Genomics’ ethical gray areas are harming the developing world

Since the first human genome was sequenced in the early 2000s, scientists have touted the breakthrough as a blessing to humanity — one that holds promise to promote human health and enhance medical treatment the world over. But around two decades later, the benefits of that scientific advancement have barely rippled out beyond Europe and North America. As of 2018, people of European ancestry —who represented approximately 16 percent of the world population at the time — made up 78 percent of all individuals whose genomes have ever been collected and studied.

Over the last decade or so, international studies on human population genetics have begun to expand genomic libraries to encompass regions of the Global South — including Southeast Asia, where I am a science reporter, and the Pacific islands. These international studies, often led by Western scientists, have contributed to a more global understanding of ancient patterns of human migration and evolution. But on some occasions, they’ve also sidestepped local regulatory agencies in the developing world, and ventured into murky research ethics terrain as a result.

DNA profile from a human sample.

A recent example — a case that simultaneously illustrates the promise, pitfalls, and pressure points of international genomics research — comes from the largest genetic study ever conducted in the Philippines, published last year in the Proceedings of the National Academy of Sciences. A team led by Mattias Jakobsson of Uppsala University in Sweden and Maximilian Larena, who was a researcher in Jakobsson’s lab at the time, collected and analyzed DNA samples from more than 1,000 Filipinos representing 115 Indigenous groups. The study determined that today’s Filipino population descends from at least five distinct waves of human migration, spanning thousands of years — a finding that they said contradicted the prevailing theory of how humans populated the islands.

One could see the Uppsala study as a model of international collaboration. The project was endorsed by the Philippines’ National Commission for Culture and the Arts, a government body that coordinates, funds, and makes policy for the preservation, development, and promotion of Philippine arts and culture. It was also done in partnership with more than a dozen local Indigenous and cultural groups in the Philippines; the paper’s appendix acknowledges more than 100 Filipinos who assisted with the study in some way, and Larena is himself Filipino. And key portions of the research plan were approved by an ethics review board in Sweden.

But many bioethicists would argue that it is not enough for researchers who do a human genomic study on foreign soil to merely collaborate with local groups. Various ethics guidelines on health-related research — including UNESCO’s International Declaration on Human Genetic Data and international ethical guidelines published by the Council for International Organizations of Medical Sciences, or CIOMS, in collaboration with the World Health Organization — advise researchers to seek approval from an ethics committee in the host country. Such reviews are critical, bioethicists say, because cultural and social considerations of research ethics might vary between countries. In low-resource countries especially, ethics reviews are essential to protect the interests of participants and ensure that data are used in ways that benefit local communities.

Nowhere in Larena and Jakobsson’s paper, or in any of the subsequent publications based on the Philippines study, does the Uppsala team mention obtaining such an ethics approval in the Philippines — and Philippines officials say they never granted the team such an approval. Asked whether his group had obtained a formal ethics clearance in the Philippines, Jakobsson pointed to the project’s endorsement from the National Commission for Culture and the Arts, and wrote that part of the commission’s mandate is to ensure that the research they support is “in accordance with the ethical principles of research involving participants from the Indigenous communities.” But the NCCA primarily supports research that is cultural, not scientific, in nature, and a government website outlining the commission’s mandate, powers, and functions makes no mention of any duties related to research ethics. In a 2021 letter, the commission’s executive director wrote that the agency “has no mandate or authority to give ethical clearance” and did not give ethical clearance for the Uppsala study. (I reached out to the commission for this story but did not receive a response.)

A failure to secure formal ethics clearance might be understandable if there were simply no official Filipino agencies equipped to provide that clearance. But the Philippines has such a body — the National Ethics Committee, or NEC, which falls under the jurisdiction of the Philippine Health Research Ethics Board — and the Uppsala researchers were no doubt aware of this. In 2014, as the researchers were laying the groundwork to begin collecting human samples, they actively sought the NEC’s approval.

That approval was never granted. Marita Reyes, then the chair of the NEC, said she noticed problems with the initial Uppsala application. For instance, it did not clearly describe how research participants would be recruited, and it lacked the proper paperwork for researchers who intend to ship genetic materials overseas, she told Undark in an email. Reyes asked the Uppsala team to fix the issues and also recommended that they collaborate with local researchers who were doing similar work at the Philippine Genome Center.

According to Jakobsson, the Uppsala researchers took issue with the stipulations levelled at their application, and they say the prospective collaborators at the Philippine Genome Center made troubling demands regarding control of the collected samples. Ultimately, the researchers withdrew their application altogether. Their rationale: They say their population genetics study was not health related, and therefore did not fall under the jurisdiction of the NEC or the Philippine Health Research Ethics Board. “Given that your good office does not have regulatory mandate on the nature of our study,” Larena wrote to Reyes in an email, “we humbly withdraw our application.” In the ensuing months, the Uppsala team would go on to collect DNA from more than 1,000 Filipinos without ever receiving express ethics approval from the NEC.

The case created an uproar in the Philippines. In a public statement, Allen Capuyan, chairperson of the Philippines’ National Commission on Indigenous Peoples, condemned the study, saying the researchers showed a “blatant disregard of critical policies governing scientific research in the Philippines.” Leonardo de Castro, a Filipino bioethicist who now chairs Philippine Health Research Ethics Board, asserted that the Uppsala study did fall under the NEC’s jurisdiction, and he called on the journal that published the Uppsala work to issue a retraction. (I first learned of the controversy in 2018 from officials at the Philippine Health Research Ethics Board; Maria Corazon De Ungria, a laboratory director at the Philippine Genome Center, later contacted me about the matter as well.)

