Great expectations: human genome research
June 2010 marks a decade since the draft human genome sequence was announced. How much of an impact has this development had on genetics, genomics and science in general? What are the ethical and legal issues arising from this work? Chrissie Giles spoke to people who worked on the project then, and those who use the sequence and subsequent research in their work today, to find out.
Professor Sir John Sulston: “The key was tackling the whole genome”
John Sulston is among the few pioneers who, in the 1980s, began to develop the field recognised today as genomics. He and colleagues began a project to sequence the genome of the nematode, Caenorhabditis elegans, in 1990 – the success of which fed directly into the plans to sequence the human genome and set up the Sanger Centre (now the Wellcome Trust Sanger Institute) near Cambridge.
“I was very committed to the whole genome approach. My philosophy, in a Douglas Adams kind of way, was that this thing is big, it’s seriously big. You’re not going to solve life by looking at a handful of genes.”
This focus on the whole genome transformed the way science is done, he argues. “As the sequence started to flow for the worm, human, fruit fly and yeast, people in sequencing labs started to get enormous amounts of correspondence from people working on other organisms who had discovered their favourite gene being matched,” he says. “There was this sense that different organisms in biology were talking to each other, and the genome work introduced a cross-fertilisation in biology that was quite novel.”
As founding director of the Sanger Centre, he was closely involved with the Human Genome Project, including in establishing the principles around data sharing. Famously agreed at a meeting in Bermuda in 1996, these conditions included that no one would take intellectual property rights over genome data, which should be made freely available within 24 hours of being produced.
For the worm community, sharing data was part and parcel of their research. Not so for those working on the human. “There were quite a few fraught political episodes,” he says. “You can get seriously rich and famous with a particular human gene if you can lay claim to it.” Still, even when the private company Celera Genomics was set up to sequence the human genome, the public project continued, committed to releasing the data as it came.
Freedom of scientific information is still part of his focus in his current role as Chair of the Institute for Science, Ethics and Innovation at the University of Manchester. “At the ›least we need much clearer and higher thresholds in not applying intellectual property to fundamental information. The battle’s not won, but the human genome is a tremendous demonstration of how valuable it is not to patent genes and other fundamental information.”
Professor Mike Stratton: “Recent discoveries are a remarkable testament to the power of the Human Genome Project”
A pathologist drawn into genetics in the mid-1980s, Mike Stratton spoke about the potential of the genome sequence to transform cancer treatment at the June 2000 announcement. Now Director of the Sanger Institute, how does he rate the progress so far?
In the 1990s, he was working at the Institute of Cancer Research, studying the genes that predispose to breast cancer. In 1994, he and colleagues located the second major breast cancer susceptibility gene, BRCA2, on chromosome 13. The identification of the gene was then achieved at the Sanger Centre in 1995, with the spin-off that the first large segment of the human genome to have high-quality, finished sequence was the megabase around and including BRCA2.
In the lead-up to the release of the human genome sequence, he began thinking about how it might be useful in understanding the origins of cancer.
“We knew that the genomes of cancer cells contain many somatically acquired abnormalities. We wanted to find these and thus identify the cancer genes involved. We saw that the now-complete normal human genome sequence would be an amazing basis to compare against cancer genomes.”
He proposed the Cancer Genome Project to the Wellcome Trust, and the “first post-genome project at Sanger” began in 2000, even before the sequence had been announced. The project’s first major finding was published in 2002: the discovery that the gene BRAF is mutated in 60-70 per cent of malignant melanomas (a type of skin cancer) and 10-15 per cent of colorectal cancers. Subsequent research, including a Trust-funded drug discovery programme, is today yielding drugs to block BRAF and thus treat melanoma, something Prof. Stratton describes as a “remarkable testament to the power of the Human Genome Project to start these lines of enquiry off”.
A fulfilment of the vision he presented at the 2000 announcement came in December 2009, when researchers at the Sanger Institute and colleagues published the first-ever complete cancer genomes. Now, researchers are working to sequence 25 000 cancer genomes, from 50 different kinds of cancer, through the International Cancer Genome Project. This will identify all the driving cancer genes and provide great insight into the processes that cause cancer.
What will this mean for treatment, ultimately? He predicts routine sequencing of cancer genomes to ensure that patients’ treatments are tailored to the mutations present. “By the end of this decade we’ll be using the genome sequence as the natural diagnostic for cancer.”
Professor Martin Bobrow: “It’s completely changed the face of biology”
Martin Bobrow, formerly a geneticist at the University of Cambridge and a Wellcome Trust Governor, was involved in the funding discussions and decisions around setting up the Sanger Centre and launching the UK part of the Human Genome Project.
What does he remember of this time? “It certainly wasn’t just another grant – it was a radical idea,” he says. He was immediately persuaded that it was “the right thing to do”, but adds that it was still a leap into the unknown. “There was quite a lot of contention as to whether it was worth investing that much money at that time, and whether the technology was going to catch up with the ideas.” Looking back, he says, it’s evident that the project worked and that the information produced was worth having.
He says that the project turned the world upside down, altering the sociology of biology and making genomics a part of every major field of biology. “Genome information is absolutely pervasive. It’s changed evolution, it’s changed all kinds of things,” he says. “Anyone who’s working on how biological systems function as physical entities sooner or later bumps up against the value of genome sequence.”
