Cordelia Langford: The stories behind the sequencing

Cordelia Langford, image courtesy of Cordelia Langford

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Cordelia Langford is the Director of Scientific Operations at the Wellcome Sanger Institute just outside Cambridge in the UK. Over the past couple of decades her career has taken her from the early days of DNA sequencing using radioactive chemicals and a ruler, through to the birth and delivery of the Human Genome Project twenty years ago and on to overseeing today’s industrial-scale sequencing pipelines, churning out millions of genomes from humans and other species all over the world. Today she runs a department of about 300 people responsible for generating the information and resources that powers the world-leading genomics research at the Institute. 

Rather than taking a conventional route into a scientific career in the UK - that’s usually A levels, a degree, and then a masters or PhD - Cordelia didn’t get the grades she needed to pursue her dream as a doctor. Instead, she took a sideways journey starting from a sixth form placement at the Laboratory of Molecular Biology in Cambridge through a range of technician jobs, to eventually doing a PhD and a role as a researcher at Cambridge University. That’s where she really fell in love with the double helix - DNA, chromosomes and all the stuff of life that makes us who we are. And the rest, as they say, is history…

Cordelia: One of the things that I found really intriguing was just wanting to know more and more about those individual constituents of cells, how they are structured. The structure of chromosomes was a major theme of my PhD when I eventually got to doing that, and my PhD specifically focused on using really cutting edge technologies and techniques to find ways of understanding how chromosomes have evolved through the evolution of mammals. I was specifically focused on developing and enhancing the techniques that we used for analysing human chromosomes, using flow cytometry and broader molecular cytogenetic techniques. So it was a combination of these different techniques that I was really getting my teeth into.

Cordelia: And I hadn't been at the University of Cambridge post for very long when my line manager, Nigel Carter, who was a researcher leading the development of these technologies, announced that he'd been appointed to The Sanger Centre as it was then known, and it was still in its very early days. And he'd been appointed to lead a brand new molecular cytogenetics lab at the Sanger. And this was met with a bit of excitement for Nigel because it had been recognised right at the start by the founders of The Sanger Centre that molecular cytogenetics could play a really key role leading towards developing the maps of the human genome.

Cordelia: So he was appointed, and I'm really glad to say he realised that flow cytometry would also have to play a major part. I then gained a position at The Sanger Centre then, and I joined 29 years ago and I was, I think, employee something like number 70 or something like that. And I can still remember my first day. Because I'd love to share that there was a lot of excitement. There was a buzz of people talking about The Sanger Centre, and in some cases, some people were saying, "The technology that's being used for sequencing the genome, it's just gonna mean that no one can ever compete with this." 

Cordelia: And of course we know that that's now wrong, but also this excitement of this one core just game-changing project that I think people were really motivated to be a part of. So it was an absolute privilege to be able to gain a role and could contribute to that and be there at the start as well. 

Kat: I did my undergraduate projects at the Human Genome Mapping Project, which is like a sort of little enclave within the Sanger Centre, and that was back in 97, 98. I did two summer studentships there and it was A) a much smaller site, I think it's now enormous. It’s really like “This was all fields when I was here!” But yeah, it was incredibly exciting seeing the early days of the sequencing starting to happen. 

Kat: But also it was not very good. It was very slow. You could do a few hundred base pairs at a time. So I wonder if you could talk then about going from those days when it's like the technology's really just starting, going to move from being able to see chromosomes to actually read DNA sequences and start to do more stuff to probe what's actually going on with the Genetics of cells as they're doing their thing and, you know, making life happen.

Cordelia: I appreciate that you're saying that it felt like it was really slow at the time, but I'd come from an earlier lab where we were using the previous techniques for sequencing a tiny bit of a genome. This was actually of a parasitic nematode worm, and using the radioactive techniques that just took forever, every single base. I can see, you are nodding and you probably remember this because we had to run these huge gels. It took ages and every single base had to be manually read, running a ruler across an autoradiograph of the gel. It was an incredibly slow process, but at the time was cutting edge. 

Cordelia: Fast forward a couple of years to The Sanger Centre, and there were automatic machines that were, again, using fluorescent techniques to automatically run those sequencing experiments and having a digital readout. That at the time seemed just mind-blowing with the amount of sequence that could be done! But again, looking back it was still, you know, maybe a few hundred bases every so often and we were just sort of celebrating this amazing capability. 

