The Illusion of Inclusion: Q&A with Dr. Keolu Fox
Dr. Keolu Fox is a Native Hawaiian geneticist and Indigenous rights activist. He has a PhD in Genome Sciences and is an Assistant Professor of Anthropology at UC San Diego, as well as an advisor to Variant Bio. Broadly speaking, Dr. Fox looks at the relationship of genomics to society, and of Indigenous communities to science. Here, he elaborates on issues raised in his recent article, “The Illusion of Inclusion: The ‘All of Us’ Research Program and Indigenous Peoples’ DNA,” which was published in The New England Journal of Medicine on 30 July 2020.
This interview has been lightly edited and condensed for clarity.
Sarah: To begin with, why is it that most large-scale studies of human genetic variation to-date are severely lacking in terms of diversity?
Keolu: There’s a two-fold reason for this. One is that there is a very obvious colonial legacy of exploitation of Black and Brown people. That legacy in part makes those communities of people and those individuals reluctant to participate in those types of studies. Because as far as underrepresented, marginalized, Black and Brown communities go, there hasn’t really been much impact in terms of the speculative future that was promised and what was delivered. So there’s this schism between intent and impact.
Second, there is this aspect of what is easy and what is comfortable for an investigator. If you’re a white investigator, it’s a lot easier for you to engage communities that look like you. Because you have a lot more in common with them, you know what to say to get them to agree to participate in your study and sign your consent form. The dialogue and negotiation is much easier, and because of that, it’s more comfortable for you, and people do what’s comfortable. So those are two of the key reasons why there’s been this effect.
Sarah: Could you share an example of an Indigenous population with specific variant signatures in its genomes, and what that has taught us?
Keolu: There are a number of examples, but it’s really important to couch this in the fact that the full spectrum of human genetic variation that we observe is generally speaking a reflection of our diaspora as a species of human beings. The variation that we see, ranging from our skin and hair color to our susceptibility to disease in a lot of cases, is a result of our history and the unique diaspora that each community of people has undertaken.¹
So I can talk to you about certain genetic mutations that are signatures of that journey. One of the best ones is HBB sickle cell and malaria, which is found mostly in Equatorial Africa. That is a reflection of an evolutionary arms race with pathogens. Another one would be ABO variation in balancing selection in many different populations of people. Nothing has shaped our genomes more than pathogens in our history. That speaks to our place and subsistence methods and modalities. Another one that is equally as interesting is altitude adaptation. You see signatures in Himalayan and Andean populations in genes like EPAS1 and EGLN1. Those are a reflection of subsisting at high elevation for, in some cases, many millennia.²
Nothing has shaped our genomes more than pathogens in our history.
Now you asked me to give you one example and I won’t. The point is, we don’t know which examples are real and which examples are not, because there are a lot of what Stephen Jay Gould and Richard Lewontin called evolutionary “just-so stories.” I had a professor once who said, “Give me two genes and I’ll tell you a story.” I can look at and make the case for certain genetic mutations being under selection if I use the right statistical methods. I can build you a narrative about how extraordinary this community is under these conditions, and I can tell you what their diaspora and history are.
The stories I just told you are ones that I would call A+ and A- stories, because they’re really high up there in terms of what we know about the physiology, and what we know about the communities and their diaspora. But there are other stories, like the CREBRF and “thrifty gene” theory [see here for more on this], that I would call an F- story. It’s also a reflection of the time, because when James Neel came up with the “thrifty gene” theory it was believed that the Austronesian diaspora happened by accident and that Polynesian, Micronesian, and Melanesian people “drifted” and ended up in places like Raiatea, the Tuamotus, the Marquesas, and Hawai’i.
This completely discredits the voyaging and navigational achievements of our ancestors.⁴ The original moonshot, the most impressive voyaging and navigational feat in history, is part of our diaspora. So when you say that we got there by accident and you build an evolutionary narrative around a gene and talk about a genetic variation in it, you’re discrediting our achievements as a voyaging people and our migratory history and diaspora. You’re also implying that there’s an innateness to the reasons why we have problems with metabolic disease, which is more a reflection of colonialism and replacing our traditional foodways and subsistence lifestyle–from subsisting on the reef to spam, white rice, and soy sauce.
