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COLORADO DIVISION OF WILDLIFE 6060 Broadway • Denver, CO 80216

(303) 297-1192 • www.wildlife.state.co.us

C O L O R A D O D I V I S I O N O F W I L D L I F E

Prying Into PrionsInvestigating Chronic Wasting Disease

Dr. Elizabeth (“Beth”) Williams was alife-long student, contemplating problemsshe encountered with an open mind andviewing them as new opportunities tolearn. Beth’s innate curiosity, combinedwith her careful and thorough approach to diagnostic pathology, allowed her tosucceed where others had previously failed inunraveling the cause of amysterious but little-knowndisease of captive mule deercalled “chronic wastingdisease”. The realization thatthe chronic wastingsyndrome seen in captivedeer was in fact one of ahandful of diseases in the transmissiblespongiform encephalopathy groupopened the door to three decades ofresearch and scientific progress toward abetter understanding of chronic wastingdisease, as well as other prion diseasesof animals and humans. Although notableprogress has been made, there is stillmuch work to be done before ourknowledge and technology is sufficient tocontrol and manage these diseases witheffectiveness comparable to our capacityto deal with diseases caused by moreconventional pathogens. Because futureadvances likely will depend in no smallpart on the creativity and inquisitivenessof a new generation of scientists, it seems

only fitting that the Colorado Division of Wildlife dedicates this high schoolscience education module Prying intoPrions—Investigating Chronic WastingDisease to the memory of Dr. BethWilliams. We hope this tool will helpstimulate growth and training, and will

help foster a similarpassion for life-longlearning in our nextgeneration of scientists.

We also recognize thatno successful scientistaccomplishes much ofconsequence in isolation,and thus we want to

acknowledge and thank the many otherresearchers, biologists, pathologists, andtechnicians in Colorado, Wyoming, andelsewhere who have contributed to thebody of knowledge on chronic wastingdisease and other prion diseases. Thechallenges the Division of Wildlife andother management agencies have facedin addressing chronic wasting diseasewould have been far more daunting in the absence of the firm foundation ofknowledge provided by their collectiveefforts.

Michael W. MillerSenior Wildlife VeterinarianColorado Division of Wildlife

In Dedication to

Dr. Elizabeth (“Beth”) Williams

Photo by the Rocky Mountain News, providedcourtesy of Dr. Jean Jewell, University of Wyoming.

Education Advisors and Reviewers:

Lisa Evans, Northeast RegionEducation Coordinator, DOW

Leigh Gillette, Southwest RegionEducation Coordinator, DOW

Linda Groat, Southeast Region RuralEducation Specialist, DOW

Renée Herring, Watchable WildlifeCoordinator, DOW

Stan Johnson, Northwest RegionEducation Coordinator, DOW

Tabbi Kinion, Project WILDCoordinator, DOW

Debbie Lerch-Cushman, Metro DenverEducation Coordinator, DOW

Steve Lucero, Southeast RegionEducation Coordinator, DOW

Jeff Rucks, Head of Education, DOW

Graphic Design:

Darren Eurich, State ofColorado IntegratedDocument Solutions (IDS)

Illustrations:

Darren Eurich

Marjorie Leggitt

Classroom Observations andEducator Interviews:

Wendy Hanophy, DOW

James Philips

Administrative Assistance:

Chris DiMarco

Project Coordinator and Editor:

Wendy Hanophy, DOW

Writers:

Wendy Hanophy, DOW

Larry Ann Ott, Retired Educator,Adams County School District 12,Colorado

Printing:

State of Colorado IntegratedDocument Solutions (IDS) Print Operations

Acknowledgments

Funding for this project was provided by US Fish & Wildlife Service WildlifeConservation and Restoration Program Grant No R-11-1, Great Outdoors ColoradoTrust Fund (GOCO) and the sportsmen of Colorado.

The Colorado Division of Wildlife gratefully acknowledges the following individuals:

For content advice and critical review:

Dr. Michael W. Miller, DVM Colorado Division ofWildlife, Wildlife Research Center, Fort Collins, CO

Dr. Jean E. Jewell, University of Wyoming,Veterinary Science Department, Wyoming StateVeterinary Laboratory, Laramie, WY

For assistance in developing the field test:

Nicole Knapp, Science Educator, BSCS

Anne Tweed, Senior Science Consultant, McREL(Mid-continent Research for Education andLearning)

Pam Van Scotter, Director, BSCS (BiologicalSciences Curriculum Study) Center for CurriculumDevelopment

Field-test Educators:

Marylin Achten, Aurora Public Schools, Aurora, CO

Jane Ballard, Berthoud High School, Berthoud, CO

Ann Campbell, Legacy High School, Broomfield, CO

Scott Campbell, Douglas County High School,Castle Rock, CO

Kate Henson, Jefferson Academy, Broomfield, CO

Jeff Keidel, Buena Vista High School, Buena Vista, CO

Robert Lancaster, Walsh High School, Walsh, CO

Matt Landis, North Park High School, Walden, CO

Mark Little, Broomfield High School, Broomfield, CO

Rick Moeller, Mountain View High School,Loveland, CO

Lyn Neve, Swink High School, Swink, CO

Jill Smith, McClave High School, McClave, CO

Debbie Yeager, Moffat County High School, Craig, CO

© Copyright 2007 by Colorado Division of Wildlife. All rights reserved. Permission granted to reproducehandouts for classroom use. All illustrations are copyrighted by the artists and may not be reproduced ortransmitted in any form or by any means, electronic or mechanical, or by any information storage or retrievalsystem, without permission in writing. For permissions and other rights under this copyright, please contactColorado Division of Wildlife, 6060 Broadway, Denver, CO 80216, Attn: Wendy Hanophy.

Prying Into Prions Investigating Chronic Wasting Disease

Module Overview . . . . . . . . . . . . . . 1

Lesson 1: A Brain Wreck Educator’s Overview. . . . . . . . . . . . 6

Molecules And Cells . . . . . . . . . . 10

A Brain Wreck . . . . . . . . . . . . . . . 11

Lesson 2: Pathological Proteins? Educator’s Overview. . . . . . . . . . . 14

Pathological Proteins? . . . . . . . . . 18

Silly, Silly Protein Structure . . . . . 21

Lesson 3: We Moose Crack The Code

Educator’s Overview. . . . . . . . . . . 34

We Moose Crack The Code . . . . 87

Decode That Gene . . . . . . . . . . . . 91

Lesson 4: Cannibalism,Forgetfulness, And SleeplessNights

Educator’s Overview. . . . . . . . . . . 94

Cannibalism, Fogetfulness, And Sleepless Nights . . . . . . . . . 98

Table Of ContentsTable Of Contents

Lesson 5: Oh…Deer Educator’s Overview. . . . . . . . . . 104

Oh…Deer . . . . . . . . . . . . . . . . . . 110

Lesson 6: Here To Stay, Not Gone Tomorrow

Educator’s Overview. . . . . . . . . . 124

Here To Stay, Not Gone Tomorrow . . . . . . . . . . 130

Glossary . . . . . . . . . . . . . . . . . . . . . . . . . 136

Table Of ContentsTable Of Contents

1P r y i n g I n t o P r i o n s

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What is CWD?Chronic wasting disease (CWD) is a fatal

neurological disease found in deer, elk andmoose. It belongs to a family of diseasesknown as transmissible spongiformencephalopathies or prion diseases. Thedisease attacks the brains of infected deer, elkand moose, causing the animals to becomeemaciated, display abnormal behavior andlose coordination, and eventually die.

Chronic Wasting Disease (CWD) has beenrecognized in free-ranging deer in Coloradosince 1985, but how long it has been presentor how it arose are unknown. Unlike allinfectious diseases known at the time, thepathogen for transmissible spongiformencephalopathies or TSEs was identified as a protein. Stanley Prusiner, the scientist whoisolated the protein, named it a “prion,” which is short for “proteinaceaous infectiousparticle.” The prion protein exists in twoforms. The normal form is found in manytypes of cells, including those in the centralnervous system. The pathological prion formhas the same chemical composition, but adifferent shape. This abnormally shaped prionprotein damages the brain tissue and convertsother normal prion proteins in cells into thesame abnormal shape!

Why Study CWD?The idea that form dictates function is a

central tenet of science and biology. There isprobably no better group of diseases thatillustrate this concept than TSEs such aschronic wasting disease—diseases caused bya simple change in the form of a protein. Tounderstand these diseases, students must

first understand what proteins are, how theyare made and how they fold and misfold.

Students are often unenthusiastic aboutstudying the basic chemistry of life—thestructure of proteins, lipids, carbohydrates,and nucleic acids. They can be equallyapathetic learning about protein synthesis and gene expression. Prion diseases,unfortunately, are fear-provoking and seem to compel human interest, providing a relevantcontext to study life’s molecules andprocesses.

Why is the Colorado Division ofWildlife Providing this Module?

Chronic wasting disease was first noticedby researchers at Colorado’s Foothills WildlifeResearch Facility in 1967. Captive mule deerthat were being maintained for nutritionalstudies began to lose weight. They becamelistless, started slobbering and drooling, andseemed constantly thirsty. Some stoppedsocializing with other deer. Most of theaffected deer died within months. This newaffliction was named chronic wasting disease.

