Pontus Skoglund: Ancient DNA, new discoveries

Image courtesy of Pontus Skoglund

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We’re now moving from a trip to Bermuda to a trip to the past. Pontus Skoglund leads the Ancient Genomics Laboratory at the Francis Crick Institute in London. He is the winner of this year’s Balfour Lecture, a Genetics Society award celebrating contributions to genetics from an outstanding young investigator; the scientific equivalent of BAFTA’s Rising Star Award. His research explores how ancient DNA can unlock the secrets of human evolution, disease and population migration in prehistory, and he’s looked at everything from the domestication of dogs to plagues in the Middle Ages. So I wanted to know which question he’s most excited to study…

Pontus: It changes with, you know, every week or something like that. So if I was going to pick something this week, I think soon we will be able to look at evolution in the genetics of human traits including diseases in quite fine scale, including in the past sort of one or two thousand years, which is a period of course where societies became more complex, people lived in denser communities, more infectious disease... So it will be really interesting to understand our genes adapting in terms of immunity to disease. I think it will be very cool. 

Pontus: And in our lab we will also study ancient pathogen DNA - bacteria and viruses - which of course evolve themselves. People listening to this will of course have followed COVID, everyone was sort of tracking the different variants, lineages and strains that would arise in real time, but that's something that's only been possible due to genomic technology to do in the sort of past very few decades, like maybe 20, 30 years.

Pontus: So, how do these bugs evolve, you know, on short timescales within human populations during these kinds of outbreaks? Perhaps we can use ancient DNA to understand that in a better way. 

Sally: So I noticed you were studying Yersinia pestis, Black Death, your famous fleas on the backs of rats killing, what was it, 25% of Europe or something crazy like that?

Pontus: Yeah, I think it's even more, I mean, they don't know exactly, but probably at least 40%.

Sally: What kind of questions do you ask? Because you mentioned the link to COVID and there we're really like, week by week, month by month, what are the new traits that are coming out? How are they more virulent? How are the viruses changing to be better at being infectious? Are you able to make that fine scale predictions about the Black Death from the 14, 15, 1600s? 

Sally: What sort of questions are you asking? Is it: how fast does it evolve? Is it: what does it evolve into? Is it all of them? 

Pontus: Yeah, that's a great question! Viruses do tend to evolve quite a bit quicker than bacteria such as Yersinia pestis. 

Pontus: People have looked at this in the past, at the Black Death, you know, why was it that so many people died? So not us, but another group a few years ago got the first Black Death Yersinia pestis genome. And then they compared it to present day Yersinia pestis that's still around in a few places in the world. And they couldn't really see any major difference in its genes that, you know, would have changed them to be more virulent. 

Pontus: I think the scientific view currently is that even if the Black Death might not have been genetically different itself, maybe people were more immunosuppressed at the time, they were sort of living less healthy lives which resulted in this massive death rate in Europe.

Sally: And you mentioned you're not only looking at the evolution of the ancient diseases themselves but how human genomes have evolved in response to them. And I know there's plenty of rumours because the plagues and the Black Deaths of the Middle Ages caused so much of an evolutionary selection pressure that that's why we see various resistance genes in European populations as well.

Sally: Are those the sort of questions that you're looking at? 

Pontus: Exactly, yeah. That's absolutely one of the main hypotheses, but we still have quite, you know, very little human DNA data from this time period. But that's going to build up from our group and from multiple other groups that are increasing this data set to understand this more near-time evolution.

Sally: And how do you study that? Do you just look at a load of genomes from before the disease, a load of genomes from after the disease and kind of do a spot-the-difference? 

Pontus: Yeah! Basically like that, or even better, you go in and have a time series of genomes over a longer time period. And you can see, well, does evolution seem to speed up at particular times? Does that match with anything that we know about, maybe epidemics such as the Black Death? 

Pontus: Then we look at millions of different places in our genome and, you know, they sort of form millions of hypotheses that we can test. Were they undergoing natural selection or not? Do they stick out compared to the rest of the genome?

Sally: I think ancient genomics is the area of genetics that really highlights the importance of technology and technological advances because you've just mentioned that you're sequencing billions of fragments already. 

