The history of the Human Genome Project

It’s been 25 years since the first draft of the Human Genome Project was unveiled - a magnificent milestone that promised to transform our understanding of biology and medicine. Here’s the then US president, Bill Clinton:

Bill Clinton - More than a thousand researchers across six nations have revealed nearly all three billion letters of our miraculous genetic code. With this profound new knowledge, humankind is on the verge of gaining immense new power to heal. Genome science will have a real impact on all our lives. It will revolutionise the diagnosis, prevention, and treatment of most, if not all, human diseases. In coming years, doctors will increasingly be able to cure diseases like Alzheimer’s, Parkinson’s, diabetes, and cancer by attacking their genetic roots.

But that dramatic moment in 2000 was the product of work that began much earlier. Long before powerful sequencing machines or global databases, a small number of researchers began to imagine a radical possibility: what if we could decode not just individual genes, but the entire human genome? Much of that early vision took shape here in Cambridge, the city where DNA’s double helix was first described in 1953. By the time the genome project was taking form, Cambridge scientists - including those at the newly founded Sanger Centre - were at the heart of the effort to turn a dream into data. One of those scientists was Richard Durbin. A mathematician by training, he became a key figure in the development of genome sequencing and analysis, and helped lead the UK’s contribution to the Human Genome Project...

Richard - We knew about genes and some of their functions because we can damage them. We can make mutations in them, and then they don't work properly. And it's a bit like saying if you break the chain on a bicycle, then however hard you pedal, you never get anywhere. So it's involved in transmitting power to the wheels. So that sort of genetics was done for the whole of the 20th century, really. And then Watson and Crick, actually here in Cambridge, discovered that the genetic material was made of DNA, and they worked out that genes were these regions of DNA sequence. And so to study them better and understand what was going on, we wanted to get hold of these genes, the one that made the chain work, and find out what it actually was. And that allowed you to both do experiments and give us a lot of insight, actually, into how it works at a molecular level.

Chris - Did you start with the human, though? Did someone just walk into work one day and say, let's sequence a human? Or was the field already going in that direction, and the human was the next step?

Richard - We're all interested in human biology. We're interested in how we are made and how we work. But we're very complicated. And for a long time, people have also worked on simpler organisms. And famously, there's two very simple organisms, the fruit fly and a little worm, C. elegans. And in that system, people had started in the 1980s to find the genes in the genome. It's a much smaller genome than the human genome, one-thirtieth of the size. But it was a big endeavour. It took any one person several years to find a gene in the 1980s and to find its sequence and to start to study it. And really, people began to have the vision that we could speed all that up if we did a proper job to start with and made a library where you could go and just pull out of the library the book of this particular gene and start working immediately on it. And that was the vision that grew in the 1990s. And we started with these simple organisms, worms and flies.

Chris - Did we have the technology then in the early 90s to read a genome end-to-end like that, like you would pick up a book and just pick your way through all the letters and the words? Or did that take a step forward in technology to even make people begin to conceive of doing that?

Richard - Well, people knew that there was a sequence from the 1950s and 60s. But it was only in the end of the 1970s that Fred Sanger, also here in Cambridge, worked out how you could read decent lengths of sequence. So you could read hundreds to thousands or so DNA bases at a time. It was that that people were starting to apply in the 1980s. And in principle, there was no reason not to just scale that up. You could do something on this scale of hundreds to thousands. We knew that we had to get up to millions. The C. elegans genome is 100 million bases long. So it was a challenge. But you take one step at a time and you can walk 100 miles.

Chris - So the idea of sequencing a human came out of doing the same thing for a worm. But a human is a totally different ballgame. I mean, that's 3 billion genetic letters long. That was pretty awe-inspiring at the time, I would think. What was the original time scale that was conceived when someone put up the idea of doing this?

Richard - Originally, I think the sort of official kick-off date was in 1990 with a goal of 15 years. You know, in fact, we did it under time.

Chris - It was a big spend, though. I mean, it came in at something like 3 billion. That would have bought you a Large Hadron Collider or put you a reasonable space project in space, big telescope or something. So this was a big spend. How did scientists convince policymakers and the people with the readies that they should spend a lot of money on this?

Richard - It is a lot of money. Not everyone did buy into taking on this very big industrial-scale project. A lot of scientists tend to forget how opposed they were who now rely on the data.

Chris - I spoke to some at the time when this was coming out because I was a medical student at the time. There were a lot of naysayers who said, this is all fanfare, it's all hot air, this is all hype, this hasn't done anything.

Richard - We're now 25 years on and I think it's completely transformed biological science. I think it's now pretty clear that we're living in the era of sequencing genomes. I believe in 100 years or 1,000 years people will look back and say this was a key point in science, like the discovery of gravity or the discovery of quantum mechanics at the start of the 20th century.

Chris - Some people say this is like biology's Moon landing.

Richard - Yeah, I think it's completely transformational for the science of life.

Chris - One of the things that was said at the time is that it's one thing having a map of all the genes and where they are, but we still don't know what they do. Have we kind of got there now? Have we gone through all the 20,000 genes? Do we understand what they all do? Or is there still a huge amount to find out?

Richard - No, we absolutely don't understand what they do. We know more about what they do than we knew 20 years ago or 50 years ago. But it's the job of the present and the future to understand what they do and how they work and how we can work with them. For example, we know now in a much clearer way how cancer is a genetic disease, how mutations in cells in our body that cause those cells, which now have a different genome because of mutations, to change their behaviour and start to grow and act in ways that are not in the interest of the rest of the body. And we can study them using the power of genomics. But we do need computers and data analysis tools to study them, to use that information. Genomics goes hand-in-hand with computing.