Professor Stephan Beck: “It was the opportunity of a lifetime”
Working at the Sanger Institute from 1996 to 2007, as Head of Human Sequencing from 1998 onwards, Stephan Beck had a hands-on role in the human, mouse and zebrafish sequencing projects.
“It was clear to everyone that it was going to be an iconic project,” he says. “But there was also the sense of simply getting on with it.” This was essential, he adds, as the researchers had to do everything faster, cheaper and more efficiently week by week.
By the time the draft sequence was released in 2000, he had started the Human Epigenome Project, to look at chemical markers placed on the DNA that can show whether a gene is active or not, across the whole genome. “While the human genome sequence gives us information on where the genes and regulatory elements are, it cannot tell us how the genome is regulated.” Looking at the epigenome, he argues, would help us to understand which genes are switched on in particular cells in particular biological contexts.
Not as high-profile as the sequencing work, the epigenome work had a slow start. However, the recent launch of the International Human Epigenome Project should change this, with its plans to map 1000 epigenomes.
Now Professor of Medical Genomics at University College London, he remains on the cutting edge of research to understand how genetic and epigenetic variations relate to common diseases. “We have the same goal as when we started on the Human Genome Project: to ensure findings translate into benefit for human health. What I hope to see in the next ten years is that we understand how all the genetic and epigenetic variation in the human population causes disease,” he says. “But this doesn’t happen overnight.”
Dr Ewan Birney: “It was a crazy time”
Ewan Birney was completing his PhD under Richard Durbin at the Sanger Institute at the height of what he calls the “race for the genome”. Having taught himself programming as an undergraduate, he has been working in bioinformatics – using IT to analyse biological data – ever since.
He recalls some “interesting positioning” between Craig Venter’s Celera Genomics and the public project, in which there was a sense that even if the public project ‘caught up’ with data generation, the private company had the edge on data analysis. “Making sure that we could compete in terms of presentation and analysis of the data was a key strategic driver,” he says, adding that Celera researchers were using his algorithms to analyse the genome sequence, just as he was.
Indeed, he says that, to some, the Human Genome Project was the making of bioinformatics. “While bioinformatics had consistently been on the rise, there’s a feeling that it really became part of mainstream molecular biology around that time,” he says.
A major part of the human sequencing project was making the information accessible and useful to researchers. As part of this, he moved next door to the European Bioinformatics Institute after he had completed his PhD, to help launch Ensembl. Ensembl is a freely available set of annotated genome databases, and now one of the most accessed websites in Europe. He also works on ENCODE, to study noncoding regions of DNA.
But what’s next for the field? There’s work to be done before genome sequencing becomes a routine part of healthcare, he thinks, particularly as the genetic associations identified in studies have posed a conundrum. “There’s great statistical power but it’s not predictive – it’s really annoying!” Why, for example, is knowing the height of a person’s brother so much better for predicting their height than studying the known genetic associations for height they carry?
The first aim is to find a way to make these genetic associations “usefully predictive”. “I’m a relentless optimist,” he says. “I’m pretty sure that we will crack some proportion of this problem over the next ten years.”
Dr Matt Hurles: “The direction of my career changed completely”
In 2000, Matt Hurles had begun a postdoc, looking for variants on the Y chromosome to trace prehistoric migration. The work he did for his PhD became obsolete and outscaled virtually overnight by the work made possible because of the sequence release.
“The first piece of the Y-chromosome sequence that came out actually completely changed the direction of my career,” he says, as it contained one of the variants he was trying to track down for population prehistory. “In trying to investigate the molecular basis for that variant I ended up stumbling across structural variation, and how one can predict the likely location of these that might cause disease, just from the primary genome sequence.”
His work since has focused on understanding how these variants are associated with common diseases. He thinks that while we’ve learned a lot about common diseases, what we have learned hasn’t been that useful: “It’s not ten or 20 mutations for each condition having a fairly major effect in the population, it’s hundreds and thousands.”
But the success or not of the genome goes beyond understanding common diseases, he argues. “We’ve learned a fair amount about the genetic basis of rare diseases, which has led to a five-fold increase in diagnosis for patients with such conditions.” There’s also the potential to learn a huge amount more about human history, and how genomes work, including the role of non-coding sequence in health and disease.
The data produced is only one side of the sequencing’s legacy: it also catalysed the development of new technologies and applications. “Knowledge and technology go hand in hand, one catalyses the other. Thanks to the Human Genome Project, we now have the technology to do the blindingly obvious experiment – to sequence the genomes of patients and compare those to people that don’t have the disease.”
Daniel Vorhaus: “There are a lot of legal questions to consider”
As an undergraduate at the time, Daniel Vorhaus remembers the human sequence announcement primarily as a news event. Now an attorney at Robinson, Bradshaw & Hinson in North Carolina, USA, he focuses on legal and policy areas related to genomics and personalised medicine.
As this was an emerging field, there weren’t classes on these topics when he was at law school; for him, the really interesting part of his job is working to try to get law and policy to catch up as closely as possible to the science. “There are gaps in how we’re dealing with genetic and genomic information and the privacy and consent issues associated with that,” he says. “This includes how genomic tools are used in medicine, and issues such as genetic discrimination and direct-to consumer genetics tests.”
“In the next ten years, or sooner, people will be able to sequence their genomes,” he says. “Yet it’s inconceivable for most to think about what they can do with their own DNA sequence.” The answer, he thinks, will include private-sector development to make this information more accessible. “We need to help people be consumers of their own health information,” he argues, “so people can dive into this information, even when they’re healthy.”