African genetics and ethics

The story of the largest ever study of African people's genetics - and the ethical issue that came after...
14 December 2019
Presented by Phil Sansom
Production by Phil Sansom.


A globe with the view looking over Africa.


There are very few African studies in genetics. And on the whole, there is a big European bias in the field. In Europe there are resources of hundreds of thousands of individuals' data, like the UK Biobank, and so that's where most research take place. But there's a potential problem: the subtle differences in DNA may start to make a difference the more genetics is used to diagnose and treat diseases. All this is why a number of institutions have collaborated to survey thousands of people's genomes in rural Uganda. In this episode we cover the results of Africa’s biggest ever genetics study; and the controversy that happened when they tried to take the next steps.

In this episode

Three children walking bikes on a dirt road in Uganda.

01:35 - Brand new genes from Ugandan villages

The largest ever African study in genetics involved multiple organisations, ten years, and 25 villages...

Brand new genes from Ugandan villages
Deepti Gurdasani; Segun Fatumo, MRC/UVRI & LSHTM Uganda Research Unit

There are very few African studies in genetics - and a study in the journal Cell addresses that problem with, alongside other data, an unprecedented resource of DNA from people in rural Uganda. One of the authors,- Deepti Gurdasani, previously worked on it at the Sanger Intitute in Cambridge. But, as she tells Phil Sansom, she was one part of a big project...

Deepti - ...a collaboration with the Medical Research Council Uganda and the Uganda Virus Research Institute that has occurred over a decade. And a lot of this work was actually led by Segun Fatumo who has trained in genome wide association study analysis through this process.

Phil - Segun Fatumo is a scientist who’s originally from Nigeria who became one of the key figures here.

Segun - I came to the University of Cambridge and Sanger to do a postdoc.

Phil - Segun worked closely with Deepti to create what they now call the Ugandan Genome Resource.

Deepti - This is very much the first large-scale dataset that examines genome sequences, genetic diversity within Uganda, as well as looks at the association between genes and different clinical traits.

Phil - Where in Uganda exactly are we talking about?

Deepti - Southwestern rural Uganda. Essentially 25 villages...

Segun - So we went to the rural communities to talk with the leadership of the villages, make them understand what we are trying to do.

Phil - Were people interested? Were they keen?

Segun - Yes. I think... It's very interesting to let you kn ow that in Africa, people are very receptive to research compared to what you will see for example in the Western world.

Deepti - This is a community that was quite primed to medical research as they had participated in other studies before.

Segun - Since 1989 every year...

Deepti - And they were very keen to participate in a study that looked at risk factors for things like heart disease, diabetes, and high blood pressure. These are diseases that are becoming more and more common in different parts of Africa. Also, everyone in the study got free treatment for their high blood cholesterol or high blood pressure or things that could increase their risk for heart disease.

Phil - What did you get out in the end? How many people's genes or data did you get?

Deepti - So in the end we had data on about 6,400 individuals from this region. We had whole genome sequencing data on 2,000 individuals. This is one of the largest and most comprehensive studies that has been carried out within Africa.

Phil - Those are unprecedented numbers for genetics in Africa - thousands of whole genomes. But there are some smaller datasets from places like Egypt and South Africa that Deepti could get access to.

Deepti - We combined the data with other resources that we had access to within Africa to develop a dataset of about 14,000 individuals. And we looked at the association between different genes and a number of diseases including diabetes, high blood pressure, high cholesterol levels.

Phil - Were you surprised by what you eventually got out the other end?

Deepti - Yes. I think the biggest surprise for us was looking at the new genes we found associated with disease. And almost all of them were driven by genetic variants that were only found in African populations.

Phil - The team found a bunch of stuff - new genes and version of genes that are linked in different ways to your health. Some of this genetic variance barely exists outside of Africa. And according to Segun Fatumo, some of it straight-up doesn’t exist outside of Africa.

Segun - Genetic variance is more diverse in African populations compared to other populations.

Phil - It's where we all came from, isn't it.

Segun - Yeah, that's exactly it. So that's where we all came from. So what that means is that there are some variations that you will find in African population that you would never find elsewhere.

Phil - In some of these cases it feels like if the only dogs you’d ever seen before were chihuahuas, and you assumed they were all tiny and fluffy, then one day you saw a great dane. Both Deepti and Segun told me about one gene variant in particular.

Deepti - One that particularly stands out was an association we found between a particular genetic variant that causes a blood disorder called alpha thalassaemia.

Segun - Alpha thalassaemia.

Deepti - It's a blood disorder that leads to anaemia, which is very common in Africans. So it's found in about 22% of Africans. And it's almost absent in European pop ulations, but in Africa, in regions where malaria is endemic, having this particular disorder can protect you from severe malaria and actually helps survival.

Phil - Really? So one disorder helps you... stops you getting another disease?

