opening up the lab

FindingsSEPTEM B E R 2 0 1 2

U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICESNational Institutes of HealthNational Institute of General Medical Sciences

THESE STOR IES AND MORE

PAGE 9 How Bacteria DefendThemselves Against Fluoride

PAGE 1 0 Five Foul Things That Are Also Good for You

PAGE 1 4 Cellular Stress Relievers

PAGE 2

Opening Up the LabImproving Access toScience for Peoplewith Disabilities…with neuroscientistBrad Duerstock

On the Cover

1 Yeast cell frozen in time, Carolyn Larabell, University of California, San Francisco, and Lawrence Berkeley National Laboratory2 Vibrio bacteria, Tina Carvalho, University of Hawaii at Manoa3 G protein, Protein Data Bank4 Cascade reaction promoted by water, Tim Jamison, Massachusetts Institute of Technology5 Mouse fibroblast cells, Torsten Wittmann, University of California, San Francisco6 Spinal nerves, Lawrence Marnett, Vanderbilt University7 Spinal cord tissue, Brad Duerstock, Purdue University 8 Spinal nerves and section of spinal cord, National Institute of Neurological Disorders and Stroke, National Institutes of Health9 Brad Duerstock, Andrew Hancock, Purdue University 10 Bread mold, Namboori B. Raju, Stanford University 11 DNA, Judith Stoffer12 Cell undergoing apoptosis, Hermann Steller, Rockefeller University13 Tetrahymena, Rupal Thazhath and Jacek Gaertig, University of Georgia

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Featuring

1 Up Close With: Brad Duerstock

2 Opening Up the Lab: Improving Access to Science for People with Disabilities

7 DO-IT for Science

Spotlights on Hot Science

4 Just Found: Does Cholesterol Play a Role in Alzheimer’s?

9 Just Found: How Bacteria Defend Themselves Against Fluoride

10 Five Foul Things That Are Also Good for You

12 Chromosomal Caps in Sickness and in Health

14 Cellular Stress Relievers

16 Cilia: Biology’s Brooms

Edited by Alisa Zapp Machalek

Contributing Writers

Emily Carlson

Amber Dance

Stephanie Dutchen

Alisa Zapp Machalek

Kirstie Saltsman

Production Manager

Susan Athey

Online Editor

Jilliene Mitchell

Produced by the Office of Communications and Public Liaison

National Institute of General Medical Sciences

National Institutes of Health

U.S. Department of Health and Human Services

http://www.nigms.nih.gov/findings

Findings | S E P T E M B E R 2012 1

ANDREW HANCOCK, P

URDUE U

NIVERSITY

Up Close With

HOBBIES

Gadgetry, architectural design

FAVORITE MUSIC

Rock and roll, bluegrass

HISTORIC FURNITURE

Revolving bookstand like

the one Thomas Jefferson

used at Monticello

BIZARRE COLLECTIBLE

Ecuadorian shrunken head

(replica made from goatskin)

FAVORITE GENRES

History, science fiction

FAVORITE CUISINES

Mexican, Japanese

“The sense of discovery andthe impact on others arebig motivations for me.”

Brad DuerstockNEUROSC I E N T I S T, A S S I S T I V E T E C HNO LO GY D E S I GN E R

National Institute of General Medical Sciences2


A crash, then all goes black. When you come to, you can’t feel part of your body. You will never move normally again.

Paralysis from accidents or medical conditions affects millions of Americans,forever changing their daily lives and future plans.

For those who want to work in labs, the road is being smoothed and widened by Brad Duerstock, a researcher at Purdue University in WestLafayette, Indiana.

Duerstock is building and modifying scientific equipment, adjusting the physical layout of labs and creating an online networking site. His goal is toencourage more people with impaired mobility or limited vision to pursuecareers in science, technology, engineering and math fields.

“Science can be pretty inhospitable to peoplewith disabilities. But that doesn’t mean it’s impossible,” he says.

He speaks from experience. A quadriplegic sinceage 18 due to a spinal cord injury, Duerstock stud-ies nerve injury and repair. Throughout his trainingand career, he’s had to invent new ways to getthe job done.

“It takes fortitude,” he says. “You have to perse-vere. You have to be creative. You have to figureout your own solutions and make your own path.”

A New PathDuerstock grew up in Indiana in a family of teach-ers and principals. An excellent student interestedin science and medicine—and a star member ofhis high school’s swim team—he planned to become a physician.

About 3 months before graduation, during a swim practice at school, he had a diving accident.

“It happened so fast. I don’t even remember hitting my head and breaking my neck,” he says. “All of a sudden, I was floating face down and couldn’t move my body.”

