A biological dream team: Multidisciplinary research in functional genomics
1 December 2000
Only a few years ago, DNA sequencers talked in terms of thousands of nucleotides, the As, Gs, Cs and Ts that make up the DNA of our genomes. Now, their efforts have made billions of nucleotides of sequence available to researchers, with the genomes of more than 30 organisms having been sequenced and the first draft of the human genome completed. But these nucleotides do not tell us what genes do, how cells work, how cells form tissues and bodies or what goes wrong in disease. “The genome is just the raw information,” says Ted Bianco, head of the Trust’s Functional Genomics Development Initiative. “We’re still like the person standing at the bottom of the hill, with a great slope to climb.” Getting up the slope is the task of functional genomics – high-throughput large-scale analysis of gene function.
The Trust’s newest grants scheme – funding for integrated, thematic research in functional genomics – is also one of its most open and ambitious. “We want to help build multidisciplinary collaborations that can really drive functional genomics,” says Dr Bianco. “With the genome in hand, there are so many different ways you can use it to investigate a biological question. Microarrays, proteomics and bioinformatics are all extremely powerful, and we want to bring together the people with the basic biological knowledge with the people who have this kind of technology and the skills to develop new technology. Multidisciplinarity is our keyword.”
Attack on many fronts
Multidisciplinary research – whether planned or by chance – can lead to some remarkable breakthroughs. Over the last two years, for example, great strides have been made in our understanding of the control of sleep. Studies of the patterns of gene expression, of brain receptors, and of the genetics of narcoleptic dogs – which spontaneously fall asleep when aroused – have all coalesced to pinpoint a pair of neuropeptides called the hypocretins/orexins. These molecules appear to regulate our body’s wake–sleep cycle, driven by our internal biological clock. “It’s a fabulous story,” says Dr Bianco, “but in many ways it happened by chance. If we can bring together the expertise, we can provide an environment where such breakthroughs happen more frequently and by design.” The Wellcome Trust is taking two approaches to bring together such expertise. The first approach is to support multidisciplinary research at a single centre – an example being the new Diabetes and Inflammation Laboratory at Cambridge. Using family collections, bioinformatics, microarrays and animal models, among others, Professor John Todd and colleagues aim to track down the genes that predispose to type 1 diabetes. Similarly, the Wellcome Trust Centre for Human Genetics in Oxford is augmenting its formidable expertise in genetic linkage analysis and structural biology with new functional genomics technologies, helped by a grant from the Joint Infrastructure Fund for a functional genomics laboratory.’
The second approach – helping research groups to collaborate on a single topic – is the focus of the thematic functional genomics funding scheme. “We want to encourage researchers to collaborate, wherever they may be,” says Dr Bianco. “As long as the lead applicant for a thematic project is eligible under normal Trust rules and is based in an eligible institution in the UK, we can also consider funding collaborations with other research groups from anywhere in the world.” This marks something of a departure from the Trust’s other funding programmes, as collaborators can be considered from, for example, the USA or from commercial companies, or UK Research Councils or cancer charities (although the Trust’s charitable status imposes some constraints). “Most of the research groups are likely to have existing funding, but collaborations can add value to existing research programmes by enabling groups to work together,” says Dr Bianco. “And we anticipate that some individuals or groups with unique skills or expertise will be involved in more than one consortium.”
Hi-tech, new tech
The benefits of marrying biology and high-technology have been demonstrated – par excellence – by the factory approach to genome sequencing. Miniaturisation, robotics and computing all have a role to play in the development of hi-tech functional genomics apparatus, with microarrays and proteomics leading the way at present. “Science-driven technology development will be essential for the thematic projects,” says Dr Bianco. “It has often been difficult in the past for biologists to get funding for technology development. But we think that many other fields can bring their expertise to functional genomics: engineers, chemists, physicists, computer software and hardware developers.”
Some technologies may be available only in the commercial sectors, so companies will also be welcome to work in the consortia. Outsourcing to companies has become a common and often cost-effective method of dealing with routine portions of research projects, but collaborations can set up a two-way dialogue that can benefit both the company and the academics. “We don’t foresee any problems,” says Dr Bianco, “and it may be that the Trust would contract for services directly on behalf of a number of consortia. We’ll look at everything on a case-by-case basis.”
As with all collaborations, good preparation at the start can avoid problems at a later date. “It’s particularly important that the partners address their IPR [intellectual property rights] policy at an early stage,” says Dr Bianco. “We do anticipate that a number of projects funded through this scheme will make discoveries or developments that have the potential for commercial exploitation. And if these findings are to be moved through to become something useful in healthcare, one doesn’t want to be mired in legal wrangles. There will need to be a coherent IPR policy so that findings are readily exploitable.”
The themes of the research projects are, at this stage, completely open for discussion. “Again, the diabetes study is a good example,” says Dr Bianco. “They have a simple biological question – what genes predispose to type 1 diabetes – and they are using several different approaches to find the answers. But we have no preconceived ideas about the biological questions the collaborators could address – there are so many exciting areas in human biology, infectious diseases or neuroscience that are just ripe for analysis.” With a budget of £30 million, the Trust expects to fund three to five thematic functional genomics projects over five years. “The number of projects is not set in stone at this stage, but this shows the scale and scope of the research projects we’re looking for and the extent of the backing that we can give them,” says Dr Bianco. “The criteria for success will be whether the proposals are ambitious yet realistic, and how far down the line they can take a research field forward – both in terms of biology and of technology – and really make an impact.”
Functional genomics refers to the high-throughput analysis of the function of hundreds or thousands of genes at once. It encompasses several other ‘-omics’ (see below), as well as the development of software tools to handle and interpret the collossal amounts of data generated by such experiments (bioinformatics).
The goal of structural genomics is to determine the structure of most or all proteins encoded by a genome. Structures canprovide important clues to function, and provide an opportunity for rational drug design based on an understanding of a protein’s 3D shape and function.