Sally: Where do you kind of see the future going? Like what big technology is on the horizon? Or if you could invent a new technology that would really revolutionise your field, what would it do?

Pontus: Actually your question, I think, is relevant to one thing that we're also interested in, which is ancient proteins. So ancient protein sequencing if you will, or determination of ancient protein sequences, is a frontier that could really make a big difference. And the reason for that is that DNA degrades much quicker than proteins and indeed there's virtually no chance we can get DNA from some of the most fascinating points in time and place for the evolution of our species, Homo sapiens.

Pontus: Many of these questions are about, you know, the past million years and in warm places like Africa, where DNA degrades really quite quickly. Proteins - there's a chance that they are preserved, and if we can improve the techniques and the retrieval of them so that we can get enough of them to have statistical power to, you know, sort of map our ancestry back in time to different parts of Africa and different other parts of the world, different human species, that would be a massive leap forward.

Sally: So you've got the same technical problems now with proteins that DNA had 20 years ago. If I gave you a large enough, pure enough sample, you'd be fine. But the trouble is getting a large, pure sample of the protein, there's just so little of it and it's degraded. 

Pontus: Yeah, exactly. And so for me personally, that's what makes it so exciting.

Pontus: It's like rolling back time to where we were when I started in ancient DNA, where people were like, " We don't really know if this is going to be a thing, ancient genomics at all." 

Sally: It sounds like it's a really interdisciplinary group that you've got going on then at the Crick. Is it more interdisciplinary than most genetics groups, would you say, working with this older stuff? Or is it just a different kind and you don't hear as much about it? 

Pontus: I mean, definitely it's very interdisciplinary. You know, it's one foot in archaeology and one foot in biology in a sense. So yeah, in our group we have people who are archaeologists, and mathematicians who work with the data. Molecular biologists, forensic scientists who retrieve the DNA, evolutionary biologists...

Pontus: And that's, you know, what makes it so fun to me, learning things from different angles. Every day, I might be reading a different type of article to try to learn new things. 

Sally: And you recently won the Balfour Lecture Prize from the Genetic Society celebrating early career researchers. Congratulations, first of all. 

Sally: What would you say is the difference then in that step up from being a PhD student within a group to becoming the group leader yourself? What are the different skills you have to have? 

Pontus: Well, the way science works, right, you're kind of trained and selected to become a principal investigator quite often on sort of your technical skills, you know, not necessarily due to your skills in leadership or management or interpersonal skills. Of course, they're important in research, but it's very much a shift in focus.

Pontus: And so, yeah, what happens is you spend a few years being a PhD student, a few years being a postdoc, and you've been really trained to drive your own research using technical skills - in my case, coding, computational work... And by the way, you don't have to be a wizard, I basically didn't know any coding until I started my PhD, so I sort of learned it on the job.

Pontus: But when you become a PI - Principal Investigator - the focus shifts to making sure that other people have the chance to be trained to do those things. 

Pontus: So it is a general sort of issue that people aren't necessarily trained for that principal investigator role, but having that new challenge is very exciting. I mean, just very rewarding seeing people grow in their skills, develop their careers. That's really rewarding. But yeah, it's definitely something to, I think in science, think about more how to prepare people for that people-focused role. 

Sally: What advice would you give to people who are maybe doing their GCSEs, in secondary school, starting university, if they're thinking that maybe this is an avenue they want to go down?

Pontus: Sometimes we try to say that science is fun and you know, we're passionate about science and that's one way of looking at it. For me, I like it because it's inspiring and it's problem solving. 

Pontus: You know, I can't resist getting into new questions. That's kind of what is exciting. And so with this ancient DNA approach, recently even ancient proteins, there's so many things about the human past and evolution that you can address.

Pontus: I remember sitting in university in undergrad class, there was a lecture about human origins. And I remember, I was like, "I should really be savouring this, this is really exciting, you know, I'll probably never hear about human origins as part of what I should be doing daily again." and I sort of repeatedly have had this feeling when I've done master's projects in this topic, and my PhD, and my postdoc... And even now I sort of feel like I should savour it because it's really inspiring and it's really a privilege to be able to work with it.