Predicting the future of genomics

I passionately believe genomics is good - good for society, good for knowledge. There are lots of places in the world that do the deep, detailed work of understanding genes and genomes, but there are very few places on the planet that do large-scale biology. Sanger is one of two leading, global, genome institutes. And so the opportunity to influence the direction of the Institute is just hugely exciting. A big responsibility, but hugely exciting.

I think firstly, I’m a custodian. The Institute will exist long after I've stepped down, as genomics is going to revolutionise opportunities for society throughout the 21st century.

We have five fantastic scientific programmes at the Institute that have got really exciting plans for the future. I think they will all have big impacts – and so supporting and delivering that science is going to be a key, early objective. We've also just hired 10 new faculty and I’m really excited to see what they're going to do. We're already firing on all cylinders.

But there is one new programme of activity that I want to introduce. It has a working title of ‘generative genomics’ and will be led by Ben Lehner. And this will focus on editing and engineering genes and genomes, at scale. We want to learn the rules of predicting how genes and genomes work, and ultimately to generate new genes and new genomes that can do useful things for society.

This is about recognising the long view – the 100-year lifespan of genomics. At the beginning, we started by just describing what's out there. At the end, we can predict how everything works, and we can design new things. And right now, we're at this inflection point between description and prediction. This programme of work will be a key first step in that more predictive world.

I think there are multiple strands to prediction. There's prediction in a healthcare sense - which patient is going to respond best to which drug – often termed precision medicine. The Sanger Institute is already playing a big role there and I see this continuing. We can take some of the nascent technologies that we can apply at scale, and show whether they're useful or not, for particular, clinical problems. Those technologies might be in genetics, somatic mutations, or single-cell atlasing. I think there is a question of what can these deep molecular measurements do for the clinical world.

Also, there is the question of what can these technologies do for public health surveillance of pathogens. How can we predict what's going to happen, and intervene sooner?

And then there's the prediction in terms of engineering biology. Can we design a gene that could be used to treat a specific disease, for example? Or one that might clear up pollution? Can we fundamentally understand biology well enough that we can predict which genetic variants will cause disease and which won't? Can we design genomes that test our predictive understanding?

So I think there's a combination of new technologies, generating data at scale, the complex computational analyses of those data, and then working to see whether those are useful for society.

We can do proof of concept projects that enable society to say, this is useful, this isn't useful. It's about empowering society, not telling people what to do.

Before joining the Sanger Institute, Matt was researching prehistoric migrations in the Pacific, working at Cambridge University alongside archaeologists and linguists, using genetics as an independent record of the past. We spoke about his early career and training.

Because my professional cricket career didn’t work out? Actually no, early on in my education I didn't know what I wanted to do. And I deliberately made choices to keep my options open.  I chose my A levels on that basis, and my biochemistry degree at the University of Oxford, too – I couldn’t decide between biology and chemistry.

I was coming to the end of that degree, and it was more obvious to others that it was to me that I was going to go into a career in science.

I used to write science articles for the student newspaper. As I read popular science books, I kind of bored people about them. I got incredibly into my research projects. I remember one of my friends turning around to me and saying, “Well, of course you're going to go and do a PhD, you’re the most passionate about this, out of all of us.” And until he said that, it hadn't been that clear to me. When I reflected on it and looked at myself through other people's eyes, I could see they were right.

I initially made some investigations into a PhD in bioethics. We had a really impressive lecturer who was passionate about it, and I’ve always been interested in that intersection between genomics and society. But he never replied to my email. So I ended up going into human population genetics, which was an area that I'd covered as part of my undergraduate projects and found fascinating. From there, I've followed what I'm interested in.

During Matt’s postdoctoral studies in Cambridge, the human genome sequence was first published. This enabled him to see where the genetic markers he’d been working on for many years were located.

I completely stumbled across something I hadn't been expecting. I saw a deletion of a large chunk of DNA that causes male infertility. This region happened to be close by, and related to, one of the genetic markers I was looking at.

I found that fascinating that one could identify these large segments of DNA that were medically relevant, that had been lost in some individuals compared to others. I realised that was the thing I wanted to go and do next. But I was in completely the wrong place to do it. I was fortunate that the Sanger Institute was pivoting from being a ‘sequencing factory’ to being a faculty-led Institute at the time.

Matt joined the Sanger Institute and was appointed to a junior faculty position, he says ‘by the skin of his teeth’.

I guess it was the speed at which technology changed. In my PhD in the late 90s, I remember we were doing assays where we might look at three, four or five genetic markers at once. And there were these technologies - microarray technologies - that were suggesting that we might be able to look at hundreds of 1000s of markers at once. And that seemed impossibly advanced, compared to where we were. But those technologies matured very, very rapidly.

Suddenly, we moved from having to spend several billion dollars to characterise one human genome, to where we could do studies looking at 1000s of human genomes. And sequencing technology kept advancing.

An individual's PhD three-year project became an afternoon experiment. That happened again, and again and again.

It’s a bit like asking me if I’ve got a favourite child! Or, it’s like one of my daughter's questions for me which is, “What's your favourite plant?” I'm a keen gardener. My answer changes every two weeks.

But, I guess the projects I think back to most are the ones that have changed my thinking. The project that caused me to pivot between tracing prehistoric migrations to looking at the deletions and duplications across the genome was a key moment.

Or, projects that have had a big impact on people. I see emails or tweets from family members of those involved in our research who’ve had a diagnosis from the DDD project, what that’s meant to them, and how it’s transformed their lives. There is one I remember particularly, with Sadaf Farooqi in Cambridge. We identified some genetic deletions that were associated with severe childhood obesity. In some families, children had been put into care, because of perceived parental neglect – there might have been a morbidly obese parent, a morbidly obese sibling, and then another morbidly obese child. But finding that all of those individuals shared this genetic deletion - it resulted in those children going back to their families.

That was a key pivot for me because it meant that the skill set I had could be used to change people's lives in a much more direct way than I previously perceived. And so that really caused me to think that working in the rare disease space was something I wanted to do a lot of.

Work-life balance is really important. I think interests outside of work can make one more productive.

My brain seems to puzzle on things in the background, while I’m gardening. I don’t think about work, or anything in fact, when I’m gardening, but sometimes after five hours outside the solution to a problem will just appear.

If I’m not at work, or in the garden, you’ll likely find me cycling – ideally up mountains, but often in my garage.