MICHIGANAGRICULTURAL

EXPERIMENT STATION

SUMMER 2005 VOL. 23 NO. 2

futures

2 | FUTURES

Asthma, cystic fibrosis, Lyme disease, pre-mature birth, campylobacteriosis and dis-eases caused by West Nile virus, E. coli andbovine viral diarrhea viruses afflict hundredsof thousands of people and animals eachyear, many times with devastating effects.

Keeping people and animals healthy is alarge and important part of the MAES mission;many times animal health research andhuman health research are intertwined. Forexample, Susan Ewart, acting associate deanfor research for the College of VeterinaryMedicine and director of the MSU MolecularRespiratory and Equine Genetics Laboratory,started studying pulmonary diseases in hors-es that keep the animals from reaching theirpeak performance. Today, one of her researchprojects is searching for the genes responsi-ble for human asthma. Her long-term goal isidentifying people with genetic susceptibilityto the disease and then offering them coun-seling about their environment, diet andexercise tailored to their specific needs.

In this issue of Futures, we feature theresearch of a number of scientists that isfocused on finding treatments and ways toprevent illness in humans and animals.

MAES researcher Jack Harkema, universitydistinguished professor in the Department ofPathobiology and Diagnostic Investigation,uses mice and rats to study chronic respirato-ry diseases that are similar to those inhumans. Research by Harkema and scientistsat the University of North Carolina has shownthat airway dehydration plays a major role inthe lung problems that cystic fibrosis patientshave. Kurt Williams, MAES veterinary pathol-ogist, has identified a disease in cats thatmimics idiopathic pulmonary fibrosis, alethal disease in humans that has no treat-ment because scientists don’t know whatcauses it. Thanks to Williams’ research, scien-tists may soon be able to start new studies onthe mechanisms of the disease.

The MSU Diagnostic Center forPopulation and Animal Health (DCPAH) pro-tects the state’s people and animals from dis-ease and potential biological attacks or out-breaks. Dedicated in September 2004, thenew facility allows MSU scientists to run

more than 1.3 million tests per year, makingit one of the top three diagnostic labs in thecountry and the only lab with a biosafetylevel III (BL-3) necropsy floor. The DCPAH iscertified to work with nine agents of concernthat are on the federal government’s overlaplist (meaning they affect both animals andhumans).

Bovine tuberculosis reemerged inMichigan 11 years ago, prompting quaran-tines and closed markets for Michigan beef.In response, MAES-funded research hashelped state agencies to create bovine TBeradication strategies and MSU Extension toeducate communities. As a result, rates ofbovine TB in white-tailed deer are fallingand markets are starting to reopen toMichigan beef.

In honor of MSU’s 150th anniversary in2005, each issue of Futures this year featuresa special sesquicentennial article highlightingthe intersection of MAES and MSU history.The MAES has supported research in veteri-nary science since it was created in 1888.Keeping livestock healthy and free from dis-ease has been the focus of much research,and many times this work has benefitedhuman health. I. Forest Huddleson, whoenrolled at the Michigan Agricultural Collegeas a graduate bacteriology student in 1915,was an early pioneer in brucellosis research,and his work made major strides in control-ling the disease.

We hope you enjoy this issue of Futuresand that it helps you understand more aboutthe MAES and the research it funds. If youhave comments about this issue or wouldlike to subscribe (it’s free!), send a note toFutures Editor, 109 Agriculture Hall, MichiganState University, East Lansing, MI 48824-1039, or send an e-mail to depolo@msu.edu.

For the most current information aboutthe MAES, I invite you to subscribe to the freeMAES e-mail newsletter. Sign up by visitingthe MAES Web site at www.maes.msu.edu/news.htm. Scroll to the bottom of the pageand complete the subscription form. You canalso view this and past issue of Futures on theWeb site as well.

::: Jamie DePolo

Biomedical Research for Animal and Human Health

Summer 2005 | 3

MICHIGAN AGRICULTURAL EXPERIMENT STATION ::: Summer 2005 Vol. 23 No.2

35 Stressed Out at the Cellular LevelUsing technology that allows them to track animals’responses to stress from diseases, giving birth,shipping and other environmental factors at thecellular and molecular levels, MAES researchers arebeginning to understand why stress may makeanimals sick or more susceptible to disease.

40 A Legacy of Combating Disease in People and AnimalsThis issue’s special sesquicentennial featurehighlights the brucellosis research by I. ForestHuddleson.

42 Research in the News

43 Directory

All photography by Kurt Stepnitz and Greg Kohuth, University Relationsphotographers, except where noted.

Cover photoilllustration by Christine Altese.

4 MAES Aims Research at Bovine TBBehind the headlines about the decade-long fightagainst bovine tuberculosis in Michigan has been asteady stream of MAES-supported research aimed atsquelching the disease.

12 Breathe EasyBy studying respiratory disease in horses, mice, catsand other animals, MAES scientists hope to providenew options for treatments and understand whythese diseases are becoming more prevalent inhumans.

20 On the Front Line of Michigan SecurityThe new Diagnostic Center for Population andAnimal Health protects the state’s people andanimals from disease.

26 Battling Bad BacteriaAs part of the national Food and WaterborneDiseases Integrated Research Network, MAESscientists are working to understand and controlhigh priority bacterial pathogens such as E. coli andCampylobacter.

32 How Do Diseases Emerge?Like a biological crime scene investigator, MAESresearcher Ned Walker pieces together the path thatdiseases take from insects to humans.

Jamie DePolo, Editor

Christine Altese, Art Director

John C. Baker, Acting Director

Doug Buhler, Acting Associate Director

Doreen Woodward, Assistant Director

Geoff Koch, Writer

Tom Oswald, Writer

Futures is published quarterly by the Michigan Agricultural Experiment

Station. To receive Futures free of charge write to Futures Editor, 109

Agriculture Hall, MSU, East Lansing, MI 48824, or call (517) 355-0123.

Permission to reprint material in this issue is granted, providing the

meaning is not changed. Credit given to the publication as the source of

the material is appreciated. Use of trade names is for identification only

and does not imply endorsement or criticism of the products.

12

futures35

4 | FUTURES

MAES AimsResearch

at Bovine TB

Summer 2005 | 5

Recent data released by the Michigan Department of Natural Resources (MDNR) suggests that this

research is hitting the target.

Rates of bovine TB in the white-tailed deer population, which has acted as a reservoir for the disease,

continue to fall. And a year after the U.S. Department of Agriculture (USDA) relaxed guidelines for some

of the state’s cattle producers, markets are gradually opening again to Michigan beef.

“The success is a classic case of how a land-grant university serves its state,” said Scott Winterstein,

MAES fisheries and wildlife researcher, who studied how deer behave when fed by hunters as well as how

the animals range and migrate through the environment. “MAES researchers generated information

that helped state agencies to craft TB eradication strategies and MSU Extension to educate

communities.”

The news wasn’t always so good. In the mid-1990s, the disease started showing up in deer harvested

in northern Michigan. Scientists were stumped — the general consensus at the time was that bovine TB,

a contagious lung disease usually spread between cattle packed together in close quarters, couldn’t

sustain itself within free-ranging deer populations.

In 1998, a cow in an Alpena County beef herd tested positive for the disease. Things spiraled

downhill from there, and in 2000, the USDA revoked Michigan’s TB-free status. The decision restricted

movement of cattle and reduced out-of-state demand for Michigan beef and dairy products. �

From a clash between hunters and farmers to an unprecedented epidemiological

puzzle, bovine tuberculosis (TB) has posed many challenges to Michigan since the

disease reappeared in the state in 1994. Yet behind the headlines about the decade-long

fight against bovine TB has been a stream of MAES-supported research aimed at

squelching the disease.

6 | FUTURES

DON’T FEED THE ANIMALSOne element of the state’s disease-

control strategy was to restrict deer feed-ing, which causes deer to congregatearound feed piles. Private hunt clubs andother landowners increasingly had beenfeeding deer culled vegetables and grainsduring the winter. The goal was to boostthe deer population that would be wait-ing when the hunters arrived the next fall.

The supplemental feeding restrictions,which went into effect in 1998, sparkedcontroversy. Hunters, many of whombelieved that cattle operations were thesource of the disease, worried that oneharsh winter would cause mass starva-tion of deer. Farmers fired back, sayingthat their livelihood was at stake.

MAES research informed the state’sregulatory decisions, helping to ensurethat science-based policies prevaileddespite the charged atmosphere. MAESepidemiologist and veterinarian JohnKaneene was part of a team of scientistswho analyzed the connection betweensupplemental feeding and bovine TB indeer.

The team surveyed more than 200 res-idents in the core infection area abouttheir deer feeding and baiting habits from1995 to 1997. Then the researchers looked

at the prevalence of bovine TB in thesame geographic area during the sametime period.

Increases in the number of feed sitesin a given area, number of deer fed peryear, and amount of fruit and vegetablesor grain dumped in feed piles all wereassociated with higher rates of bovine TBin the deer population.

“The outbreak of bovine TB inMichigan and the role of supplementalfeeding in support of the outbreak shouldserve as a cautionary example of an unin-

tended effect of a human intervention inthe ecology of wildlife species,” Kaneeneand his co-authors wrote in a 2003 Journalof Wildlife Diseases article that describedthe research results.

Today, seven years after it went intoeffect, the supplemental feeding banremains in place throughout the LowerPeninsula, and calls by hunters for it to belifted have mostly subsided.

DISEASE TRACKERS: ACROSSMICHIGAN AND ACROSS TIME

The role of supplemental feedingwasn’t the only question about the dis-ease. Scientists and regulators also hadlittle idea how bovine TB was transmittedand maintained in the deer population —important information in shapingMichigan’s wildlife disease surveillanceprogram.

Kaneene and Winterstein joined col-leagues at MSU, the MDNR, the MichiganDepartment of Community Health(MDCH) and the USDA to look for ananswer.

Dan O’Brien, an MDNR veterinarian,led efforts to compile data from post-mortem examinations of more than60,000 deer. The animals came from all 83Michigan counties and represented afraction of the deer harvest from 1995 to2000. This Herculean and macabre task —it involved taking tissue samples fromdeer heads delivered by the truckload —was performed by MDNR and MSU staffmembers, many of whom today work inthe new Diagnostic Center for Populationand Animal Health (DCPAH) on MSU’ssouth campus.

“This was very much a combinedeffort, with MDNR collecting the deerheads, establishing a database, and mak-ing preliminary exams to determine sexand age of animals; while all the grosslesion evaluation, histopathology andsample collection for necessary TB cul-ture were performed by MSU personnel,many of whom are supported in part bythe MAES,” said Scott D. Fitzgerald, anMSU veterinarian and pathologist, whoalso worked on the postmortem exami-nations. “Without the enormous efforts ofthese people, there would be no data ondeer TB prevalence, geographic distribu-tion and so on, which was critical to theMDNR and to all the researchersinvolved.”

MAES fisheries and wildlife researcher Scott Winterstein studied how deer behaved differentlywhen fed by hunters — important information for state agencies crafting TB eradicationstrategies and MSU Extension’s work educating communities. “The success [in addressing bovineTB] is a classic case of how a land-grant university serves its state,” Winterstein says.

Through much of the 1990s, private huntclubs and other landowners would feed deerculled vegetables and grains during thewinter. The practice boosted deer populationsand also created crowding conditions thatfacilitated the animal-to-animal spread of TB.

Summer 2005 | 7

Researchers analyzing data from thesesurveillance efforts found that bovine TBprevalence varied widely by geographicarea. Deer from the core infection areawere almost 150 times as likely to be TB-positive as deer from other areas.

Over the years, MDNR and MSU staffmembers have tested well over 100,000deer from around the state for bovine TB.

But O’Brien’s results, published in a 2002article in Preventive Veterinary Medicine,suggested the merits of more targetedtesting.

Today, with the prevalence of bovineTB dwindling, the MDNR is concentratingits surveillance activities in the core infec-tion area, saving money and applying itslimited resources more efficiently.

As a side benefit, the study’s resultsalso may have helped to limit any remain-ing ill will between cattle producers andhunters.

During the outbreak, cattle producers

Some of the most wrenching stories have been

of farmers who’ve been forced to destroy their

herds more than once.

MAES epidemiologist and veterinarian John Kaneene is studying the root of false positives —animals that react to the TB skin test but subsequently turn out to be free of the disease. It’simportant work because false positives lead to “unnecessary culling of cattle, increased timecosts associated with handling of cattle, increased cost of follow-up testing, and psychologicalstress to producers and veterinarians,” wrote Kaneene and several collaborators in a 2005research article.

Over the years, Michigan Department ofNatural Resources and MSU staff membershave tested more than 100,000 deer fromaround the state for bovine tuberculosis.

8 | FUTURES

said that the MDNR surveillance strategywas flawed because it relied on hunters tovoluntarily submit their deer for testing.These farmers suggested that hunterswere withholding deer with obvious signsof the disease to avoid attracting unwel-come regulatory attention to theirfavorite hunting haunts.

The study, which analyzed datafrom deer harvested by the MDNR andby hunters, found no evidence of suchshenanigans. It was where the deer sam-ples originated and not who did the har-vesting that mattered most in positive TBtests, the authors reported.

UNCOVERING ON-FARM RISKSMAES research also has focused on

issues that matter most to Michigan cat-tle producers and dairy producers, manyof whom have suffered extensive finan-cial and emotional costs in dealing withthe disease.

Some of the most wrenching storieshave been of farmers who’ve been forcedto destroy their herds more than once.

Mike and Kathy Warner used to ownand operate an Alpena County farmwith Black Angus cattle. In 1998, they

destroyed their herd when their farmbecame the first one in Michigan wherebovine TB was found. The Warnersbought another herd, but in 2002, work-ers at an out-of-state slaughterhousefound a lesion on an animal from theirfarm. They were forced to destroy theirentire herd again.

“We won’t bring cattle on this farm

again,” Mike Warner told the AssociatedPress, which reported in August 2002 thatthe Warners had decided to sell theirfarm.

The Warners’ tragedy was an exampleof another gap in knowledge about thedisease — no one knew what environ-mental and farm management condi-tions were associated with bovine TBshowing up or reappearing on northeast-ern Michigan cattle farms.

To close the gap, MAES epidemiologistKaneene, along with colleagues fromMSU, the MDA and North Carolina StateUniversity, collected data from 17 infect-ed farms and 51 control farms. Throughin-person interviews, questionnaires,state wildlife disease surveillance recordsand satellite imagery, the researcherscame up with a short list of risk factors.