ANDREW HANCOCK, P

URDUE U

NIVERSITY

BY STEPHANIE DUTCHEN

Opening Up the LabImproving Access to Science for People with Disabilities

Spinal nerves (green) connect our skin andmuscles to the spinal cord, allowing us tofeel and react to our environment.

LAWRENCE M

ARNETT, V

ANDERBILT

UNIVERSITY

Just Found Just Found Just Found Just Found

National Institute of General Medical Sciences 4

me as athletics. When I couldn’t com-pete athletically anymore, I competed academically.”

He also had to learn new ways to get around, eat, dress, bathe, opendoors, check e-mail, talk on thephone, take notes, study and take exams.

Throughout his hospitalization andrehabilitation, Duerstock kept up withhis schoolwork and maintained hishigh grades.

“My teachers were amazing,” heremembers. “They would send memy assignments and make photo-copies of handouts while I was in the hospital, and some would visitregularly to privately tutor me.”

This commitment paid off. The firsttime Duerstock left the hospital wasto deliver his high school commence-ment speech—as valedictorian of his class.

After the ceremony, he had to goback to the hospital.

College ChoiceDespite his stellar academic record,some doors were still closed to him.He’d been appointed to West PointMilitary Academy, “but I quickly knewthat wasn’t going to happen,” hesays. West Point has strict physicalrequirements for its cadets.

So Duerstock decided to attend anearby university, Purdue, which heknew was “famous for engineering.”He switched his planned major from premed to an interdisciplinaryengineering program focused on biomedical engineering.

At the time, “Purdue didn’t havemuch in the way of accommoda-tions,” he remembers. “But theywere working to comply [with therecently passed Americans withDisabilities Act of 1990] and wantedto find ways to accommodate me.”

Medically speaking, he had injuredhis spinal cord between the C4 andC5 vertebrae in his neck. He couldno longer move his legs, arms,hands or wrists. He eventually recov-ered movement in his biceps andcan rotate the lower portion of hisright arm.

“I was a competitive swimmer formost of my life up to the accident. It was tough,” he says. “But fortu-nately, I had other things to rely on.Academics were as important to

I like being able to decide

C4

C5

Duerstock injured his spinal cordbetween the C4 and C5 vertebrae.

Does Cholesterol Play a Role inAlzheimer’s?Scientists have long known that cholesterol plays a number ofroles—both good and bad—in thebody. Now, they suspect it mightalso contribute to the developmentof Alzheimer’s disease.

To visualize how this might happen, a team of researchersdetermined the structure of anAlzheimer’s-related protein knownas APP. To study the protein undernormal conditions, the scientistsplaced it into laboratory-mademembranes, which mimic its natural environment.

The scientists, led by CharlesSanders at Vanderbilt UniversityMedical Center in Nashville,Tennessee, showed that APP canhook up with cholesterol in the artificial membranes. Based on other studies, the researchers believe that cholesterol then drivesAPP into specialized membraneareas known as lipid rafts. There,enzymes hack off pieces of APP,transforming it into a substancecalled amyloid beta, which accu -mulates in the brains of those with Alzheimer’s.

If this process promotes the disease, as the scientists believe, a drug that prevents APP from connecting to cholesterol might forestall Alzheimer’s, a condition that affects up to 5 million people in the United States.

—Alisa Zapp Machalek


white blood cells, inflammation,bleeding, tissue death from lack ofoxygen and biochemically induceddamage to nerve cells.

“There’s a lot of things going on insecondary injury,” Duerstock says. Somany things, in fact, that “it’s reallyhard to find the critical culprits.”

Duerstock and his colleagues arehunting down these culprits using avariety of tactics. In one, they exam-ine healthy and damaged nerve cellsunder a microscope to identify ana -tomical changes. Several years ago,they devised a way to compu tation -ally combine the images from manymicroscope slides to create a 3-Dview of specific cells and moleculesat the center of the spinal cord, wherethe most severe injuries occur.

They also look for molecules thatcause or reveal secondary injury.Right now, they have their eyes onacrolein—the substance you smellwhen cooking oil burns. Acroleinincreases dramatically after a spinalcord injury and fatally damages thenerves it touches. So it could be amajor player in secondary injury.

In their search for treatments thatlessen or repair nerve damage—orthat stimulate the growth of new,healthy nerves—Duerstock and others are investigating a compoundcalled polyethylene glycol or PEG,which is known to seal rupturednerve cell membranes. In animalstudies of spinal cord injury, PEG significantly reduced tissue damageand improved the animals’ ability to move.

