South of the Grand Canyon in Arizona, in a valley that roads stilldon’t reach, the Havasupai tribe has

for centuries lived a cloistered existence inthe high desert. Isolation in a geologicalwonderland has allowed the tribe’s 600-pluscurrent members to protect their ancientculture. But the flipside is a restricted genepool that has given the Havasupai one ofthe highest incidences of type 2 diabetesanywhere in the world.

Such populations offer geneticists thechance to discover rare gene variants under-lying disease that would be difficult to detectin more diverse groups. And in the early1990s, with the tribe’s blessing, a team fromArizona State University (ASU) in Tempebegan searching for a genetic cause of theHavasupai’s diabetes.

Instead of a genetic breakthrough, theresearch project has spawned lawsuits claim-ing $75 million in damages, filed by tribalmembers who claim that their rights wereinfringed. The accused researchers strenu-ously deny any wrongdoing, and blame thedispute on a series of misunderstandings.These problems seem to have been inflamedby personal differences among the scientistsinvolved. But the case illustrates the sensitiv-ities associated with conducting geneticresearch on Native American populations —which, enriched by gambling revenues, arenow in a position to assert their legal rights.

Medical geneticists are watching the law-suits carefully, as some believe the resultscould cast doubt on the future of geneticstudies being conducted on Native Americanpopulations across the United States. In themeantime, the Havasupai reservation, some

240 kilometres northwest of Flagstaff, isclosed to researchers.

“What concerns me deeply is that the allegations have resulted in a moratorium onbiomedical research on the Havasupai reser-vation, excluding this and other communi-ties from discoveries with the potential toaddress their health concerns,” says ThereseMarkow,who led the Havasupai project dur-ing her years at ASU, and is now at the Uni-versity of Arizona in Tucson.

Family rootsTo investigate the genetics ofdisease in small, remote popu-lations, it is important to determine just how geneticallyisolated a group really is. Withmodern molecular tools, researchers canexamine a tribe’s genetic history, revealingwhere tribal ancestors migrated from, andthe degree to which they have interbred, overthe years, with other groups — includingAmericans of European extraction.

These are sensitive subjects for NativeAmericans. Details about migration maychallenge the received cultural wisdom abouttribal origins, and the question of who is‘more native’can be particularly contentious.

In decades past, Native Americans feelingviolated by intrusion into such territorywould have had a hard time challengingresearchers from a major university. But thebalance of power is shifting. Gambling onreservations produces millions of dollars in

revenue, and has made native tribes a politi-cal force. Given their remote location, theHavasupai do not run a casino,but they sharein revenue from those Arizona tribes that do.And the state’s tribes work together on vari-ous issues, hiring well-connected lobbyistsand high-powered attorneys to protect theircollective interests.

The growing influence of Native Ameri-can tribes has already been used to block

the publication of studiesdeemed culturally offensive — adevelopment that has splitresearchers working with nativecommunities (see ‘The heart ofthe matter’, overleaf). Some seeit as unacceptable censorship;others argue that the tribes’

cultural sensitivities must come first.Against this background, the Havasupai

experience illustrates just how badly thingscan go awry. The project began with greatpromise — melding Markow’s interests ingenetics with the expertise in social anthro-pology of John Martin, an ASU colleaguewho had worked with the tribe for more than40 years. Martin knew several generations ofHavasupai and had created a genealogicalhistory of tribal families.

At the beginning of the twentieth cen-tury, a combination of disease and naturaldisasters had reduced the Havasupai toabout 165 members, with only about 40 menand 40 women of reproductive age. As thepopulation recovered from this bottleneck,

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When twotribes go to warMedical geneticists and isolated NativeAmerican communitiesafflicted by inheriteddiseases should havemuch to gain fromworking together. Butthe relationship can gosour, as Rex Daltonfinds out.

“Native American tribesare so understudied. Ifthis litigation continues,all research is going tocease.”

— Daniel GarriganC

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the rate of diabetes began to climb. In 1991,when Markow’s study began, 55% of Hava-supai women and 38% of the men were dia-betic. Martin had also observed a mentalcondition that he suspected to be schizo-phrenia — and which his family charts indi-cated may have originated with a tribalshaman in the late nineteenth century.

On the trailMarkow and Martin put together a pro-posal to study diabetes, schizophrenia anddepression in the Havasupai, which wasapproved by ASU’s human subjects com-mittee in 1991. Initially, the study was conducted with university funds and agrant of some $90,000 from the NationalAlliance for Research on Schizophrenia andDepression in New York. Later on, therewould be small grants from the NationalScience Foundation and the National Insti-tutes of Health.

Working with the Havasupai meant hiking, riding horseback or taking heli-copters into the reservation. Tribal memberswho volunteered for the study signed a con-sent form in which they agreed to provideblood samples, plus hand and fingerprints,for genetic studies into behavioural andmedical disorders.