Predictably, risk increased as rates ofbovine TB rose in nearby cattle opera-tions and local deer populations. Largercattle herds (it’s a crowding disease) andponds or creeks in cattle housing areas(TB can survive for extended periods inmoist, wet conditions) also were associat-ed with greater risk.

By contrast, risks decreased as therewas more open space around the cattleoperation, probably because deer preferlandscapes that afford some cover andprotection. Risk also decreased as pro-ducers restricted deer access to cattle byhousing cattle in barns, barnyards orfeedlots, and by using electrified wire orbarbed wire for livestock fencing.

The highlight of the study, publishedin September 2002 in the Journal of theAmerican Veterinary Medical Association(JAVMA), wasn’t identifying the risks inthe first place. Everyone knew that keep-ing potentially infected deer away was agood idea. Rather, the real accomplish-ment was to begin measuring the relativebenefits of changing farm managementpractices to cope with the disease.

Kaneene has extended his cost-benefitwork since the paper was published. He’s

False positives add significant cost to thestate’s testing efforts. In a normal herd, 5percent of the animals will have false-positive results.

How the Medieval MonarchsDealt With TB

Lifelong Midwesterners mightrecall seeing farm kids with scrofula— swellings of the lymph nodes ofthe neck, usually resulting from abovine TB infection.

During the Middle Ages, TB of thelymph glands of the neck was verycommon and was known variously asscrofula, struma and the “King’s Evil.”For centuries it was believed that the“royal touch” could cure this disease,and many English and French mon-archs were in the habit of touchingtheir afflicted subjects during majorreligious holidays.

Andre Du Laurens, an anatomistand Paris court physician, was a firmbeliever in the effectiveness of the“royal touch” and reported that KingHenry IV, who reigned from 1589 to1610, often touched and healed asmany as 1,500 individuals at a time.

::: Geoff Koch

MAES research informed the

helping to ensure that

prevailed despite the

Summer 2005 | 9

working with MAES agricultural econo-mist Chris Wolf on a software programthat considers both the epidemiology ofthe disease and the economics of life onthe farm.

Is it worth it to put up woven wire — amore effective but more expensive alter-native to barbed wire? With the softwareprogram, an MSU Extension agent couldvisit a farm with a laptop, spend a few

hours walking around collecting dataand, with a tap of the “Enter” key,answer the question.

Kaneene hopes the software programwill be completed and in use by 2006.

FINDING THE ROOT OF FALSE POSITIVES

The MAES also has supported researchto improve the testing of the state’s cattlefor the disease. From January 2000 toDecember 2003, the MDA, the USDA andprivate veterinary practitioners testedevery cow in the state for the disease.Testing more than 1 million animals costtaxpayers tens of millions of dollars.

Testing a cow for TB involves injectingthe skin near the animal’s tail with a pro-tein derived from TB bacteria. If the skinaround the injection site becomes raisedand swollen, then the entire herd is

Eradication — A Complex and Difficult Task

John Baker, acting directorof the MichiganAgriculturalExperimentStation andassociate deanfor research inthe MSUCollege of

Veterinary Medicine, was alsoinvolved in the state’s bovine TBeradication efforts.

In March 2002, Baker was part of adelegation from MSU, the MDA andthe MDNR to Washington, D.C., thatsuccessfully made the case for $6 mil-lion in federal funding for the bovineTB eradication effort. He also madeseveral visits to the core infection areato participate in education and out-reach activities with state regulators.

For a time, bovine TB was a hugelycontentious issue in Michigan, large-ly because of all the confoundingvariables associated with the disease.

“To a veterinarian, the eradicationof bovine TB in cattle is straightfor-ward,” Baker said. “Use testing toidentify the infected animals andherds, and then remove these ani-mals from the population.”

A range of issues and questionscomplicated these eradication efforts,however. First, there was doubt aboutwhether bovine TB bacteria could beself-sustaining in the deer popula-tion. Then, there were questionsabout the role of supplemental feed-ing in boosting deer populations andfostering disease transmission. And,of course, there’s the importance ofdeer hunting to the economy andculture of Michigan.

“Moving forward, any successfuleradication program needs toembrace not just sound scientificprinciples of infectious disease con-trol — it also needs to address thesociological dynamics of this diseaseproblem in Michigan,” Baker said.

::: Geoff Koch

MSU veterinarian and pathologist Scott Fitzgerald was one of several researchers who conductedpostmortem examinations of more than 60,000 hunter-harvested deer from around the state inthe late 1990s. Today, Fitzgerald is studying whether other species, including crows, might act asreservoirs for the disease.

state’s regulatory decisions,

science-based policies

charged atmosphere.

10 | FUTURES

quarantined and subjected to additionaltesting.

False positives — animals that react tothe skin test but subsequently turn out tobe free of the disease — add significantcosts to the state’s testing efforts. In a nor-mal herd, 5 percent of the animals willyield false-positive results, according tothe MDA.

In a February 2005 JAVMA article,Kaneene and several collaborators shedlight on one aspect of the false-positivepuzzle — the potential of other commonbacterial infections in cattle to gum uptesting efforts.

Cattle can carry other types of TB-related bacteria, such as the strain caus-ing Johne’s disease (pronounced “Yo-nees”). Johne’s disease causes diarrheaand weight loss in cattle and can afflict upto 20 percent of the cattle population insome U.S. regions. Unlike bovine TB,Johne’s disease isn’t associated with athreat to human health, and it is not sub-ject to anywhere near the same regulato-ry scrutiny.

Scientists had suspected that cattlecarrying the bacteria associated withJohne’s disease might be more likely toreturn false-positive results when testedfor bovine TB. But in looking at more than1,000 cattle from 10 Michigan herds,Kaneene and MAES researchers DanGrooms, Steve Bolin and Carole Bolin sawscant evidence of such a link.

As a result, researchers may have tolook elsewhere in their efforts to reducethe number of false positives. It’s impor-tant work because false positives lead to“unnecessary culling of cattle, increasedtime costs associated with handling ofcattle, increased cost of follow-up testing,and psychological stress to producersand veterinarians,” wrote the scientists,whose work on false positives continues.

Kaneene and others are working onways to trim these costs by cutting thetime it takes to get a definitive answer onwhether an animal is TB-positive. AndFitzgerald, the MSU veterinarian andpathologist, is studying whether otherwildlife populations — such as pigeons,ducks and opossums — might also act aslow-level reservoirs of bovine TB.

Bovine TB was supposed to havebeen wiped out in the United States.Among the first regulations in the coun-try for protecting the food supply wasthe Meat Inspection Act of 1906. It wasinspired in part by the 1906 novel TheJungle by Upton Sinclair, whichdescribed unsanitary conditions inChicago stockyards.

“There were men who worked in thecooking rooms, in the midst of steamand sickening odors, by artificial light;in these rooms the germs of tuberculo-sis might live for two years, but the sup-ply was renewed every hour,” Sinclairwrote.

The Meat Inspection Act requiredinspection of cattle, hogs, sheep andgoats intended for interstate com-merce, as well as the monitoring ofslaughter and processing procedures.Bovine TB remained a problem, howev-er, largely because the bacterium thatcauses the disease has an extremelyslow rate of growth and a tendency toremain dormant.

In the early 1900s, scientists under-stood that the bovine form of tubercu-losis was distinct from the human form.Evidence was mounting that the bovineform could be passed between animalsand humans, and that in humans thebovine type could produce symptoms— lesions, coughing attacks and chron-ic wasting — clinically indistinguish-able from those of the human strain.

It was an era when TB was responsi-ble for one out of every nine U.S.deaths. And by one estimate, 10 percentof these deaths were from the bovinestrain of the bacteria. Death was onlyone measure of the disease’s cost —countless others were permanentlycrippled or lingered in pain as theywasted away.

In response, in 1917 the federal gov-ernment embarked on a national cam-paign to eradicate bovine TB from theUnited States. The campaign led to anunprecedented peacetime use of thestate’s police power as federal and stateauthorities sent testers to every dairyand cattle operation in the nation andordered the destruction of 3.8 million

animals, with only partial compensa-tion to the owners.

This campaign brought the diseaseunder control by 1941, generatingreturns to the livestock sector of roughly10 times the total program costs andsaving tens of thousands of human lives.

As TB eradication progressed, itbecame apparent that testing on farmswas becoming increasingly inefficientas a method to locate diseased animals.In 1959, the emphasis was switched totracing animals with lesions found bymeat inspectors at slaughter.

If an animal tested TB positive at aslaughterhouse, then an epidemiologi-cal investigation was launched to locatethe lesioned animal’s herd of origin andany other herds that may have beenexposed to this animal. To eliminateany possibility of TB remaining in aherd, it was recommended that all ani-mals in an infected herd be destroyed.

Since the second half of the 20th cen-tury, this epidemiological detective workhas been the main method used tolocate TB-infected herds. To encouragethe collection and submission of tissuesamples at slaughter, meat inspectorsare given a cash award if the submittedtissue is found to be infected with TB. Asecond, larger award is made when theherd of origin is located.

In 1979, Michigan was among thelast states to be granted TB-free statusby the USDA. By the 1990s, annual sur-veys found only a smattering of cattleherds nationwide to have tuberculosis.

Then a new problem arose.Following the discovery of TB in an elkexported from the United States,Canada banned the importation ofcervid species (animals in the deerfamily, including elk) from the UnitedStates in December 1990. TB was con-firmed in an elk herd in the UnitedStates in 1991.

In 1994, tuberculosis was confirmedin a deer shot by a hunter in Michigan’snortheastern Lower Peninsula. By 1995,the disease was identified as self-sustain-ing in Michigan’s wild deer population.

::: Geoff Koch

I Thought We’d Wiped Out TB — Bovine and OtherwiseA brief history of the disease in the United States leading up to Michigan’s mid-1990s

Summer 2005 | 11

LOOKING AHEAD TO TB-FREESTATUS?

Though open questions remain,there’s much to celebrate in the state’sfight against bovine TB. In the core infec-tion area in the northeastern LowerPeninsula, the disease prevalence hasdropped by 65 percent since 1995, theMDNR reported in March.

In April, Minnesota reopened cattletrade with parts of Michigan deemedlower risk by the USDA. Michigan hasasked the federal government to declarethe Upper Peninsula free of bovine tuber-culosis. If the USDA agrees, the UpperPeninsula will become the first part ofMichigan to regain TB-free status since itwas revoked statewide in 2000.

Perhaps the best news is that theimpact on human health has been negli-gible. Though cattle on 34 farms andclose to 500 deer have tested positive, theMichigan bovine TB strain has turned upin only two of the state’s residents.

In one case, the strain was found dur-ing an autopsy of an elderly person whodied in 2002. Bovine TB was not the causeof death, the MDCH reported.

And in January 2005, a hunter who cuthis hand while gutting a deer became thefirst living person diagnosed with theMichigan bovine TB strain. The man, whokilled the deer in Alcona County inOctober and sought medical attentionafter spotting telltale lesions in the ani-mal’s chest cavity, was treated withantibiotics and is expected to recover,according to the MDCH.

Throughout the course of the out-break, the MAES was one of a handful ofcontributors to the effort to fight the dis-ease. Other MSU scientists and MSUExtension educators were involved, aswere people from an alphabet soup ofstate and federal agencies.

But the MAES research — whichhelped to cool rhetoric between huntersand farmers, guide regulatory efforts,ease strains on cattle producers and vet-erinarians involved in testing efforts, andanswer questions about the basic scienceof the disease — has yielded practicalbenefits.

“Academic scientists sometimes workon basic research and may have to waitfor a long time to see the application oftheir results in solving a specific prob-lem,” Kaneene said. “But here, it wasrewarding to see our research applied tomake real progress against this disease.”

::: Geoff Koch

From January 2000 to December 2003, the MDA, the USDA and private veterinary practitionerstested every cow in the state for bovine TB. Testing more than 1 million animals cost taxpayerstens of millions of dollars.

“Any successful eradication program needs to

embrace not just sound scientific

principles...but also the sociological dynamics

of this disease.”

12 | FUTURES

Breathing seems to be the most reflexive andsimplest thing to do. How many of us actu-ally notice when we take a breath? But forpeople with asthma, cystic fibrosis andother respiratory diseases, breathing can

become a challenging, complicated task.According to statistics in “Epidemiology of

Asthma in Michigan: 2004 Surveillance Report,” pub-lished by the Asthma Initiative of Michigan and theMichigan Department of Community Health, almost214,000 children and more than 654,000 adults inMichigan currently have asthma. The percentage ofadults with asthma in Michigan (9.3 percent) isslightly higher than that of the country (7.7 percent).Seventeen percent of public middle and high schoolstudents in Michigan say that they have asthma now.The prevalence of asthma is higher among black stu-dents than white students.

Nationally, 20.3 million Americans report havingasthma, and 9 million children under 18 have beendiagnosed with asthma, according to statistics fromthe American Academy of Allergy, Asthma andImmunology. From 1982 to 1996, the prevalence ofasthma increased by 97 percent among women and22 percent among men. Overall the prevalence ofasthma increased 75 percent from 1980 to 1994.Asthma rates in children younger than 5 increased

more than 160 percent during the same period. In2000, there were 10.4 million asthma-related outpa-tient visits to physician offices and hospital clinics(4.6 million of these involved children under 18).Approximately 5,000 deaths from asthma occurannually, and direct healthcare costs related to asth-ma in the United States total more than $9.4 billionannually; indirect costs (lost productivity) addanother $4.6 billion, for a total of $14 billion. In-patient hospital services represented the largest sin-gle direct medical expenditure, more than $4 billion.

MAES researcher Jack Harkema, university distin-guished professor in the Department of Pathobiologyand Diagnostic Investigation, uses mice and rats tostudy chronic respiratory diseases that are similar tothose in humans.

“Mice have respiratory systems that are similar tohuman systems,” Harkema said. “They also havesimilar immune systems and inflammatory respons-es to respiratory disease. We can use these animalmodels of human respiratory disease to investigatethe cellular and molecular mechanisms that underliethese diseases in the lung.”

In humans, chronic respiratory diseases are asth-ma, cystic fibrosis, chronic obstructive pulmonarydisease (COPD), emphysema and chronic bronchitis.

Cystic fibrosis is a genetic disease affecting

Breathe EASY

By studying respiratory diseases in horses, mice, cats and other animals,

MAES scientists hope to provide new options for treatment and

understand why these diseases are becoming more prevalent in humans.