Duerstock realizes that his researchcould ultimately help not only the estimated 1.3 million people in theUnited States with spinal cordinjuries, but also those with nervedamage from traumatic brain injury,diabetes, infections or neurodegener-ative diseases like Alzheimer’s andParkinson’s.

“The sense of discovery and theimpact on others are big motivationsfor me,” he says. “Being a researcher,you might have a broader impact onsociety than you would as a practic-ing physician.”

Now, as a faculty member at hisalma mater more than 20 years later,he helps accommodate studentswith disabilities by creating assistivetechnology for use at home, schoolor work.

Investigating InjuryDuerstock first got a taste of re searchas a senior in college at Purdue’sCenter for Paralysis Research. Hewas fascinated by the work and wenton to earn a Ph.D. in neuroscience.He now conducts his own research in areas ranging from neurotrauma to assistive technology.

“I like being able to decide what Iwant to research,” he says. “I canlook at whatever piques my interest.That independence appeals to me.It’s very exciting.”

A major focus of his research is on chronic (long-lasting) injuries tothe spinal cord and central nervoussystem. What especially interestshim is secondary injury.

Secondary injury is caused by thebody’s massive response to the ini-tial trauma to nerves, bones andblood vessels. It includes a flood of

what I want to research. That independence appeals to me.

This 3-D reconstruction of an uninjuredsection of rat spinal cord shows graymatter (dark gray) and white matter(transparent). Duerstock devised thistechnique to enable researchers toexamine the center of the spinal cord. BRAD DUERSTOCK

Section of Spinal Cord

Spinal nerves (orange) carry messages to and from the spinal cord. NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE, NATIONAL INSTITUTES OF HEALTH

Skin

White Matter

Gray Matter

Muscle

Sensations (temperature, texture,

etc.)

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onse(like jerk

ingawa

y from pain)

They can then adjust the micro-scope using a variety of methods,including keyboard, mouse or trackball.

Duerstock is also working to makeAccessScope available to othersremotely through his networkingsite. He envisions users logging inthrough a Web browser and per-forming microscopy from anywhere.

As Duerstock points out, assistivetechnology frequently has broaderbenefits than originally intended.

“Often what can be considered goodassistive technology simply means creating a device that excels in userdesign or usability,” he says.

Science needs people from different backgrounds to

“Microscopes require you to perchand lean forward to peer into theeyepieces,” Duerstock explains.“That’s not something easily achievedby a wheelchair user.” Nor is it easyfor people with vision loss, he adds.

So, instead of using eyepieces,AccessScope displays images on acomputer screen, where they caneasily be enlarged to help all typesof users.

Users who can’t see the instrumentreadouts can use third-party screen-reading software to hear them.

Those with limited hand control dueto paralysis, arthritis, carpal tunnelsyndrome or other motor impair-ments can control an acces sibleslide loader to automatically placeslides on the microscope stage.


A Wider ScopeDuerstock always strives to be self-sufficient, conducting experimentsand gathering data himself ratherthan relying on others in the lab.Often, that means creating newtools—like the accessible micro-scope he calls AccessScope.

“The light microscope is one of thefundamental pieces of equipmentused in a biomedical lab. Having thattool available is critically important,”he says. “AccessScope has allowedme to work for hours independently.”

Duerstock started buildingAccessScope when he was a postdoctoral researcher. Althoughdesign ed for people with upper-limb mobility impairments like his, it also turned out to help people with limited vision.

Devices that make life easier for people withdisabilities often benefit others. Sidewalk rampswere created for wheelchair users, but theyalso help people pushing strollers, wheelingluggage or riding bicycles.

AccessScope is a high-tech light microscope that Duerstock modified to be accessible for peoplewith limited hand and arm mobility, wheelchair users and those with impaired vision.

ANDREW HANCOCK, PURDUE U

NIVERSITY


look at problems in different ways.

IAS—It’s About ScienceDuerstock’s most ambitious and far-reaching project yet is the $2 million Institute for AccessibleScience, or IAS.

Based at Purdue and begun in 2010, it includes a fully accessible lab and the IAShub.org online net-working site.

The hub is designed for people inter-ested in improving accessibility forthose pursuing science careers. Itoffers something Duerstock says hedidn’t have right after his injury—connection, inspiration and supportfrom like-minded people. It serves asa virtual community where students,scientists, parents and teachers canshare their experiences with over-coming obstacles.

The hub includes helpful articles andWeb sites, participant profiles, a dis-cussion forum and a blog. It also listsfunding ideas for scientists whobring students with disabilities intotheir labs.

