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Genetics and Healthcare: Q&A with Prof Carlos Bustamante
- Last time we spoke, you were teaching population genetics at Stanford University. What are you working on now?
I am president and CEO of a company called Galatea, based in Miami, and we’re building a biobank called the Biobank of the Americas. I’m also a professor at the University of Miami this year at the Herbert School of Business. I retain a title as a professor at Stanford University, though I’m on leave at the Stanford University School of Medicine.
For the better part of 15 years, we’ve been working on understanding the role that what we might call ‘biogeographic ancestry’ plays in health and disease, and by that we mean the geographic origin of one’s parents and grandparents and great-grandparents, and where in the globe they were born. So what role does ancestry play in health and disease, and tied to that is what role do different genetic variants that may have arisen at different points in human history play in health and disease?
- Why did you decide to leave academia (for now) to focus on this venture?
One problem with existing biobanks and commercial ventures is that it ends up being biased in terms of who is enrolled in these kind of studies. In fact, about 95% of the participants are of European descent. We called attention to this about 12 years ago and unfortunately, it hasn’t improved. That has two consequences. Firstly, most of what we know is only coming from a small portion of human diversity. Secondly, it cannot translate broadly across multiple groups. So, if we think about the health disparities that exist, we may actually be making health disparities worse by not making genomics more inclusive.
So I’ve called attention to that issue, I’ve tried to work as an academic in that space, and then most recently have taken on this role in a community setting, building ties directly to the community by recruiting for a 10 million person biobank that can make this change. Our goal is to try to create a structure, particularly around Latin America, that can accelerate our learnings in the region.
The goal is to take on the challenge of enrolling individuals of so-called ‘admixed ancestry’ in and throughout the Americas. We define the Americas from Alaska to Chile. That includes individuals that have Native American, First Nations, and African ancestry.
What I’m excited about is this opportunity to bring the fruits of the genomics revolution to these understudied populations, and for me that means stepping out of my comfort zone and leaving the academy if not temporarily, perhaps permanently.
- You specialise in human population genetics. How does that affect healthcare?
We learned from a study in Iceland that individuals that come from a founder population have genetic characteristics that make them ideal for mapping. Iceland is about 700,000 people in a population that’s around six or seven hundred years old. That’s not dissimilar to Cuba, the Dominican Republic, Puerto Rico, Colombia, or Venezuela, where I’m from. Each of these ends up being similar but different in terms of the founding of the population’s exact groups and where they came from, so they provide an ideal ground for finding the genetic basis of complex and inherited disease. The gene for Huntington’s disease was actually mapped in Venezuela, partly because there was a village that had a massive overrepresentation of affected individuals.
Some genes follow a logic to do with human migration. There are gene frequencies that follow the Silk Roads, tied to thousands of years of human migrations. This is very well understood – there’s nothing controversial here. This is who your parents are and who their grandparents are; the genetics of inheritance and the effects of frequencies changing over time.
Genomics England has really transformed how we think about genetics and health through the integration of genetic data with the healthcare system. A lot of what we know about host factors for Covid has come from the National Health Service in Britain, tying the health record outcomes to genome sequencing, as well as what 23andMe and other large-scale efforts have done, and that’s been awesome.
But it is in some sense more of the same well-studied populations, and we still don’t know why certain groups aren’t doing as well. An example in the United States would be Native Americans, who had an incredible response as a community. They’ve done an amazing job of testing and vaccination, yet they have some of the worst outcomes and we don’t totally understand why. This unfortunately parallels what has happened at different points in history with infectious diseases.
I’d like to understand both what may be at the root of some of these associations and then ultimately what can we do about it in terms of accelerating the development of new medications and treatments, particularly in underserved communities.
- What do you think are some of the common misconceptions that arise when people conflate race and genetics?
I think that genetics has always had a checkered history when it comes to the ‘r’ word. Anthropologists would tell you this is just a fact of being a participant observer, we’re always going to bring our own biases to bear. I would say that there’s a key tie-in also to administrative structure; you can’t disentangle the colonial part of history from the cataloguing of people part of history, and the role that all played. It’s not a coincidence that all of this happens at the same time.
One very clear statement to make is that the vast majority of variation is within and not among groups; that’s been a truism of human genetics for as long as we’ve had genetic markers to study. Something like 85% of genetic variation is within a given group, another eight to ten percent among groups in a given region, and another eight to ten among regions. Which means the vast majority of variation is still within one group. An example is ABO blood group, you basically find ABO blood group in almost any town you visit. There’s no town in Britain where everybody’s type B blood.
That said, I feel like we need to embrace the diversity of the human species. We are so beautifully phenotypically diverse, and I think it’s just wonderful that you walk from Chile to the tip of Alaska, or from Cape Town to the tip of Norway, and every village kind of looks like the village next to it, but at the extremes you’ve got this incredible diversity of what it means to be human and what it’s meant to be human across hundreds of thousands of years of human history.
The tapestry that makes up the human gene pool is on one side a common gene pool; we’re one species, and there’s one human race. From a religious perspective, we would never want to conflate the value of a soul with a genome. Each human life is unique and beautiful, and we have an obligation to steward how we represent that.
So we bring mathematical models to bear, and the most salient models for me show a continuum that begins to eventually meet what we know from the history of the human diasporas and the migrations. Those representations, while imperfect, really make it impossible to hold the view that there are three, five, seven, or even 15 basic human groups. There’s really this continuum. And it’s due to the fact that we’ve been this one human gene pool, even as groups have fused and moved over time and space.