Deepti - Yes. It's really interesting. There's several blood disorders that have been diagnosed in Africans, the alpha thalassaemia variant and sickle cell anaemia, both of which protect against severe malaria. They actually help you survive. So we found that this was associated, this particular variant was associated with a marker for diabetes, which we call glycated haemoglobin. This is a marker that's used commonly to diagnose diabetes everywhere in the world, but we found that this genetic variant changed the levels of glycated haemoglobin independently of whether somebody had diabetes or not.

Phil - Glycated haemoglobin - haemoglobin is the stuff in your red blood cells that carries oxygen around the body, and glycated means it’s bonded with sugar. So it’s linked to blood sugar. It’s a really common type of health checkup, and in some ways it’s more helpful than a straight-up blood sugar test - because glycated haemoglobin gives the average blood sugar levels over the past two or three months, so you can spot long-term patterns - and hopefully, diabetes,

Phil - But here’s the rub: Deepti is saying that her alpha thalassaemia gene changes your glycated haemoglobin. That means a diabetes test is no longer a diabetes test.

Deepti - Yes, so we may be picking up people with alpha thalassaemia rather than picking up people who have or don't have diabetes.

Phil - I see. So there's actual... not only are there big differences in the genetics, there's real world implications.

Deepti - Yes, exactly. And this is what we find in African studies. African populations respond differently to drugs. They have genetic variants that cause particular markers to change. So we really have to rethink how we diagnose diseases in African populations and how they respond to drugs, et cetera. When we studied genetics specifically in these populations.

Stylised heart with a pattern of colourful arteries and veins surrounding.

08:28 - Cholesterol genes are not universal

The known genes behind cholesterol don't apply for Ugandans - because environments are so different...

Cholesterol genes are not universal
Karoline Kuchenbaecker, UCL

Using the Uganda Genome Resource - an unprecedented data set of thousands of people's DNA - researchers investigated the genes behind blood fats like cholesterol. Blood fat levels are one of the big risk factors for cardiovascular disease. And in Europeans and Asians, the genes involved are already known. But it seems that many of those genes don't work the same when it comes to Ugandans. Phil Sansom spoke to lead author Karoline Kuchenbaecker, who did this work while at the Sanger Institute...

Karoline - A lot of the studies we've done only included people of European descent and that's quite important because now we know about thousands and thousands of parts of the genome that link to diseases. Imagine that's all just applicable to white people, that would be a major problem for a country like the UK. So, what we did is we studied cholesterol in different groups, so we had data from China, Japan, from the UK, Europe, and also from Uganda. What we found was actually quite surprising. There was a group of genes that affect cholesterol in white people but doesn't do so in the Ugandans.

Phil - How is that possible?

Karoline - One hypothesis to explain this difference in this case is that some of the genes make you eat more unhealthy foods that contain a lot of cholesterol. Now, take the same gene in rural Uganda. You can't just drop into McDonald's, it's impossible. The gene wouldn't affect your cholesterol because it can't make you eat more unhealthy food. That's a very simple example. The biology behind some of the other genes might be more complicated or more biological in the sense that even if you eat unhealthily, it affects how your body metabolizes, but my guess is that it's really all about diet.

Phil - And is cholesterol something that we already knew a lot of the genes that were, I guess, we thought were responsible for it?

Karoline - Yes, definitely. So cholesterol has been very well studied because it's so important. Cholesterol is one of the major risk factors for cardiovascular disease. The genetic aspect of it is becoming more and more clinically relevant. We're beginning to use in clinics to screen people to understand the diseases, to identify people at risk, but based on what we found, it would only be applicable for people from European background.

Phil - Yeah, it seems like a pretty big deal, right?

Karoline - Yeah. I mean part of the reason is just that we didn't have data for anyone else for such a long time. And then there was the general assumption that everything would be universal. So yeah, it's a major problem that we have to address.

Phil - Why have most studies been done for only white people?

Karoline - In the early days of genetics, we wanted to make sure that the findings were actually correct and if you look at a group that's more similar to each other, that's actually easier. You feel more confident, but then this has become a sort of thing that everybody does. I think there's also a bit of a racial bias in terms of most researchers in the countries where this research is done are white. It wasn't, yeah, it wasn't recognized as a problem for a long time.

Phil - Now, what groups do you actually mean when you say that? Cause I know there's no such thing as like a genetic race of white people versus a genetic race of black people. That's all debunk science.

Karoline - You're completely right. Genetics operate on a continuum. When I say groups, I'm a bit artificially putting people together. What has happened is that between these so-called groups, there are some small genetic differences and that happened in our population history. There's a lot of mixing. It's a continuous thing, but most of the time the people who have been studied are the ones who have predominantly European ancestry and they are also of course different to some extent, but there are very few people with more African ancestry that have been included in these studies and even across Europe. The three countries that have been studied really extensively is the US the UK and Iceland.

