifthese data support your hypotheses (Conclusions). Turn in your individual

    reports containing your answers to Data Sets 1-3 and the Conclusions section ona separate sheet of paper by the start of the next class period.

    Table 1.Source Concentration of BMAA (mg/g)Cyanobacteria 0.003Cycad roots-no association 0.0Cycad roots-cyanobacteria association 0.037

    Data Set #1. You made a trip to Guam, collected samples from the sourcesshown in Table 1, and measured the concentration of BMAA in each source. A)

    Provide a simple interpretation of the results in Table 1. B) Is the ecologicalinteraction between the cyanobacteria and cycad plant an example ofpredation, mutualism, commensalism or competition? Include in your answerthe result of the interaction from the perspective of both species. C) List threeother classes of organisms that form similar associations with cyanobacteria.The following website will be useful:http://plantnet.rbgsyd.nsw.gov.au/PlantNet/cycad.

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    Data Set #2. Your group is interested in the Marianas flying fox bat because itis known to be a major seed-disperser for cycad trees on Guam, evidenced bythe fact that BMAA is found in bat skin (4 mg/gram). Your collaborator hasbeen studying the population density of this bat, and sent you data regardingthe population levels of this bat over the last 100 years (Figure 1). Explain howthe results from Figure 1 are relevant to the mystery surrounding ALS and theChamorro people.

    Data Set #3. The results from data set #2 are very intriguing. You want toknow what the nature of the interaction is between the Chamorro people andthe fruit bat. Consult the scientific literature to answer this question andprovide a citation for your source.

    Conclusion #1. Based upon the data you have obtained, draw the possible flowchart(s) depicting the movement of BMAA through the Guam ecosystem wherethe final endpoint could result in human interaction. Do your results supportyour original hypothesis that there may be multiple points for humaninteraction with the BMAA compound?

    Conclusion #2. Do your conclusions prove that BMAA is the compound that isresponsible for causing ALS? Explain your answer.

    References:Monson et al., (2003) Conservation Biology 17:678-686.

    0

    10000

    20000

    30000

    40000

    50000

    60000

    70000

    1900 1910 1920 1930 1940 1950 1960 1970 1980 1990 2000

    year

    Figure 1.A record of theflying fox bat population

    size over the last 100years.Figure based on datafrom Monson et al., 2003.

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    Handout #3IN CLASS EXERCISEThis in class exercise is designed to simulate a scientific research meeting.Your research group has been invited to present your research related to ALSand Chamorro people of Guam at the Annual International meeting on ALS and

    Motor Neuron Diseases. Pair up with the group sitting in front or behind you(see screen for details). Discuss your answers to the worksheets (A and B) sothat each person in the group is familiar with all of the data. Answer the twoquestions (front and back) and turn in your answers as a group along with yourindividual answers to worksheet A or B. Be sure to put your names and groupnumbers on this sheet to receive credit. Also, please take a minute tocomplete the brief post-survey.

    Question #1. After assimilating all of the data, propose the most likely reasonfor the increased incidence of ALS among the Chamorro people following WWIIand why it subsequently returned to normal levels. Include the following

    information in your explanation:A) Evidence that supports your hypothesis.B) A flow chart depicting the concentration of BMAA as it moves through

    the Guam ecosystem. State the ecological phenomenon that isrepresented by the flow chart.

    C) A list of the critical contributions each type of researcher (neurologist,plant biologist, ecologist) made towards your hypothesis.

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    Question #2. Based on what you now know about ALS and the Chamorropeople, could this information impact ALS incidence in US population in thepresent day? Explain.

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    Post Survey

    Question #1. Rank the importance of the following Bio 152 fields of study tosolving particular case study (1-most important, 3-least important).

    Plant Physiology ______Animal Physiology ______Ecology ______

    Question #2. Rate the contribution that the following professionals madetowards solving this case (0-no contribution, 10-large contribution).

    Plant Physiologist ______Animal Physiologist ______Ecologist ______

    Question #3. How confident are you in your ability to identify and analyze realworld problems that require integration of knowledge from plant/animalphysiology and ecology to solve? ______

    A. not confidentB. somewhat confidentC. confidentD. very confident

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    Final exam question

    Cycads are known to have lived over 200 million years ago - even before thedinosaurs roamed the earth. Although once abundant across the globe, thecycad population is now greatly reduced. Efforts are underway to preserve

    these ancient species. You have been asked by the Environmental ProtectionAgency (EPA) to investigate the toxicity of the herbicides Diquat and Fluridonewith respect to cycad ecology and human health.