In 1977, Elizabeth Williams, studying for her doctorate in veterinary medicine at Colorado State University, identified CWD as a new transmissible spongiformencephalopathy. In 1985, CWD wasdiscovered in free-ranging deer and elk inColorado. That same year, a handful of cattlefrom various areas in the United Kingdombegan dying of a strange illness. Examinationof the dead cattle’s brains revealed abnormal,microscopic holes. The new disease wasnamed bovine spongiform encephalopathy or BSE.

Module Overview

Prying Into PrionsInvestigating Chronic Wasting Disease

2 P r y i n g I n t o P r i o n s

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Kingdom discovered a new variant of a humantransmissible spongiform encephalopathycalled Creutzfeldt-Jakob disease (CJD). CJDnormally occurs in older people, but in 1996 a few teenagers started showing classic CJDsymptoms. Biopsies of the brain tissue ofthese victims revealed that the new variantCreutzfeldt-Jakob disease, vCJD, involved thesame prion strain as BSE. It became clear thatall transmissible spongiform encephalopathiescould potentially be a human health problem.

The Colorado Division of Wildlife (DOW)has many very good reasons to study CWDand share what is learned with the public.Wildlife biologists want to contain the disease,protect wild herds, and protect the publichealth.

More is currently known about thedistribution and ecology of the disease inColorado than in any other place on earth.The DOW is a leader in investigating thedisease, and providing information andeducation about CWD to the public. In fact,efforts made by the Colorado Division ofWildlife serve as models for other wildliferegulatory agencies. One part of the DOWpublic information and education effort is to foster an informed citizenry, capable ofmaking good decisions regarding wildlifeconservation and management. The DOWhopes that you and your students enjoylearning about CWD and other importantwildlife issues, so that you are better able to partner with us in our efforts in KeepingColorado Wild!

What is This?This six-lesson module, designed for

approximately two weeks of classroominstruction, begins by presenting aninteresting group of emerging diseases—transmissible spongiform encephalopathies(TSEs). After students discuss the variety of evidence that scientists must collect todetermine the origin, infectious agent, androute of transmission of a transmissible

disease, they explore the role of proteins inliving organisms, the chemistry and behaviorof proteins, and the genetic code that createsprotein (DNA, transcription, and translation).Throughout the module, they look at andevaluate experimental design. The module is designed to supplement or replace theactivities found in most high school biologytextbooks that address the chemistry of life,DNA and the genetic code, and proteinsynthesis. It is the third module developed by the DOW to address the specific learningobjectives of high school students. Materialsare inquiry based, develop critical thinkingskills, supply evidence to support eachconcept, and include real data from recentresearch projects.

Using Prying into Prions:Investigating Chronic WastingDisease in Your Classroom

The lessons in this module are designed to be taught in sequence. For each activity,students assume the role of researchersstudying an emerging disease. As theyevaluate and analyze information concerningCWD and other transmissible spongiformencephalopathies, they explore the larger role of proteins in living organisms.

There are DOW Education Coordinatorsthroughout the state who may be able toprovide additional support or resources onCWD and other biology topics. Feel free tocontact your Education Coordinator at anytime—they would love to hear from you:

Leigh Gillette, Education Coordinator, SW Region415 Turner Drive Durango, CO 81303 970-375-6709

Stan Johnson, Education Coordinator, NW Region711 Independent AvenueGrand Junction, CO 81505970-255-6191


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Science1: Students apply the processes of scientific X X X X X Xinvestigation and design, conduct, communicate about, and evaluate such investigations.

2: Students know and understand common properties, X Xforms, and changes in matter and energy.

3: Students know and understand the characteristics X X X X Xand structure of living things, the processes of life,and how living things interact with each other and their environment.

5: Students understand that the nature of science X X X X Xinvolves a particular way of building knowledge and making meaning of the natural world.

Lesson 6: Here To Stay, NotGone Tomorrow

COLORADO MODEL CONTENT STANDARDSLesson 3: We Moose

Crack The Code

Lesson 4: Cannibalism,

Forgetfulness, AndSleepless Nights

Lesson 5: Oh…Deer

Lesson 1: A Brain Wreck

Lesson 2: Pathological

Proteins?

Linda Groat, Rural Education Specialist, SE Region2500 S. MainLamar, CO 81502719-336-6608

Steve Lucero, Education Coordinator,SE Region4255 Sinton RoadColorado Springs, CO 80907719-227-5203

Lisa Evans, Education Coordinator,NE Region317 W. ProspectFort Collins, CO 80526970-472-4343

Debbie Lerch-Cushman,Education Coordinator, Denver Metro Area6060 BroadwayDenver, CO 80216303-291-7328

Correlation to the Colorado ModelContent Standards

Prying into Prions: Investigating ChronicWasting Disease supports teachers in theirefforts to provide the knowledge and skillsspecified in the Colorado Model ContentStandards and the corresponding grade levelassessment frameworks.

History4.1: Students understand the impact of scientific X X X Xand technological developments on individuals and societies.



Crack The Code



Lesson 5: Oh…Deer



Proteins?


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Mathematics1: Students develop number sense and use numbers X Xand number relationships in problem-solving situations and communicate the reasoning used in solving these problems.

6: Students link concepts and procedures as they Xdevelop and use computational techniques, including estimation, mental arithmetic, paper-and-pencil,calculators, and computers, in problem-solving situations and communicate the reasoning used in solving these problems.



Crack The Code



Lesson 5: Oh…Deer



Proteins?

Reading and Writing1: Students read and understand a variety of materials. X X X X X X

2: Students write and speak for a variety of purposes Xand audiences.

3: Students write and speak using conventional X X X X X Xgrammar, usage, sentence structure, punctuation,capitalization, and spelling.

4: Students apply thinking skills to their reading, X X X X X Xwriting, speaking, listening, and viewing.

5: Students read to locate, select, and make use of X X X Xrelevant information from a variety of media, reference,and technological sources.



Crack The Code



Lesson 5: Oh…Deer



Proteins?

Civics2.1 Students know the organization and functions of X X Xlocal, state, and national governments.

2.4 Students know how public policy is developed at X Xthe local, state, and national levels.

3.1 Students know how and why governments and X X Xnongovernmental agencies around the world interact politically.

3.3 Students understand the domestic and foreign X Xpolicy influence the United States has on other nations and how the actions of other nations influence politics and society of the United States.



Crack The Code



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Learning ObjectivesAfter completing this activity, students will be able to:

• Explain why several diseaseshave been grouped together ina category called transmissiblespongiform encephalopathies(TSEs).

• Explain why a state wildlifeagency might devoteconsiderable resources—time,money, and people—to studythese diseases.

• Reflect upon and discuss theirprior knowledge about thecause, transmission, andtreatment of disease.

• Recognize the variety ofevidence that scientists mustcollect to determine the origin,infectious agent, and route oftransmission of a transmissibledisease.

BackgroundThis lesson is designed to

engage your students’ interest inan unusual group of diseases—transmissible spongiformencephalopathies—and prepare

them for the exciting activities in this module. The reading and questions are designed to make connections betweentheir past and present learningexperiences. Students will applytheir knowledge about infectiousor transmissible diseases to thescientific research of a newdisease.

Transmissible spongiformencephalopathies (TSEs) are a rare group of degenerativediseases that affect the brain and central nervous system. Allare untreatable and fatal. Thesediseases are transmissiblebecause they are capable ofbeing transferred from oneanimal to another, spongiformbecause they cause theappearance of microscopicsponge-like holes in the brain of the affected animals, andencephalopatic because they are neurodegenerative diseasesof the brain.

TSEs have been found inmany mammals, includinghumans. The first known TSE,scrapie, was described in sheepin Great Britain and WesternEurope over 250 years ago. Thename scrapie comes from one of

Educator’s Overview

A Brain Wreck

SummaryStudents read an article about an interesting group of

emerging diseases—transmissible spongiform encephalopathies(TSEs). They reflect upon and discuss what they already knowand understand about disease to prepare themselves to studyTSEs.Duration

One or two 45-minute class periods

VocabularyBovine spongiform

encephalopathy(BSE)

Creutzfeldt-Jakobdisease (CJD)

Emerging disease

Infect

Pathogen

Sporadic disease

Transmissiblespongiformencephalopathies(TSEs)

Variant Creutzfeldt-Jakob disease(vCJD)

Zoonotic

Lesson 1



the symptoms of the disease. In addition to excessive lip-smacking, strange walking gaits,and convulsions, sheep with this disorder appear to itch. Theanimals will compulsively scrapeoff their fleece against rocks,fences, or trees.

Another TSE of livestock wasdiscovered in Great Britain in theearly 1980s—bovine spongiformencephalopathy (BSE)—commonly called “mad cowdisease.” Nearly 200,000 cattle inGreat Britain and thousands inother countries have sincesuccumbed to BSE.

Creutzfeldt-Jakob disease(CJD) is the most well-known ofthe human TSEs. It is a rare typeof dementia that affects aboutone in every one million peopleworldwide each year. Otherhuman TSEs include kuru, fatalfamilial insomnia (FFI), andGerstmann-Straussler-Scheinkerdisease (GSS). Kuru wasidentified in people of an isolatedtribe in Papua New Guinea andhas now almost disappeared. FFI and GSS are extremely rarehereditary diseases, found in justa few families around the world.

A new type of CJD, calledvariant CJD (vCJD), was firstdescribed in 1996 and has beenfound in Great Britain and severalother European countries. Theinitial symptoms of vCJD aredifferent from those of classicCJD and the disorder typicallyoccurs in younger patients.Research suggested that vCJDresulted from human infectionwith BSE.