Summer 2005 | 13

MAES scientist N. Edward Robinson,who holds the Mathilda Wilson Chair,is studying heaves, an asthma-likedisease in horses. Robinson iscollecting data to determine howprevalent the disease is in Michigan.

14 | FUTURES

approximately 30,000 children and adults in theUnited States. A defective gene causes the body toproduce thick, sticky mucus that clogs the lungsand leads to life-threatening lung infections. Thesethick secretions also obstruct the pancreas, pre-venting digestive enzymes from reaching the intes-tines to help break down and absorb food. Themucus also can block the bile duct in the liver,eventually causing permanent liver damage inabout 6 percent of people with cystic fibrosis. Butit’s usually lung disease that kills cystic fibrosispatients.

“The primary gene associated with cystic fibrosiswas identified a while ago,” Harkema explained.“We suspected that the alteration in this specificgene may cause other genes to malfunction in thelungs, which resulted in a lack of water in the air-ways and the development of abnormally thickmucus.”

Based on research by Harkema and his col-leagues at the University of North Carolina, ChapelHill, scientists now know that dehydration of theairways is a major factor in the development of thelung problems in cystic fibrosis patients. Theirresearch findings were published in the May 2004issue of Nature Medicine.

“We now understand that adequate airwayhydration is critical for normal lung defense frombacteria,” said Marcus Mall, of the School ofMedicine at the University of North Carolina andthe study’s lead researcher.

In people with cystic fibrosis, lung airwaysabsorb an excessive amount of salt, which reducesthe amount of water in the mucus lining the air-ways and causes it to become very thick and sticky.The hair-like cilia that ordinarily move the thin,watery mucus out of the lungs stop working whenthe mucus gets too gooey. Stuck in the airways, themucus develops into a fertile breeding ground forcountless infectious bacteria.

Harkema and the UNC researchers geneticallymodified the lungs of mice to absorb extra salt andwater, and a cystic fibrosis-like lung disease result-ed. The new mouse model doesn’t contain the cys-tic fibrosis genetic disorder, only its characteristiclung disease. Their work demonstrated for the firsttime that over-absorption of sodium ions out of theairway is sufficient to cause mucus dehydration andthe development of cystic fibrosis-like lesions in thelungs of mice.

“Cystic fibrosis doesn’t normally develop in ani-mals,” Harkema said. “This was the first time thatpulmonary pathology similar to that in cystic fibro-sis patients was convincingly developed in a labora-tory mouse. We hope this model will be used byother scientists to design better drugs for treating

Jack Harkema (left), MAES researcher and MSUdistinguished professor, has found that dehydration of the airways is a major reason why cystic fibrosispatients develop lung problems. Harkema andUniversity of Michigan scientists collaborated to designand build AirCARE 1 (right), the country’s only mobileair research lab.

Summer 2005 | 15

this devastating disease. These genetically alteredmice may also be used to study other chronic respi-ratory diseases, such as asthma and chronic bron-chitis. Of course, the ultimate goal is to developeffective ways to prevent this deadly disease.”

Harkema and his colleagues at MSU also arestudying the effects of air pollutants on the respira-tory system.

The Ozone EffectOzone is an alternative form of oxygen that con-

tains three oxygen atoms rather than two and isusually found in the Earth’s upper atmosphere. It’sresponsible for filtering out much of the sun’s ultra-violet radiation. But closer to the Earth’s surface,ozone is a problem. It’s produced as part of indus-trial air pollution and is the main component ofsmog. Ozone is very reactive and corrodes masonry,causes paint to darken and is unhealthy to breathe.

“We’ve found that the airways produce moremucus when they’re exposed to ozone,” Harkemasaid. “Exposure to high concentrations of this irri-tant found in urban smog may cause individualswho already have too much mucus in their airways[people suffering from asthma, chronic bronchitisor cystic fibrosis] to produce even more mucus,which results in clogged airways and difficulty withbreathing.”

Working with James Wagner, also a researcherin the MSU Department of Pathobiology andDiagnostic Investigation, Harkema has uncovered asymbiotic relationship between ozone and otherpollutants and allergens.

“Ozone increases inflammation in the lungs, nomatter what the original source of the inflammationis,” Harkema explained. “It makes asthma or allergysymptoms worse and may cause asthma attacks.Jim Wagner and I are working with researchers atthe University of California-Berkeley to developantioxidant compounds that would reduce ozone’saggravation of these symptoms. The Berkeley scien-tists develop these novel compounds, and at MSUwe test them on laboratory rodents to see if theywork. If the treatment is effective in laboratoryrodents, then these compounds will be used byresearchers at the University of North Carolina, whowill design clinical studies to determine their effec-tiveness in preventing pollution-induced exacerba-tion of chronic lung disease in humans.”

To study ozone and particulate matter air pollu-tion in communities with high levels of asthma andother respiratory diseases, Harkema and scientistsfrom the University of Michigan are workingtogether on the Collaborative Air Research Effort(CARE). They designed and built AirCARE 1, the

only mobile air research laboratory of its kind in thecountry. The 53-foot-long, 8-foot-wide, 36,000-pound trailer contains three specially designed lab-oratories that allow scientists to conduct inhalationtoxicology studies of real-world air pollution.

“So far, most of our work has been done insouthwest Detroit,” Harkema said. “There are highlevels of childhood asthma in that part of the city,and we’re finding that the kids there are exposed tohigh levels of particulate matter.”

Harkema explained that the EnvironmentalProtection Agency (EPA) is especially interested inparticulate matter because research has shownthat, as levels of particulate matter in air pollutiongo up, deaths and hospital admissions increase.

“We’re not sure if it’s related to the size of the par-ticles or the chemical composition,” he said. “Thoseare things we’re starting to work on with the mobilelab. The U-M researchers can identify where theparticles are coming from — fingerprinting them,so to speak. We think that the metal content mightbe important, but it could also be the size of theparticle. The smaller the particle, the more toxic itmay be. High numbers of ultrafine carbon particles[nanoparticles] are often found in urban air pollu-tion. We want to determine if these very, very smallparticles are actually the most toxic to the lungs andthe rest of the respiratory tract.”

The overarching issue for the scientists is theeffect that the mixture of contaminants in the airhas on the lungs.

“We’re looking at whether the combination ofpollutants, allergens and bacterial agents worktogether and cause bigger problems for people thanif they were just exposed to one at a time,” Harkemaexplained. “In other words, what happens if you’reexposed to particulate matter and ozone? Or bacte-ria and ozone? Does the order matter? And howdo environmental pollutants affect infectiousdiseases?”

A Genetic Fingerprint for AsthmaCombining the influence of environmental

factors with genetic makeup to determine who issusceptible to asthma is the research goal of SusanEwart, acting associate dean for research for theCollege of Veterinary Medicine and director of theMSU Molecular Respiratory and Equine GeneticsLaboratory.

“I’m an equine specialist,” she said. “I startedstudying pulmonary diseases in horses that keepthe animals from reaching their peak performance.As I got deeper into the research, I found that miceare easier to work with. But I still do work withhorses.”

16 | FUTURES

Using mice as models, Ewart is attempting tolocate the exact genes responsible for asthma.

“We know there are a number of genes involved,and we also know that many diseases, such as asth-ma, are caused by both genetic susceptibility andenvironmental factors,” Ewart explained. “So if youinherit the palette of genes responsible and areexposed to the environmental aspects, then you getthe disease. Our long-term goal is to be able to iden-tify people with genetic susceptibility to these typesof chronic diseases and then offer them counselingabout their environment, diet and exercise that istailored to their specific needs.”

Using two strains of mice — one that was verysusceptible to asthma and one that was very resist-ant — Ewart and her research team placed therodents in identical environments and then trackedwhich ones developed asthma. They then looked atthe genetic makeup of these mice to see if therewere specific genes that were in all the asthmaticmice.

“We know the general location of the genes andhave pulled a subset for further study,” she said.“We want to narrow it down to the specific genesinvolved.”

In 2003, Ewart began collaborating with WilfriedKarmaus, an epidemiology researcher at MSU, andhe introduced her to Hasan Arshad, a researcher atthe David Hide Asthma and Allergy Research Centreon the Isle of Wight in the United Kingdom. In 1990,Arshad and his colleagues recruited 1,400 of the1,500 children born that year on the Isle of Wight to

participate in a longitudinal study on allergies, nowin its 15th year.

The investigators have collected informationabout the children’s environments and data fromphysical exams at ages 1, 2, 4 and 10. Using thisinformation, they hope to identify how each allergicdisease progressed through each child, whetherthere were combinations of allergies and whetherdisease onset was early or late. Ewart is studying theDNA from these children to identify genes that con-tribute to allergic disease progression.

“We’re studying the natural history of any aller-gic disease in each child,” Ewart said. “Over thecourse of time, this can change. Some infants canwheeze and look like they will develop asthma, butit resolves itself. They seem to grow out of it. Othershave no symptoms as an infant and develop asthmaas preschoolers; this is more common in males.Others will have no symptoms until adolescence;this is more common in females. We want to knowwhy this happens and get a better sense of who getswhat when.

“It’s very complex to figure out if there are simi-larities or differences in the kids’ genetic makeups,”she continued. “For example, do all kids who getasthma as infants have similar genetics? There is alot of information to sort out.”

According to Ewart, there are only a few longitu-dinal studies of children and asthma, and only one

By using mice as models, Susan Ewart (right), directorof the MSU Molecular Respiratory and Equine GeneticsLaboratory, is trying to discover the exact genesresponsible for asthma. Because the disease is causedby genetic susceptibility AND environmental factors,people who have the genes could be given counselingfor their specific needs.

Summer 2005 | 17

other includes genetic information, so this researchis rather distinctive. In 2006, the children will turn16 years old, and the researchers are looking forfunds to study them at this important stage in theirdevelopment.

“In my lab, we go back and forth betweenhuman information and our mouse models,” shesaid. “We use what we see in mice to augment ourhuman studies, and we test what we see in humansin the mice. It’s allowed us to start to answer somequestions about how asthma functions at thegenetic level.”

Help for HorsesHeaves is an asthma-like equine disease that is

chronic in older horses. Horses develop it whenthey inhale dust that contains mold and other aller-gens. Heaves causes coughing and difficulty breath-ing. In the South, horses on pasture are the onesthat usually develop heaves, primarily in the sum-mer and usually when it’s hot and humid. In thenorthern United States, heaves usually affects hors-es kept in a barn and is usually associated with poorventilation and giving hay as feed. There is no curefor heaves, but the symptoms can be alleviatedsomewhat by controlling the horse’s environmentto reduce exposure to dust and with medications.

“We understand the physiology of heaves quitewell,” said N. Edward Robinson, MAES large animalclinical sciences researcher, who holds the Mathilda

Wilson Chair. “What we don’t understand is whysome horses are susceptible and some horsesaren’t. It’s similar to people with asthma. There’s anoveractive airway inflammation response thatseems to have a genetic predisposition.”

Since the 1600s, scientists and horse ownershave known that dusty hay can trigger heaves.Recommendations for owners of horses withheaves include keeping the horse away from hayand keeping the animal outside year round.

Even though Robinson has been studying heavesfor many years, he is still amazed that no statisticsare available on the prevalence of airway diseases inhorses in the United States.

“We have some data on severe cases of heavesbut none on less severe cases, so we don’t reallyunderstand how the disease begins,” he said. “Andwe aren’t sure if the recommendations for the treat-ment of heaves are good for its prevention. So wedecided to start collecting data on the prevalence ofthe disease in Michigan and the factors that affectits development. We also want to know if it’sinevitable that horses progressively get worse whenthey get heaves. In the past, it’s been a gloom-and-doom scenario when an older horse developed achronic cough.”

Robinson and his colleagues took mucus sam-ples from 260 horses in Michigan and also looked atthe cell types in the mucus to see if the lungs wereinflamed. They found that about 20 percent of

Heaves has been a problem inhorses for hundreds of yearsand is chronic in older horses.The condition can be triggeredby dusty hay. There is no cure,but the symptoms can becontrolled with medication andchanges to the horse’senvironment.

18 | FUTURES

Michigan horses have some type of airway inflam-mation, many with no clinical signs, especiallywhen they’re on pasture in the summer. They alsofound that large round hay bales — rather thanother types of bales and pasture — are associatedwith the most severe inflammation. Being outsidein the winter also increased the risk of airwayinflammation, which contradicted the recommen-dations for horses with heaves.

“In the winter, the horses with the healthiest air-ways are those that are kept inside and eat fromsquare hay bales,” said Robinson. “In the summer,being outside is good. In the past, we have recom-mended keeping horses outdoors year round as thebest way to keep the airways healthy. But we mighthave to temper our recommendations. Round balesmight not be the best way for a horse to eat hay,especially if it’s outdoors in cold weather.”

Round bales are convenient for producersbecause they require little labor and are more eco-nomical to produce. Robinson speculated that thebales caused more inflammation because horsesbury their noses in the bales when they eat to get tothe good hay inside and in doing so directly breathein the dust from the hay.

To track the progression of the disease, Robinsonwould like to follow 10-year-old pleasure horses forseveral years and see what happens.

To gather more data on the effects of airwaydiseases, Robinson collaborated with SusanHolcombe, associate professor of large animal clin-ical sciences, to study the consequences of inflam-mation on racing performance in racehorses at the

Thistledown Racetrack in Cleveland. The scientistsexamined 150 horses each month for 16 months.Holcombe looked at the effect any inflammationhad on the horses’ performance, and Robinsonlooked at the prevalence of inflammation.

“We found that most inflammation and theassociated mucus occurred in younger horses, andfor each subsequent year the horse was there, theprevalence went down,” Robinson explained.“Most importantly, small accumulations of mucusin the airways significantly decreased racingperformance.”

The results on prevalence of airway disease inracehorses match data from Britain and Australia,where similar surveys have been done. The nextobjective is to figure out the cause of the inflamma-tion. Researchers in Britain think the cause is bacte-rial, but Robinson and his colleagues are beginningto look at the horse’s environment to see if thosefactors have an effect.

Searching for Treatments for a Deadly Lung Disease

Idiopathic pulmonary fibrosis (IPF) is a lethaldisease that damages the air sacs in the lungs, lead-ing to scarring of the lungs and reduced transfer ofoxygen to the blood. More than 200,000 people inthe Untied States have IPF (the “idiopathic” in thename means researchers do not know what causesit) and there are no effective treatments or cure forthe disease. IPF occurs more often in people 50 andolder and most people with IPF survive only about5 years.