“[Mentoring such students] mighttake a little more work, but the fund-ing and technologies are out there,”he says. “And inclusion really haslong-term benefits, not only for theindividual with a disability, but alsoin bringing a greater diversity ofpeople into science who have differ-ent perspectives to offer. Scienceneeds individuals from differentbackgrounds to look at problems indifferent ways.”

DO-IT for SciencePerforming bypass surgery using sheep hearts. Touring Microsoft’s headquarters. Working in a forensics lab.

High school students in the DO-IT Scholars program do thesethings and more during a 2-week sneak peek of college life atthe University of Washington in Seattle.

DO-IT Scholars is a college-prep program in Washington statefor students interested in careers in science, technology, engi-neering or math. But it’s also much more.

DO-IT stands for Disabilities, Opportunities, Internetworking, and Technology. As you’ll learn from the many videos posted onits site (http://www.uw.edu/doit), DO-IT Scholars describe itusing words like fun, connection, learning and independence.

DO-IT Scholars have vision, hearing or mobility impairment; cerebral palsy;autism; or some other disability.

The 3-year program provides computerhardware and software, including anynecessary assistive devices. It trainsscholars to use technology to accom-plish things they might never havethought possible.

The program hooks its participantsinto a broad, supportive and empow-ered network of other students withdis abilities. It nurtures leadershipskills, self-advocacy and lifelongfriendships.

Many alumni continue to be involved in the program years afterthey’ve graduated by serving as mentors for younger scholars.

The DO-IT Scholars program began in 1993. It’s been so suc-cessful that programs in Japan and South Korea have used it as a model for some of their own activities. —Alisa Zapp Machalek

I’d like to think that after I leave the world, I’ve

Access ABILityTo create the lab—dubbed theAccessible Biomedical ImmersionLaboratory, or ABIL (sounds like“able”)—Duerstock recruited aninterdisciplinary team.

Engineers, ergonomics specialists,scientists, architectural designers andothers renovated a standard “wet” lab to accommodate the needs andsafety concerns of wheelchair users,people with vision loss and otherswho need to work in the lab.

Among ABIL’s modifications:

• Wider doors and aisles so wheel-chair users can enter and turnaround without knocking into delicate equipment.

• Lower lab benches for commontasks like pipetting, creating slidesand using microscopes.

• Lower, shallower sinks so people in wheelchairs can see and reachto the bottom.

• Faucets mounted on the side rather than the back of sinks sothey are easier to reach. Ditto forthe spray nozzle and distilled water dispenser.

• Easy-to-flip levers instead of roundknobs that are harder to grasp.

• Emergency shower controls andeye wash centers adjusted forwheelchair users and easier forpeople with visual impairments to locate.

Other issues are harder to address.

“Wheelchair users can’t back awayfrom a chemical spill easily orquickly,” Duerstock points out. “Plus,you have a lap.” Spills into the lap can go unnoticed for a while if you’velost feeling in your legs.


ABIL’s first big test will come from a group of undergraduate studentswith mobility or vision limitations. Upto six students will use the lab anddevise some of their own modifica-tions while collaborating on researchprojects with Purdue scientists.

At the time of this writing, the students hadn’t arrived yet. To findout what they had to say about theirexperience at ABIL, check online at http://publications.nigms.nih.gov/findings.

Lower counter sowheelchair users canbetter access surfaceand see into sink

Sink handles are levers,not knobs, and arelocated within reach

BRAD DUERSTOCK

No cupboard doorsso wheelchair userscan approach sink

When Duerstock looks at a laboratory, he easily envisions changes that would make the spacemore accessible to wheelchair users.

BEFORE

AFTER

BRAD DUERSTOCK

improved it in some small way.

How BacteriaDefend ThemselvesAgainst FluorideFor decades, people have preventedtooth decay using fluoride, which isfound naturally in the environmentand added to toothpaste, mouthwashand public water supplies. Fluorideworks by strengthening tooth enameland attacking the bacteria that causecavities.

But scientists have recently dis covered that many bacteria—including those that decay teeth—can defend themselves againstfluoride.

A research team led by RonaldBreaker of Yale University in NewHaven, Connecticut, found that bac teria use a bit of RNA called ariboswitch to sense and respond tohigh levels of fluoride. When fluorideattaches to it, the riboswitch activatesspecific genes that appear to encodeproteins called fluoride transporters.The researchers suspect that bacteriause these transporters to rid them-selves of fluoride, avoiding its effects.