Another TSE, chronic wastingdisease or CWD, was first notedin Colorado in the late 1960s

in captive deer. It has beenwidespread in free-ranging deerand elk in northcentral Coloradoand southeastern Wyoming sinceat least the early 1980s. Recently,the disease has also beendiscovered in moose in Colorado.

Chronic wasting disease is an important wildlife health issue,and potentially a human healthissue. Researchers at theColorado Division of Wildlife haveaggressively studied this diseaseand have worked to contain it. Inaddition, the agency has workedhard to keep the public safe andinformed. All new developmentsand understandings about CWDare shared with the public. Allhunters can test their animals for CWD and can decide whetherto consume or dispose of themeat. This is a new—emerging—disease, and there is still much to learn.

Teaching Strategies1. Thoroughly read the studentmaterials for Molecules And Cells,and A Brain Wreck.

2. Optional: There are somefundamental concepts about thebiochemical nature of life thatyour students must understandbefore beginning this module.Students’ prior knowledge shouldinclude these ideas:

• Living things are made up ofmolecules, which are made ofvarious atoms.

• Atoms join together to makemolecules by sharing or givingup electrons.

• The chemical properties ofmolecules are determined bytheir ability to bond with othermolecules.

Materials andPreparation

• Optional: StudentActivity Page:

Molecules AndCells—onephotocopy

per student

• Student ReadingPages: A Brain

Wreck—onephotocopy

per student

• A large, visiblewriting surface (i.e.

chalkboard,whiteboard,

butcher paper)


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This may seem straightforward, but it isn’t.Students don’t always know what we thinkthey know. Many students, even in highschool, have misconceptions about atoms andmolecules and their role in living organisms.

High school students often havedifficulty thinking about living organisms aschemical systems. They often confine theconcept of molecules to things encountered in physics and chemistry. Many may think that living organisms are not made up ofmolecules, only cells. Specific to proteins,students may think that proteins are made up of cells and that molecules of protein arebigger than the size of a cell. Or, they may onlyassociate protein with diet—things that theyeat—such as meats, cheeses, etc. If yoususpect that your students may have thesemisconceptions, or are just curious, you maywant to have your students do the activitypage Molecules And Cells before beginningthis module. Discuss the answers provided in the key and clarify any misconceptions.

This activity could also be done rightbefore the second lesson in this module.

3. Give each student a copy of the studentreading pages: A Brain Wreck.

4. After giving students sufficient time to reador after reading the material as a class, askstudents to work in groups of three or four tobrainstorm answers to each question. Instructeach student in the group to record thegroup’s answers. An alternate strategy wouldbe to “jigsaw” the questions and ask eachgroup to answer just one of the questions.

5. As a class, discuss the information thatwas recorded by each group. It may be helpfulto ask each group to appoint a spokespersonand to allow each group to speak in turn until no more new ideas are added to thediscussion. Record all answers in a visibleplace (i.e. chalkboard, whiteboard, butcherpaper).

6. Keep in mind that this discussion is to elicit what students collectively know aboutdisease and to get them thinking about thetask that a scientist might face whenconfronted with a new disease. Keep thediscussion open and encourage students toask questions of each other. See the keybelow for possible responses to the questions.

7. Do not erase or throw away the responsesto the questions. The students can look backon these responses as they move on toLesson Two: Pathological Proteins?

AssessmentStudent discussion about the causes,

transmission, and treatment of disease servesas an assessment for this engagement activity.

ExtensionsStudents may want to discuss or review

Koch’s postulates, a four-step procedure foridentifying specific pathogens (disease-causing agents):

1. The pathogen must be found in an animalwith the disease and not in a healthyanimal.

2. The pathogen must be isolated from thesick animal and grown in a laboratoryculture.

3. When the isolated pathogen is injectedinto a healthy animal, the animal mustdevelop the disease.

4. The pathogen should be taken from thesecond animal and grown in a laboratoryculture. The cultured pathogen should bethe same as the original pathogen.

KeyStudent Activity Page: Molecules and Cells

All items on the list contain molecules.The following items contain cells: apple,mouse, bacteria, human, lettuce, liver, anddonut. (Some components contain cells,such as the wheat flour. Other componentsare just molecules, such as salt).

Items that are part of the mouse includeprotein, fat, and liver. Bacteria could also beplaced on the list, since most multicellularorganisms contain bacteria. Mice eatapples, donuts, and lettuce to get nutrientssuch as vitamin C, fat, and protein that thebody needs.



If students describe fat (lipid) or proteinas containing cells, try to clarify that they are molecules contained in cells.Particularly with advertisements for thingssuch as liposuction or thigh cream, manymay think that fat is a cell. Also, becausestudents eat certain food items to getprotein, they may think that some cells arejust protein cells. In reality, all cells containsome amount of fat (lipid) and proteinmolecules.

Student Pages: A Brain Wreck

1. What is disease? A disease might beanything that prevents a cell, tissue, organ,or organ system from working normally.

2. What causes disease? Most students willsay that germs cause disease. Others willbe more specific and mention bacteria,viruses, and hopefully fungi, parasites such as protozoa and “worms” such asringworms, tapeworms, and flatworms.Hopefully students will mention geneticdiseases such as cystic fibrosis or sicklecell anemia. It may be a stretch, buthopefully some students will mentionaging, and environmental toxins (this couldinclude lifestyle choices such as diet ordrug use) as a source of disease.

3. Can you have an infection without havinga disease? The idea that infections don’tnecessarily cause disease may be toughconceptually for students and could resultin an interesting class debate. Most of uscontain microbes and micro-organismsthroughout our bodies. Some of these arebeneficial—like the bacteria in our gut thathelps us digest certain foods. If beinginfected—that is, having another organisminvade or go inside our bodies—alwayscaused disease, we’d be in big trouble.

4. Are infectious diseases preventable? In aperfect world, where science could identifyevery pathogen and a way to defeat eachof them, infectious diseases might bepreventable. This question has no correct,or “absolutely certain,” answer but allowsfor great discussion.

5. Are infectious diseases the same astransmissible diseases? This could also be

an interesting discussion. This could beargued either way. If someone has atapeworm infection, can he/she transmit it to another person?

6. How can diseases be transmitted fromone organism to another? In other words, howmany ways can you think of to transmit aninfectious disease? High school studentscan usually think of most of the ways thatpathogens are transmitted, including:direct contact (bites, shaking hands,exchange of body fluids, etc.), air, water,and food.

7. What makes an organism immune orsusceptible to a disease? Hey, it’s a greatquestion. Some of the world’s finest mindsare still working on answers. Maybe one ofyour students will be some day be one ofthem. It is known that many organismsdevelop immunity to a disease once theyrecover from the disease. It is known thatnon-virulent strains of some viruses can beused to create vaccines to make organismsimmune to that virus. There also seems to be a genetic predisposition to somediseases, and scientists are working onvarious “gene therapies” to prevent ortreat these diseases. This question was included because it is one that hasbeen looked at extensively by scientistsinvestigating transmissible spongiformencephalopathies.

8. The scientists who began studying TSEshad only the small amount of informationabout each disease that was presented in thereading. If you were in their shoes, how wouldyou figure out what was going on? Answerswill vary. Encourage as many ideas aspossible. Do not dismiss any ideas. Ideally,write the class answers in a visible place tolook back upon when students move on toLesson 2. Essentially, the scientists lookinginto TSEs acted as “detectives” to trackdown the cause or causes of the newdiseases. Students may suggest looking for common locations where the diseaseappeared, to check to see if something inthe environment caused the illness. Somemight suggest looking for other things thatthe victims may have in common, from dietto genetic similarity.

Lesson 1


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Circle items on this list that containmolecules and underline those itemsthat contain cells.

Apple

Protein

Mouse

Bacteria

Human

Donut

Explain your choices.

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Look at the list again. What items on thelist are parts of the mouse? Explain.________________________________________________________________________________________________________________________________________________________________________________________________________________________

____________________________________________________________________________________________________________

What does the mouse eat? Why?________________________________________________________________________________________________________________________________________________________________________________________________________________________

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Student Page

Molecules And Cells

Fat

Vitamin C

Lettuce

Chlorophyll

Liver

Deer Mouse



A woman trembles as she stumblesforward in her thatched hut. Herunsteady gait seems strangely matchedto her slurred speech. Anxious relativessadly shake their heads, for they realizethat this daughter of the Fore tribe ofNew Guinea will soon be dead.

In a highColorado meadow,a mule deer doetrembles on herwide-legged stanceas her herd moves onwithout her. Drooling,she lowers her ears thenshe stumbles toward thenarrow mountain brook inan effort to quench anuncontrollable thirst—a thirstthat will last the remainingmonths of her life.

A young Englishman burstsout in laughter then is overcomeby a bout of crying as his parentspush his wheelchair from the doctor’soffice. Their physician has just explainedthat the most recent CAT scan showscontinued deterioration in the youngman’s brain and that their son’s illness is terminal.

In the Scottish Highlands, a ram’shead trembles slightly. He obsessivelyscratches and rubs against a large tree,apparently to relieve itching. He smackshis lips and bites his feet. Alarmed by asudden noise, the ram falls down inconvulsions.