We need to sit with the complexity of what the pattern tells us, and begin to tease apart the labels that we put on there from the labels that naturally arise from the data self-aggregating and telling us the story.
- What are some more helpful and less helpful ways you’ve seen of thinking about genes?
When we think about do genes matter – absolutely. Let’s think about blood and transplants, that’s how the whole thing started in the first place. We know that it is important to understand immunological markers that have to do with drug response, for example.
To me the reason to move away from using race in genetics – number one because it’s a loaded term, number two because it’s inaccurate model for reflecting true human genetic variation, and number three because it reifies a concept that has historically been ugly and dangerous in terms of separating people.
You can’t simplify it to the point that you don’t sit with the complexity of the situation, which is that people from different parts of the world have different ancestors. Those different ancestors have different gene frequencies at times, and that has some implications for how we understand the spectrum of human biology – which is a shared biology. Those are things that we can sit with and understand, and at the same time come back to a fundamental point that because we are all human we are all deserving of human dignity, irrespective of anything else. And you don’t go to biology for that, actually. There’s what we call the naturalistic fallacy, just because something happens in nature doesn’t make it right. That’s why we have ethics and philosophy and religion, to guide us.
Many of us who care passionately about this are constantly humbled by it. The human genome continues to reveal itself to us and reveal its mystery to us, and genetics is an incredibly powerful tool by which we can study biology. But ultimately it’s not about the As, Cs, Ts and Gs. That’s like saying the typeface is the most important part of the document. Yes, it’s a feature, but probably not the most important feature. And the interpretation changes over time and your own understanding of it changes over time. So if that’s true for text, imagine what it’s like for something that’s written in a language that we’re only beginning to decipher now, and that is in and of itself an interactive code because it encodes all the cells of the body. It’s a miracle that we can even begin to decipher it and make logic of some of the pieces. Of the pieces we have been able to make sense of, I would say we’ve been able to translate it into improvements for the lives of many, including people who have been unfortunately afflicted by inherited disease through no fault of their own. Our ability to decode DNA and translate that into life-saving therapies is a gift, and we have to take that responsibly.
- Are there any ethical challenges you feel could be present in your work, but maybe people don’t know about?
I would say that the first and foremost issue is one of access to therapies, and the opportunities that could be afforded if we were to take a more open approach to the discovery and development of pharmaceuticals.
I’m a firm believer that pharmaceuticals can bend the cost curve. Preventative deployment of medications can avert disease in the future, but not everybody has access even to the medications that we know they should. So getting people on the right medications at the right time is not a solved problem in any way, shape, or form. As we think about the next generation of medications and averting the widening of health disparities, that to me is one of the biggest issues that we really need to get ahead of. If we just think about it as an allergic reaction to certain medicines, and those allergic reactions happen not to be equally distributed among individuals with different ancestries and ancestors, then by definition, by not studying uniformly everybody’s ancestors, some groups are going to be disproportionately impacted.
There are questions about what diseases do we focus on, how do we focus on that, and why do we take on certain challenges and not others? And the role that “race” plays in that is complicated. For example, why do we focus on cystic fibrosis, which is the most common inherited rare disease among Europeans, and not sickle cell anaemia, which is the most common inherited rare disease of individuals of West African ancestry? Why start with one and not the other? We should do both, right? Of course, we want to heal both. And in fact, from an academic perspective, we’ve understood the genetics of sickle cell far longer than we have the genetics of cystic fibrosis.
I think the UK is rightly proud of the National Health Service, because for all its faults, it does make a basic access to health a priority for the country. The USA has its own very complex history of how it’s treated different groups, and the role of race and medicine has been extraordinarily difficult. So when we think about race and medicine and genetics and healthcare, obviously it isn’t going to be easy or straightforward, and we’re going to need to be revisiting this in a constant way to make sure that we’re trying to do a little bit better every time.
If we think about what’s happened over the last two years and the lack of faith that folks have had in scientific progress, questions around vaccination – why is there a mistrust of science? Well, partly it has to do with people’s experience, and what they feel as unequal access and outcomes. I think we have to get ahead of that issue if we want to continue to have people’s trust, which is integral to having their buy-in to be part of research, so we can continue to develop the next generation of medicines that enable precision medicine and scale for everybody. It’s a virtuous cycle that can continue to feed itself if you do it right.
- What role do you think churches and people of faith should have in these conversations around ethics and access, and the appropriate use of some of these emerging technologies?
I consider myself a religious person. So to me it is really important to have multiple points of view that influence how I think about and interact with the world.
Look, I’m a scientist. I love science as a way of knowing, but I also believe that there are limits on what we can and cannot know, and certainly know at a given point in time and know through certain approaches. I would say because we are human, religion has an incredibly important role, and I think it should continue to have a very important role because it’s been instrumental in guiding us, even if imperfectly.
Ultimately, if we’re true to our notion that diverse groups end up making better decisions because they’re able to more broadly understand the collective decision making process, then I would absolutely want my religious brethren at the table helping us think about these issues. And I think we would probably agree that dogmatism of any flavour can be difficult and dangerous and has gotten us in trouble more often than not. And there’s dogmatism in science as well as in religion.
I have been humbled time and again in my own personal decision making. As I think about trying to have an impact in the world, especially in the world of health, wanting to have conversations around how we improve people’s lives and the decisions that we jointly make about how we deliver health care, it’s very important to have all of these stakeholders at the table. I’m so glad that you guys are having these conversations because I find them personally very illuminating and refreshing. The seminar I gave last year was a highlight of the year for me. So I thank you for the opportunity to have these conversations.