The original moonshot, the most impressive voyaging and navigational feat in history, is part of our diaspora.
Sarah: How would you personally feel about participating in the National Institutes of Health (NIH) “All of Us” Research Program?
Keolu: I wouldn’t. Because I don’t think it’s the best use of hard-earned taxpayer dollars that’s allocated through the federal government. And because it lacks imagination as an initiative that’s going to move personalized medicine to the next level. It’s not well thought out in that sense because it’s more of the same. It’s like, “What order of magnitude of people have been sequenced in this country? OK, now let’s go to the next order of magnitude and hope that generating this much data is going to lead us in a certain direction.”
If we zoom out and begin to ask questions about what the actual impact has been of precision medicine, we start in 2001 with the unveiling of the draft genome of the Human Genome Project with Bill Clinton and Francis Collins, and we look at the speculative future that was promised in that moment and the amount of money that has gone into delivering prediction, prevention, and personalization of the next generation of medicine and therapy based on your participation, I don’t think we’ve gotten enough out of it. I think some of the avenues where genetics and surveys of the spectrum of human genetic variation have been successful have more to do with rare disease and Mendelian disease. There’s far less that has actually contributed to understanding common complex disease.
I’m not trying to blame everyone, because I’ve participated in this, I’ve worked at the National Institutes of Health and the National Human Genome Research Institute. I’ve worked for some of the largest labs in the world when it comes to surveying human genetic variation involving analysis and innovation in population genetics in a number of different places. And the schism between the intent and the impact is very obvious. Now we’re twenty years–two decades!–into this and we’re still asking the same questions.
Another thing that I think we need to bring attention to and that I brought attention to in the piece [I wrote] is that data is not just data anymore. When the Human Genome Project was initiated in 2001, the number one commodity on Planet Earth was oil. In 2020, the number one commodity on Planet Earth is data itself–raw data, including digital, sequenced information.⁵ This is the commodity that by all means symbolizes and represents why Facebook, Amazon, and Google are the largest companies in the world. We use the same exact terms to describe aggregating, manipulating, and “mining” raw data. We use the same terms that we would use when we talk about extracting coal, blood timber, blood diamonds, oil, you name it. This is a resource that is mined, and aggregated, and used to model things. It’s used to predict and develop things. Now we’re watching the emergence of a totally different economic ecosystem. We’re watching these large databases like the “All of Us” Research Program become a tool to be utilized to model and predict and prevent the development of new drugs. That’s exactly what it’s going to be used to do.
[I]n 2001, the number one commodity on Planet Earth was oil. In 2020, the number one commodity on Planet Earth is data itself.
The Precision Medicine Initiative turned into the “All of Us” program, as it was later rebranded, because they wanted to include as many minorities and underrepresented populations as possible. Because they know that geographically sequestered populations have these unique evolutionary histories and will have genetic mutations that are globally rare but specific to that community. As we look into these populations in a field where 90% of surveys of human genetic variation have been in individuals of Western European ancestry,⁶ we know that we’re going to find these low-hanging fruits, so to speak, in minority populations. But we also know that there are no policies in place to represent their interests and safeguard against the aggregation, collection, and utilization of that data and information. Any other resource that we talk about disenfranchising people of would be considered a human rights violation. But in the case of data it’s so new and nebulous and ill-defined, we haven’t begun creating conversations around big data as a resource and what that means, who owns what, and who has access to what.
Any other resource that we talk about disenfranchising people of would be considered a human rights violation.
One other important point is how does this benefit people? Because if you can use that information to fast-track the development of new treatments, who are they going to benefit? Is it going to benefit big pharma? Yes, I think so. Are there agreements set up to ensure that the communities of people who that information was derived from will benefit from the development of a drug? Will they even get it at cost? Will they get it subsidized? Will they get a portion of those proceeds if the development of a drug is successful? What about expediting research and development because we know that this allows you to zero in on potentially medically impactful domains on a protein? This changes the whole scale of R&D, which is why and how pharmaceutical companies justify how much money they need and what their budgets are, and their stockholdings, which are trillions of dollars at this point. There’s a huge conversation that we need to have in that space because right now there are no safeguarding mechanisms to ensure that those communities benefit from the generation of those types of drugs. The “All of Us” program is not a very good example because they haven’t thought all of this stuff through. It’s extremely complicated and it’s at such a large scale, and if you look at the design of it, it’s like packaging up this giant dataset and putting a bow on it and having the United States federal government take that over the goal line and hand it off directly to big pharma. And there’s something wrong with that. Because we, [as taxpayers], are paying for it.