Can the illnesses of the New Guineatribeswoman, the mule deer, the Britishteenager, and the Scottish sheep berelated? In a broad sense, it appears so.All are degenerative disorders of thecentral nervous system. Although eachillness has a different name—kuru,chronic wasting disease (CWD), variant

Creutzfeld-Jakob disease (vCJD), orscrapie, microscopic examinationreveals a characteristic sponge-likeappearance in the brain tissue ofeach victim. They are just three ofmany diseases called transmissiblespongiform encephalopathies or

TSEs. These diseasesare transmissiblebecause they arecapable of beingtransferred from oneanimal to another,spongiform becausethey cause the brainto look like a hole-ridden sponge undera microscope, and

encephalopathies because they arediseases of the brain (pathy is Greek fordisease; encephalo is Greek for brain).

Why Learn about TransmissibleSpongiform Encephalopathies?

Most people cannot repeat“transmissible spongiformencephalopathies” three times quickly.Some cannot even pronounce the wordsonce slowly! So, how are transmissible

Student Pages

A Brain Wreck

Mule Deer


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spongiform encephalopathies transmitted?Why should you care? Why should theColorado Division of Wildlife care?

Let’s start with that last question. TheColorado Division of Wildlife (DOW) is thestate agency responsible for protectingand managing wildlife and habitat, andproviding wildlife related recreation. TheDOW employs trained biologists and otherspecialists to “manage” wildlife—to usescientific knowledge to maintain healthypopulations of wildlife and its habitat.Chronic wasting disease (CWD) was firstrecognized in Colorado in 1967, in acaptive research herd of mule deer. Itwasn’t until 1977 that scientists suspectedthat CWD was a transmissible spongiformencephalopathy, and that it might pose asignificant threat to the health ofColorado’s deer and elk.

Protecting the state’s deer and elk wasone good reason for DOW biologists tostart trying to unravel the TSE mystery.But other important reasons soonpresented themselves. In 1984, unusualbehavior was noted among cattle on afarm in Sussex in the United Kingdom (UKor England). They wobbled and staggeredand appeared fearful. Then they died.Brain samples collected from one of thosecattle looked a bit like Swiss-cheese.Scientists called this new disease bovinespongiform encephalopathy or BSE.Since the original discovery, BSE has beendetected in more that 182,000 cattle inmore than 35,000 different herds in theUK, and in more than 3,800 cattle in othercountries throughout the world! Thisdisease seemed highly contagious, thoughno one knew how it spread. Could CWDbe spread as quickly?

Sporadic Creutzfeldt-Jakob disease(CJD) has been reported for centuries.This rare disorder affects about one in amillion people. Sporadic diseases like

CJD occur occasionally and at randomintervals in a population. Most victims arebetween 63 and 66 years old and die ofthe disease within a year of diagnosis.Autopsies show that each victim’s brain is riddled with microscopic holes.

In 1996, two British teenagers and one29 year old displayed many symptoms ofclassic CJD. Further research linked thisnew variant Creutzfeldt-Jakob disease(vCJD) of the young victims to infectionwith the BSE pathogen (disease causingagent). The probable cause wasconsumption of BSE-contaminated meatproducts. The “Mad Cow” scare began.Countries worldwide began screeningcattle for BSE, to insure a safe foodsupply.

Let’s get back to that question aboutthe DOW. Deer and elk are game animals.That means that licensed hunters canharvest and eat these animals. When itwas evident that BSE was zoonotic, thatis, the disease could be transmitted tohumans by eating meat from diseasedcattle, similar concerns were raised abouteating deer and elk that might be infectedwith CWD.

The DOW has three very good reasonsto study CWD. Wildlife biologists want tocontain the disease, protect wild herds,and inform the public about the disease.Later, you will learn about your statewildlife agency’s efforts.

Studying TSE’s—Looking for theCause and the Cure

Whenever a new or emerging diseaseappears, scientists try to figure out whatcauses the illness, if it is transmitted, how it is transmitted, and how it can becontrolled or cured. If a pathogen is



found, scientists then need to find out howit gets into—infects—the animal. Let’s putyou in the role of one of these scientists.Consider each of these questions andwrite down your thoughts about each:

1. What is disease?

________________________________________________________________________________________________________________________________________________________

2. What causes disease?

________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________

3. Can you have an infection withouthaving a disease?

______________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________

4. Are infectious diseases preventable?

______________________________________________________________________________________________________________________________________________________________________________________________

5. Are infectious diseases the same astransmissible diseases?

______________________________________________________________________________________________________________________________________________________________________________________________

6. How can diseases be transmitted fromone organism to another? In other words,how many ways can you think of totransmit an infectious disease?

______________________________________________________________________________________________________________________________________________________________________________________________

7. What makes an organism immune orsusceptible to a disease?

______________________________________________________________________________________________________________________________________________________________________________________________

8. The scientists who began studyingTSEs had only the small amount of information about each disease that waspresented in the reading. If you were intheir shoes, how would you figure outwhat was going on?

______________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________

P r y i n g I n t o P r i o n s

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Learning ObjectivesAfter completing this activity,students will be able to:

• Explain why an understandingof protein is essential forstudying TSEs.

• Identify five important roles thatproteins have in livingorganisms.

• Identify the importance of aprotein’s three-dimensionalshape to its role in anorganism.

• Identify amino acids as thebuilding blocks of proteins anddescribe how they attach toone another.

• Describe the four levels ofprotein structure ororganization.

• Construct paper models of α-helix and β-sheet secondaryprotein structures.

• Create a cross-linked polymerand explore its physicalproperties.

• Infer the effect of temperaturechanges on the function ofprotein in the body.

BackgroundUnlike all infectious diseases

known at the time, the pathogenfor transmissible spongiformencephalopathies or TSEs wasidentified as a protein. StanleyPrusiner, the scientist whoisolated the protein, named it a “prion,” which is short for“proteinaceaous infectiousparticle.”

The prion protein (PrP) existsin two forms. There is a normalcellular form (PrPc) that is foundin many types of cells, includingthose in the central nervoussystem. No one knows the exactpurpose of the normal prionprotein, but it seems to havesome role in long term memory.Then there is a pathological form(PrPres). The “res” in PrPres standsfor “resistant,” because this formresists destruction! It resists


Pathological Proteins?

SummaryStudents read about the discovery of protein as the

pathogen for TSEs and about the important roles of protein inliving organisms. They construct two paper models of α-helixand β-sheet secondary protein structures. Students thencreate Silly Putty®, a cross-linked polymer, and test its bounceunder various temperatures. Students infer how temperaturemight affect the function of a protein, which is also a cross-linked polymer.

Duration Two 45-minute class periods (A thirdclass period may be necessary if students have little prior knowledge ofchemical bonding)

VocabularyAlpha helix (α-helix)

Amino acid

Amino group (-NH2)

Amino-terminus (N-terminus)

Amyloid fibers

Assay

Astrocytes

Beta sheet (β-sheet)

Carboxyl group (-COOH)

Carboxyl-terminus (C-terminus)

Cross-linkage

Dehydration synthesis

Dipeptide

Disulfide bridge

Domain

Fold

Hydrogen group

Hydrophobic

Loop or turn

Pathogen

Peptide bond

Polymer

Polypeptide

Primary protein structure

Prion

Protein

Quaternary proteinstructure

R group

Secondary proteinstructure

Tertiary protein structure

14

Lesson 2


Lesson 2: Pathological Proteins?

Materials andPreparation • Student Pages:

Pathological Proteins?—one photocopy

per student

• Student Activity Pages:Silly, Silly Protein

Structure—one photocopyper student

• Student Activity Page:Polypeptide Chains—one

photocopy per student

• Transparent tape—one roll for each group

of four students

• Scissors—one to four for each group of four

students, depending on availability

• Safety goggles—one per student

• Lab aprons (if available)—one per student

• Graduated cylinders ormeasuring cups with

metric units—one pergroup of four students

• Rulers—one per group of four students

• Clear 8-oz. (or larger)plastic cups—5 for each

group of four students

• All-purpose white gluesuch as Elmer’s®—

washable glue is not as effective

• Plastic spoons—5 for each group of four students

• Plastic Ziploc™ bags—one per student

• Borax®. Borax® can befound in stores as a

laundry detergent. Placeone tablespoon (much

more than students will need) in a Ziploc™

bag for each group of four students.

• Permanent marker—oneper group of four students

• Water

• Paper towels

• Newspaper (to protect the working surface)

• Access to arefrigerator/freezer or

to a cold water and an ice water bath

“digestion” from proteaseenzymes in the cell, and cansurvive temperatures of 600ºCfor more than 15 minutes.Further, it is not destroyed bysome common disinfectants andis not quickly broken down byionizing or ultraviolet radiation.

The structure of proteins hasalways tantalized biologists.Proteins have many differentfunctions in living organisms andeach function is unquestionablylinked to the molecule’s three-dimensional shape. By studyingthe components and structuresof proteins, scientists andstudents are better able tounderstand how they functionnormally and how some proteinswith abnormal shapes can causedisease.

Teaching Strategies1. Thoroughly read the studentmaterials for PathologicalProteins? and Silly, Silly ProteinStructure.

2. Give each student a copy ofthe student reading pages:Pathological Proteins?

3. Give students sufficient timeto read the materials or read thematerial as a class.

4. Check for understanding.Ask students if they have anyquestions about the scientists’discovery. Have them look attheir list of “causes of disease”from Lesson 1. Did they haveprotein on their list of items thatcaused disease? Make surestudents understand the termsused in the reading. If possible,you may want to demonstratethe structure of an amino acidusing a model made from

Styrofoam balls. Note: If yourstudents have little knowledge ofchemical structure or chemicalbonding, you may need to backup a bit and spend a day makingmodels of molecules and talkingabout how atoms share, gain, orlose electrons to bond with otheratoms.