Cordelia: Over the years, I think everyone who was there at the start was thinking, "Oh, it's all gonna be done in five years. Because obviously, the people who organise, they'll all be done in five years and then we'll move on and do something else. What a thrill!" 

Cordelia: But of course what we now know is that clearly the technology needed to advance, and it certainly did so, whether it was through enhanced, so-called capillary sequencing where we were still using the technique that was designed by Fred Sanger. So Fred Sanger, the Nobel Prize winner, after whom The Sanger Centre, and now The Sanger Institute was named. So we were using that technique, albeit at an increased scale over the years. 

Cordelia: But it wasn't just the technology that was scaling. It was also the membership, and the number of people and staff who were working at The Sanger Centre at the time dramatically increased.

Cordelia: So we went from around 70 people all the way up to 400 and those 70 to 400 or so people, we were all working on one project. Everyone knew everyone's name. There were a lot of fantastic milestones and celebrations, and it was a bit of a sort of party atmosphere, albeit with a really serious job to do.

Cordelia: And it was very collaborative because the realisation was that no one place could sequence the human genome. So there was an increase in people, and as the first draft of the human genome was completed, the data that was now available opened up all sorts of possibilities. 

Cordelia: So The Sanger Centre itself was then reinvented as a research institute where there were researchers and faculty with different types of scientific focus, all of which centred on using genomic information to then dig in and understand much more about the workings of cells, the workings of organisms that would be implicated in helping us understand more about the development of disease.

Kat: I do love that idea, like, "Yeah, five years job done. We'll have the genome, we'll know everything!" And like, "Oh yeah, no. Now we need to understand how it works..." 

Cordelia: Well, you've said it perfectly because I still remember to this day, even when the first draft - so it took longer than five years, as we know - but when the first draft was completed, again, I think I was thinking, "Oh great, we're probably gonna now be able to cure cancer!" 

Cordelia: And I can remember saying something similar to that, to John Sulston and he said, "Oh, hang on you know, not so fast. That was hard work. Now the hard work really start, this is just the beginning. We have literally just got to the starting line." 

Cordelia: And that was a little bit sort of mind-blowing because again, it sort of felt like - well, hang on we've been working really hard to get to this milestone. But of course, as soon as you get to a major scientific milestone, it just opens the door to another series of really exciting and enticing corridors and you one then chooses a path to go down.

Cordelia: So he was absolutely right of course. And I mean, what a wise and knowledgeable researcher and scientist. But at the time it was really shocking to hear that we didn't just stop and then suddenly cure cancer. 

Kat: Yeah, when I wrote my book Herding Hemingway's Cats, I did write a bit about this idea of like: now we've got the code, the language in which God wrote life, and we're gonna have all the answers! And two decades later it's like, yeah, it feels like we've only now really started to get the technology to actually unpack what the genome is, how it works, how it's different between people, all these kinds of things.

Cordelia: Indeed and I think coming back to the technology, you can probably tell I really love the technology. 

Kat: Yes, big old nerd! 

Cordelia: During that time frame where we were transitioning and building as a research institute, there was probably the most significant introduction of new sequencing technology that's still referred to as next generation sequencing, even though it's been through a number of rounds of enhancements since then. 

Cordelia: But Next Generation Sequencing or NGS was a very different way of running sequencing technology that meant that many millions and in some cases, billions of strands of DNA could be sequenced in parallel, in one sequencing reaction. And that really, I think, was such a significant game changer that unlocked the imagination and the inspiring thinking of many more scientists. And we take Next Generation Sequencing for granted today. 

Cordelia: What I love saying is having been part of the original human genome sequencing project, there are numerous quotes of 10 years, thousands of people, billions of dollars to sequence one genome and that was a draft. And now in the departments that I'm involved in running today, we have multiple Next Generation Sequencing instruments where a single human genome, or the equivalent of a single human genome is turned out every six minutes or so for the approximate cost of about $400 or something like that.

