Sanger, science and genomics in the next five years
Earlier this year, Professor Mike Stratton became the third Director of the Wellcome Trust Sanger Institute. A few weeks ago he gave a presentation to Wellcome Trust staff, outlining his strategic vision for the Institute.
Under its previous Director, Professor Allan Bradley, the Institute broadened its mission and began to explore how genes influence biology. A series of scientific programmes and collaborations – including the International HapMap Project and Human Epigenome Project – investigated how variation in genomes leads to disease (natural variation). And researchers explored gene function in knockout mouse and zebrafish model organisms (experimental variation).
Stratton aims to build on Sanger’s leadership in genome analysis and bioinformatics to develop cellular systems, which will integrate biological knowledge of genes, proteins and metabolites. Synthesising all this knowledge in massive, high-tech databases will help researchers deepen understanding of how diseases develop and identify new therapeutic targets.
Scale and mission
Sanger’s massive scale and programme of scientific research distinguish it from other sequencing centres. The science at Sanger is characterised by vast production platforms, which generate genome-scale datasets. According Stratton, it’s hard to find others of a similar size elsewhere in the world.
The Institute was the first in the world to invest on a large scale in the powerful new next-generation Illumina GA II sequencers, of which it has about 40. The colossal amounts of data spawned by those machines are stored, managed and analysed by vast IT platforms at the European Bioinformatics and Sanger Institute Data Centre, which together form one of the largest biological data centres in the world. The animal facility at the Institute is also one of the largest globally, with around 50 000 mice and 100 000 zebrafish.
Under Stratton, Sanger researchers will continue to study human genetic variation – both in healthy individuals, to tell us how populations have evolved, and in people with disease, to understand how genes influence disease.
They will also be studying variation in the genomes of pathogens, such as the malaria parasite, and their vectors (the anopheles mosquito, in the case of malaria). Variation in all three genomes – host, pathogen and vector – together determines the spread and virulence of a disease, and how well patients respond to therapy.
Another critical line of work will be the further investigation of the biological differences between the variant and standard genes: how the difference in the DNA sequence affects what the person and the disease looks like.
Stratton hopes to improve the translation of scientific discoveries made at the Institute to real clinical treatments. A new therapy targeted at melanomas containing the BRAF mutation has already proved successful in trials, and this week saw the announcement of a new spin-off company for monoclonal antibodies. Other projects are in the pipeline. All these, Stratton said, are heralding a new era of ‘personalised’ medicines tailored to the genetic make up of individual patients and cancers.
The aim is to use a broad spectrum of translation models, some of which are already in operation at the Institute, to speed up improvements in human health in both the developing and the developed world. Sanger’s policy of open access to research data – championed by its first Director, Sir John Sulston – ensures that researchers across the globe have free, unrestricted access to research results, and that the findings reach the widest possible number of people.
Other plans include a project using molecular technologies to monitor the burden of cancer left in patients after treatment, a database of chromosomal abnormalities in children with developmental disorders, and exploring the therapeutic potential of induced pluripotent stem (IPS) cell technology.
In the next five years, the Sanger Institute aims to deliver the sequences of around 4 000 cancer genomes (and corresponding normal genomes). It also aims to deliver 40 000 human genome sequences (from both healthy and ill individuals), plus the genome sequences of 10 000 malaria parasites, 2 500 mosquitoes, and the genome sequences of more than 30 000 other pathogens (bacteria, viruses and parasites).
Sanger scientists also aim to create mutant mouse models systematically knocking out 1 000 genes one by one to explore the function of genes in the body. And they will knock out up to 8 000 genes in the zebrafish. If sequencing technology improves a bit more, Stratton believes the researchers could realistically knock out every one of the zebrafish’s estimated 23 000 genes by 2016, making it a landmark project.
By then, Stratton wants Sanger to have a fourth area of interest, in addition to the three existing: genome sequencing, bioinformatics, and mouse and zebrafish models. Stratton said large-scale cell culture platforms, using new tools such as IPS cells, will make it possible to really explore biology at a truly large scale, in a high-throughput environment, which will start to produce new therapies.
What will all this actually mean for science?
By 2016, Stratton hopes that, in conjunction with the International Cancer Genome Consortium, Sanger scientists will have discovered all the cancer genes and mutational processes operative in cancer, and established the foundations of future drug development in the field.
He looked forward to our increasing understanding how human populations have evolved and the genetic basis of many rare and common diseases in European and African populations. This, he said, will establish a basis for the clinical genetic diagnosis of patients for a large number of inherited diseases, and a framework for new treatments for them.
Meanwhile, uncovering the biological consequences of host, vector and parasite genome variation in malaria will make it possible to develop new tools to combat drug and insecticide resistance, and generate new leads for drug and vaccine development.
And understanding how pathogen and host genomes interact during infection, and how this influences pathogen evolution in the community, will make it possible to track pathogens – both globally and from room to room within NHS hospitals. Stratton believes there will be a revolution in pathogen diagnostics in the next five years, and that Sanger can play a role in informing and influencing that.
The vast amounts of information generated will be glued together by Sanger’s ever expanding and evolving bioinformatics platform, he said. That informatics framework will support the new personalised, genomic medicine, that Stratton believes will develop in the next decade.
In ten or 20 years time, he says, it is conceivable that we will all have our genomes sequenced as a routine. And the Sanger Institute will make a major contribution to understanding what these sequences mean, and – through its public engagement programme – become a leading voice in society’s consideration of how they should be used to improve human lives and health.