Phil - But you keep saying ancestry, it sounds like that's the key thing, right?

Karoline - Absolutely. We are really defining the space on genetics.

Phil - You did just say that you thought that some of the gene variants for cholesterol were different for Ugandan people based on the environment they lived in. Isn't in this case, the environment the more important thing rather than where you come from?

Karoline - Yes, it could be, but it tells us that when we studied genetics, in a way a lot of geneticists think this is an easy thing to do because genetics is sort of very clear, right? You carry a gene variant or you don't and it doesn't change. The takeaway message from this is that genetics are happening in environments. There's so much variation, and of course genetics are so complex that it would be a silly assumption to think that they're just working the same way everywhere.

Phil - What are the implications, also, if you, maybe you live in the U K and you go to see your doctor about your cholesterol, but you're from Uganda, or you've got a parent from Uganda or grandparent or something like that? Is this information then going to make a difference?

Karoline - Yes. So if you have a grandparent from Uganda and you go to the hospital and you want to know about your genetic risk for high cholesterol, we can't help you in a way.

Pen lying next to a checkbox on a piece of paper with I Agree written beside it.

16:16 - Allegations of commercialisation at Sanger

Whistleblowers accused the Sanger of commercialising data without permission...

Allegations of commercialisation at Sanger
Deepti Gurdasani; Segun Fatumo, MRC/UVRI & LSHTM Uganda Research Unit

After analysing an unprecedented dataset of African people's DNA, the obvious next step is to use that data and feed it back into research methods, with the aim of building capacity for science in Africa. Now that scientists know which genes are most interesting to study in African populations, they can tailor their research. For geneticist Deepti Gurdasani, that was the vision anyway - until a question of consent derailed the entire thing. She speaks to Phil Sansom...

Deepti - In order to study hundreds of thousands of Africans, we wanted to build an efficient and cost-effective tool.

Phil - What do you mean by tool?

Deepti - It's essentially a chip. It's a small chip with wells in it. So it's not able to build a full picture of somebody's DNA sequence, but it's able to provide a picture of between a hundred thousand to a million points across the genome that would best reflect the genetic diversity in Africa.

Phil - So did you develop the chip?

Deepti - So we essentially looked at the consents and the ethics, and noted that we would need to go back to the communities and the ethics committees. And the process was taken out of our hands. And senior managers at the Institute took this over and made the decision to go ahead and manufacture a product, and commercialise it.

Phil - When you say commercialise, are you talking like a 23andme DNA test?

Deepti - No, no. By commercialise I mean: the array was sold to the Wellcome Sanger Institute by Thermo Fisher. And there was essentially a purchase order placed by Sanger which made clear that the Sanger would receive certain fees in return.

Phil - I'm confused. You were developing the chip, you were at the Sanger. Why are suddenly the Sanger the ones buying stuff?

Deepti - We can't actually manufacture the chip. The chip has to be manufactured by a commercial organisation because we don't hold the technology. And this is a commercial arrangement because Thermo Fisher is profiting from sales to Sanger, if that makes sense.

Phil - Oh, the chip company is profiting.

Deepti - Exactly.

Phil - You give them the data...

Deepti - As scientists, we are only able to say, "oh, these are the genetic variance that we find in Africans. Like we found this alpha thalassemia variant, we want this to be on the chip," if that makes sense. It's like, for example, identifying a particular gene that a particular drug might work on, but the manufacture of the drug is done by a pharmaceutical company, you know?

Deepti - There were two parts to the commercialisation. So the first part to the commercialisation was that Sanger would buy the chip. Thermo Fisher would profit from it, they would buy the chip for research. The second phase of commercialisation was - which never took place because we intervened - was that the chip would be sold to third parties, other research institutions, other bodies across the world, and Sanger would receive a royalty share from that. Other partners were also supposed to receive a royalty share for that. But like I said, there was actually no consent or legal agreement to actually cover commercialisation. And in the end when we intervened, none of that took place.

Phil - Right. Ultimately commercialisation gives money to both Thermo Fisher and the Sanger.

Deepti - Exactly, yes.

Deepti - They wanted to buy the chip for African research, so essentially the chip was being developed to do a much larger study of about a hundred thousand individuals across Africa and this was very much a project that we wanted to lead on.

Phil - What was the permission issue?

Deepti - So there are different levels of permission issue. There was a permission issue with the actual consent from participants, because if you look at the consent for many of the data resources that were involved in developing this chip, they only had very restricted consent. So for example, some of them had only consented to the use of data for diabetes. Some of them had only consented to the use of data to study people's ancestry and history of their populations. So the consent from participants didn't actually allow the use of their data in this way. And definitely not for the development of a commercial product for many of these. But even for research use, broader research use would have required us going back to the ethics committees and potentially even to the communities to ask their permission before proceeding.