Because dusty hay plays a role in heaves, Robinson compared various types ofhay bale shapes and sizes, as well as pasturing, to see which caused the mostrespiratory inflammation in horses. He found that large round bales areassociated with the most severe inflammation, probably because the horses haveto bury their noses in the bales to get at the good hay.

Summer 2005 | 19

Currently, there is no animal model for thedisease that causes similar changes in the lungs ofanimals. Because of this, researchers have a difficulttime understanding the disease and testing pos-sible treatments.

Today, thanks to the work of MAES veterinarypathologist Kurt Williams, people with IPF maysoon have renewed hope, and researchers may beable to start new studies on the mechanism of thedisease.

Through his work in the Diagnostic Center forAnimal and Population Health, Williams has identi-fied a disease in cats that is very similar to IPF inhumans. According to Williams, laboratory micecan get lung fibrosis, but it doesn’t look like IPFmicroscopically and doesn’t progress as the diseasedoes in humans. In cats, as in humans, the diseaseis progressive and invasive.

“IPF causes complex changes in the lungs,”Williams explained. “In my work in the DiagnosticCenter, I noticed that the lung tissue of some cats

that came in seemed to have undergone similarchanges. So we started collecting data and pub-lished a paper on our findings in 2004. I’m veryinterested in what can be done to help people withIPF, as well as cats with the disease.”

Using his discovery, Williams hopes to develop anew animal model of IPF. He is now studying theconditions that may cause the disease, as well asinvestigating what happens at the cellular level inhopes of uncovering a treatment. His next step is totry to recreate the disease and study how it developsin the lung.

“I’ve enjoyed studying a real-world disease andthen being able to apply some of my work to helppeople,” Williams said. “In people, IPF is relativelyuncommon, but because it’s untreatable, it’s devas-tating. We went from the necropsy floor to the lab —there is a lot to be learned from the DiagnosticCenter, and it’s a tremendous resource for MSU andthe state to have.”

::: Jamie DePolo

MAES researcher Kurt Williams found a disease that affects cats’ lungs that is very similar toidiopathic pulmonary fibrosis, a lethal lung disease in humans. By studying how the diseaseprogresses in the lungs of cats, Williams hopes to figure out the conditions that cause the disease.

20 | FUTURES

Summer 2005 | 21

The new Diagnostic

Center for Population and

Animal Health protects

the state’s people and

animals from disease.

On a typical day, the MSU Diagnostic Center for Populationand Animal Health (DCPAH) receives between 600 and1,200 pieces of mail. Most of these contain samples of bloodor other tissues of animals that are suspected of harboringa disease.

“There may be one sample per box or 300 per box — wedon’t know until it’s opened,” said Steve Bolin, MAES patho-biology and diagnostic investigation researcher, who is also

chief of the DCPAH Immunodiagnostics and Parasitologysections and serves as associate director of the center.“Each sample comes with a form that tells us which tests torun — more than one test may be done on each sample.Our technicians sort everything into specific refrigeratorsfor each lab. A signal light then goes on in the lab to let themknow that a new sample is in and ready for testing. Now thatwe’re all in one building, rather than being spread outacross five buildings on campus, the intake process is moreefficient.”

Dedicated in September 2004, the new DCPAH facilityallows MSU scientists to run more than 1.3 million tests peryear, making it one of the top three diagnostic labs in thecountry, according to Willie Reed, DCPAH director, who isalso chairperson of the Department of Pathobiology andDiagnostic Investigation in the College of VeterinaryMedicine. The tests range from rabies to West Nile virus tobovine tuberculosis (TB) to chronic wasting disease, andthe center’s clients are in all 50 states and several foreigncountries.

“Our mission, as it has been for the past 30 years, is toprotect animals and humans from the health threats ofdisease and toxic substances,” Reed said. “We do thisthrough accurate and rapid detection of infectious dis-eases to prevent spread and minimize animal losses andhuman illness.”

“We don’t offer treatment, just diagnosis,” said Richard“Mick” Fulton, chief of the Anatomic Pathology-Necropsy

On the Front Line

of MichiganSecurity

Carole Bolin, MAES scientist, is chief of the Bacteriology Sectionof the Diagnostic Center for Population and Animal Health.Because of the Diagnostic Center, Michigan is a national modelfor integrating systems for animal and human health.

22 | FUTURES

Section of the DCPAH. “We figure out why the animal died oris sick. Our clients range from private citizens and privateveterinarians to state and federal governments.”

The original collection of campus labs, known as theAnimal Health Diagnostic Laboratory, was created in the1970s in response to the accidental introduction of PBB, achemical fire retardant, into the food supply.

“We grew rapidly,” Reed said, “and became one of thebusiest labs in the country in terms of the number of testsrun and the complexity of problems we dealt with. Thebovine TB issue that started a few years ago underscored theneed for new facilities — located in one spot — so samplescould quickly and easily be examined and go to differentlabs for tests. We were struggling to handle the large numberof deer and cattle submitted to the lab. We wanted to be ableto make more rapid diagnoses safely and securely. With ourold setup, we couldn’t make the final diagnosis of bovine TBhere at MSU. We had to send the samples to the USDA lab inAmes, Iowa, which increased the turnaround time for pro-viding the results of the tests. In our new facility, we canmake the final diagnosis here, which is more efficient foreveryone.”

“Our old immunodiagnostics section lab was just abouttwice the size of my office in the new building,” said Bolin,showing off his somewhat compact new office space. Heruns tests for diseases such as bovine TB and West Nile virus.“Sometimes we’d have to tell people that we couldn’t testtheir samples because we were so cramped for space. Theyhad to wait a week.”

Situated a bit south of the main MSU campus, the newDCPAH facility houses labs, offices and classrooms in one

building that provides better personnel safety, high levels ofbiocontainment and the ability to offer expanded services.Because protecting human and animal health is criticallyimportant to Michigan, the state funded the construction ofthe facility through a special appropriation. State officialsand MSU scientists analyzed emerging disease trends andtried to create a facility that was ready to handle just about

anything that could potentially happen.“We tried to take everything into account when we

were planning and designing the building,” Reedsaid. “We wanted to be able to deal with anything andeverything — as much as we could possibly thinkahead, we did.”

The result is a diagnostic center that is one of themost advanced in the nation. The DCPAH is a mem-ber of the USDA National Animal Health LaboratoryNetwork and the Centers for Disease Control (CDC)Laboratory Response Network. Both networks aim todiagnose and report diseases of concern, such aschronic wasting disease, foot-and-mouth disease,classical swine fever and avian influenza.

“For example, the BSE [bovine spongiformencephalopathy] case in Washington in 2003 trig-gered the national surveillance program, so we wereready to do testing as needed,” Reed explained. “Thelabs in the networks perform just as federal labs doand have to have the capabilities to handle theseagents of concern. Our goal is to detect them quicklybefore they spread. The USDA controls which facili-

ties can run tests for these high-risk agents.”

Cutting-edge CapabilitiesThe Diagnostic Center encompasses 10 sections or labs:• Anatomic Pathology (which includes Surgical

Pathology, Immunohistochemistry and Necropsy).

• Clinical Pathology.

• Endocrinology.

• Immunodiagnostics.

• Bacteriology.

• Parasitology.

• Virology.

• Nutrition.

• Toxicology.

• Epidemiology.

It also includes administrative, computer services andquality assurance units. Except for the EpidemiologySection, which analyzes incidences of disease and otherdata and issues reports on trends, all the sections offer spe-cific diagnostic tests for clients. Scientists from the MichiganDepartment of Natural Resources also share a lab to testdeer for bovine TB and to detect diseases in other wildlife.

Steve Bolin, MAES scientist and associate director of the center, runs tests for bovinetuberculosis, West Nile virus and chronic wasting disease in his lab. Last year, thecenter did 6,000 tests for chronic wasting disease in four weeks — a huge volume of work.

Summer 2005 | 23

“The Diagnostic Center is equipped to address animalhealth in all species, from fish and wild animals to agricul-ture and companion animals,” Reed said. “Not all labs canoffer all these services.”

The DCPAH has several biosafety level III (BL-3) labs andcontainment facilities. They are used to support the state’sbovine TB eradication program, as well as to identify dan-gerous pathogens that threaten both human animal health,

such as strains of Salmonella that are resistant to multipledrugs and West Nile virus.

“No other diagnostic center has a BL-3 necropsy floor,”Reed said. “This gives us a unique opportunity to partnerwith state government to address emerging diseases.”

“If some type of biological attack or outbreak occurred,it’s probable that it would be seen in animals first,” saidCarole Bolin, MAES pathobiology and diagnostic investiga-tion scientist, who is chief of the Bacteriology Section. “Weare certified to work with nine agents of concern that are onthe federal government’s overlap list, which means theyaffect both animals and humans.”

For security reasons, she couldn’t name the specificagents the DCPAH is certified for, but the federal govern-ment’s list includes the pathogens that cause anthrax,eastern equine encephalitis virus and tularemia. Over thepast 20 years, nearly 75 percent of the approximately 30 newdiseases discovered in humans were zoonotic, meaning theyare transmissible between animals and people. Of the morethan 1,650 human disease conditions, nearly 60 percent arecaused by pathogens that also infect animals.

“Because agricultural animals are outside much of thetime, they may be the first ones to contract anything inaerosol form — many of the agents on the overlap list can betransmitted via aerosols,” Carole Bolin said.

TAKING ANIMAL DIAGNOSTICS TO AFGHANISTANOver the course of his 24-year career as a vet-

erinarian, Mick Fulton was involved in the designand building of two animal diagnostic laborato-ries, including the progressive new DiagnosticCenter for Population and Animal Health(DCPAH) at MSU. In March, the associate profes-sor of pathobiology and diagnostic investigationwent to Afghanistan to help Kabul Universitybuild a necropsy laboratory there, one of the firststeps in helping the war-torn country begin tofeed itself.

“They had an old curriculum and an old build-ing,” Fulton said. “I helped them redesign theirnecropsy lab and developed an equipment list forthem. Once the necropsy lab is up and running,they’ll be able to train students. This is the firststep toward a national program.

“It’s all part of a plan to provide the Afghanswith a disease surveillance and reporting system,”he continued. “This will, we hope, help them bemore self-sufficient in feeding their people.”

Besides assisting with some of the design andbuilding of the DCPAH, Fulton also was involvedwhen a similar facility was built while he was a

resident and faculty memberat Purdue University.

“I’ve been through thebuilding process, so I knowabout space requirements,equipment requirements andgenerally how to get thesethings started,” he said.

Fulton was asked by theUSDA to help in Afghanistanand was in the country for twoweeks.

“It’s a great opportunity tobe asked by your governmentto use your skills to help otherpeople,” he said. “You have toweigh the benefits from thegood parts and the bad parts,and in this situation, the goodparts outweighed the bad. I was a little apprehen-sive about the visit, but we had no problems at all.”

::: Jamie DePolo and Tom Oswald

Mick Fulton, chief of theAnatomic Pathology-NecropsySection, helped KabulUniversity, in Afghanistan,build a necropsy lab.

Willie Reed, director of the Diagnostic Center, says the facilityallows MSU scientists to run more than 1.3 million tests peryear, making it one of the top three diagnostic labs in thecountry.

24 | FUTURES

“If it is suspected that these agents of concern areinvolved, the Diagnostic Center does the testing,” she con-tinued. “We have a grant from the Michigan Department ofCommunity Health [MDCH] to serve as an auxiliary lab inthe Centers for Disease Control network. MDCH coordi-nates this. We’re also ready to act as a backup to theDepartment of Community Health. For example, if therewere a suspected anthrax outbreak, it might require thou-sands of tests, which would overwhelm the MDCH lab. Wehave the resources to provide the people and the space to dothe testing.”

(There are also agents of concern that affect onlyhumans, such as smallpox, as well as agents that are a threatonly to plants, such as Ralstonia solanacearum, race 3, bio-var 2, which causes wilt disease in potatoes, tomatoes, pep-pers, geraniums and eggplant. [For more on emerging plantdiseases, see p. 20 in the winter 2005 issue of Futures.]

“The DCPAH is why Michigan is a leader in coordinatingand integrating systems for animal and human health,”Carole Bolin continued. “We are a national model. The cre-ation of the Diagnostic Center facility, which consolidatedservices and lab space, has helped with this great integra-tion. If something happens, we have the inherent capabili-ties, we have the knowledge and training, and we have thesurge capacity to handle a large volume, which is key. Yes, wehave labs that focus on nine specific agents. But moreimportantly, we also have the advantage of having peoplewith the knowledge to question things that they recognize asdifferent. And we have the infrastructure in place that allowsthem to act on it.”

“The Diagnostic Center represents a long-term commit-ment to public and animal health and safety, and better pre-pares Michigan to handle emerging issues,” said Dan Wyant,former director of the Michigan Department of Agriculture.“This facility is a shining example of what can be accom-

plished with strong state, university and industry partner-ships and collaboration — a model that Michigan has cometo be known for.”

Tracking Chronic Wasting Disease and WestNile Virus

Chronic wasting disease (CWD) is a fatal neurologicaldisease of farmed and wild deer and elk. The disease hasbeen found in wild and captive mule deer, white-tailed deerand North American elk, and in captive black-tailed deer.CWD belongs to the family of diseases known as transmissi-ble spongiform encephalopathies (TSEs). TSEs include anumber of diseases affecting animals or humans, includingbovine spongiform encephalopathy (BSE, mad cow disease)in cattle, scrapie in sheep and goats, and Creutzfeldt-Jacobdisease (CJD) in humans. Though CWD has not been foundin humans or livestock, its close relationship to BSE and CJDhave put it on the USDA Animal and Plant Health InspectionService (APHIS) hot topics list.

In deer and elk, CWD causes loss of body condition,behavioral changes, excessive salivation, increased drinkingand urination, depression, and eventual death. CWD isalways fatal. There is no known treatment, vaccine or liveanimal test for CWD. The disease has been found in wilddeer and elk in Colorado, Wyoming, Nebraska, Kansas,Montana, Oklahoma, South Dakota, New Mexico,Wisconsin, New York, Alberta and Saskatchewan.

CWD has not been detected in Michigan to date. In con-junction with the state departments of Agriculture andNatural Resources, DCPAH scientists are working to helpensure that the disease remains out of Michigan and that, inthe event it is discovered, Michigan has a coordinated,immediate and effective response plan to minimize itsimpacts.