    You discovered that when the herbicide Diquat is used in combination withanother herbicide, Fluridone, the growth of cyanobacteria (blue-green algae)strains found in freshwater is stimulated. As you may recall, cyanobacteriahave been shown to produce BMAA, a neurotoxin. Explain the human healthconsequences of drinking water or consuming fish from these waters due to theincreased growth of BMAA-producing cyanobacteria. How might the process ofbiomagnification be involved?

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    IX. ANALYSIS AND EVALUATION

    Handout #1 and Pre/Post Survey Analysis:Handout #1 was administered in order to engage the students in the case and

    to uncover any misconceptions and/or bias towards the relevance of particularfields of study. This activity was effective in engaging the students in the casebased on the detail in the responses and the wide range of responses (seebelow). A bias towards the utility of animal physiology and ecology versusplant physiology disciplines was uncovered (Figures 1 and 2). However, it maynot have seemed obvious to the students that plant physiology would play arole in solving the mystery based on the description of the case. This bias wascorrected based on the post-survey results that show a substantial increase inthe students views of the importance of plant physiology toward solving thecase (Figure 1 and 2). Overall, the confidence of the students in their abilityto integrate and apply knowledge of biological concepts towards solving real-

    world problems increased after completion of the case (Table 1).

    Question #1. The majority of the students were interested in whether or notALS was a genetic disease and whether the environment had a significant effecton development of ALS. It was evident that a few students (approximately10%) had done research on the Internet and knew about the case. However,the majority did not and simply researched the causes of ALS. A summary ofstudent responses is listed below.

    - Is there something unique about the genetics of the Chamorro people (populationgenetics, genetic mutation)?

    - What are the causes of ALS (environment, genetics, how is it spread, differentcarriers)?

    - Where there changes in the environment (altered resources, introduction ofsomething foreign, diet, was there a toxin, food or water sources, dietary changes,

    bat or cycad tree, water contamination, bacteria contamination, plant species)?- Did the US influence have something to do with it (factory development, US

    military spread a disease to trigger ALS, chemical in the ammunition, isolation to

    cash economy switch, WWII chemical problems)?- Was there a change in the ability to diagnose ALS? (new diagnostic tests)- Where there changes in cultural/geographic factors (change in other plant and

    animal species on the island, more prevalent in men than women, diet/lifestyle of

    people affected, where in Guam did it originate, where in Guam is it associated)?- Where there changes in immigration/emigration patterns, trade patterns?- Are there immune system problems in the Chamorro people?

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    Question #2. The majority of students chose a biochemist, neurologist,geneticist and ecologist for their research team. However, a large number ofadditional researchers were added to the list (see below).

    List of Researchers on TeamLimnologistMicrobiologist

    Archaeologist

    BiologistMedical Specialist/physician

    Dietician

    Zoologist

    Soil ScientistBotanist

    Physiologist

    GeneticistGeologist

    Neurologist

    BiochemistEcologist

    Anthropologist/Historian

    Military OfficialOceanographer

    Translator/Chamorro nativeEpidemiologist

    Communicable disease scientist

    Environmentalist/Earth Scientist

    Specific people:Stephen Scelsa (ALS Specialist)

    Sandra Banack (Ecologist)

    Albec Messing (neurologist-glial cells and astrocytes)Barry Ganetzky (neurogenetics, molecular genetics)

    John Hawks (human evolution and genetics)

    Kenneth George (Southeast Asian CultureMakiko Nagai (Motor Neuron Biology -SOD1)

    Biane Bo Re (Motor Neuron Biology -SOD1)

    Oliver Sacks (neurologist, cycad theory)

    Paul Cox (neurologist, cycads and bat link)Haldre Rogers (bat ecologist)

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    Figure 1. Student-ranked importance of plant physiology, animalphysiology, and ecology. Students were asked to rank the importance of the

    following fields of study to solving this particular case study. (1-mostimportant, 3-least important) both prior to and after completion of this case(pre-survey n=148, post-survey n=154; error bars represent standard error).While the importance of ecology remained the same in the pre and post-analysis, students gave plant physiology a more important ranking aftercompletion of the case relative to the ranking prior to the case.