[I]t’s like packaging up this giant dataset and putting a bow on it and having the United States federal government take that over the goal line and hand it off directly to big pharma.
Sarah: As you note in your article, many Indigenous communities in the US have ample reason to be wary of participating in government endeavors such as the “All of Us” Research Program. What might the difference be in participating in research via a private company such as Variant Bio?
Keolu: Control and benefit-sharing. Those are two key components. It’s very important to think about control, access, and privacy. If communities choose to want to participate in the commodification of that information via the development of a drug with a company that they deem reputable and that has their best interests at heart and wants to move forward with strategies for benefit sharing–whether on a community/organization level or an individual stakeholder or stock/share modality–then that is their decision. There are a lot of complexities to how this works, but it’s not a one-size-fits-all thing. When a community reaches a consensus that they want to move forward with a project, then they iteratively go through the process of creating a partnership [around it].
Sarah: Just now, and in your article, you mentioned two possible benefit-sharing models that ensure more equity for study participants: individual-interest models (also known as shareholder models) and collective-interest models, the latter of which Variant Bio has adopted in the form of long-term benefit sharing. What might the advantages of a collective-interest model be, compared to an individual-interest model, and is one model more suited than the other to the Indigenous contexts that you’ve worked in both in the US and around the world?
Keolu: I can’t stress enough how important it is that we move away from a one-size-fits-all language. Just because something worked in one community doesn’t mean it’s going to work in another. We may be able to port some ideas, and there may be some similarities, but everything is unique in terms of what is going to be the best case scenario.
And this is just the beginning of this process–I want to stress that. A company like Variant Bio is considering this, and maybe there are other examples in other kinds of companies and institutions that are thinking about resources. As we borrow and recombine ideas, it’s going to become more advanced and more context-specific. [For example], we can borrow ideas from relationships between the Botswana government and local diamond-mining companies that are involved in resource and benefit sharing and how those modalities work into a local government infrastructure.⁷ In that case you collect diamonds and sell them for a price, and a piece of that revenue then goes back into the circular economy, into education programs, medical or healthcare programs, and cultural revitalization programs.
You can borrow ideas from Native American casinos. You may have a certain image of casinos. But in terms of their financial modeling and what they’re thinking about in terms of the way that that revenue is converted back into the community, they’re quite innovative.
Other companies are really thinking about this individual stockholder model. We can borrow ideas from the oil industry and their relationships with the Alaska state government and local communities there. People are doing this, and the American federal government is already engaged in financial mechanisms that result in long-term benefit sharing such as dividends per year, per person.⁸ You’ve seen the government distribute massive amounts of money during the COVID pandemic through a stimulus package. Small businesses file different sorts of paperwork to get access to that. These are other mechanisms for financial distribution. We also saw a landmark court case with respect to South Africa and the San community getting proceeds from rooibos tea.⁹
[In short], there are a lot of places for us to draw ideas from around how to negotiate with individual communities about what has been successful and what can be successful, and what types of emerging technologies are going to provide options for safeguarding information in terms of privacy and access. Variant Bio is one of the first companies to take this seriously in the digital sequencing information space. But all I see in the future is more innovation benefiting our communities. Because once that shatters the status quo, everyone will have an ethical obligation to do that.
Variant Bio is one of the first companies to take this seriously in the digital sequencing information space. But all I see in the future is more innovation benefiting our communities. Because once that shatters the status quo, everyone will have an ethical obligation to do that.
The questions that the communities need to be asking are: Why would I participate if I’m not going to get anything out of this? Why do I care if you get to graduate one of your graduate students and use this data to make a publication to apply for more grants to buy a Tesla and put your kids in private school when we still have basic issues with access to clean water and a number of other societal issues?
Sarah: How might Variant Bio ensure it abides by the “Common Rule” of human-subjects research?