“The test for CWD involves looking at the animal’s lymphnodes,” said Steve Bolin. “Last year we did 6,000 tests, mostin about four weeks. The test is a time-consuming processand the most we can do in a day is 400 — and that’s doingone right after another with no breaks. Since we starteddoing testing in 2002, we’ve tested about 20,000 deer andhaven’t found any positives. We encourage hunters to killanimals that look sick and submit them for testing and urgethe public to call and report sick-looking deer or elk.”

West Nile virus was first found in the United States in1999. Carried by birds, the virus is transmitted by mosqui-toes and can infect humans and horses. People can becomeill with flu-like symptoms, but if West Nile virus enters thebrain, it can cause life-threatening encephalitis (inflamma-tion of the brain) or meningitis (inflammation of the liningof the brain and spinal cord). Most cases of this type of dis-ease occur in elderly people and people with impairedimmune systems. Currently, there are no vaccines and nodrug treatments for West Nile virus in humans. A West Nile

Jon Patterson, MAES researcher, serves on the MichiganArbovirus Surveillance Group. He tests for West Nile virus inbirds and also keeps track of the cases of West Nile in horsesthat come into the Diagnostic Center.

Summer 2005 | 25

vaccine is available for horses.“West Nile virus is an arbovirus — arthropod-borne

virus,” explained Jon Patterson, MAES pathobiology anddiagnostic investigation researcher in the AnatomicPathology-Necropsy Section of the DCPAH, who has servedon the Michigan Arbovirus Surveillance Group since 1992.“In 1992, we were focused primarily on eastern equineencephalitis. Then West Nile started to be of interest. From1999 to 2003, people would send in whole birds and wewould look for a specific West Nile virus protein in the birds’hearts and kidneys.”

Today, the testing is much more efficient. If a bird is sus-pected to be infected, a swab is taken from its mouth andthat is sent into the DCPAH.

“We can do these tests in 15 minutes and report resultsfaster, so that communities can take action against mosqui-toes,” Patterson said. “We have good participation fromlocal health departments because they can see the value. Ifwe find the virus in birds, it allows us to forecast infectioncoming in people and horses. Besides the bird testing, I alsokeep track of the cases of West Nile in horses that come intothe DCPAH.”

The bird family Corvidae, which includes large birdssuch as blue jays, crows, ravens and magpies, is the mostsusceptible to West Nile virus infection. The virus also hasbeen found in more than 250 other avian species, though inbirds not in the Corvidae family it is not immediately fataland some even recover. Corvids usually die within a day ofthe onset of symptoms. Researchers want to know how WestNile virus behaves in both corvid and non-corvid birds tobetter understand the mechanism of the disease.

“A virus usually interacts with its animal host in a veryspecific manner,” Patterson said. “An avian or mammaliancell requires the right receptor to become infected. If wecould identify that receptor, we might be able to develop avaccine.”

In addition to his West Nile work, Patterson also partici-pates in chronic wasting disease and bovine TB surveillance.The DCPAH performs about 2,500 necropsies (postmortemexams of animals) per year.

“Besides helping and educating our clients, we’re alsoeducating students,” Patterson said. “Every vet student atMSU is required to take a rotation through the DCPAHnecropsy section. We examine all types of animals — fromlions to guinea pigs and everything in between. This newfacility is allowing us to make people more aware of the con-nection between animal health and community health.”

Tracking Disease in CattlePreventing and controlling intestinal diseases in cattle is

one area of MAES microbiology and molecular genetics sci-entist Roger Maes’ research. Bovine viral diarrhea (BVD) isone of the diseases that Maes, who also serves as chief of the

DCPAH Virology Section, is studying.Affecting both dairy and beef cattle, BVD is complicated

because it is caused by several strains of BVD virus. Thoughit does not cause disease in humans, BVD can be difficult tocontrol and very expensive for cattle producers because itcauses abortion, early embryonic death, pneumonia, fever,lameness and immunosuppression, as well as diarrhea.

Infected cattle shed billions of viral particles per day, so thedisease is highly contagious. Most animals that contract thedisease die after about 2 years; those that are infected in thewomb can become persistently infected and are known ascarrier animals. The disease costs producers millions of dol-lars per year in lost calves and reduced production.

“If a fetus is exposed to BVD between 50 and 100 days ofgestation, the developing calf can’t recognize it and fight it,so the calf is always infected with it,” Maes explained. “Theseanimals are permanent carriers of the disease.”

According to Maes, the virus is in all the tissues of a per-sistently infected animal, so a test can be run even on asmall piece of skin from the ear. If the test is positive for BVD,the calf is culled. The DCPAH tests about 30,000 samples peryear. The new skin tests allow producers to collect samplesfrom their cattle themselves. A number of BVD vaccines areavailable, but because the disease is caused by severalstrains of the virus, a vaccine may not protect against alltypes of the virus.

“We’re working to educate producers about persistentlyinfected cows and how to identify them,” Maes said. “Thiswill help protect herds from infection. BVD is a reportabledisease, but it is not scrutinized as closely as bovine TB orchronic wasting disease.”

::: Jamie DePolo

MAES scientist Roger Maes’s research focuses on preventing and controllingintestinal diseases in cattle, such as bovine viral diarrhea. He is working toeducate producers on how to identify persistently infected cows to protecttheir herds.

26 | FUTURES

As part of the national Food and

Waterborne Diseases Integrated

Research Network, MAES scientists are

working to understand and control high

priority bacterial pathogens.

Battling

Summer 2005 | 27

It’s been jokingly portrayed in television adsas the illness no one wants to name out loud, butdiarrhea affects large numbers of people everyyear. In the United States, according to statisticsfrom the National Institute of Allergy andInfectious Diseases (NIAID), diarrhea is the secondmost common infectious illness, accounting forone out of every six (16 percent) of all cases ofinfectious diseases. Bacterial and viral infections ofthe gastrointestinal tract can lead to diarrhea, andthe agents that cause the illness are known asenteric pathogens. Many of these pathogens aretransmitted through contaminated food or water.The World Health Organization says that diarrhealdiseases account for 15 to 34 percent of all deathsin certain countries — conservative estimatesplace that death toll at 4 million to 6 million peryear, with most of these occurring in children, theelderly and the immunocompromised.

“These pathogens are difficult to control, haveno vaccines and have been identified as high prior-ity by the National Institutes of Health [NIH],” saidThomas Whittam, MAES food science and humannutrition and microbiology and molecular geneticsscientist, who heads the Microbial EvolutionLaboratory and is a Hannah distinguished profes-sor. “Our objective is to get over the hurdles andunderstand these tough-to-control pathogens.”

Two years ago, the NIH awarded a team ofresearchers led by Whittam a $10.2 million researchcontract to explore the genetics of microorganismsthat cause food- and waterborne infectious dis-eases. The award made MSU a part of the Food andWaterborne Diseases Integrated Research Network(FWD IRN), a network of research laboratorieslaunched by NIAID, and established theMicrobiology Research Unit (MRU) in the NationalFood Safety and Toxicology Center at MSU. TheMRU at MSU is one of two such units nationwide.NIAID has established eight such research units

nationwide in four research areas: microbiology,immunology, clinical and zoonoses. As principalinvestigator and project leader for MRU, Whittamalso participates as a member of the FWD IRN exec-utive committee.

“The FWD IRN links researchers together tocarry out research and make breakthroughs ontough organisms,” Whittam explained. “There istremendous variability in these pathogens and alack of animal models to study how the pathogensbehave. MSU’s strength is in bacterial pathogens —that’s why we’re a part of this.”

The list of priority organisms was created fromwork done previously at the NIH. Ten years ago, theagency issued a call for proposals for research con-tracts on enteric pathogens. This led to the creationof the Enteric Pathogen Research Unit (EPRU),which developed the priority list. Before Whittamcame to MSU in 2001, he was part of the EPRU.

In the MRU, Whittam and the other three projectleaders — MAES large animal clinical sciences andmicrobiology and molecular genetics researcherLinda Mansfield, large animal clinical sciencesresearcher Mahdi Saeed, and microbiology andmolecular genetics researcher Vince Young — areconducting research in the following areas:

• Advancing molecular techniques and data-bases to identify pathogenic strains of E. coliO157:H7, Campylobacter and Salmonella.

• Investigating factors involved in the emer-gence of new Salmonella strains.

• Developing animal models for understandingCampylobacter infection and pathogenesis.

• Developing microarray technology specificallytargeted for rapid detection of diversepathogens.

Tracking E. coliMuch of Whittam’s research focuses on E. coli.

He pioneered the application of population geneticmethods to study variation in bacterial species. Hiswork has revealed that the major disease-causingvarieties of E. coli are organized into clonal groupsand that some of these groups have evolved multi-

Bad Bacteria

ple times. His investigations into E. coli O157:H7demonstrated that the pathogen recently descend-ed from a non-toxin-producing strain that causesinfant diarrhea, and that the acquisition of a viru-lence plasmid and toxin genes were crucial steps inthe pathogen’s emergence.

In the MRU, Whittam has developed a DNA fin-gerprint database for Shiga toxin-producing E. coli

(STEC). (The Shiga toxin is what causes disease.)The database is designed to facilitate research onShiga toxin-producing E. coli by providing a stan-dard reference collection of well-characterizedstrains and central online accessible databases.

“Our database is for research purposes,”Whittam explained. “Other scientists can send ussamples and we’ll be able to characterize it forthem.”

Whittam is also working on developing animalmodels to study hemolytic uremic syndrome(HUS). HUS is one of the most common causes ofsudden short-term kidney failure in children. Mostcases occur because the digestive system has been

infected with E. coli from con-taminated meat, milk or water.The Shiga toxin in the bacteri-um leads to kidney failure. Notall children who ingest E. coli

develop HUS, however. And HUS is not always fatal.After being seriously ill, some children do recover,though most of them are left with permanent kid-ney damage.

“There is a variation in susceptibility, and we’renot sure why that is,” Whittam explained. “Is there asubstrain of E. coli that causes HUS? Or is that par-ticular person more susceptible for some reason?There is no good animal model that mimics kidneyfailure or damage in humans for us to study thesequestions.”

To start to tackle these questions, Whittam isworking on a rabbit model. Some breeds of rabbitsare susceptible to a similar disease.

“Many of the intestinal diseases transmitted byfood and water have been tough to control, andvaccines have often failed,” Whittam said. “If we canmimic the human diseases in laboratory animals,we can have a way to test new therapies, developnovel candidates for vaccines and learn to controlinfections in human populations.”

To facilitate animal model research throughoutthe FWD IRN, the MSU MRU sponsored an animalmodel workshop in April for network scientists.

“We presented our models and the other scien-tists presented theirs,” Whittam said. “We discussedwhat makes a good animal model for pathogenesisstudies and identified priority animal models forinflammatory bowel disease as well as HUS.

“Animal model research is sometimes difficultto get funding for,” he continued. “It almost hasto work before you can say you want to study it.

28 | FUTURES

“�ur objective is to get over the

hurdles and understand these

tough-to-control pathogens.”

MAES scientist Thomas Whittam,who has appointments in thedepartments of Food Science andHuman Nutrition andMicrobiology and MolecularGenetics, heads the MicrobiologyResearch Unit at MSU. Much ofhis research focuses on Shigatoxin-producing E. coli.

But of course you have to do research before youknow that.”

Whittam also is collaborating with Dele Davies,chairperson of the MSU Department of Pediatricsand Human Development, to study Group BStreptococcus (GBS).

Though many people carry GBS and are notaffected, it can be deadly in people with weakenedimmune systems. It is the most common cause ofblood infections and meningitis in newborns whenpassed from mother to baby during delivery.

“The bacteria colonize in the vaginal tract andthe woman has no symptoms,” Whittam said. “Notmuch is known about the dynamics of the colo-nization process. We don’t know what effectsantibiotics have. And if the infection is treated andthen comes back, is it the same strain of GBS or isit a different one?”

Whittam is applying the same techniques heused to create the STEC DNA database on GBS. Bycataloguing well-characterized strains of the bac-terium, researchers will be able to start to identifywhich strains are present and causing infection.

GBS also causes mastitis in cows, and GBS out-breaks have increased in the past 20 years.

“We’re seeing more different types,” Whittamsaid. “There have been outbreaks in nursing homes.The very old and the very young are at risk. The bac-terium originated in cows, but the type in humansis distinct. This project has just started, and I’m veryexcited about the work.”

Controlling CampylobacterWhat’s the No. 1 food-borne bacterial pathogen

in the United States? If you said E. coli orSalmonella, you’d be wrong. It’s Campylobacter,and, much like the other two pathogens, it causes

bloody diarrhea, vomiting, cramps and fever. Butbecause its associated disease, campylobacteriosis,happens as isolated, sporadic events, not as largeoutbreaks, most people haven’t heard of it. Thebacteria live in the gastrointestinal tract of animalsand people. Chickens, pigs and dairy cows can allbe infected with Campylobacter but have nosymptoms. A few people who are infected withCampylobacter don’t have symptoms, either.Most people, however, develop short-term bloodydiarrhea. In immunocompromised people,Campylobacter can spread to the bloodstream andcause a life-threatening infection.

The bacterium is estimated to affect more than2.5 million people each year — more than E. coli orSalmonella. People pick it up mostly by handlingraw poultry or eating raw or undercooked poultrymeat. Even one drop of juice from raw chickenmeat can infect someone. Campylobacter can sur-vive cold temperatures and can live in water, and itcan colonize and spread in chicken processingchilling tanks. Some researchers speculate that

Summer 2005 | 29

MAES researcher Linda Mansfield is working to findan animal model for Campylobacter, the No. 1 food-borne bacterial pathogen in the United States. Morethan 2.5 million people contract campylobacteriosiseach year, most from eating or handling raw orundercooked poultry.

freezing might kill it, but it has been found onfrozen chicken. Thorough cooking will kill thebacterium. Like the other pathogens on the MRUpriority list, Campylobacter has no vaccine foreither animals or humans.

“You usually get campylobacteriosis about 24hours after you’ve been exposed to the bacterium,”

said Linda Mansfield, MAES scientist and MRUproject leader. “In most people, the symptomsaren’t severe and they don’t go to the doctor. Untilrecently, it was thought that there were no long-term effects from it. But recent research has linkedit to Guillain-Barré syndrome and Reiter’s syn-drome, both of which are autoimmune disorders.”