To parry this bacterial defense system, scientists could try to blockthe fluoride transporters or disablethe fluoride riboswitch. Either way,the goal would be to stop bacteriafrom escaping a fluoride build-up. —Amber Dance

Just Fo

und Ju

st Found Ju

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Bringing Lessons Home Duerstock hasn’t brought architec-tural innovations just to the lab. In2001, he also designed his ownaccessible home.

“Architectural design interests me alot,” says Duerstock. “Before using a wheelchair, I had never thoughtmuch about it. But afterwards, wheneverything became inaccessible tome, one of my earliest desires wasto be able to control my environ-ment—to create my own space.”

He designed each aspect of thehouse—from the thickness of thecarpet to the automatic openers oninterior doors—to make his life easier and more efficient.

He lives in the home with his wife, Li Hwa, and their dog, Luke, and cat, Xiao Hei.

Luke, a yellow Labrador retriever, isanother sort of assistive technology.Duerstock got him several years agofrom the Indiana Canine AssistantNetwork, an organization that arran -ges for prison inmates to trainassistive dogs and then matches the dogs with owners.

For Duerstock, Luke is a big helpopening sliding doors (he tugs on arope tied around the handle), carryingthings and picking up objectsDuerstock drops.

“That used to be a big frustration—if I dropped my pen on the floor, itmight as well have been on themoon, because I wasn’t going to getit unless I had some assistance,” says Duerstock.

In return, Duerstock devised somecreative ways to give Luke the atten-tion dogs crave. He plays fetch withLuke using a remote-controlled ballthrower, and he modified a candy dispenser to dole out kibble treats.

Occasionally, he brings Luke to workfor extra petting—although he has tobe careful, because the lab is not yetaccessible for dogs with uncontrol-lably wagging tails.

While Duerstock doesn’t know ifthere will be a cure for spinal cordinjury and paralysis in his lifetime, he does hope to advance the field.

In the meantime, his assistive tech -nology innovations and leadership ofthe IAS promise to make it easier forpeople with disabilities to work in labsand make discoveries of their own.

“I like knowing that what I do can ultimately impact others,” Duerstocksays. “That is very satisfying to me.I’d like to think that after I leave theworld, I’ve improved it in some small way.” � � �

FIND MORE

See Duerstock and Luke in action several times in a video from the Indiana Canine Assistant Network at http://tinyurl.com/caninenet

Check out the networking site Duerstock and others created athttp://iashub.org

Read Duerstock’s tips for building an accessible and energy-efficienthome at http://web.ics.purdue.edu/~bsd/building.html

Learn how scientists can receive funding to support students with disabilities in their labs at http://www.nigms.nih.gov/Research/Mechanisms/PromoteDiversity.htm

FecesOur guts are host to many bacteria, and researchers are analyzing the bac terial colonies in our poop to better understand what they do.

Specifically, scientists involved in theNIH-led Human Microbiome Project(http://commonfund.nih.gov/Hmp) areusing genomic tools to identify thesecommunities in the gut and otherhotspots—the nose, mouth, skin andvagina—to learn how they help main-tain health or set the stage for disease.

In one study investigating the role of the gut’s microorganisms in obesity,researchers obtained stool samplesfrom pairs of female twins who wereeither both obese or both lean, as wellas from their mothers. They found thateach individual carried her own uniquecollection of bacteria. But the overallbacterial communities were more similar among family members thanthey were between unrelated people.

This information will contribute to a rapidly increasing body of knowledgeabout how microbes influence our physiology and how we might manipulate them to increase their benefit to us.

Five Foul Things ThatAre Also Good for YouBy Emily Carlson

Usually, we think of mold, feces, nitric oxide, hydrogensulfide and rat poison as rank, toxic or both. But scientists funded by theNational Institutes of Health (NIH) are learning more about the helpful rolesthese substances can play.

MoldIf you’re a homeowner, mold is definitely a four-letter word. But to scientists,it’s a very important organism. The widely used antibiotic penicillin comesfrom a mold called Penicillium. This mold’s bacteria-killing ability was discovered accidentally by Alexander Fleming in 1928 when it drifted in from another lab, landed on Fleming’s petri dish and killed the bacteria on it.

Today, Neurospora crassa—a mold that can turn sandwich breadorange—is helping scientists answer questions about how species arise and adapt as well as how cells and tissues change their shapes in different environments. And because it produces spores on a 24-hour cycle, this bread mold is also useful for identifying the molecular timepieces that govern sleep, wakefulness and other rhythms of life.


Bread mold (Neurospora crassa) is helping scientists learn about biological processes.Nasal

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The discovery of nitric oxide’s role in the body, particularly the cardio-vascular system, netted a NobelPrize in 1998.