Keolu: The immediate thing I think of is: Don’t design drugs that people can’t buy or afford. Or if you design a drug using a community’s genomes then they should get free access or at-cost access to the development of drugs, i.e. subsidized access. That’s a whole other conversation that [companies] need to have.
You have to remember that there are at least 60 million documented people that do not have access to healthcare in this country. And that’s shameful and sad. It’s an indictment of how broken our healthcare system is. But that is by design. It’s also why a lot of these pharmaceutical companies can charge so much money for a drug. Think about Vertex. Vertex’s [drug cocktail for cystic fibrosis, Trikafta,] costs $300,000 a year.¹⁰ If we surveyed a million people and they knew how much Trikafta costs and how much it cost to develop, I don’t think opinions would be very favorable. I’m not talking about the efficacy of the drug and the scientific achievement that it is. I’m talking about the audacity to charge people that much money for a drug. That can’t happen in the future. And as we begin to fill in more of the spectrum of human genetic variation and that leads to the development of more drugs, that can’t be business as usual. We have to shatter that as an idea. Frankly, it’s against the Common Rule. I challenge everyone that can vote to think about the types of things that you support with regards to healthcare systems and the development of drugs because that just can’t be normal in this country.
I challenge everyone that can vote to think about the types of things that you support with regards to healthcare systems and the development of drugs.
Sarah: How might the benefits generated from discovering globally rare but locally common population-specific variants reach not only all Americans–including its Indigenous and minoritized populations–but also “all of us” on a global scale?
Keolu: Depending on how the benefit sharing happens–the individual agreements and partnerships with communities–there’s going to be a diversity of the way that pans out. I think it’s going to be cool and people are going to innovate, and I’m excited to see what individual communities come up with. And that’s the most important kernel here: What does that community want? If their main issue is creating a circular economy or a financial ecosystem because they want to have access to clean water, and that’s the priority that year, then great, let’s do that. But these policies should have the flexibility to move toward other avenues of development like sustainable energy platforms, scholarships and educational opportunities, and cultural revitalization programs.
Cultural revitalization programs in particular are really important because they perpetuate the rituals of the community and ensure diversity in the future. For example, they ensure that children learn hula and the Hawaiian language, and our stories and history in our native tongue. I want to see a lot of that. Because that is really what makes this planet such a spectacular place. Supporting and maintaining the diversity of culture and all of the different ways that that benefits things.
Because that is really what makes this planet such a spectacular place. Supporting and maintaining the diversity of culture and all of the different ways that that benefits things.
Selfishly, I think about this like an Indigenous Futurist. There are conversations, for example, about what does the world look like without police? What types of culturally sustainable practices can we cultivate if we support Indigenous communities financially, and what does that mean? How do you enable systems for Indigenous people to buy their land back and then develop that land in ways where they see an Indigenous future, where they’re allowed to propagate their future? That, I think, is the ultimate move. That’s the opposite of colonialism and bioprospecting. It’s like you take a colonial modality, which is extracting information from Indigenous peoples’ genomes, and knowing that that variation reflects our relationship to our ‘aina, our land, over tens of thousands of years, and you’re using proceeds of that information in the development of drugs to help that community buy their land back from their colonial overlord — that is poetic justice.
- https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5154245/
- https://science.sciencemag.org/content/355/6320/64
- https://www.britannica.com/place/Raiatea
- https://www.sciencemag.org/news/2020/07/polynesians-steering-stars-met-native-americans-long-europeans-arrived
- https://www.economist.com/leaders/2017/05/06/the-worlds-most-valuable-resource-is-no-longer-oil-but-data
- Mills MC, Rahal C. 2019. “A scientometric review of genome-wide association studies.” Communications Biology 2:1–11. Retrieved from: https://www.nature.com/articles/s42003-018-0261-x
- https://www.newyorker.com/magazine/2020/02/03/the-woman-shaking-up-the-diamond-industry
- https://www.businessinsider.com/alaskans-spend-permanent-fund-dividend-2019-2
- https://www.nature.com/articles/d41586-019-03374-x
- https://www.statnews.com/pharmalot/2020/04/27/vertex-cystic-fibrosis-drug-prices-icer-trikafta/