Guillain-Barré (pronounced Ghee-yan Bah-ray)syndrome (GBS), also called acute inflammatory

demyelinating polyneuropathy and Landry’sascending paralysis, is an inflammatory disorder ofthe nerves outside the brain and spinal cord. Itcauses rapid weakness and often paralysis of thelegs, arms, breathing muscles and face. GBS is themost common cause of rapidly acquired paralysisin the United States, affecting one to two people inevery 100,000. The disorder came to public atten-tion briefly when it struck a number of people whoreceived the swine flu vaccine in 1976.

Reiter’s syndrome is a type of arthritis that pro-duces pain, swelling, redness and heat in the joints.It is one of a family of arthritic disorders calledspondylarthropathies, affecting the spine and usu-ally involving the joints of the spine and the jointsin the pelvis that connect the tailbone (sacrum) andthe large pelvic bone (illium). It can also affectmany other parts of the body such as the arms andlegs. People with Reiter’s syndrome have inflamma-tion of the joints, urinary tract and eyes, and soreson their skin and in their mouths.

“There are definitely lasting effects after peopleare infected with Campylobacter,” Mansfield said.“Our goal is to prevent the infection from happen-ing in the first place.”

The consequences of E. coli and Salmonellainfection have been well publicized, butCampylobacter has not received much media atten-tion — even though Mansfield estimates that 80 to90 percent of the chicken available in stores hasCampylobacter on it. She’s working to develop ananimal model so campylobacteriosis can be studiedto find the ways in which it can cause disease and todevelop new treatments and preventive measures.

“The only models we have to studyCampylobacter are swine and ferrets,” Mansfield

30 | FUTURES

MSU’s strength and experience in studying bacterialpathogens is why the university received a $10.2million research contract to explore the genetics ofmicroorganisms that cause food- and waterborneinfectious diseases. The award made MSU part of thenational Food and Waterborne Diseases IntegratedResearch Network.

“�here are definitely lasting effects

after Campylobacter... Our goal is

to prevent the infection from

happening in the first place.”

said. “We’re trying to develop amouse model for it becausethey’re easier and faster towork with.”

Mansfield is working with several strains ofmice with dysfunctional immune systemsbecause they allow her to see any response themice have immediately and also because campy-lobacteriosis is a more serious disease in theimmunocompromised. She fed the bacterium tothe rodents orally to see if the Campylobacter would

colonize and produce invasive disease. So far, mostnormal mice appear to be resistant, and many ofthe mice with defective immune systems are highlysusceptible to this bacterium. These results showhope that these mouse models will ultimately helpMansfield’s research.

“The normal mice may not have the right recep-tors for Campylobacter on their cells or they may beintroduced to another bacterium at a young age

that makes them immune,” she said. “Another like-ly explanation is that a normal immune system isneeded to fight off Campylobacter. We’ve only beenworking on this for about a year, and we’re continu-ing to test different strains of mice for the bestmodel of what happens in humans with disease. Wehave noticed that some of the mice have developeda condition that is similar to inflammatory boweldisease (IBD) in humans.”

Mansfield said some researchers suspect thatsome people develop IBD because they wereexposed at an early age to Campylobacter or othermicroorganisms.

“It’s a provocative idea and underscores all themore our need for animal models,” she said. “Weneed the models to study how the disease develops,to develop vaccines and to test new treatments. Theideal would be to develop a vaccine for animals,especially chickens, that would protect people sowe wouldn’t have to vaccinate people.

“Some strains of Campylobacter have developedresistance to antibiotics, which is another reasonwhy an animal vaccine would be good,” she contin-ued. “Then, if the vaccine worked well, we wouldn’thave to worry about antibiotic resistance fromCampylobacter showing up in people.”

Because chickens have a higher rate ofCampylobacter infection than pigs or dairy cows,the U.S. Department of Agriculture is focusing oneliminating the bacterium in poultry. This is expect-ed to dramatically reduce infections in humans.

“Then we’ll focus on what’s left,” Mansfield said.::: Jamie DePolo

Summer 2005 | 31

Linda Mansfield and Vijay K.Rathinam, a veterinarian workingon his doctorate in Mansfield’s lab,are trying to develop a mousemodel to study Campylobacter.Swine and ferrets are also affectedby the bacterium, but mice areeasier to work with. The goal is todevelop a vaccine for chickens toprotect people from Campylobacter.

Thomas Whittam is also studying hemolytic uremicsyndrome (HUS), which is most often caused by meat,milk or water contaminated by E. coli. But not everyoneexposed to E. coli gets HUS, so Whittam wonders if asubstrain of E. coli is responsible for HUS.

How Do Diseases

32 | FUTURES

Summer 2005 | 33

MAES SCIENTIST NED WALKER HAS

degrees in zoology, microbiology andentomology, and he has appoint-ments in the departments ofEntomology and Microbiology andMolecular Genetics. But he’s reallymore of a detective. Walker studieshow emerging diseases, such as WestNile virus and Lyme disease, emerge.

In other words, how do these diseases move throughthe environment and end up infecting people?

“I take a landscape ecology approach,” Walkersaid. “Both West Nile virus and Lyme disease arerelated to the ways humans modify the environment.We change the landscape to meet our needs and atthe same time create desirable habitats for insectsand animals that are carriers or incubators of the dis-eases. Then the disease becomes established becausethe environment is favorable. It’s analogous to aninvasive species, such as the emerald ash borer.”

By identifying locations that are good habitats forthe disease carriers (known as “vectors” in scientificterms), Walker then has a list of places that the dis-eases are likely to move into and can help advise localpublic health and other officials there on possibleprevention strategies.

“Geographical information systems [GIS] havetotally revolutionized this area of biology,” saidWalker, who uses these geospatial computer model-ing tools to map relationships between various typesof information. “We now have the ability to layerdata, which helps us make correlative relationshipsbetween data that we couldn’t do before.”

Instead of looking at databases full of numbers ofwhere West Nile virus has been found in crows inMichigan, where human cases have been found,where desirable mosquito environments are found,mosquito populations for the state, and other datasets full of numbers, Walker can now generate onemap with all the variables on top of one another,allowing him to identify potential outbreak areasmuch more easily.

“It helps us formulate areas of future study,”Walker explained. “We can look at smaller and small-er pieces of the landscape, and as we do this the bio-diversity goes down. The range of hosts narrows, andsome are more susceptible than others.”

Tracking West Nile Means TrackingMosquitoes

West Nile virus (WNV) was discovered in theAfrican country of Uganda in 1937. Carried by birds,the virus is transmitted by mosquitoes and can infect

Emerge?Like a biological

crime scene investigator,

MAES researcher Ned Walker

pieces together the path

that diseases take from

insects to man.

34 | FUTURES

humans and horses. It was first found in this country in1999 in New York City. Since that time, WNV has beendetected in 47 states. The disease was first detected in 10Michigan counties in 2001 in dead crows. The first humancases of WNV were reported in 2002. The state created the

WNV Working Group in 2000 andimplemented a surveillance sys-tem to monitor dead birds andmosquito ponds and advise localofficials about mosquito sup-pression tactics.

People older than 50, thosewho are immunocompromisedand people with underlyinghealth conditions have the high-est risk of developing severe dis-ease. Most people infected withWNV have no symptoms; about20 percent have mild, flu-likesymptoms. Those who develop asevere form of the disease canexperience headache, high fever,stiff neck, tremors, seizures orconvulsions, paralysis, coma andpossibly death.

Many scientists think that theWNV cycle involves two types ofmosquitoes: one that bites onlybirds and one that bites bothhumans and birds. But Walkersuspects that the mosquitoesthat supposedly bite only birdsalso bite humans.

“The Culex pipiens mosquitolikes to come inside at night, and it may be biting people,”he explained. “West Nile virus outbreaks usually happenduring hot, dry weather when the mosquito that bites peo-ple and birds isn’t around.”

Recent research that Walker did in Detroit and Chicagoalso offers clues to why WNV outbreaks seem to be clus-tered in specific areas.

In both cities, Walker and his research associates foundthat WNV outbreaks were clustered in middle-class suburbssuch as Royal Oak and Ferndale. These areas are home tomany new housing developments.

“I think the outbreaks are related to the way storm wateris channeled in these neighborhoods, such as with streetcatch basins and storm water retention ponds,” Walker said.

Walker suspects these man-made urban bodies of waterare perfect breeding grounds for the mosquitoes that trans-mit WNV.

“We’re now talking to scientists in the Department ofCivil and Environmental Engineering about the design ofthese systems and the legal basis for their installation,” hecontinued. “This is another example of how we’ve passed

legislation designed to help the environment and it’s hadunexpected outcomes.”

To fight WNV, Walker advocates eliminating mosquitoenvironments and organized community mosquito sup-pression. He’s also a fan of bed nets to protect people fromindoor biting at night.

Tracking Lyme Disease Means Tracking TicksLyme disease got its name from the town in Connecticut

where it was discovered in children in 1975. It was firstreported in Michigan in 1985 and has been confirmed inonly a few counties in the state. Lyme disease is caused bythe bacterium Borrelia burgdorferi, which is spread to ani-mals and people by infected black-legged ticks. Most of theannual 24,000 cases are in 12 states: Connecticut, Delaware,Maine, Maryland, Massachusetts, Minnesota, NewHampshire, New Jersey, New York, Pennsylvania, RhodeIsland and Wisconsin.

Lyme disease in humans is usually not a life-threateningillness; most often it’s similar to a mild case of the flu. Butserious problems involving the heart, joints and nervoussystem may develop in some individuals. The most tell-talesign of Lyme disease is the bull’s-eye rash that developsaround the tick-bite site. Arthritis is the most commonlong-term effect of Lyme disease.

Dogs, cats, cattle, horses and other domestic animals arealso susceptible, and their symptoms may include fever andlameness. Wild animals such as deer, raccoon and micehave no symptoms and apparently suffer no ill effects fromthe disease.

There is no human vaccine, but there is one for dogs.In Michigan, most cases of Lyme disease have been clus-

tered around Menominee County because black-leggedticks are found there. However, Walker and other scientistsbegan hearing reports that black-legged ticks were beingfound on the west side of the Lower Peninsula.

“The baby ticks were getting on birds and movingaround the state,” he explained. “White-footed mice andchipmunks are also carriers of the disease and are favoritehosts of baby ticks. The spread of the disease correlates tofavorable tick habitat — they like deciduous forests and dry,sandy soils.”

Walker has developed a computer model that highlightsfavorable tick habitats around the state and shows possiblelocations for disease outbreaks. The state is using the infor-mation to monitor the areas and provide more education,such as the poster Walker helped develop (available fordownload at http://www.michigan.gov/emergingdis-eases/0,1607,7-186-25796-104336—,00.html).

“Grand Haven and Saugatuck are hot spots for tickhabitat,” Walker said. “We’re starting to see more humanand dog cases in these areas. We’re hoping we can beproactive and educate people about ways to protect them-selves against ticks and Lyme disease.”

::: Jamie DePolo

Mosquitoes are responsible forspreading West Nile virus from birdsto people. After studying outbreaksof the disease in Detroit and Chicago,MAES scientist Ned Walker thinksstorm water retention ponds in newdevelopments may play a role asbreeding grounds for mosquitoes.

S T R E S S E D O U TAT THE

CELLULAR LEVELFunctional genomics — research that determines the functions

of genes and the proteins they encode in determining traits,

physiology or development of an organism — is growing

rapidly. The MSU Center for Animal Functional Genomics

(CAFG) was created in 2001 with funding from the MAES, the

Michigan Animal Industry Initiative and the Office of the Vice

President for Research and Graduate Studies. Using technology

that allows them to track animals’ responses to stress from

diseases, giving birth, shipping and other environmental

factors at the cellular and molecular levels, CAFG researchers

are beginning to understand why stress may make animals sick

or more susceptible to disease.

“We are no longer looking at just the physical outcome — did

the animal get better — but also at the cellular and gene levels

to see what impact was actually realized,” said Paul Coussens,

director of the CAFG.

“In functional genomics research, we don’t force preconceived

ideas on the system — we let the cells tells us what’s going on,”

said Jeanne Burton, head of the Immunogenetics Laboratory.

Coussens and Burton, both MAES animal science researchers

and members of the CAFG, study the genes that are expressed

or suppressed when the immune systems of animals respond

to an infection or other stresses. Because human and animal

systems are similar, their work offers exciting possibilities for a

new understanding of the human immune system as well as

new types of treatments. �

Summer 2005 | 35

Premature birth rates in the United States continue to rise

rapidly, despite efforts to predict premature birth and

control it. Using cows as a model to understand why early

birth happens may offer prevention strategies for

pregnant women and their doctors.

According to statistics from the March of Dimes, between 1981and 2002 in the United States the rate of premature birthincreased 29 percent. In Michigan between 1992 and 2002, thepercentage of babies born prematurely increased more than 10percent. In an average week in Michigan, 2,619 babies are born;304 of those (11.6 percent) are premature. In 2002, the total hospi-tal bill for all babies born in the country was $33.8 billion. Almosthalf of that — $15.5 billion — was for babies with any type of diag-nosis of prematurity or low birthweight. The United States has agoal to reduce premature births to 7.6 percent, but rates keepgoing up instead of down.

At an American College of Obstetricians and Gynecologistsmeeting in May, Kenneth Ward, chairperson of obstetrics andgynecology at the University of Hawaii, said that premature birthis the No. 1 problem in obstetrics today.

“The process of giving birth can also be a problem in dairycows, and dairy cows that have difficult, still or premature birthsoften become sick with opportunistic infectious diseases such asmastitis [a painful infection of the mammary gland that alsoaffects women],” Burton said. “Our goal is to keep cows healthy.We’re studying stress and sex hormones that influence the timingof birth in cows and are starting to understand the role they playin the molecular and cellular processes that lead to normal andabnormal births and how they influence cows’ ability to fightinfections such as mastitis.”

Caused by bacteria such as Escherichia coli and Staphylococcusaureus, mastitis causes the udder to become red, swollen andpainful to the touch. The bacteria and the body’s immuneresponse also can damage milk-producing tissue, causing scar tis-sue and abscesses to form and ultimately reducing milk produc-tion. Mastitis sometimes becomes so severe around the time ofbirth that cows even die from it because bacterial toxins andinflammatory molecules secreted by the immune system spreadthrough the blood and cause multiple organ failure.