Cordelia: And that in itself means that scientists can think bigger. They can think so much further. What is it that I need to do to be able to generate statistically relevant and interpretable data? How can I best apply the access to this technology in order to be able to translate my scientific questions into improving human health or the health of the globe actually?

Kat: I do get the feeling that we've gone from this sort of artisan DNA sequencing, you know, you're doing it by hand, you're marking off little autoradiograph bands, to being able to do this on an industrial scale. It's a whole pipeline, like a sample goes in, DNA comes out, analysis is done, information is there. 

Kat: As the process has been scaling, you've been involved in the operations as everything's kind of scaled up. You know, more things come with more problems. What have been some of the biggest challenges that have had to be solved as the entire process of genomics has scaled up?

Cordelia: For me, my main answer always starts with: you can have as much technology at your fingertips, but none of it happens without highly skilled people.

Cordelia: So one of the real unique advantages of The Sanger Institute is teams of motivated technical specialists as well as teams who are involved in supporting the delivery of the technical work. And what these people are able to do is to become trained and knowledgeable, to be able to do the work around that really brings that technology to life.

Cordelia: There's also something about the environment. So the sorts of laboratories that we run our sequencing in, for example, here at Sanger, are custom built. They're designed to enable us to have sufficient flexibility to adapt and to bring in new technologies or new instrumentation as they develop. But also large enough and with the right sort of airflow and power supplies and waste systems that enable us to work at that industrial scale that you mentioned earlier, and that it does feel like that sometimes.

Cordelia: It's a mix of industrial scale technology with amazing technologists and specialists that are bringing it to life and making it happen.

Kat: I did want to ask, out of all the collaborations you mentioned, people coming to you to sequence quite strange things. Are there any that stick in your mind as being particularly like, "Wow okay, we'll give that a go!" 

Cordelia: I immediately think of the 25 genomes projects. For the 25th anniversary of the Sanger, it was decided or proposed to sequence 25 new genomes. And in fact, the idea was that these would be genomes of a range of British species. And in fact, it was a great public engagement exercise because students in schools and from other groups were invited to lobby for what species they would like to be sequenced. 

Cordelia: And it's still an absolute thrill to think that the very first non-human genome in this context that we sequenced was that of the Golden eagle. And there's something really iconic about the Golden Eagle. And so of course when we looked at the sample, it looked exactly the same as a human genome sample or a pathogen genome sample because it's a clear liquid. But in there, there's the genome or DNA from a golden eagle that's, you know, a protected, iconic species. That was really exciting. Being able to say, "We've just sequenced the Golden Eagle." There was something thrilling about it. 

Cordelia: It was this 25 genome project that, for me, felt like a real game changer. And actually every single genome that came, there were some plants, insects, mammals, birds, et cetera. Every genome that came had its own challenges in terms of how do you handle the material respectfully, how do you extract the DNA so that it's then got sufficient quality to be able to generate genomes. And the key here is that we were trying to create so-called reference genomes. What that means is that there isn't a genome that can be used as a reference, and that we need to put extra effort and extra interpretation and layer on extra technologies when we are reading a genome for the first time to create a so-called gold standard reference genome.

Cordelia: So that was very exciting. The completion of that 25 genomes project was so successful that it actually led to the creation of a brand new research program at Sanger, which is referred to as the Tree of Life Program. And it's contributing to the Earth BioGenome Project, which has the ambition of sequencing all life on earth. So there's a Twitter feed that comes out which is telling us about the latest moth or latest plant that's been sequenced and referenced. It's a real thrill. 

Kat: Part of the job of the researchers at The Sanger Institute is to sequence pathogens. So I do have to ask you about the big pathogen that everyone knows about: about COVID-19.

Kat: So what were you up to there? What did you have to do to respond to the pandemic from a sequencing perspective? 

Cordelia: When news started filtering through of the emerging pandemic, a number of the scientific leads at Sanger started to put our heads together. And I was pleased to be able to make some creative suggestions about how we might be able to use our skills, experience and scale, perhaps to deploy our capability towards helping to analyse COVID or help in some way, whether it was diagnosis or downstream analysis. 