5. Tell students they will bedoing a lab activity to learn moreabout protein folding. Explainthat is it necessary to know how and why proteins fold tounderstand how they mightmisfold and cause disease.

6. Assign students to groups offour. Give each student a copyof the laboratory activity Silly,Silly Protein Structure and theactivity page PolypeptideChains.

7. Instruct the groups toattempt to complete Activities 1 and 2 of Silly, Silly ProteinStructure by the end of the classperiod. Tell them that they wouldneed to complete these activitiesat home if they are not able tocomplete them in class becauseyou will need the next day’sclass time to do activity 3.

8. Tell students that you willassist their group if needed. Thediagrams and pictures shouldmake these activities fairly self-explanatory. Ask students tokeep the models that theycreate. They may help thestudents’ understanding offuture lessons in the module.

9. Activity 3 is a simple andenjoyable lab activity, but it doespresent some hazards. Pleasereview the safety issues andprecautions with students.Students should not ingest anyof the lab materials. Borax®

should be kept away from eyes


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and goggles should be worn. Hands shouldbe washed thoroughly at the end of theactivity. Silly Putty® should not be put in asink, on carpet, or in hair.

10. After students complete the activity,review their results as a class. Be sure torelate the behavior of the Silly Putty® polymer to protein polymers (see Key).

11. Optional: Most high school biologyclasses include a laboratory experiment toanalyze the effect of pH and/or temperatureon enzyme activity. You may wish to havestudents do the experiment to furtherreinforce the impact of protein shape onprotein function.

AssessmentAsk students to draw the basic structure

of an amino acid and label the four groups.Ask students to describe how thesemolecules join together to form a protein.Using diagrams and/or descriptors, askstudents to depict the primary, secondary,tertiary, and quaternary structure of protein.Lastly, ask students to explain the importanceof a protein’s three-dimensional shape andwhy a change in that shape may be important.

Extensions• Students can learn more about each

individual amino acid and view microscopyphotos of them at

http://micro.magnet.fsu.edu/aminoacids/index.html

• Many protein shapes have been determinedexperimentally. When scientists decipherprotein structures, they submit their findingsto the Protein Data Bank. Students can viewvarious protein structures at

http://www.rcsb.org/

Students can enter the protein that they areinterested in looking at in the search box.

KeyActivity 3: Silly Polymers

10. Form the Silly Putty® into a ball. Using aruler to measure, drop the ball from a heightof 30 centimeters. How high does it bounce?Answer will vary

11. Now, place your ball in a refrigerator orice bath for 10 minutes. Again, bounce theball from a height of 30 centimeters. How highdid it bounce this time? Why do you think thishappened? Answers will vary, but the ballshould bounce higher than the first drop atroom temperature.

12. Now place your ball about 6 inches from a light bulb for about 5 minutes and againcheck how high it will bounce when droppedfrom a height of 30 centimeters. How high didit bounce this time? Why do you think thishappened? This time, the ball will deformwhen dropped and may not bounce at all.

13. Now put your Silly Putty® ball in thefreezer or in an ice bath for 10–20 minutes.Check how high it will bounce when droppedfrom a height of 30 centimeters. How high didit bounce this time? Why do you think thishappened? If frozen, the ball is likely toshatter rather than bounce.

14. Try to transfer your observations of thebehavior of Silly Putty® to the behavior ofprotein. Remember that proteins are the workhorses of the cell or body. Why might achange in temperature, such as when aperson is exposed to extreme heat or cold,cause problems? In extreme temperatures,the bonds that give a protein its shape maybreak and other bonds may form. Theshape of the protein would change, and it would not be able to “do its job.” It ispossible that the organism could die orlose important functions.



Notes

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Lesson 2

Scientists who have been studyingTSEs over the past few decades havelearned things that have completelychallenged commonly-held beliefs aboutinfectious diseases. Their findings willprobably surprise you. Researchers lookedfor all the usual pathogens (disease-causing agents). In all of the animals withTSEs, including humans, they tried to findthe bacteria, virus, fungus, protozoan, orhelminths (parasitic worms) responsible forthis group of diseases.

After painstaking and careful research,scientists did not find any of the usualcauses of disease! They concluded thatTSEs are not caused by bacteria orviruses. They aren’t caused by parasites.Scientists discovered that in the brain cellsof each TSE victim, a normal protein hadchanged its shape. This abnormallyshaped protein damages the brain tissueand converts other normal proteins in cellsinto the same abnormal shape!

Prusiner’s Amazing Discovery Dr. Stanley Prusiner began his medical

residency in July 1972 at the University ofCalifornia San Francisco in theDepartment of Neurology. Two monthslater, he admitted a female patient whowas experiencing memory loss anddifficulty performing some routine tasks.She was dying of Creutzfeldt-Jakobdisease (CJD), thought to be caused by a “slow virus” infection. He learned thatscientists were unsure if a virus was reallythe cause of CJD since the pathogen hadsome unusual properties. The disease

captivated Prusiner’s imagination and he decided he wanted to research thedisease. He began to read about CJD andthe seemingly related diseases—kuru ofthe Fore people of New Guinea andscrapie of sheep.

He proposed methods to study thesupposed “slow virus.” Since scrapie-infected sheep were readily available, hefocused his research on them. The taskwas daunting. The work was tedious,slow, and very expensive. He had todevelop an assay—a test or procedure topurify the scrapie pathogen and determinewhat it was made of.

Prusiner had anticipated that thepurified scrapie agent would turn out to bea small virus and was puzzled when thedata kept telling him that the disease-causing agent contained protein but notnucleic acid. He named the agent a prion, which is short for “proteinaceousinfectious particle.” The prion protein (PrP)can be found in two shapes. The normalform (PrPc) is found in many types of cells,including those in the central nervoussystem. Then there is a pathological form(PrPres). The “res” in PrPres stands for“resistant,” because this form resistsdestruction! It resists “digestion” fromprotease enzymes in the cell, it survivestemperatures of 600ºC for more than 15minutes, it cannot be destroyed by somecommon disinfectants or even by ionizingor ultraviolet radiation.

Proteins were never thought to beinfectious on their own. If you look backon your class discussion of disease,protein probably was not listed as a cause

Student Pages

Pathological Proteins?



of disease. It definitely wasn’t on the list ofthe scientists when they began studyingTSEs. The idea that proteins could bepathological (disease-causing) wascounter to everything that scientists knewor believed at the time. How can proteinstransmit disease? How can these diseasesbe treated or prevented? These questionsare among the most challenging andinteresting in medicine today.

What are Proteins?Life would be impossible without

proteins. As enzymes, proteins are thedriving force behind all biochemicalreactions in living things. As structuralelements, they make up bones, muscles,hair, skin, and parts of all cells. Asantibodies, proteins recognize invadingelements and allow the immune system toget rid of the intruders. As hormones, theyregulate growth and body processes.Other proteins transport nutrients into thecell and move waste out. You might saythat proteins are the workhorses of life—they are how life gets things done.

Proteins are named after Proteus, anancient Greek god of the sea, who couldchange himself into any shape he felt like.Proteus, also known as the “Old Man ofthe Sea,” could foretell the future—butonly if someone could catch him. Hechanged form to avoid capture. Proteusoften turned himself into a sea lion tosleep on the beach at night. At othertimes, Proteus might be a sea serpent andsink a ship. Or—he could become a hugetidal wave and wipe out a small coastalvillage.

Just like Proteus, proteins are capableof assuming many forms. Why is theshape of a protein so important? Theshape of each protein gives it a uniquefunction. Hemoglobin’s shape lets it carry

oxygen. Collagen’s shape makes it a goodconnective tissue. Insulin fits in spaceslike a key, enabling it to regulate bloodsugar.

Before any protein can carry out itsfunction, it must take on its particularshape, known as a fold. What happens if proteins don’t fold correctly? Diseasessuch as BSE, scrapie, Creutzfeldt-Jakobdisease, CWD, Alzheimer’s, an inheritedform of emphysema, and even manycancers are believed to result from proteinmisfolding.

How are proteins made? How do theyfold and misfold? Some of the worldsmost prominent scientists are studyingthis, and you are about to join them.

Proteins are PolymersProteins are polymers, very large

molecules made up of smaller molecules.In Greek, the word poly means “many”and mer means something like “unit, part,component, building-block or element.” Allproteins, no matter how complex, are builtfrom hundreds or thousands of smallermolecules called amino acids. There areonly 20 different amino acids. Twentyseems like a small number to make themany types of proteins that exist, butthere are only 26 letters in the alphabet,and millions of books, letters, poems andsongs have been written with them!

Amino AcidsWhat do amino acids “look” like

and how do they link together? Like allmolecules, amino acids are made ofatoms. An atom of carbon is at the centerof each amino acid. Carbon atoms canshare four of their electrons with other


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atoms or atom groups. In amino acids,the central carbon shares electrons withfour groups of atoms. Each amino acidhas an identical amino group (-NH2),carboxyl group (-COOH) and a singlehydrogen group. It is the fourth group,the R group, of the molecule that makeseach of the 20 amino acids differentfrom one another.

Amino acids always link together inthe same way. The link, called a peptidebond, occurs between the carboxylgroup of one amino acidand the amino group ofanother. Whenthe two aminoacids connect,the carboxylgroup loses anegatively chargedOH molecule and theamino group loses apositively charged H atom—theyjoin by losing a drop of water! Thisis called dehydration synthesis—making something while losingwater. Other names for thisprocess are dehydrationreaction, dehydrationlinkage, andcondensation reaction.Don’t get confused ifyour teacher or textbookuses a different name.