Hydrogen SulfideWe generally associate hydrogen sulfide with the smell of rottingsewage. But some of our body’scells produce small quantities of this gas, and research indicates thatthis happens when their protein-making factories start churning outbad products.

The stinky gas seems to help cellsslow down protein production or, if the situation is bad enough, stopproduction and commit suicide.

Understanding the normal roleof hydrogen sulfide mayhelp sci entists developtreatments for diseaseslinked to excess cellularsuicide like Alzheimer’sand Parkinson’s.

Nitric oxide. BEN MILLS, WIKIPEDIA COMMONS

Hydrogen sulfide. BEN MILLS, WIKIPEDIA COMMONS

Nitric OxideNitric oxide is a toxic pollutant thatwe most often smell in car exhaustfumes, but it is critical to our cardio-vascular health, brain function andimmune system. It transmits signalsin most living creatures to helpdilate arteries, activate nerve cellsand increase the number of whiteblood cells to kill invading bacteriaand parasites.

Interestingly, Tibetans living at highelevations—where there’s lessoxygen in the air—have muchmore nitric oxide in theirblood than do people livingcloser to sea level. Scientistsbelieve that this extra nitricoxide dilates the Tibetans’blood vessels, increasing bloodflow to ensure that sufficient oxygengets to their tissues.

Humans and bacteria live together closely—and,for the most part, peaceably. Scientists are seekingto understand some of the roles bacteria play inhuman health and disease by analyzing bacterialcolonies from a few microbial hotspots.

Rat PoisonWarfarin, one of the world’s most prescribed medicines, stems from a substance on spoiled sweet cloverthat caused cattle to mysteriouslybleed to death in the 1920s.

Shortly afterward, researchers iden tified the cause of death—an anticoagulant molecule foundnaturally in the plant.

Chemically manufactured versionsof the molecule were first marketedas rat poisons and later as a newclass of drugs that now includeswarfarin.

Each year, 2 million Americans starttaking warfarin to prevent dangerousblood clots that can lead to heartattacks, strokes or even death. Peoplemight also take it after major surgeryto avoid other clotting problems.

Prescribing the right dose of warfarin is tricky because, forgenetic and other reasons, somepeople need higher doses and others need lower ones. Scientistsare currently studying warfarin to better understand how a person’sgenetic makeup can affect his or her response to medicine. �

Warfarin, a commonly prescribed anticoagulantmedicine, was initially marketed as a pesticide.


Telomeres Aplenty When a cell divides into two daughtercells, it has to copy its DNA. But theDNA replication machinery cannotreach the very ends of chromo-somes, so each time a cell divides,its chromosomes lose 25 to 200 letters at their tips. Telomeres serveas dispensable DNA that bufferschromosomes from losing any vitalgenetic information. Telomeres alsoprevent chromosomes from stickingtogether.

Researchers have known since the1930s that telomeres cap chromo-somes, but it was not until the1970s that they figured out whatthose caps are made of.

The team that solved this puzzle—and won a 2009 Nobel Prize for thework—was led by Elizabeth Blackburnat the University of California, SanFrancisco, and included Carol Greider,now at Johns Hopkins University inBaltimore, and Jack Szostak atHarvard Medical School in Boston.

Another key player was the modelorganism they used—a pond-dwelling creature called Tetrahymenathat is an extra ordinarily rich sourceof telomeres.

The scientists discovered thattelomeres are long repeats of thesame sequence of DNA. In people,they consist of the DNA sequenceabbreviated TTAGGG repeated about 2,000 times.

Chromosomal Caps in Sickness and in HealthBy Amber Dance

Every cell in your body has its own Doomsday Clock,ticking down the number of times it can safely divide. This clock takes theform of a cap, called a telomere, on the ends of each chromosome. Like the plastic aglets on the tips of shoelaces, telomeres keep chromosomes from fraying. But they get shorter every time the cell splits.

When its telomeres have shrunk to a certain point, a normal cell is supposedto die. But cancerous cells can avoid death by maintaining or even lengthen-ing their telomeres.

Shortened telomeres have been linked to age-related diseases like arthritis,hypertension, stroke and diabetes, as well as the aging process itself. Andsome research suggests that chronic stress—both psychological and cellular—can also dramatically shrink telomeres.

If scientists could figure out how to control telomeres, they might be able totreat certain diseases of aging as well as cancer.

The microscopic, single-celled swimmer Tetrahymena thermophila has about 20,000 chromosomes,each with telomeres on their ends. Human cells, in contrast, have a mere 46 chromosomes.

