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HeLa, the Havasupai, and Informed Consent

HeLa cells are back in the news, with a Comment from Kathy Hudson and Francis Collins in Nature celebrating researchers’ collaboration with the descendants of Henrietta Lacks on the use of their famous relative’s cancer cells.

Lacks unwittingly supplied her cervical cancer cells to researchers in 1951, and the cells went on to become a laboratory staple. Her race and economic status –black and poor – compounded the issue of informed consent, and her story became a staple of biology 101.

I’ll leave the HeLa news to the other bloggers, and as usual, pursue a different angle.

A case similar to that of Henrietta Lacks, but that more directly involves DNA, is that of the Havasupai Indians. They gave blood for DNA testing after signing an informed consent document that some say was much too broad. They thought their DNA was being tested only for diabetes susceptibility genes, according to many documents.

In revisiting the case for this blog post, I discovered holes in the story that reveal an underlying “he-said, she-said” situation with the “he saids” all but drowning out the “she said.” Yesterday I spoke to the she, the scientist accused of misleading the Havasupai into providing DNA for one purpose, only to use it later for several, unacceptable to them, others.

This week, the facts of the case.

The Havasupai have lived in a small village called Supai at the bottom of the southwest corner of the Grand Canyon since splitting from other descendants of the prehistoric Hohokam Indians in Mexico in 300 B.C.. In the early 1880s, they were put on a reservation of 188,077 acres.

Today the Havasupai number about 500, and their culture is a curious mix of old and new. They have a website that offers tours and camping vacations to see their spectacular waterfalls. The website warns in red letters that the Havasupai are not affiliated in any way with another website run by a company out to make a profit using the Indian name. Supai is accessible by helicopter or primitive trails, and pack mules deliver the mail. Forget about UPS or Federal Express.

The isolation of the Havasupai and a population bottleneck in their past restricted the gene pool, intriguing researchers at Arizona State University. In 1963, anthropology professor John Martin began visiting, and gained the trust of the people.

In 1989, a tribe member approached Martin concerned about the alarming number of cases of diabetes. Martin began a collaboration with his colleague, geneticist Therese Markow, to investigate whether the people had inherited susceptibility to type 2 diabetes. They’d collect blood samples to see if genetic markers distinguished those at high risk of the disease. A precedent was well known in genetics circles – the Pima Indians.

During the Middle Ages, the Pima Indians separated into two populations, one settling in the Sierra Madre mountains of Mexico, the other in southern Arizona. By the 1970s, the Arizona group had given up farming and consumed an unhealthy diet – and developed the highest rate of type 2 diabetes on the planet. Half of them had the disease by age 35, and weighed on average nearly 60 pounds more than their relatives to the south, who maintained the active and low-calorie diet of their ancestors. The Pima, it turned out, had an HLA genotype that predisposed them to develop diabetes in the presence of the environmental triggers.

In 1990, Markow and her team visited the settlement, seeking blood and taking handprints and fingerprints. Much of the media coverage that would follow years later  quoted from the part of the informed consent document that said the Havasupai DNA could be searched “to study the causes of behavioral/medical disorders.” Confusion began when evidence emerged that the DNA had been used to study schizophrenia. Apparently the Havasupai did not equate schizophrenia with “behavioral” disorders, perhaps in the way some people I know taking Metformin for very high and erratic blood sugar levels do not realize they have diabetes.

I’ve read the informed consent document, which an institutional review board had approved. It’s a single page of numbered items. Here are two of interest:

Item #10: “I have been informed that any questions I have concerning the research study or my participation in it, before or after my consent, will be answered by Dr. Therese Markow,” and has her phone number.

Item #12: “I have read the above informed consent. The nature, demands, risk, and benefits of the project have been explained to me. I knowingly assume any risks involved, and understand that I may withdraw my consent and discontinue participation at any time …”

Of the 650 Havasupai at the time, 200 gave blood samples.

Years passed. And techniques to search DNA improved.

In 2002, John Martin the anthropologist learned that a PhD student was about to give a dissertation talk, part of which was about using microsatellite markers to analyze Havasupai DNA. These markers, which tally short DNA repeats, hadn’t been around in the early 1990s when the Havasupai donated their blood.