Two molecules linkedby a peptide bond arecalled a dipeptide. A chainof molecules linked by

peptide bonds is called a polypeptide.A protein is made up of one or morepolypeptide chains.

NNRR

CC

HH

HH

HH

CC

OO

OOHH

AminoGroup

CarboxylGroup

NNRR

CC

HH

HH

HH

CC

OO

OOHH

NNRR

CC

HH

HH

HH

CC

OO

OOHH

Wateris lost

NNRR

CC

HH

HH

HH

CC

OO

OOHH

NNRR

CC

HH

HH

HH

CC

OO

OOHH

Water is lost

PeptideBond



Proteins must fold into their correct 3-D shape before they can do anythinguseful. The structure of a protein as itfolds can have as many as four levels orsteps of organization. Most proteins havethree.

Primary Protein Structure The first or primary structure is

determined by the number, kind, andorder of the amino acids joined together.The amino acid sequence is geneticallydetermined (we’ll talkmore about that later).Think of this structureas a long beadnecklace or a piece ofspaghetti. When theprotein is like this, itcannot do any work. It is just a longpolypeptide chain.

Each end (terminus) of thepolypeptide chain has a name. The firstamino acid in the chain has its aminogroup (NH2) and this end of the chain is called the amino-terminus or the N-terminus. The last amino acid to beadded still has its carboxyl group (-COOH) and is called the carboxyl-terminus or C-terminus. We wouldn’tbother you with all these “terms” aboutterminuses but the front end and backend of a protein are important. Theprotein always starts folding at thefront end.

Student Activity Pages

Silly, Silly Protein Structure

Amino-terminusor N-terminus

H

H

CN

R

C

O

OH

HH

HH

CCNN

RR

CC

OO CN

R

C

H

HO

CCNN

RR

CC

HH

HH

HH

OO

Carboxyl-terminusor C-terminusHH

HH

CCNN

RR

CC

OO

OOHH

H

H

CN

R

C

O CCNN

RR

CC

HH

HHOO

CN

R

C

H

H

H

O

Beginning of an amino acid chain…

…end of an amino acid chain.


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Secondary Protein StructureOnce the amino acid chain forms,

it doesn’t just randomly wad up into a twisted mass. Short sections of thepolypeptide chain, called domains, foldinto recognizable shapes. These shapesare the secondary structure.

The two most common secondarystructures are a coiling alpha (αα ) helix ora folded beta (ββ ) sheet. Sometimes aportion of the amino acid chain does notform a definite shape and looks just like aloop or turn in the chain. The shapes arecaused by hydrogen bonding. Hydrogenbonds are weak attractions between the

positively-charged hydrogen of the amino group of one amino acid and thenegatively-charged oxygen of a carboxylgroup of another. Whether a certainportion of the chain coils in an α-helix,folds into a β-sheet, or just loops or turnsis determined by the R groups of theamino acids in the chain.

Primary Protein Structure

Domain 1 Domain 2 Domain 3 Domain 4

Secondary Protein Structure

(ββ-sheet) (αα-helix)


Loop or Turn

Loop or Turn



Tertiary Protein StructureThe tertiary structure determines a

protein’s function. More complex foldingcreates a tertiary structure. As with thesecondary structure, this folding isdetermined by the properties of eachdifferent amino acid in the chain. Lots ofdifferent kinds of interactions happenbetween the R groups. Some of the Rgroups are positively charged and formionic bonds with R groups that arenegatively charged. Some R groups arehydrophobic, they are not charged, andlike oil, repel water. The parts of the amino

acid chain that are hydrophobic squishinto the center of the protein molecule toavoid the liquid in the cell environment.

One type of chemical bond between R groups is really special. Cysteine is theonly amino acid that has an R group thatcontains the element sulfur. The cysteine R groups can link together to form strongbonds called disulfide bridges or cross-linkages. These special bonds help formthe ultimate shape of each protein. Mostanimals cannot live without cysteine intheir diet.

ββ-sheet

αα-helix

Tertiary Protein Structure

+ -

DisulfideDisulfideBridgeBridge

DisulfideBridge

Loop or Turn


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Quaternary Protein StructureNot all proteins have quaternary or

fourth-level structure. In this level, two ormore polypeptides are joined togetherby many different kinds of chemicalbonds to make the finished protein.These proteins are usually prettygigantic, on a molecular scale.

Quaternary Protein Structure



Protein Structure and PrionDiseases

As mentioned before, the prion proteinexists in two forms, normal (PrPc) andpathological (PrPres). The differencebetween PrPc and PrPres is in their tertiarystructure. The change is caused whenmany of the α-helices in the normalprotein misfold into β-sheets.

Because of their abnormal shape,PrPres proteins tend to stick to each other.Over time, the PrPres molecules stack up toform long chains called amyloid fibers.

Amyloid fibers are toxic to neurons (nervecells) and ultimately kill the cells. Cellscalled astrocytes crawl through the braindigesting the dead neurons, leaving holeswhere neurons used to be. The amyloidfibers are left behind. Then, when tissuefrom the brain of a victim of a TSE isexamined under a microscope, one cansee holes, clumps of amyloid fibers, andlarge numbers of astrocytes, all uniquefeatures of spongiform diseases.

PrPc

PrPres

β-sheet


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Activity 1: Fold an α-helixThe α-helix or right-handed coil shape

is caused by the hydrogen bonds that formin the carboxyl and amino groups of everyfourth amino acid.

Materials Needed:

• Student Activity Page: PolypeptideChains

• Scissors

• Transparent tape

Procedure:

1. Cut out the strips labeled PolypeptideChain 1a and Polypeptide Chain 1b alongthe dotted lines.

2. Using transparent tape, join the C-terminus of Polypeptide Chain 1a to the N-terminus of Polypeptide Chain 1b.

3. Circle the H atom on the amino groupof every fourth amino acid beginning withamino acid #1 (amino acids #1, 5, 9, and13).

4. Circle the O atom on the carboxylgroup of every fourth amino acid beginningwith amino acid #4 (amino acids #4, 8, 12,and 16).

5. Hold theN-terminusend of thepolypeptidechain inyour lefthand. Usingyour righthand, begin a right-handed coil.

Using transparent tape, join (with ahydrogen bond) the H atom of the aminogroup in amino acid #1 to the O atom inthe carboxyl group of amino acid #5.

6. Continue to coil and hydrogen bondthe following atoms of the polypeptidechain:

a. H atom of amino group of amino acid#5 with O atom of carboxyl group ofamino acid #8.

b. H atom of amino group of amino acid#9 with O atom of carboxyl group ofamino acid #12.

c. H atom of amino group of amino acid#13 with O atom of carboxyl group

of amino acid #16.

7. Congratulations, you haveconstructed an α-helix or right-

handed coil.

HH

HH

CC

10

NN

RR

CC

OOHH

HH

CC

8

NN

RR

CC

OO

CCNN

RR

CC

HH

HH

9

OO

CCNN

RR

CC

HH

HH

7

OO

Transparent Tape

HH

HH

CC

6

NN

RR

CC

OOHH

HH

CC

4

NN

RR

CC

OOHH

HH

CC

2

NN

RR

CC

OO

CCNN

RR

CC

HH

HH

5

OO

CCNN

RR

CC

HH

HH

3

OO

CCNN

RR

CC

HH

HH

HH

1

OO

HH

HH

CC

6

NN

RR

CC

OOHH

HH

CC

4

NN

RR

CC

OOH

H

CN

R

C

O

CCNN

RR

CC

HH

HH

5

OO

CCN

RR

CC

HH

H

3

OO

CN

R

C

H

H

H

O



Activity 2: Fold a β-sheetThe β-sheet also has hydrogen bonding

between the amino and carboxyl groupsbut in this case the polypeptide chain isfolded back on itself to give a flattishstructure.

Materials Needed:

• Student Activity Page: PolypeptideChains

• Scissors

• Transparent tape

Procedure:

1. Cut out the strips labeled PolypeptideChain 2a and Polypeptide Chain 2b alongthe dotted lines.

2. Using transparent tape, join the C-terminus of Polypeptide Chain 2a to the N-terminus of Polypeptide Chain 2b.

3. Circle the H atom on the amino-groupof every fourth amino acid beginning withamino acid #1 (amino acids #1, 5, 9, and13).

4. Circle the O atom on the carboxylgroup of every fourth amino acid beginningwith amino acid #4 (amino acids #4, 8, 12,and 16).

5. Hold the N-terminus end of thepolypeptide chain in your left hand. Holdamino acid #4 in your right hand. Fold sothat the O atom on the carboxyl group ofamino acid #4 touches the H atom of theamino group of amino acid #1 (sideways H bond).