Cordelia: We went along, we were invited to a meeting held at the Wellcome head office on March the 11th, 2020. And this was a sort of summit workshop meeting that was convened to bring together health specialists as well as genomic analysts and pathogen specialists, as well as viral genome specialists to say: what is it that we could do to help deploy our genomics infrastructure across the UK to help towards healthcare, diagnosis, the pandemic and research generally.

Cordelia: And so it was from that day that we came back to the Sanger and within my teams, the decision had been made that we would need to close campus to protect our staff. But we were asked and certainly stepped up to the plate to create a really high throughput pipeline that was dedicated solely to sequencing the genomes of the COVID-19 viruses.

Cordelia: So having never sequenced a COVID genome before, we'd had a little bit of experience of sequencing viruses, a lot more of sequencing large scale human genomes and a lot more of sequencing, large-scale pathogen genomes, bacteria in particular. So we put all of our knowledge, and by the end of the first week, so one week after that Wellcome meeting, we'd sequenced our first 100 COVID genomes.

Cordelia: And so very quickly we scaled up to being able to handle millions of samples every week and sequencing tens of thousands of COVID genomes. So there are teams now that are still sequencing COVID genomes, providing national surveillance. It's at a much lower scale though, so there are far fewer samples going through, but still samples going through every day, every week.

Kat: You are now Director of Scientific operations at the Sanger, and I did just want to talk a little bit about the role of scientific operations because we interview a lot of researchers, professors, or these kinds of people who are, you know, waving the pipettes around and doing the talks at conferences. And I think we don't really think about the role of operations in making science happen and particularly making big science happen, whether that's something like The Sanger Institute or whether it's a big physics project like CERN or the telescopes that go into space. So what is scientific operations and why is it so important in making these things happen and particularly happen at scale?

Cordelia: Obviously I'm biased, but I think scientific operations is where everything happens or operations generally. What we mean by scientific operations at a very high level is it's a department with a collection of teams of people, each of whom have got a specialist role, and what they're doing is working together and running their own particular functions to generate data, generate biological resources or relevant information that actually is creating the data for the science. We're doing it at a huge scale here at Sanger, and this is what is powering the interpretation of our research. 

Cordelia: Probably most people think, oh, well, I imagine that there's a large number of laboratories. And there are, and our particular areas of expertise at Sanger within scientific operation stretches from flow cytometry through to large scale tissue culture. We have gene editing using CRISPR and other techniques. We have cellular analysis as well. We also have started to have a team of people who are specialists in relatively new, so-called spatial genomics and spatial technologies.

Cordelia: But we also have a very large, and probably the most well-known area is that related to sequencing. And there are a number of teams that handle different types of samples and they perform different types of sequencing techniques as well. 

Cordelia: But it's not just laboratories. We also have a core department who are responsible for developing our strategy and running all of the teams. There are business services - there's change management, project management, business analysts, delivery of our strategy, relationship management - that all convene that very much form the central hub of our activities that enable us to run so smoothly. We also have a team who are specialists in quality. These are quality assessment and quality assurance managers and supplementing, enabling us to keep at the cutting edge. We have research and development scientists too. So we have to be able to make sure that we are improving all the time and enhancing our capabilities. Our research and development scientists work very closely with our faculty, with our researchers to make sure that we're developing and building and running the most cutting edge tech. 

Kat: It's been absolutely fascinating speaking to you, and I could carry on speaking to you all day.

Kat: But before we wrap up, I wondered if there's just one particular favourite story that you have looking back over your time at the Sanger. 

Cordelia: There are many. There are many, many. I'm gonna reflect on a recent story because in a way it's sort of something that could apply over many years. It actually does go back to during the pandemic.

Cordelia: Because it was such difficult and challenging times for the whole globe, and one particularly felt it, with people that I worked with. And having found that there was a way that we felt we could contribute and make a difference during these incredibly challenging times. We crafted an email to all staff acknowledging that these were very difficult times, but asking for volunteers.

Cordelia: And I actually cried when I saw how many people volunteered to just step up and say, "Actually, I wanna be part of this. I don't care what I do. I wanna be part of it." 

Cordelia: That for me reflects the culture and the values and the essence of what it is to work at Sanger's. That everyone pitches in, everyone wants to contribute whatever the cause.

Cordelia: And that's a key thing that certainly keeps me coming to work every day and is an incredibly fond and very positive memory.