Meanwhile, the Uppsala researchers have maintained that they “are absolutely certain” that they abided by basic ethical principles of research involving humans, and they say that investigations by a Swedish ethics review board, by Uppsala University itself, and by scientific journals have cleared them of any wrongdoing.

Nevertheless, I believe the case exposes a glaring shortcoming in the regulation of international genomics research: Even if bypassing a formal ethics review does not violate the letter of the law on human genomic research, it at least seems to go against the spirit of trust and transparency that are the foundation for healthy international scientific collaboration — principles enshrined in the UNESCO and CIOMS guidelines. The Uppsala team is hardly the first to wade into this gray area of research ethics. In 2018, I wrote about a team of mostly Danish and American scientists who conducted a genetic study of Bajau traditional divers in Indonesia and also failed to obtain ethics approval from a local review board.

Was the Uppsala team right to conclude that their study fell outside the jurisdiction of the Philippines’ health research regulatory framework? Some people seem to think so. In a letter of support to the researchers, an attorney with the National Commission for Culture and the Arts — the Philippines group that supported the study — affirmed that the nature of the Uppsala project was “exclusively cultural” and fell under NCAA’s jurisdiction, rather than that of the National Ethics Committee or the National Commission on Indigenous Peoples. Hank Greely, a professor of law at Stanford University who specializes in biosciences, including bioethics, said that the study published in PNAS didn’t appear to be health related and suggested it’s reasonable to argue that health research guidelines shouldn’t apply in this case, although that wouldn’t mean that no ethical standards should apply.

But other bioethics experts — including Triono Soendoro, the chair of the Indonesian Society of Ethics Committee for Research and Services — say that ethics standards like those developed by CIOMS and enforced by the Philippine Health Research Ethics Board were clearly meant to apply broadly to research involving human biological samples, even studies that have non-medical purposes. Population genetics research that identifies subjects by social or ethnic group, as the Uppsala study does, “is certainly covered by CIOMS,” said Eric Juengst, a bioethicist and professor at the University of North Carolina at Chapel Hill.

Human genomic science is too important, too consequential, to allow this precarious state of affairs to persist. If we want science to serve the whole of humanity, we need a strong set of universally binding rules on research ethics — rules that clearly give local authorities a voice on matters of research ethics in all studies involving human genetic sampling, not just those that are obviously medical in nature.

In the Uppsala case, for instance, a formal ethics review might have offered important safeguards to ensure participants were fully aware of how their samples would be used and stored. Although participants signed informed consent forms that laid out many details of the research, a copy of the form obtained by Undark did not mention that samples would be shipped out of the country, to Sweden, for sequencing and analysis. This information could conceivably have influenced a subject’s decision to participate. (In a follow up email after publication, the Uppsala researchers provided seven letters — dated after the publication of this essay — signed by individuals attesting that they were involved in the sampling process and affirming that participants were aware their samples would be shipped to Sweden.)

Formal ethics reviews are also crucial for ensuring that low-resource countries can freely and independently access data that might benefit the health and wellbeing of their people. Even genetic data obtained for purposes unrelated to health may later prove beneficial for medical purposes. Data generated from more than 1,000 samples collected in the Uppsala study is now stored in the European Genome-Phenome Archive, where a Data Access Committee now has sole power to determine who can use it for future studies — although one condition must be that such research is in accordance with consent provided by study participants. (The archive’s website doesn’t specify the members of the Data Access Committee assigned to the Philippines data set, but it lists Larena as the contact person.) Research institutions in the Philippines are not guaranteed to be able to make use of data from the largest human genetic sampling ever conducted on its own soil (though Larena and Jakobsson indicated in an email after this essay's publication that some researchers in the Philippines have been granted access through a data sharing consortium).

The international scientific community must be proactive in raising the standards of global research ethics. Prestigious journals, the gatekeepers of science, should ensure that researchers who collect human DNA samples make every effort to secure formal ethics approvals in the countries where the sample collection is performed. They should also be transparent about investigations of ethics misconduct and involve ethicists from developing countries in those investigations whenever possible.

Human genomic science should not stop at merely satisfying our curiosity. It should also serve the poor and the marginalized. Otherwise, if history is any guide, it will lead only to increasingly extreme disparities between the Global North and the Global South.

UPDATE: A previous version of this piece stated that a group of Uppsala researchers had initially withdrawn their application to a Philippines research ethics authority because their proposed study “was cultural, not health related.” While the Philippines National Commission for Culture and the Arts described the work as cultural, the researchers themselves describe the work as a study of "heritage." The piece has been edited to remove this error. The piece also imprecisely described the data stored in the European Genome-Phenome Archive. It is data generated from the more than 1,000 genetic samples collected. The 1,000 samples themselves are not stored in the archive.

This piece has also been updated to clarify whether participants in the study knew that their DNA samples would be shipped to Sweden for analysis. As the piece originally stated, consent forms signed by study participants did not mention this transfer. Following publication of this essay, however, the researchers produced statements — dated March 2, 2022 — from seven individuals involved in the sampling process attesting that study participants were informed of the shipment plans. The essay has been updated to reflect this.

The piece also questioned whether institutions in the Philippines would be able to make use of the data collected by the Uppsala team. In an email sent to Undark after publication, Larena and Jakobsson indicated that some researchers in the Philippines have already been granted access through a data sharing consortium.

This article was originally published on Undark. Read the original article.