HH

HH

CC

10

NN

RR

CC

OOHH

HH

CC

8

NN

RR

CC

OO

CCNN

RR

CC

HH

HH

9

OO

CCNN

RR

CC

HH

HH

7

OO

Transparent Tape

HH

HH

CC

6

NN

RR

CC

OOHH

HH

CC

4

NN

RR

CC

OOHH

HH

CC

2

NN

RR

CC

OO

CCNN

RR

CC

HH

HH

5

OO

CCNN

RR

CC

HH

HH

3

OO

CCNN

RR

CC

HH

HH

HH

1

OO

HH

HH

CC

6

NN

RR

CC

OOHH

HH

CC

4

NN

RR

CC

OOH

H

CN

R

C

O

CCNN

RR

CC

HH

HH

5

OO

CCN

RR

CC

HH

H

3

OO

CN

R

C

H

H

H

O


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6. Continue to fold and hydrogen bondthe following atoms of the polypeptidechain:

a. Fold back in the opposite directionso that the O atom of carboxyl groupof amino acid #8 is on top of the Hatom of amino group of amino acid#5.

b. Reverse the fold again and so thatthe O atom of carboxyl group ofamino acid #12 is on top of the Hatom of amino group of amino acid#9.

c. Fold back in the opposite directionso that the O atom of carboxyl groupof amino acid #16 is on top of the Hatom of amino group of amino acid#13.

7. Congratulations, you have constructeda β-sheet.



Activity 3: Silly PolymersYou’ve done a lot of brain work, so its

time to get silly. You are going to cross-link a polymer to create Silly Putty®! Since thereis no feasible cross-linking activity that youcan do with proteins in your classroom, thissilly substitute will give you an idea of howthe shape and function of proteins mightchange when cross-linking occurs. Theobjective is to cross-link a polymer andobserve the changes in the physicalproperties as a result of this cross-linking.You will also observe changes in thephysical properties of your cross-linkedpolymer in different temperatures.

The glue contains a polymer calledpolyvinyl acetate resin. This polymer has astructure a bit like the secondary structure ofprotein, like long strands of spaghetti. Whenwater is added, the glue becomes runny,and these strands separate from each other.The Borax® acts as a cross-linker thatchemically “ties together” the long strandsof the polyvinyl acetate. The strands can nolonger slip and slide past one another. TheSilly Putty® will be “stiffer.” The Silly Putty®

is held together by very weak intermolecularbonds, similar to the hydrogen bonds thatjoin portions of the polypeptide chains inproteins. Like proteins, the Silly Putty® is not“rigid” or “solid.” There is flexibility aroundthe weak bonds and throughout the cross-linked polymer.

Materials Needed:

You will work in groups of four. Eachperson needs:

• 1 clear 8-oz. (or larger) plastic cup

• 1 plastic teaspoon

• 1 plastic Ziploc™ bag

Each group of 4 needs:

• 1 clear 8-oz. (or larger) plastic cup (which the group should label “Borax®”)

• 1 clear 8-oz. (or larger) plastic cup (which the group should label “Water”)

• 1 graduated cylinder

• 1 ruler

• white all-purpose glue

• Borax®

• 1 plastic teaspoon (which the group should label “Borax®”)

• 1 permanent marker

• water

• paper towels

• newspaper (put down first to protect theworking surface)

• Access to a refrigerator/freezer or to acold water and an ice water bath

General Safety Guidelines:

• Since solid Borax® is a bleaching agentand solution will burn the eyes, gogglesand aprons should be worn.

• Some people are allergic to Borax® (mayhave skin reaction). Wash your hands afterkneading the Silly Putty® and finishing theexperiment

• It is important to label anything containingor used with the Borax®. Only reuse thesethings with Borax®. Borax® is very basicand will contaminate materials for a longtime, even after cleaning.

Procedure:

1. Place newspaper down to protect yourwork surface. Put on your goggles and labaprons.

2. Use the permanent marker to label oneplastic cup “Borax®” and another plastic cup“Water” for the group. Label one plasticspoon “Borax®.”


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3. Use the permanent marker to writeyour name on your Ziploc™ bag, yourindividual plastic cup, and your teaspoon.

4. Fill the “Water” cup with water.

5. Use the graduated cylinder to measure200 mL of water. Put this 200 mL of waterinto the cup labeled “Borax®.”

6. In your individual clear cup, put 6teaspoons of glue. Add 4 teaspoons ofwater, from the “Water” cup, to the glue.Stir.

7. Using the “Borax®” spoon, add 1teaspoon of Borax® to the water in the cuplabeled “Borax®.” Stir until most of theBorax® is dissolved.

8. Add 4 teaspoons of the Borax®

solution to your individual cup using the“Borax®” spoon. Count three seconds(one-one thousand, two one-thousand,and three one-thousand). Then gently stiryour cup using your spoon. Stir thoroughlyso that all of the glue comes into contactwith the Borax® solution.

9. Observe what is happening. Take outthe Silly Putty® and play with it. Do not tryto “dry“ it on paper towels or newspaperbecause it will stick. The Silly Putty® willnaturally dry out and become the correctconsistency as you play with it.

10. Form the Silly Putty® into a ball. Using a ruler to measure, drop the ball from aheight of 30 centimeters. How high does it bounce?

______________________________________

11. Now, place your ball in a refrigerator orice bath for 10 minutes. Again, bounce theball from a height of 30 centimeters. Howhigh did it bounce this time? Why do youthink this happened?________________________________________________________________________________________________________________________________________________________

12. Now place your ball about 6 inchesfrom a light bulb for about 5 minutes andagain check how high it will bounce whendropped from a height of 30 centimeters.How high did it bounce this time? Why doyou think this happened? ________________________________________________________________________________________________________________________________________________________

13. Now put your Silly Putty® ball in thefreezer or in an ice bath for 10 minutes.Check how high it will bounce whendropped from a height of 30 centimeters.How high did it bounce this time? Why doyou think this happened? ________________________________________________________________________________________________________________________________________________________

14. Try to transfer your observations of thebehavior of Silly Putty® to the behavior ofprotein. Remember that proteins are thework horses of the cell or body. Why mighta change in temperature, such as when aperson is exposed to extreme heat or cold,cause problems?

________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________

15. Wash your hands with soap and waterwhen you have finished the experiment

Poly

pepti

de C

hain

1a

Poly

pepti

de C

hain

1b

HH

HH

CC16

NN

RR

CCOO

OOHH

HH

HH

CC14

NN

RR

CCOOHH

HH

CC12

NN

RR

CCOOHH

HH

CC10

NN

RR

CCOO

HH

HH

CC8

NN

RR

CCOOHH

HH

CC6

NN

RR

CCOOHH

HH

CC4

NN

RR

CCOOHH

HH

CC2

NN

RR

CCOO

CCNN

RR CC HH

HH

15 OO

CCNN

RR CC HH

HH

13 OO

CCNN

RR CC HH

HH

11 OO

CCNN

RR CC HH

HH

9 OO

CCNN

RR CC HH

HH

7 OO

CCNN

RR CC HH

HH

5 OO

CCNN

RR CC HH

HH

3 OO

CCNN

RR CC HH

HH

HH

1 OO

Poly

pepti

de C

hain

2a

Poly

pepti

de C

hain

2b

HH

HH

CC16

NN

RR

CCOO

OOHH

HH

HH

CC14

NN

RR

CCOOHH

HH

CC12

NN

RR

CCOOHH

HH

CC10

NN

RR

CCOO

HH

HH

CC8

NN

RR

CCOOHH

HH

CC6

NN

RR

CCOOHH

HH

CC4

NN

RR

CCOOHH

HH

CC2

NN

RR

CCOO

CCNN

RR CC HH

HH

15 OO

CCNN

RR CC HH

HH

13 OO

CCNN

RR CC HH

HH

11 OO

CCNN

RR CC HH

HH

9 OO

CCNN

RR CC HH

HH

7 OO

CCNN

RR CC HH

HH

5 OO

CCNN

RR CC HH

HH

3 OO

CCNN

RR CC HH

HH

HH

1 OO

Polypeptide Chains




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Notes

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Learning ObjectivesAfter completing this activity, students will be able to:

• Describe the process of proteinsynthesis in five simple steps.

• Describe and distinguishbetween transcription andtranslation.

• Identify the roles of DNA,mRNA, rRNA and tRNA inprotein synthesis.

• Transcribe and translate a DNAcode.

BackgroundUnderstanding how proteins

are made in the cell and howthey fold is essential tounderstanding how proteinsmight misfold and cause disease.This activity is designed todemonstrate how the geneticcode contained in DNAdetermines the type of proteinsthat the organism produces. It is an overview of the processof protein synthesis.

Each protein is made usingthe genetic information stored inthe genome, the entirety of

hereditary information of anorganism. Each gene—unit of heredity—in the genome is a sequence of DNA(deoxyribonucleic acid) thatcodes for one unique protein.

DNA a polymer made up offour different nucleotides. Eachnucleotide consists of a 5-carbondeoxyribose sugar, a phosphategroup, and a nitrogen base. Thesugar and phosphate group areidentical for each nucleotide, butthere are four different bases:adenine, thymine, guanine, andcytosine—abbreviated A, T, C,and G.

DNA Nucleotide

Each carbon of the sugar isnumbered. The phosphate groupis attached to the 5' carbonatom, and the nitrogen base isattached at the 1' carbon. The


We Moose Crack The Code

SummaryStudents read an article that explains how proteins are made

from genetic information in the cell—that is, protein synthesis.They then complete an activity that simulates transcription andtranslation in order to decode a humorous message in a “gene.”