Mastitis is one of the most costly infectious diseases affectingthe U.S. dairy industry, resulting in losses of more than $2 billionannually. The highest rates of mastitis occur in the first few weeksfollowing the birth of the calf.

Burton and her research team — which includes scientistsfrom the Republic of Ireland’s version of the experiment station,Teagasc — are examining interactions between a key birthing hor-mone, glucocorticoid, produced by the adrenal glands, and neu-trophils, a type of white blood cell that normally protects animals

from opportunistic infectious diseases such as mastitis. Humansalso have glucocorticoids and neutrophils.

Glucocorticoids are secreted when the body is under stress.They get their name from their effect of raising blood sugar (glu-cose) levels needed for the acute “fight-or-flight” response.Cortisol (also called hydrocortisone) is the most abundant gluco-corticoid in cows and humans. Cortisol and the other glucocorti-coids also have a beneficial anti-inflammatory effect on the body,but this effect then reduces the body’s acute immune response toinfection, including neutrophil responses to bacteria that causemastitis.

Neutrophils are normally short-lived and fast acting. Storedbriefly in bone marrow and blood, they are the first line ofimmune defense, and thousands can accumulate in minuteswhen the body detects an infection. Neutrophils are filled withprotein enzymes and oxygen free radicals to fight infection andare responsible for the swelling and pain around the infection site.Neutrophils spill out the enzymes and free radicals that fight theinfection but can also hurt surrounding healthy tissue if not tight-ly regulated. After spilling their killing molecules to fight infection,neutrophils must die quickly to prevent further inflammatory tis-sue damage. The average life span of neutrophils in healthy ani-mals is about 12 hours.

“We know that higher levels of glucocorticoids in the cow’sblood are associated with an increased susceptibility to infectiousdisease, including mastitis,” Burton said. “Neutrophils have glu-cocorticoid receptors that rapidly change the expression of genesin the cells, so they’re dramatically affected by the higher levels ofthe hormones during stress. We’re looking at circulating neu-trophils to see what is happening to them when blood glucocorti-coids are high during birth and other stressful times, such as trucktransportation.”

Giving birth is a stressful situation for a cow’s body, so gluco-corticoid levels go up. In addition, birth is stressful on the soon-to-arrive calf. When it’s time for the calf to be born, it appears totake over the mother’s neutrophil system by secreting largeamounts of glucocorticoids that go into her bloodstream. Usingfunctional genomics technology, Burton’s research team hasfound that glucocorticoids change neutrophils into a differenttype of cell than they are when there is no stress.

“The glucocorticoids appear to be reprogramming the neu-trophils so they have a different function,” Burton explained.“Instead of expressing genes that help them fight bacterial infec-tion, the neutrophils now use other gene systems that enablethem to remodel the structural proteins of tissue, such as colla-gen. If you think about this, it’s very important at birth for tissuessuch as the cervix, placenta and fetal membrane to change, tosoften and rupture so the calf can pass through. As it turns out,much of this critical tissue remodeling is done by neutrophils thathave diverted their efforts to the reproductive tract and placentaunder the influence of fetal and maternal glucocorticoids.”

In the past, it was thought that neutrophils just became dys-

36 | FUTURES

Ensuring a Happy Birthing Day

functional during birth. This was the explanation for why cowshad more infections at this time — the neutrophils were dysfunc-tional. While there isn’t a name for this second role of neutrophils,they’re definitely not dysfunctional. They’re just “altered func-tional,” according to Burton — transformed by the glucocorti-coids and maybe too busy helping with the birth process to fightinfection in the mother.

“Is it possible that successful birth of a healthy calf has a high-er priority in an evolutionary sense than temporary infection-fighting ability in the birthing cow?” Burton asked rhetorically. “Iask myself, ‘Why is nature doing this?’ I think biologically we’restill cave people. Stress hormones bring out the ‘fight-or-flight’response in us. In our chronically stressed lives today, that’s notvery helpful. But if we think back to how things were, it makessome sense. The stress response that leads to glucocorticoid pro-duction usually meant a fight or flight, after which body tissuesmight have been seriously damaged. It could possibly have beenmore important to animal survival that neutrophils be repro-grammed for urgent tissue remodeling and repair than to bepoised to fight a possible infection.

“Shortly after the tissues are repaired, new neutrophils arenormally produced in bone marrow, and these cells can resumethe business of fighting infections,” Burton continued.“Amazingly, neutrophil responses are very similar during fight-or-flight reactions to stress and the birth process.”

The transformed neutrophils can’t flip back to their infection-fighting former role. Once they’ve been changed, they staychanged until they die. The transformation also allows neu-trophils to live slightly longer than normal, possibly because ofthe time it takes to do tissue remodeling. Burton has found thatthese transformed neutrophils can live 36 to 48 hours, aboutthree to four times the life span of an untransformed, infection-fighting neutrophil, and long enough to help a successful birthhappen.

She’s also studying how the whole neutrophil system returns tofighting infection.

“After a normal birth, it takes about a day andhalf for the glucocorticoid levels to drop back tonormal,” Burton explained. “However, it appears totake about two to three weeks for the neutrophilsystem in the bone marrow to revert back to creat-ing bacteria-fighting neutrophils. And that’s usuallywhen mastitis hits the hardest. Now that we have abetter understanding about what makes birth hap-pen at the cellular and molecular levels, we’rethinking about how we might facilitate the timingof the birth process and a quicker return to normalinfection-fighting capabilities of neutrophils.”

But in a stressful or premature birth situation,glucocorticoid levels may remain high, which maydelay the neutrophil system’s reversion to diseasefighting. This might explain why cows that havedifficult births or abort the calves have moreinfections.

Because of the parallels in neutrophil responsesto stress between cows and humans, Burton hasbegun collaborating with human medicine scien-tists studying premature birth in women.

With premature birth rates rising, scientists are looking for acause. Burton’s work with cows suggests that stress and stress glu-cocorticoids may play a role. In a normal birth situation, the babyinitiates the birth process by secreting glucocorticoids. In astressed or premature situation, the mother’s body may be initiat-ing the birth process. A single mother-to-be who works, goes toschool and has little or no support network may be undertremendous stress, which could cause her glucocorticoid levels tobe chronically higher than normal. Might this contribute to pre-mature birth? Undetected infections also can bring on potentstress responses. Might undetected infections also contribute topremature birth?

“We’re working to meld the bovine information with thehuman information,” she said. “Ultimately, we’d like to knowwhat causes premature birth and if it can be controlled. Inhumans, the process is more complex. There may be undetectedstress from subclinical infection at a distant site or damage toblood vessels in the uterus or placenta. Nutrition also may play arole, as may drug and tobacco use. The causes may not always behormonal. But it’s very exciting. It could be that we can help pre-vent premature birth in women by understanding the effects ofstress hormones on neutrophils of birthing cows.”

Summer 2005 | 37

MAES researcher Jeanne Burton (center) and Kelly Buckham (left) and Patty Weber(right) examine an autoradiograph of genes that are differentially expressed in bovineneutrophils as cows progress through parturition. Buckham is a Ph.D. candidate andWalsh fellow visiting Burton’s lab from Ireland. Weber is the Burton lab coordinatorand head technician. In the back, at the far left, Sally Madsen-Bouterse, another Ph.D.candidate in Burton’s lab, sets up a quantitative real time RT-PCR assay to examineneutrophil gene expression during glucocorticoid treatment of the cells.

A genetic “fingerprint” of bovine immune system response

to Johne’s disease is helping researchers understand how

the disease progresses.

The bacterium Mycobacterium avium subspecies paratuber-culosis (MAP), known as paratuberculosis, causes Johne’s (pro-nounced “YO-nees”) disease in cattle. A chronic intestinal infec-tion, Johne’s causes diarrhea, weight loss, decreased milk produc-tion and death. The disease incubates in infected cows for 2 to 7years, and even though they may show no symptoms, the animalscan begin shedding large numbers of bacteria — up to severalthousand organisms in 1 gram of feces. Cattle that are heavilyinfected will also shed the bacterium in milk. Currently, there areno vaccines or antibiotics that will cure Johne’s disease.

There is some evidence, though it is controversial, that theMAP bacterium is infectious in people. Some scientists have con-nected MAP to Crohn’s disease because the organism has beenfound in a significant portion of Crohn’s disease patients.

“Johne’s is a significant, global problem in the dairy industry,”said Paul Coussens. “Producers lose more than $1 billion per yearin the United States because of it. There is also an increasing con-cern for human health because of the growing connection ofparatuberculosis with Crohn’s disease. Paratuberculosis has beendetected in the intestinal tissue of about 70 to 90 percent ofCrohn’s disease patients.”

Paratuberculosis is a very potent pathogen, and the immunesystems of cattle react strongly to it. Macrophages, large whiteblood cells that devour invading pathogens, are some of the firstto respond. But researchers have found that the paratuberculosisbacterium actually lives inside macrophages in the bovine gut.

“Macrophages are supposed to engulf and kill these invadingbacteria,” Coussens explained. “But for some reason, the invadershave taken over the cell that is supposed to kill them. We want toknow how paratuberculosis survives in the macrophage.”

In addition to surrounding and killing pathogens,macrophages also stimulate other immune cells, such as T cells,by presenting them small pieces of the invading pathogen. T cellsare lymphocytes, smaller white blood cells that attack and destroybody cells that have become infected or become cancerous. T cellsalso secrete cytokines, proteins that act as messengers betweencells. There are three main types of T cells: killer T cells (cytotoxicT cells), helper T cells and suppressor T cells.

When a cow is first exposed to paratuberculosis, its immunesystem responds by creating more killer T cells to fight the infec-tion. However, after a cow has been infected with paratuberculo-sis for a long period of time, this killer T cell response stops. Theimmune systems shifts to trying to create antibodies to fight theinfection, but this is ineffective.

“If a cow has been infected with paratuberculosis, it can beasymptomatic and live with the disease as long as the T cells arefighting it,” Coussens explained. “But when the killer T cell

response stops, then the animal begins to develop Johne’s dis-ease. That’s the second big question: why does the T cell responsestop? We know a lot about the immune system, but there is a lotmore we don’t know.”

So Coussens decided to look at what was happening at the cel-lular level — which genes were being expressed at which timesand what happened as a result of this expression.

Coussens and a graduate student in his lab, Abe Aho, foundthat in cows with paratuberculosis, two proteins — interleukin-1alpha (IL-1α) and tumor necrosis factor receptor-associated pro-tein 1 (TRAF1) — were present in much higher levels than inuninfected cows.

“You wouldn’t normally find these genes expressed at suchhigh levels in cells,” Coussens said. “But they were highlyexpressed in the gut tissues in the cows that had been exposed toparatuberculosis.”

Both IL-1α and TRAF1 are messenger proteins of the immunesystem and are involved in fighting infection. IL-1α is expressedby macrophages to fight infection. TRAF1 helps to carry signalsfrom the environment outside the cell to the nucleus, so TRAF1ultimately determines how the cell responds. Other research sug-gested that high levels of IL-1α can cause the symptoms of Johne’sdisease: weight loss, fever and chronic diarrhea.

“When we looked at the cells in the intestines of infected cows,we saw only macrophages — not neutrophils or T cells,” Coussenssaid. “Interleukin-8, another messenger protein, is also highlyupregulated in infected cows, so we should see T cells and neu-trophils. But they’re not there. The T cell response has juststopped.”

While examining macrophages in culture, Coussens and visit-ing scholar Shi-Kai Chiang made an interesting discovery. IL-1αenhances TRAF1 expression, and high levels of TRAF1 disrupt

38 | FUTURES

Fingerprinting Disease

By identifying the genetic signature of cattle infected with paratuber-culosis, MAES scientist Paul Coussens wants to create a new diagnostictool for that disease and possibly other illnesses. His work is at theforefront of what’s known about the immune system and may haveimplications for humans.

normal communications between macrophages and T cells. Highlevels of TRAF1 also kept the macrophages alive longer.

“So these macrophages become the perfect place for paratu-berculosis to live without being detected,” Coussens explained.“IL-1α pulls other macrophages into the area by telling them tocome and fight the infection. As new macrophages come in tofight, they’re exposed to high levels of IL-1α, which enhancesTRAF1 expression in incoming macrophages. Now the newmacrophages can’t communicate with T cells to tell them some-thing is wrong and they don’t die like they’re supposed to — it’s aperfect hiding place.”

This process happens over time, about 2 to 5 years. In trackingthe immune system response, Coussens started to see high levelsof another cytokine, interleukin-10 (IL-10), as the T cell responsewas dropping off. He suspected this might be responsible for thediminished T cell response.

“Interleukin-10 represses the immune system, it doesn’t killanything,” Coussens explained. “IL-10 can shut off the activationof T cells. Its job is to prevent long-term chronic inflammation. It’svery hard on the body to be fighting an infection for years at time.So by the time an animal with paratuberculosis presents symp-toms of Johne’s disease, there are virtually no T cells fighting theinfection.”

Coussens’ work is at the forefront of what’s known about theimmune system and may have implications for human chronicdisease. People infected with tuberculosis who develop the dis-ease also have little or no T cell response to the infection, andunderstanding more about bovine immune systems will offerclues to the human immune system.

“We think that because the infection is so long-lasting, thebody decides that this is the way it’s supposed to be and that theimmune system is over-reacting,” Coussens said. “It’s basicallysaying, ‘This bacteria must be a normal part of the microflora’ —the non-pathogenic organisms that normally live in the intestinewithout causing any disease.”

So cows that are infected with paratuberculosis, whether ornot they are showing clinical symptoms of Johne’s disease, haveimmune systems that have been changed so they express higherlevels of different genes than uninfected cows. By determiningthis genetic fingerprint or signature of infected cows, Coussens isworking to create a new diagnostic tool for paratuberculosis andpossibly other diseases.

“In collaboration with scientists from University CollegeDublin, we’re looking at other diseases, such as bovine tuberculo-sis, brucellosis, trypanosomes [African sleeping sickness], todetermine if there are gene expression signatures of each,”Coussens said. “We want to know if any of the signatures are sim-ilar — does the immune system respond in the same way to anyof these diseases? Some of the general gene expression patternsare indeed the same, but we also see differences between eachtype of infection. In collaboration with other scientists from theU.S. Department of Agriculture National Animal Disease Centerin Ames, Iowa, and at other land-grant universities in the UnitedStates, we have expanded this program to include several virusinfections in cattle. We now believe we can develop general signa-tures for each type of disease — so a bacterial disease has onetype of genetic signature, a viral disease has another and a para-sitic disease has another. Then if an animal presents us with an

unknown disease, we can figure out what type of general immuneresponse is happening.”