    Figure 2. Student contribution rating for plant physiologist, animalphysiologist and ecologist. Students were asked to rate the contribution that

    a plant physiologist, animal physiologist, and ecologist would make towardssolving this case (0-no contribution, 10-large contribution) both prior to andafter completion of the case (pre-survey n=148, post-survey n=154; error barsrepresent standard error). The contribution rating of the ecologist did notchange before or after completion of the case. However, the relativeimportance of the contribution that the plant physiologist made towardssolving the mystery increased substantially following completion of the case.

    0

    1

    2

    3

    4

    5

    6

    7

    8

    9

    Plant Physiologist Animal Physiologist Ecologist

    levelofcontributio

    n

    Pre

    Post

    0

    0.5

    1

    1.5

    2

    2.5

    3

    Plant Physiology Animal Physio logy Ecology

    rank Pre

    Post

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    Table 1. Percentage of student responses to survey question.Students were asked the following question:How confident are you in your ability to identify and analyze real worldproblems that require integration of knowledge from plant/animal physiologyand ecology to solve?

    A=not confident, B=somewhat confident, C=confident D=very confident

    This survey question was part of a broader active learning survey that wasgiven to the students at various intervals throughout the semester.

    Surveys 1 (n=163) and 2 (n=164) were administered several weeks prior to thecompletion of the case. Survey 3 (n=154) was administered immediately aftercompletion of the case as part of the post-survey. Survey 4 (n=154) wasadministered several weeks following completion of the case. Confidencelevels increased immediately after completion of the case with a reduction inthe percentage of A and B responses and increase in C and D responses. In theweeks following the case, confidence levels fell (lower percentage of C and Dresponses), but not to the levels they were prior to the case (Survey 1 andSurvey 2).

    Suggestions for future use of this teachable unit:Handout #1It may be useful to have the students answer these questions in class next timeto get an idea of their initial thoughts without having time for internet or otheroutside research. Handout #1 could simply become a verbal brainstormingexercise rather than a handout. The pre-survey could still be completed inclass. An in-class brainstorming exercise would prevent bias that comes fromreading about the case on the Internet as it is based on a true story.

    Handout #2The students performed very well on the two handouts. The graded averages

    were equal between Handout #2A and #2B (93.1% and 94.1%, respectively). Iwas initially concerned that one handout was easier than the other and so thegrading was not as rigorous as it could have been. One suggestion might be tosimply use these handouts as an in-class exercise and not assess a grade tothem. The handouts could be turned in for assessment by the instructor andcould be used as a stepping-stone for completion of Handout #3. In addition,individual instructors may tailor the questions to be more rigorous based ontheir specific learning goals.

    Survey 1 Survey 2 Survey 3 Survey 4

    A 8.0 9.8 0.6 7.1

    B 41.7 47.0 21.4 36.4

    C 44.2 37.8 59.7 47.4

    D 5.5 4.9 18.2 9.1

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    Handout #3The students were very actively engaged in group-to-group discussionthroughout the duration of this exercise (approximately 30 minutes). Asuggested follow-up activity would be to discuss the chemical nature of the

    BMAA substance and to generate an in-class discussion regarding some of thecontroversy surrounding the BMAA and ALS debate (see Power Point B andSection XI, References and Resources).

    Final Exam QuestionThe majority of students were able to identify and describe howbiomagnification of BMAA could take place in a lake ecosystem and they wereable to describe the effects this would have on human health. However, theanswers were not always complete. For example, many students stated thatBMAA could cause symptoms of ALS but didnt state how that would happen(e.g. increased output of neurotransmitter). Another example is that students

    would comment only on how fish consumption would effect human health andwould not comment on water consumption and human health. Giving studentsan example of a complete answer to an essay-type question, and/or gradingthe case more rigorously with additional feedback on the answers may alleviatethis problem.

    X. COMMON MISCONCEPTIONS

    The biology course for which this teachable unit was designed focuses onteaching basic concepts in plant and animal physiology and ecology. Adifferent professor teaches each of these diverse areas of biology. Students

    often leave with the misconception that these units are distinct from oneanother. The students struggle to recognize the inter-connectedness betweeneach of the units.