Duration One or two 45-minute classperiods

VocabularyAnticodon

Codon

Complementarybase pairing

Deoxyribonucleicacid (DNA)

Eukaryotes

Gene

Genetic code

Genome

Messenger RNA(mRNA)

Nontranscribedstrand (a.k.aNoncoding strand)

Nucleotide

Ribonucleic acid(RNA)

Ribosomal RNA(rRNA)

Ribosome

RNA polymerase

Promoter site

Protein foldingproblem

Protein synthesis

Transcribed Strand(a.k.a CodingStrand or SenseStrand)

Transcription

Transfer RNA (tRNA)

Translation

Triplet

Lesson 3

34

5’4’

3’ 2’

1’C

C

C

OH

C

CO

PO4H

NitrogenBaseSugar


Lesson 3: We M

oose Crack The Code


• Student Pages:We Moose Crack

The Code—onephotocopy

per student

• Student ActivityPages: Decode

That Gene—onephotocopy

per student

• Gene SequencesA through DD—One photocopyper class. Each

student needs onegene sequence

for this activity, 30are provided.

Copy duplicatedsequences as

needed toaccommodate

class size.

• tRNA “Word”Molecules—1

photocopy of each

• Four distinct“stations” in the

classroom wheretRNA “Word”

Molecules can beplaced. Those

starting with “A”can be placed at one station,

those starting with“C” at another,

and so on.

• Scissors—several at each“tRNA station”

• Chalkboard,whiteboard,

or some othervisible writing

surface

phosphate of one nucleotide isthen bonded to the 3' carbon ofthe next nucleotide to form aDNA strand. The complete DNAmolecule has two complementarystrands that coil anti-parallel toeach other and form a doublehelix. In DNA molecules, Calways pairs with G, and Aalways pairs with T.

The nucleic acid “language”of DNA is written in three letter(three nucleotide) sequencescalled triplets. To make a protein,this genetic information istransmitted in two stages. Eachof these stages requires RNA,ribonucleic acid. RNA is verysimilar in chemical structure toDNA. The 5-carbon sugar in RNAis ribose instead of deoxyribose.While both DNA and RNA containadenine (A), guanine (G), andcytosine (C) bases, the fourthnucleotide base RNA is uracil (U).There are several different kindsof RNA, each with its ownfunction.

The first step of makingprotein is transcription. Intranscription, only one strand of the DNA double helix istranscribed. RNA polymerasesare enzymes attach to the DNAat specific promoter sequencesand begin constructingmessenger RNA (mRNA). RNApolymerase unwinds the doublehelix and moves in from 5' 3'along the transcribed strand. It forms the mRNA molecule by temporarily joiningcomplementary RNA nucleotidesto the DNA nitrogen bases in this fashion:

DNA base RNA base

Cytosine (C) joins with Guanine (G)Guanine (G) joins with Cytosine (C)Thymine (T) joins with Adenine (A)Adenine (A) joins with Uracil (U)

The resulting three letter orthree nucleotides of the mRNA

that carry the genetic code arecalled codons.

The second step of makingprotein is called translation. This is the step where nucleicacid “language” is converted toprotein “language.” After the RNAnucleotides are joined to form an mRNA molecule, the mRNAleaves the cell nucleus andconnects to a ribosome (made upof ribosomal RNA-rRNA) in thecytoplasm. Translation begins atthe START codon of the mRNA.Since the codon or genetic codefor each amino acid of a proteinis three nitrogen bases long,molecules of transfer RNA (tRNA)with a complementary three-lettercode (or anticodon) attach to themRNA codon in sequence. Oneside of the tRNA molecule carriesa specific amino acid which linktogether in that sequence,making the protein. When aSTOP codon is reached, theprotein molecule is complete.

Teaching Strategies1. Thoroughly read the studentmaterials for We Moose CrackThe Code and Decode ThatGene.

2. Prior to class, make allphotocopies. Separate the‘genes’ on the sheets GeneSequences A through DD so thatyou will be able to give one genestrip to each student. Cut apartthe tRNA START molecule fromthe tRNA “Word” Moleculessheet so that you can give eachstudent a tRNA START molecule.

3. Place the tRNA “Word”Molecules sheets and scissors atfour stations around the room.Those starting with “A” can beplaced at one station, thosestarting with “C” at another, and


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so on.This will help alleviate crowding whenstudents do their activity.

4. Give each student a copy of the StudentPages: We Moose Crack The Code. Allowstudents to read at their own pace, read as agroup, or read aloud as a class—whateveryour preference.

5. After students have read We Moose CrackThe Code, reinforce the following concepts:

• The building blocks of DNA and RNA arecalled nucleotides.

• Three of the nitrogen bases of the DNA andRNA nucleotides are the same: adenine (A),guanine (G), and cytosine (C). The fourthnucleotide bases differs in the twomolecules. RNA contains uracil (U) insteadof thymine (T).

• The DNA molecule is a double helix. Thestrands are complementarily paired. Aalways pairs with T. C always pairs with G.

• Three bases of DNA will code for an aminoacid. These three bases are called triplets.

• mRNA forms complementary pairs withDNA. A always pairs with U. C always pairswith G. The three mRNA nucleotides thatpair with the DNA triplet are called a codon.

• tRNA carries an amino acid on one side andhas three nucleotides called anticodons onthe other to pair with the codon on mRNA

• DNA strands are “read” from the 5' carbonend of the strand to the 3' carbon end of thestrand.

6. On the chalkboard or other visible place,review the example given in the studentspages of base pairing and then provideadditional examples and practice.

7. Give each student a copy of the StudentActivity Pages: Decode That Gene, one gene,and one tRNA START molecule. Tell eachstudent that they have their own unique DNA

gene and they will need to transcribe andtranslate that gene to get their uniquemessage.

8. Students may require help to begin the activity. It may be helpful to begintranscription with the DNA triplet TAC as aclass. Be sure that all students have identifiedthe correct start sequence and are workingfrom top to bottom on the right side of theirgene strip.

9. While each message is humorous, eachmessage should make grammatical sense, soany nonsensical messages are due to errors intranscription and/or translation.

10. When students have completed theactivity, emphasize the importance of having aSTART and STOP signal in protein synthesis.Remind students that chromosomes—thelong strands of DNA in their cells—containthousands of genes. Each cell has theorganism’s entire DNA, but not all of it needsto be “expressed.” For example, liver cells donot need to produce the protein for eye color.Since not all proteins need to be made atonce, and some not at all, there needs to be a signal to produce a specific protein.

11. Also emphasize the problem of mutation—the addition, deletion, or change of a DNAnucleotide. The end product, in this case, thestudent’s message may not make sense. In acell or organism, the change may cause deathor disease.

AssessmentStudent should be able to write a few

paragraphs describing protein synthesis andthe processes of transcription and translationin their own words. They should be able toexplain the role of DNA, mRNA, and tRNA inprotein synthesis.

Extension• You may wish to introduce students to the

Human Genome Project, and discuss itsimportance to the study of biology.

Molecule DNA mRNA tRNA

3-Letter Code Triplet Codon Anticodon

Complementary Bases C G C

G C G

T A U

A U A


Lesson 3: We M

oose Crack The Code

Key1. Your instructor will give you a “gene,” aportion of the DNA molecule. Write down theletter(s) that identify your gene: varies

2. If you look at your gene, what directionwould the RNA polymerase enzyme move if itwere reading the left side of your gene?Bottom to top.

3. What direction would the RNA polymeraseenzyme move if it were reading the right sideof your gene? Top to bottom.

4. What does your “message” say?A. Start A moose is my best friend StopB. Start My large brain is my best feature

StopC. Start My best friend has the biggest

moose StopD. Start I have the biggest brain StopE. Start I have the smallest brain StopF. Start My best friend has the smallest

brain StopG. Start My best feature is my large brain

StopH. Start My brother has a large moose

StopI. Start I have the brain of a moose StopJ. Start My best friend is a large moose

StopK. Start My moose has the biggest

mouth StopL. Start A large moose is my best friend

StopM. Start My friend has the brain of a

moose StopN. Start My large mouth is my best

feature StopO. Start I have the best feature of a

moose StopP. Start My sister has the brain of a

moose StopQ. Start My brother has the brain of a

moose StopR. Start My sister has the best feature of

a moose StopS. Start My moose has the biggest brain

StopT. Start The friend of my sister is a

moose StopU. Start The large moose has the

smallest brain Stop

V. Start My sister has the smallest mouthStop

W. Start My moose has the smallestmouth Stop

X. Start I have the biggest mouth StopY. Start I have the smallest brother StopZ. Start I have the smallest mouth Stop

AA. Start My sister is the best friend of amoose Stop

BB. Start I have the smallest sister StopCC. Start My moose is the smallest StopDD. Start My brother is the friend of a

moose Stop

5. What “word” did the final codon code for?Why is this codon necessary? STOP isnecessary because the DNA strand hasmany genes and the RNA polymeraseenzyme needs a signal to stop making amRNA strand.

6. How does your message compare tothose of your classmates? It is different.

7. Looking at your assigned gene, how mightyour message change if the fifth nucleotidebase of the DNA strand after the TAC STARTtriplet were changed? A change in one lettermay change the word that is coded for. Themessage might change and it might notmake any sense.

8. Looking at your assigned gene, how mightyour message change if the fifth nucleotidebase of the DNA strand after the TAC STARTtriplet were deleted? A deletion of one lettermay change the word that is coded for, as well as all the words that follow. Themessage might change and it might notmake any sense.

9. In this activity, DNA coded for a message.In the actual genetic code, each triplet codesfor a specific amino acid. If this DNA strandwas coding for an amino acid chain, a protein,and a nucleotide base was changed ordeleted, what might happen? Any change inthe DNA might change the amino acid thatis coded for, so the protein that is mademay not be the same.

10. What might scientists call a change in the DNA strand (change, addition, or deletionof a nucleotide base)? They might call it amutation.