Pursuit of a genetic cause of schizophre-nia was dropped early on, after a psychiatristfound no evidence of the disease among tribe members. And as the ASU researchersbegan to examine Havasupai DNA samples,

they also ran into trouble finding a geneticlink to diabetes. Studies of another Arizonatribe, the Pima, had by then found that 81% of nearly 200 Pima diabetics carried a particular variant of a gene involved in immune recognition called HLA-A2(ref. 1). But Markow’s team could find no association between this gene and dia-betes in the Havasupai2.

The project looked set to yield nothingbut results on the general biological conse-quences of the tribe’s restricted gene pool3 —especially after cell lines created from theHavasupai blood were damaged by a freezerfailure in 1994. By the time that Markowmoved to the University of Arizona in 1999,it seemed as if all momentum had been lost.

But in 2002, the project was reinvigoratedafter genetic material was salvaged from thedamaged cell lines. Daniel Garrigan, a PhDstudent in another lab at ASU, was then ableto analyse genetic markers called microsatel-lites — repeating sequences of two or moreletters of the genetic code that vary in theirlength from person to person — to examinegenetic variability among the Havasupai.

By early 2003, Garriganhad a manuscript accepted bythe journal Genetics detailingmarkers in the Havasupai thatwere sufficiently variable touse in the search for genes pre-disposing to diabetes. Thiswas also a major part of hisdoctoral thesis — until hewalked to the podium at ASUon 4 March 2003 to deliver alecture as part of the examina-tion process.

The audience includedMartin and an acquaintance of his from the Havasupai,

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Carletta Tilousi. She publicly questionedGarrigan’s authority to perform the study.“Itwas a bizarre event,”recalls Garrigan.The daybefore the lecture, Garrigan says Martin hadwarned him that he viewed the Havasupaidata as his intellectual property. “Stop, orthere will be repercussions,” Garrigan claimshe was told. Martin agrees that he challengedGarrigan on his use of the samples,but deniesthat this was a threat.

Culture clashWhile he had made been aware of Martin’sviews on the ownership of the data, Garri-gan was stunned by Tilousi’s intervention at his lecture. Having worked among theMaya in Mexico before joining the Havasu-pai project, he thought that he was sensitiveto Native American concerns. He alsobelieved that his studies had put him on the trail of a genetic explanation for dia-betes in the Havasupai.

When Martin and Tilousi objected toGarrigan’s research, meetings were held atASU. A decision was made to withdraw themanuscript from Genetics,and to remove the

microsatellite data from Gar-rigan’s thesis.“It was disheart-ening,” says Garrigan, who isnow a postdoc at the Univer-sity of Arizona.

After the thesis showdown,the conflict intensified. Martinfirst complained to ASU’shuman subjects committee,alleging that the research hadstrayed away from the topic ofdiabetes into areas that thetribe had not agreed to. Whenthe committee investigatedthis and found no problem,Martin wrote to ASU president

Therese Markow sought agenetic cause for diabetes inthe Havasupai.

In dispute: the Havasupai tribeinitially welcomed geneticists into

its remote settlement (right), butsubsequent research has led the

Native Americans to file lawsuits for$75 million in damages.

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Michael Crow and other university officialson 11 May 2003. In this letter, he alleged thatMarkow had misused tribal DNA samples bysending them for analysis of their HLA genesto two labs in California.

Martin had by then come to believe thatthe Havasupai’s diabetes was caused bynutrition during fetal development, and his letter claimed: “no genetic research ondiabetes genes was undertaken” by anyone.He now acknowledges that this statementwas an error.

Regardless of its factual accuracy, Mar-tin’s letter came at an inopportune time forASU. Newly installed as president, Crow wasleading an ambitious plan to accelerateresearch at the university, including geneticstudies of Native American tribes. A newstate-funded research facility, the Transla-tional Genomics Research Institute inPhoenix, was also developing collaborationswith ASU researchers and Arizona tribes.

At the same time, the Havasupai werepreparing to go public with a press confer-ence, lambasting ASU over the research pro-ject. To head off an embarrassing public row,ASU opted to pay for an investigation intothe project by an independent attorney.

In retrospect, that move seems to havebeen a monumental blunder on the part of the university — one that paved the wayfor the lawsuits now filed against ASU, theUniversity of Arizona, the two institutionsthat performed the HLA gene analysis,and individual scientists including Martinand Markow.

The investigator was Stephen Hart, alawyer in Phoenix who has represented tribalgovernments and formerly served as directorof the Arizona Department of Gaming,over-seeing Native American gambling opera-tions. His report ran to nine volumes, andwas delivered to ASU and the Havasupai late last year.