    In this unit, students apply and integrate biological concepts in order tosolve a real-world problem. Students will be able to recognize where unityexists among the different areas related to Biology.

    XI. REFERENCES AND RESOURCES

    ALS resourcesALS association: www.alsa.org/research

    www.ninds.nih.gov/disorders/amyotrophiclateralsclerosis

    Cycad resourcesThe cycad society: www.cycad.orgVirtual cycad encyclopedia: www.plantapalm.comIntroduction to the cycads: www.ucmp.berkely.eduThe cycad pages: plantnet.rbgsyd.nsw.gov.au/PlantNet/cycadCo-evolution: http://www.plantapalm.com/Vce/biology/pollination.htm

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    Brenner ED, Stevenson DW, Twigg RW. (2003) Cycads: evolutionary innovationsand the role of plant-derived neurotoxins. Trends in Plant Science, 8:446-52.

    BMAA resources

    Buenz EJ, Howe CL. Beta-methylamino-alanine (2007) (BMAA) injureshippocampal neurons in vivo. Neurotoxicology, Feb 24 (Epub ahead of print).

    Cruz-Aguado R, Winkler D, Shaw CA. (2006) Lack of behavioral andneuropathological effects of dietary beta-methylamino-L-alanine (BMAA) inmice. Pharmacology Biochemistry and Behavior, 84:294-9.

    Rao et al., (2006) BMAA selectively injures motor neurons via AMPA/kainatereceptor activation. Experimental Neurology, 201:244-252.

    Duncan MW, Steele JC, Kopin IJ, Markey SP. (1990) 2-Amino-3-(methylamino)-

    propanoic acid (BMAA) in cycad flour: an unlikely cause of amyotrophic lateralsclerosis and parkinsonism-dementia of Guam. Neurology, 40:767-72.

    Flying fox resourcesBanack SA, Murch SJ, Cox PA. (2006) Neurotoxic flying foxes as dietary itemsfor the Chamorro people, Marianas Islands.Journal of Ethnopharmacology,106:97-104.

    GuBanack SA, Cox PA. (2003) Cycad neurotoxins in flying foxes: implicationsfor ALS-PDC in Guam. Neurology, 61:387-9.

    Monson et al., (2003) Conservation Implications of Chamorro Consumption offlying foxes as a possible cause of Amyotrophic Lateral Sclerosis-ParkinsonismDementia complex in Guam. Conservation Biology, 17:678-686.

    Biomagnification resourcesMurch SJ, Cox PA, Banack SA. (2004) A mechanism for slow release ofbiomagnified cyanobacterial neurotoxins and neurodegenerative disease inGuam. PNAS, 101:12228-31.

    Cox PA, Banack SA, Murch SJ. (2003) Biomagnification of cyanobacterialneurotoxins and neurodegenerative disease among the Chamorro people of

    Guam. PNAS, 100:13380-3.

    Controversy surrounding ALS mysteryMiller G. (2006) Neurodegenerative disease. Guam's deadly stalker: on theloose worldwide? Science, 313:428-31.

    Duncan MW and Marini AM. (2006) Debating the cause of a neurologicaldisorder. Science, 313:1737.

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    Cox PA and Banack SA. (2006) A nonprotein amino acid and neurodegeneration.Science, 314:1242.

    Recent reviews related to case

    Papapetropoulos S. (2007) Is there a role for naturally occurring cyanobacterialtoxins in neurodegeneration? The beta-N-methylamino-l-alanine (BMAA)paradigm. Neurochemistry International, Jan 14; (Epub ahead of print).

    Ince PG, Codd GA. (2005) Return of the cycad hypothesis - does theamyotrophic lateral sclerosis/parkinsonism dementia complex (ALS/PDC) ofGuam have new implications for global health? Neuropathology and AppliedNeurobiology, 31:345-53.

    Armon C. (2003) Western Pacific ALS/PDC and flying foxes: What's next?Neurology, 61:291-2.

    Cox PA, Sacks OW. (2002) Cycad neurotoxins, consumption of flying foxes, andALS-PDC disease in Guam. Neurology, 58:956-9.

    Chamorro cultureOfficial Guam culture page: http://ns.gov.gu/culture.html

    Fun and interestingRecipe for fruit bat soup: http://www.huntingpa.com

    Search this site for fruit bat recipes