Ultimately, Coussens sees the genetic signatures improvingthe diagnostic process. Veterinarians would not have to examinean animal for each possible infection. A simple, genomic-basedblood test could quickly determine whether the animal wasinfected, the class of disease pathogen that was causing the infec-tion and possibly even the specific organism responsible. Thiswork has obvious implications in biosecurity issues — the abilityto determine rapidly the type of infectious agent present wouldhelp to direct quick and appropriate responses from local, stateand federal agencies.

“We could test for many different pathogens at one time,”Coussens said. “It may also help us learn more about diseaseresistance and genetics — are different genes expressed in resist-ant animals?”

::: Jamie DePolo

MSU Hosts Second International Symposium onAnimal Functional Genomics

In 2003, the MSU Center for Animal Functional Genomics(CAFG) hosted the first International Symposium on AnimalFunctional Genomics. Because of the success of the first, theCAFG is planning a second symposium, scheduled for May2006 at the Henry Center on the MSU campus.

“The purpose of the second international symposium is tobring together international researchers, industry representa-tives and administrators who seek updated information on thedesign, analysis, interpretation, integration and application ofhigh throughput gene expression profiling for the study of cellsand organ systems that underlie economically relevant pheno-types in agricultural animals. The focal areas will include statis-tical genomics, bioinformatics and data mining, animal health,reproduction, and growth and metabolism,” said MAESresearcher Jeanne Burton, who, along with MAES scientistGuilherme Rosa, is chairing the event. “We’re limiting it to 130people so we can have some really good discussion.”

Burton said she and Rosa expect several key outcomes fromthe second symposium, including:

• The exchange of updated information about animalfunctional genomics research, including use of data fromanimal models and cell lines to address issues of produc-tion animal agriculture.

• The sharing of visions for future impacts and applica-tions of functional genomics research on animal produc-tion systems throughout the world.

• The discussion of strategies on how to implement newtechnologies, methodologies and gene expression infor-mation to bridge gaps between discovery and application.

The second International Symposium on Animal FunctionalGenomics, May 16-19, 2006, is designed around 11 keynotelectures to be delivered by internationally renowned function-al genomics scientists. Selected abstracts and posters also willbe presented by symposium delegates. A formal call forabstracts and details of symposium presentations, registrationand hotel booking will be announced soon on the symposiumWeb site at www.isafg.msu.edu.

::: Jamie DePolo

Summer 2005 | 39

The MAES has supported research in veterinary science

since it was created in 1888. Keeping livestock healthy and

free from disease has been the focus of much research, and

many times this work has benefited human health. I. Forest

Huddleson, who enrolled at the Michigan Agricultural College

as a graduate bacteriology student in 1915, was an early

pioneer in brucellosis research, and his work made major

strides in controlling the disease.

Through the 1940s, brucellosis, also known as Bang’s dis-

ease, was a major problem for the livestock industry. It affects

cattle, sheep, goats, pigs, elk and sometimes dogs. The disease

is difficult to detect because infected animals have no symptoms.

Producers suspect the disease only after cows spontaneously

abort or give birth to weak calves.

After receiving his master’s degree, Huddleson was named a

faculty member in 1916. He went on to receive his D.V.M. and

Ph.D. degrees from MSU in 1925 and 1937, respectively. His

research focused on brucellosis as an agent of Bang’s disease,

which at the time was not thought to affect humans.

Huddleson’s research demonstrated that the bacterium, Brucella

abortus, could be transmitted to people through unpasteurized

milk and caused a disease known as undulant fever, which is

accompanied by long-term fatigue and flu-like symptoms. He

predicted that it would become a major human disease and

was quickly proven correct.

Michigan State University is celebrating

its 150th anniversary in 2005. MSU is the

pioneer land-grant institution, and its

history is closely tied to the history of

agriculture, natural resources and rural

communities in the state. The Michigan

Agricultural Experiment Station was

founded on Feb. 26, 1888 — 33 years after

MSU was founded — and the MAES has

played a significant role in shaping

MSU’s research legacy and its priorities

for the future. Each issue of Futures in

2005 will feature a special

sesquicentennial article highlighting the

intersection of MAES and MSU history.

M I C H I G A N S T A T E U N I V E R S I T Y

S E S Q U I C E N T E N N I A L

A Legacy of Combating Disease in People and Animals

40 | FUTURES

Continuing to study brucellosis, Huddleson developed a test

to detect brucellosis bacteria in animals and a treatment for the

disease, called brucellin. Both of these products were manufac-

tured at Michigan State and then distributed worldwide to help

people and animals. Huddleson also created a treatment pro-

cedure for people with advanced disease, which can be fatal.

He was internationally known for his brucellosis research and

traveled around the world helping countries treat and control

the disease. For his work, he was presented numerous awards,

including an honorary doctorate from the University of LaPlata

in Argentina, an honorary doctorate from the University of

Kentucky, the Borden Award from the American Dairy

Association, the Kimble Award from the American Public Health

Association, and the Distinguished Professor and Distinguished

Alumnus awards from Michigan State University.

“Despite his accomplishments and renown, Dr. Huddleson

was essentially a very modest, almost retiring, man,” says

Norman McCullough, a brucellosis researcher at the National

Institutes of Health. “Dedicated to research, his personal

involvement, ‘working with his own hands’ rather than directing

others, continued until he retired. The glamour never faded.

Near the end of his career he remarked that each new

experiment was so intensely interesting that he hurried to his

laboratory each morning anticipating the possibility of a great

breakthrough unfolding from the new data to be analyzed that

day. He was a researcher who followed his problem wherever

it took him, exploiting new methodology and instrumentation as

they became available. Retrospectively, in his research methods

and scientific outlook he was often ahead of his time.”

His endless enthusiasm for research and learning lives on

through his many students, including Alfred H. Hershey, who

received the Nobel Prize in Physiology and Medicine in 1969.

::: Jamie DePolo

Summer 2005 | 41

42 | FUTURES

Grand Ledge Farmer PledgesMultimillion Dollar Gift to FundAgriculture and Natural ResourcesWork

David Morris, a farmer in Grand Ledge,Mich., has pledged an estate gift valued atapproximately $7.5 million to endowresearch, teaching and outreach activitiesin the Michigan Agricultural ExperimentStation (MAES), MSU College ofAgriculture and Natural Resources(CANR) and MSU Extension (MSUE).

Morris’ gift, announced during AgExpo at MSU, will fund four agriculture-related endowments:

• The Betty and David MorrisEndowment in Livestock Researchwill provide the MAES with discre-tionary funds for livestock research,including teaching and research fel-lowships.

• The Betty and David MorrisEndowment for Support of Programsin Communities, Agriculture andNatural Resources will provide sup-port through the MAES and MSUEfor programs affecting communities,agriculture and natural resources.

• The Betty and David MorrisDiscretionary Fund in the CANR willprovide sustained support for thecollege, allowing the dean to addresscritical issues and needs that arise.

• The Betty and David Morris Chair inState and Local Government Financeand Policy will endow an existingposition within the Department ofAgricultural Economics that workswith state and local government.This faculty position engages inresearch, education and outreachfocused on policy analysis that helpsgovernmental units attract peopleand businesses to communities,improve the efficiency and effective-ness of government services, andadvance Michigan’s economic com-petitiveness.

“It is tremendously gratifying thatDavid Morris has chosen to includeMichigan State University in his estateplans,” said MSU President Lou Anna K.Simon. “His foresight and generosity willprovide support to research, outreach andacademic programs that meet emerging

needs of Michigan citizens.”David Morris and his late wife, Betty,

operated a cash crop and livestock opera-tion focused on feeder cattle, hogs, cornand soybeans. The Morris farm, whichbecame a centennial farm in 2000, grewfrom 245 acres to 1,689 acres under theirmanagement.

“Dave Morris’ generous planned giftwill allow us to leverage other sources offunding to address critical issues,” saidJeffrey Armstrong, CANR dean. “Mr.Morris is a strong believer in using thefruits of his labor for the betterment ofothers, and we are honored to have beenchosen to help ensure that his and Betty’slegacy will enhance Michigan’s communi-ties, agriculture and natural resources forgenerations to come.”

MAES Plant Biologist Finds CornFungus is Nature’s Master Blaster

A common corn fungus is by farnature’s most powerful known cannoneer,blasting its spores out with a force that is870,000 times the force of gravity, accord-ing to research done by a team of scien-tists that included an MAES researcher.Corn growers don’t have to worry aboutbeing pegged by the fungal supergun,however — the tiny spore travels only 5millimeters (2/10 inch) before falling tothe ground.

Nevertheless, the fungus Gibberellazeae outguns the previous record holder,the fungus Pilobolus, by almost a hun-dredfold. It also outperforms a rifle,which launches its bullet with less than1/10 that acceleration.

The researchers — MAES plant biolo-gist Frances Trail and Iffa Gaffoor, a grad-uate student in her lab, and Steven Vogelof Duke University — published theirfindings in the June 2005 issue of FungalGenetics and Biology. The study was sup-ported by the U.S. Department ofAgriculture and the Michigan AgriculturalExperiment Station.

According to the scientists, the“bioballistics” of the fungus offers a dra-matic lesson in the physics of scaling. Atthe infinitesimal scale of the fungus’spore, atmospheric drag plays an enor-mous role — hence the need for anextremely high ejection speed to achieveeven the most modest spore dispersal.

The purpose of the study that revealedthe fungus’s extraordinary launch capa-bilities was to better understand the bio-logical mechanism behind the fungalsupergun. Basically, the gun is poweredby the buildup of pressure inside thespore-containing fungal fruiting body,the perithecium. Such pressure is due towater flowing across a membrane intothe perithecium as it tries to equalize theconcentration of a salt solution inside thechamber. In the case of the fungus, thequestion was whether the sugar mannitolor potassium ions were responsible forthe osmotic pressure that generated thepropulsive force.

In their experiments, Trail and Gaffoorcreated a fungal “shooting gallery” con-sisting of a small glass chamber in whichthey mounted a block of gel-like agarcontaining mature perithecia. Theyarranged the agar so that the peritheciawould launch their spores onto a remov-able glass cover slip. The researchersmeasured the length of the fungal blastsand calculated the mass of the spore.That mass turned out to be very low for afungal spore, explaining why the funguscould achieve such extraordinary launchspeeds.

Vogel fed data from the laboratoryexperiments and spore mass calculationsinto a computer program he had devel-oped to determine the ballistics of suchprojectiles. One result was the recordacceleration of 870,000 times the force ofgravity for the spores and a launch speedof nearly 80 miles an hour.

The analysis of the fungal shootingability led the biologists to determine thatthe osmotic pressure from potassium, notmannitol, likely generated the force nec-essary for the powerful blast.

An obvious question is why the funguseven bothers. Given the short range of itsspores, why bother accelerating to 80miles per hour to go a mere 5 millimeters?Because there is almost no air movementat the surface where the spore grows,according to the scientists. So the realobject of the launch is to get the sporeeven a little way from the parent so that itcan get into air currents that will allow thespore to move even farther away.

Research in the news

Summer 2005 | 43

John BakerMAES Acting Director109 Agriculture Hall517-355-0123baker@cvm.msu.edu

Carole BolinProfessor of Pathobiology andDiagnostic InvestigationAnimal Health Diagnostic Center,4125 Beaumont Road, Suite 136B517-353-2296bolinc@msu.edu

Steve BolinProfessor of Pathobiology andDiagnostic InvestigationAnimal Health Diagnostic Center,4125 Beaumont Road, Suite 220M517-432-9926bolins@msu.edu

Jeanne BurtonAssociate Professor of AnimalScience1205E Anthony Hall517-353-9702burtonj@msu.edu

Paul CoussensProfessor of Animal Science andMicrobiology and MolecularGenetics1205H Anthony Hall517-353-3158coussens@msu.edu

Susan EwartActing Associate Dean for Research,College of Veterinary Medicine242 Food Safety and ToxicologyCenter517-432-3100, ext. 117ewarts@msu.edu

Scott FitzgeraldProfessor of Pathobiology andDiagnostic InvestigationAnimal Health Diagnostic Center,4125 Beaumont Road, Suite 152F517-353-1774fitzgerald@dcpah.msu.edu

Richard “Mick” FultonAssociate Professor of Pathobiologyand Diagnostic InvestigationG304 Veterinary Medical Center517-353-3701fulton@dcpah.msu.edu

Jack HarkemaProfessor of Pathobiology andDiagnostic Investigation212 Food Safety and ToxicologyCenter517-353-8627harkemaj@msu.edu

John KaneeneProfessor of Large Animal ClinicalSciencesA109 Veterinary Medical Center517-355-2269kaneenej@msu.edu

Roger MaesProfessor of Microbiolgoy andMolecular GeneticsAnimal Health Diagnostic Center,4125 Beaumont Road, Suite 161517-432-5811maes@msu.edu

Linda MansfieldProfessor of Large Animal ClinicalSciences and Microbiology andMolecular GeneticsA181 Food Safety and ToxicologyCenter517-432-3100, ext. 119mansfie4@msu.edu

Jon PattersonAssociate Professor of Pathobiologyand Diagnostic InvestigationAnimal Health Diagnostic Center,4125 Beaumont Road, Suite 163517-353-9471patterson@dcpah.msu.edu

Willie ReedDirector, Animal Health DiagnosticCenterAnimal Health Diagnostic Center,4125 Beaumont Road, Suite 201H517-353-0635reedw@msu.edu

N. Edward RobinsonMatilda Wilson Chair in LargeAnimal Clinical SciencesG321 Veterinary Medical Center517-353-5978robins18@msu.edu

Ned WalkerProfessor of Entomology andMicrobiology and MolecularGenetics6169 Biomedical and PhysicalSciences Building517-355-6463, ext. 1595walker@msu.edu

Thomas WhittamHannah Distinguished Professor ofFood Science and Human Nutritionand Microbiology and MolecularGenetics194 Food Safety and ToxicologyCenter517-432-3100, ext. 178whittam@msu.edu

Kurt WilliamsAssistant Professor of Pathobiologyand Diagnostic InvestigationG380 Veterinary Medical Center517-432-6320will1273@msu.edu

Scott WintersteinProfessor of Fisheries and Wildlife2B Natural Resources Building517-353-2022winterst@msu.edu

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