Phil - Even though the eventual chip was designed for research?

Deepti - Yes, because the organisation that makes the chip definitely profits from it. So it is a for-profit exercise, and that is something that needs to be clearly explained to the communities who have provided the samples and the data.

Phil - So how would you go about getting the extra permission?

Deepti - We and our African partners would have essentially gone back and spoken to communities, community leaders, and asked them how they felt about developing something like this, and told them that this would be really, really useful for science across Africa, but it would mean that companies would profit. It would also have involved going back to the ethics committees and asking them, would it be ethical to proceed balancing individual consent and harm?

Phil - How long does all that take?

Deepti - Probably around six months or so.

Phil - Hang on. With the Uganda data in particular that we were talking about earlier...

Deepti - Yep.

Phil - That was like a 10 year project. So six months isn't that bad...

Deepti - No, no it isn't that bad. And you know, it's something that we've done a lot. I mean, a lot of our studies involve field studies in different parts of the world. So we are used to going back, talking to communities, talking to research ethics committees and figuring out how to go about doing these things. So it definitely wasn't a long time.

Phil - So why did it get taken out of your hands?

Deepti - I'm not really sure.

Phil - Without passing judgement... I just don't understand. You already had a procedure in place and you had a plan to get the permissions.

Deepti - Yes.

Phil - What benefit is there in not?

Deepti - I'm speculating here, but had this been fully commercialised, it's a product that would have been used very, very widely across the research community. So it's something that potentially could have resulted in a lot of financial incentive back to the organisation. The second thing that I find quite striking is that the Sanger did discuss going ahead with the University of Cambridge, which was its partner within the UK, but didn't actually seek permission from the other African institutions. And potentially there is a thinking that African institutions may not be able to challenge, legally, something like this that happens, so they can be told about this later. I think there was also a fear that the price of the array would go up if there was a huge delay. I think that was a real fear. So I think, again, one of the motivations may have been to keep the price down, but I think we argued that getting the ethics right was much, much more important than keeping the price low.

Phil - These are Deepti’s own views on the Sanger commercialisation, of course - not her employers or anyone else’s. And to be clear - this episode of Naked Genetics is not about how the Ugandan Genome Resource. And she also wants to make it clear that the problems with the array are totally distinct from the Ugandan project, which a lot of people spent a decade working on. People like Segun Fatumo, who again was one of the key figures in the Uganda Genome Resource. His view on the consent issue is different - while Deepti previously mentioned that some groups in South Africa and Egypt only gave narrow consent, here Segun is talking about Uganda only...

Segun - So I would say that there are many categories of consent. As far as I understand we had a broad consent. What that means is that the research subjects, they allowed us to use their samples for this study and also for future studies,, both in Uganda, in the UK and also in the US and other countries. So what I cannot say specifically is if it allowed for commercialisation. But what I do know is that, supposing that it does not allow for commercialisation, there are all these ways about... we have an ethics committee in Uganda and other places in Africa, which normally you apply to them.

Phil - So if you're not sure, you go to the Ugandan ethics committee.

Segun - Yeah. If you're not clear about what the consent allows for the right thing to do is to go back to the ethics committee, in this case the Uganda ethics committee and other ethics committees in Africa, and ask for approval.

Phil - It’s important to note that the Sanger has been legally cleared of all wrongdoing - by both a barrister and independent intellectual property lawyers. And they completely refute allegations of misuse that came not just from Deepti, but from partner organisations in Africa. The Sanger certainly does have a reputation for good ethics - there were at the forefront of the legal battle to prevent people patenting genes for profit. Just like now they’re at the forefront of improving research and opportunities in Africa. The very reason behind developing a tool for making that research cheaper and more accessible. I really wish that they’d agreed to my request for specific comment, because at least when it comes to the consent issue, maybe they could explain themselves. But they didn’t.

Deepti - I think it's a huge ethical issue, even above being a legal issue, because there is a lot of helicopter science that happens with African samples. And by that I mean samples get taken out of Africa, data gets taken out of Africa, African researchers aren't involved, African institutes aren't involved. The communities who contributed data aren't involved. And there is a long history of this. In the context of that, we have to be very, very sensitive to what's happened in the past and ensure that African institutes and African researchers are empowered to lead their own research and to make decisions about what happens with their samples and data.

Phil - Did the chips get made?

Deepti - They did. The chips got made, but unfortunately there are about 75,000 chips that are lying in a warehouse, which will expire in December I believe.

Phil - That's a lot of money.

Deepti - Yes, it was a lot of money. And given how much more African research we need, if this had been done properly, that money would have gone towards creating a huge dataset and looking at genetic determinants of disease in African populations that potentially could have benefited African research hugely. But unfortunately, those chips are probably never going to be used and will just expire as they lie there.


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