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The researchers also discovered howcells can maintain the length of theirtelomeres: An enzyme called telo m -erase adds more of the TTAGGGsequence to the ends of chromo-somes. This is important in a growingfetus, where cells are dividing rapidly.But in most adult body cells, telom-erase is essentially dormant undermost conditions. Certain cells canrespond to temporary stresses byupping their production of telom-erase, which prevent telomeres fromshrinking prematurely.

Telo TroubleMalfunctioning telomeres and tel -omerase can cause diseases. Forexample, most cancers make lots oftelomerase—as much as 10 to 20times the normal amount. The cellsdon’t stop dividing, and so they form tumors.

Scientists would like to turn off thetelomerase in tumors, but first they

need to learn more about telom-erase. Juli Feigon of the University ofCalifornia, Los Angeles, is working todescribe the three-dimensional struc-ture of the enzyme. Once scientistsknow the enzyme’s detailed shape,they might be able to develop drugsto gum up the works and preventcells from becoming cancerous.

In Werner syndrome, people startaging rapidly during their 20s. Theydevelop gray hair, cataracts in botheyes, hardening of the arteries andother diseases of old age. JanKarlseder of the Salk Institute in LaJolla, California, found that peoplewith Werner syndrome sometimeshave missing telomeres or parts ofone chromosome stuck to another. In a laboratory experiment using cellsthat originally came from a personwith Werner syndrome, Karlsederfound that when he provided extratelomerase to the cells, they endedup with less DNA damage than did

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The 46 human chromosomes are shown inblue, with the telomeres appearing as whitepinpoints. The DNA has already been copied,so each chromosome is actually made up oftwo identical lengths of DNA, each with its own two telomeres.

identical cells that didn’t receivetelomerase.

Another rare disease, dyskeratosiscongenita, happens when peoplecan’t maintain the telomeres in theirbone marrow, which is where bloodcells are manufactured. People withthe disease die when their bonemarrow can no longer produceenough healthy blood cells. CarolGreider continues her Nobel Prize-winning work by studying mice withbroken telomerase, which mimics dyskeratosis congenita. �


Cellular Stress RelieversBy Kirstie Saltsman and Emily Carlson

Your heart rate speeds up. Your muscles tense. Your face mayeven blush. These are just a few ways you feel your body respond tostress. But stress also can seep into your cells. Rising temperatures, toxins, infections, resource shortages and other stressors threaten howcells function—and ultimately whether you’re healthy. Scientists funded by NIH have learned a great deal about how cells respond to stress, and here are some examples.

This heat shock protein, Hsp33, wraps a protective arm around unfolded proteins.URSULA JAKOB, UNIVERSITY OF MICHIGAN

Protect ProteinsHeat can stress out cells. Warm them just three or four degrees, and theirproteins begin to unravel and stop functioning. If the proteins unravel toomuch, they tangle up with each other and form a clump that can kill thecell. To prevent this catastrophe, cells rely on a set of molecules calledheat shock proteins (or “chaperones”) that work in many different ways.Some tuck the sticky, carbon-rich regions of unfolded proteins into asmall pocket; others extend a protective arm around their unfolded neigh-bors or form barrels that sequester unraveled proteins away from anypotential tangling partners. Once things cool down, heat shock proteinshelp their “clients” refold into proper shapes.


Pass It OnEnvironmental stress can reach deep into a cell’s interior and alter the genetic material held within itsnucleus—and the changes can beinherited. A Swedish study showed that if a man didn’t have enough to eat during his life, his grandchildrenhad a higher risk of diabetes, obesityand cardiovascular disease!

Subsequent research at the Universityof Massachusetts Medical School inWorcester showed that when malemice were fed a low-protein diet, theactivity of hundreds of genes in theanimals’ offspring changed. In partic-ular, genes that manufacture fatswere more active. Although makingmore fats might be a protectivestress response to starvation, whenthere’s plenty to eat, it could lead toobesity and related diseases.

Genomic research suggests a poten-tial link between these heritablechanges in patterns of gene activityand changes in chemical markers,called epigenetic tags, affixed tocertain genes. Scientists are tryingto understand the nature of thesechanges and how they occur.

EvolveCells use intricate mechanisms tomaintain the stability of their geneticmaterial. Under stressful conditions,however, they may relax these controls.

Allowing genomic instability createsa population of genomically diversecells. Even if the original strain succumbs to the stress, there’s achance that at least one of otherstrains will survive.

Scientists tried out this theory inyeast, an organism commonly usedas a model to study human genetics.When researchers at the StowersInstitute for Medical Research inKansas City, Missouri, exposed yeastcolonies to potentially toxic chemi-cals, the yeast cells quickly gainedor lost entire chromosomes. Afterseveral generations of continuedexposure, some of the yeast cellshad evolved the ability to survive not only the original chemicals, butalso others, including drugs that normally kill yeast.