Hart’s report is a compendium of inter-views. It contains no firm findings of mis-conduct, but states that there are “issues”

with how the project was administered,the keeping of records, and whether the triberealized the full extent of the research thatwould be undertaken. In March this year,a 150-page summary of the report was submitted to the state court in Flagstaff,in support of two lawsuits claiming that the Havasupai’s civil rights were violatedwhen their blood samples were used in the research.

Deeply divided The lead plaintiff on one of the lawsuits isTilousi, who was elected last December tothe tribe’s governing council — the plaintiffon the other suit — as concerns grew aboutthe research. Tilousi says she feels mentally“raped” by the project.

The accused researchers are disturbed byHart’s report. In particular, Markow arguesthat Hart gave too much credence to the tes-timony of Christopher Armstrong, formerlya researcher at ASU. Armstrong has sincebeen convicted for dealing cocaine and wasbeing treated for drug and alcohol abuse atthe time he was interviewed by Hart.

Armstrong accused Markow of variousimproprieties, including hiding studies onschizophrenia from the Havasupai. Markow

denies the allegations. Far from exploitingthe tribe,she argues that her group did exten-sive screening for diabetes among tribalmembers and provided health education.

Martin, whose complaints helped to trig-ger Hart’s investigation, is similarly con-cerned about the report. Indeed, Martin’sprotests against Garrigan seem to haverebounded badly on him. His relationshipwith the Havasupai has been torn apart andthe suspension of research on the tribe’sreservation has halted Martin’s work. “I’mbitterly disappointed,” he says. ASU officialsare now in the process of collecting anyremaining stored blood and DNA so thatthey can be returned to the Havasupai.

Bartha Knoppers, an expert on informedconsent in genetic studies at the University of Montreal in Canada, notes that standardshave evolved since the Havasupai projectbegan.But she feels that it is difficult to judgethe conduct of the research by today’s moreexplicit standards.

In some other cases, researchers havegone back with new consent forms whenextending a project, but this is unusual.In the Havasupai case, ASU’s human subjects committee accepted that Garrigan’sresearch was an extension of the previouslyapproved project.

Whatever the outcome of the lawsuits,the researchers at the centre of the storm fearthat the publicity generated will threatenfuture genetic studies of Native Americantribes. “They are so under-studied,” says Garrigan. “If this litigation continues, allresearch is going to cease.” ■

Rex Dalton is Nature’s US West Coast correspondent.1. Williams, R. C. et al. Diabetologia 21, 460–463 (1981).

2. Markow, T. A. et al. Am. J. Hum. Genet. 53, 943–952 (1993).

3. Markow, T. A. & Martin, J. F. Ann. Hum. Biol. 20, 389–394 (1993).

4. Williams, R. C., Long, J. C., Hanson, R. L., Sievers, M. L. &

Knowler, W. C. Am. J. Hum. Genet. 66, 527–538 (2000).

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When it comes to genetic studies of NativeAmericans, anthropologist Robert Williams ofArizona State University in Tempe has learnedthat — in addition to passing scientific peerreview — it may be necessary to pass a test of cultural sensitivity.

After eight years of laboratory work on bloodsamples taken from 5,000 individuals belongingto 12 tribes across the United States, Williamswas in 1999 required to halt his attempt toinvestigate the growing incidence ofcardiovascular disease among the tribes.

His project was part of the Strong Heart Study,a large epidemiological study that has received$46 million over 15 years from the National Heart,Lung, and Blood Institute (NHLBI) in Bethesda,

Maryland. Williams suspected that the epidemicof heart disease among Native Americans was inpart caused by gene flow from interbreeding withAmericans of European origin. So he set aboutinvestigating this genetic ‘admixture’, anapproach he had previously used in studies of diabetes among Arizona’s Pima tribe4.

Every manuscript arising from the StrongHeart Study is submitted to tribal representativesfor review. Williams’ paper, dealing with thesensitive issue of interbreeding with non-NativeAmericans, was the first to be blocked. “I feel thisis political censorship,” Williams says. “This hasnever happened in my 30-year career.”

Everett Rhoades, a Native American medicalresearcher at the University of Oklahoma who

was the chair of the ethics committee thatrecommended halting Williams’ research,declined to comment for this article. Butepidemiologist Barbara Howard of GeorgetownUniversity in Washington DC, who heads theStrong Heart Study, rejects Williams’ complaintsof censorship. “I know he is frustrated,” saysHoward. “He is a good researcher. But theconcerns of Native American communities take precedence.”

Peter Savage, the NHLBI’s director ofepidemiology, adds that Native Americanvolunteers can withdraw from research and ask that their samples be destroyed at any timeand for any reason. “This is the cost of doingresearch in special communities,” he says.

The heart of the matter

Native Americans have become increasinglypolitically active — here they protest outside the football ground of the Washington Redskins.

For more news and analysis go to

www.nature.com/news

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