In March 2003, Martin invited along a student who’d stopped by, Carletta Tilousi, to hear the presentation. She’s Havasupai and had participated in what was known as “the diabetes project.” Shocked when the student’s seminar ventured beyond that particular trait, she shouted “did you have permission?

That, it turned out, depended on how you define “permission” in regards to time. And so with Tilousi’s outburst, the shit hit the fan.

A Havasupai woman

Confusion arose over whether an initial informed consent would cover later advances in genetic testing that would allow extraction of additional information. The question was quite prescient, one even more relevant in today’s genomic age when we haven’t yet finished annotating the human genome and its nearly limitless variants.

Back in 2003 and 2004, the university investigated, and ultimately found several published papers using Havasupai blood to study things other than diabetes, which turned out not to be linked to any known diabetes susceptibility genes,including the one among the Pima. Havasupai blood had been used to study schizophrenia, migration patterns and ancestry, and inbreeding – opening a bioethical can of worms. While today some of us send off our DNA to testing companies to learn all sorts of disturbing things, looking for these particular traits was devastating to the Havasupai.

The “inbreeding coefficient” of statistical genetics mentioned in some papers implied to the Havasupai taboo sex between blood relatives, for which someone would die.

The DNA tracing of migration across the Bering Strait countered tribal lore of living in their corner of the Grand Canyon forever.

The people would never have given permission to have their DNA tested for schizophrenia, a term not in the informed consent document. The Havasupai feared stigmatization.

The situation turned ugly. Rex Dalton summarized most of the misunderstandings and miscommunications well in Nature.

In 2004, the Havasupai announced a “Banishment order” keeping ASU employees out of their turf forever. They threatened a press conference, ASU calmed them down, and it went back and forth for years until the lawsuit filed in 2004 was settled. In 2010, the tribe received a tiny fraction of what they’d sued for, to build and operate a clinic and school, with the promise of destruction of the contentious DNA samples. A Perspective piece in The New England Journal of Medicine that year explored the legal and bioethical issues surrounding “future use” of biological specimens.

The lack of informed consent in the Henrietta Lacks case and the overly-broad and limited informed consent in the Havasupai case are now part of history. Informed consent documents have since changed. I read several while writing my book on gene therapy, and I can attest that today they are long, detailed, follow explicit instructions on clarity, and if the participant is too young to understand – age 7 is the minimum for informed assent, and the main character of my book was 8 years old – researchers provide the information in every medium possible.

Young Corey Haas, who had gene therapy on one eye and then, many months later, on the other eye, read simplified documents, had them read to him by the researchers and his parents, watched videos, and talked to the researchers on the phone and in person. Nothing went forward until the researchers were certain that he understood what would happen. And when it came time to fix his second eye, Corey went through the process again.

HeLa cells
HeLa cells

What happened to Henrietta Lacks and the Havasupai will likely not happen again. But turning a scientist into a scapegoat because it makes a good story might, because that is what I fear may have been the case with the Havasupai situation.

The story was compelling.  The New York Times ran a front page piece by its star genetics reporter, and the NHGRI funded an excellent write-up for use as a case study in the classroom and among other tribes. I included what I knew of the story in my textbook, and assigned it in my bioethics class. But errors of omission are notoriously difficult to spot.

And then I reread everything this week, to take my usual unusual spin on a hot news item, the HeLa announcement. But I soon grew uneasy about the media as well as the journal coverage of the Havasupai case. Something was missing; the facts just didn’t seem to add up. I was horrified to realize I’d blogged about the case and “future use DNA” based on what I’d read. Why hadn’t I seen the lapses in logic before?

Among other omissions in the media coverage and bioethics chatter that followed the settlement in 2010, hardly anyone mentioned the viewpoint of the researcher who was blamed for testing DNA for certain traits without explicit permission. And so I googled her, and that led to some surprises. I’ll pick up with the other side of the story next week.

  1. I especially appreciate your juxtapositioning the HeLa and Havasupai stories, along with issues of informed consent and institutional review boards (IRBs). I now believe that there is a need for the science community (e.g., AAAS, APA, AAA et al.) to develop more rigor in IRB documents … particularly in regards to doctoral students at small colleges and universities and in distance learning institutions.

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