In the future, scientists might be able to take advantage of this adap-tive strategy to treat cancers, whichtypically involve cells with extra ormissing chromosomes.

DieIf all else fails, a cell may commit sui-cide via a pathway called apoptosis.This strategy sidesteps the destruc-tive effects of a cell actually dyingfrom the stressful conditions, whichcan damage or kill nearby healthycells by triggering inflammation.

Scientists don’t yet understand what causes a cell to abandon itsattempts at self-preservation andcommit to apoptosis. Some researchsuggests it has to do with the accu-mulation of unfolded proteins in a cellular compartment called theendoplasmic reticulum (ER). Whenstressful conditions, like exposure to a chemical, overwhelm the ER,molecules in its membrane may signal apoptosis to start.

Because cell death could play a rolein a number of neurological and car-diovascular diseases, understandinghow cells make their life-or-deathdecision might lead to ways toreduce the damage caused by these types of conditions. �

This cell is undergoing apoptosis, as indicated by the presence of caspase-3(green), a key tool in the cell’s destruction.

HERMANN STELLE

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Chemical tags (purple diamonds) on certainDNA letters can change the activity of geneswithout altering the DNA sequence. JUDITH STOFFER


Cilia: Biology’s BroomsBy Amber Dance

Cilia in PerilMore than a dozen rare but seriousgenetic disorders stem from ciliaglitches.

For example, an error in one oranother of several cilia genes canlead to primary ciliary dyskinesia,which affects one person out of16,000. People with this syndromehave trouble keeping their lungsclear of mucus and sometimes are infertile.

FIND MORE

For more articles like those on pages 12–16, see http://publications.nigms.nih.gov/insidelifescience

Researchers have created artificial cilia thatwave like the real thing. These lab-made ciliaare revealing how the structures coordinatetheir movements and what happens when they don’t move properly. ZVONIMIR DOGIC LAB, BRANDEIS UNIVERSITY

These hairs are tiny, butmighty. Cilia, lash-like structures on a cell’s surface, sweep mucus fromthe lungs and circulate the fluidneeded for proper brain function.They shepherd a woman’s eggs fromthe ovaries to the uterus. And with-out the extra-long cilium called aflagellum, sperm would be taillessand unable to swim.

Scientists are learning more aboutbasic cilia biology and gaining newinsights into how problems with ciliacause diseases.

Getting to Know CiliaA single cilium is made up of some600 protein pieces—more thanmany other cellular structures.

Frequently, many cilia work together,rippling like a hayfield in a breeze, tokeep body fluids flowing properly.

Other cilia are non-moving loners. A single, antenna-like “primary cilium”sticks out of most cells, and scien-tists recently found that its job is tosense the environment around a celland transmit signals into the cell.

Bardet-Biedl syndrome is a geneticcondition that occurs in approxi-mately one in 150,000 people andcan lead to obesity, blindness, kidneydisease and extra fingers and toes.Researchers discovered that the dis-ease is due, in part, to impairment ofthe primary cilium’s communicationabilities.

Could scientists come up with a cilia repair system to treat these diseases? One day they might beable to use gene therapies to fixmutations that cause malformedcilia. Or they might be able to learnto grow and transplant cilia into people who can’t make the struc-tures properly on their own. �

See artificial cilia “do the wave” in a video athttp://publications.nigms.nih.gov/multimedia/video/cilia.html.

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ACROSS

3. Bacteria use a bit of RNA called a ____________________to sense and respond to high levels of fluoride.

10. The full name of the Seattle-based DO-IT program is Disabilities, ____________________, Internetworking, and Technology.

12. This enzyme lengthens telomeres.

14. As we age, telomeres ____________________ .

15. Duerstock designs ____________________ technology for people with disabilities.

16. Nerve damage can include both primary and ____________________ injury.

DOWN

1. An online networking site for people with disabilities.

2. Duerstock hopes to find ways to repair damage to this part of the body.

4. Nitric oxide increases blood flow by ____________________arteries.

5. Scientists think ____________________ may play a role inAlzheimer’s disease.

6. Cells commit suicide through a pathway known as ____________________ .

7. This substance increases dramatically after a spinalcord injury.

8. One of Duerstock’s inventions was an accessible____________________ .

9. Cancer cells often contain extra or ____________________chromosomes.

11. Accessible tools can help people who have ____________________or visual impairments—and everyone else, too.

13. Penicillin comes from ____________________ .

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