In a major boost to the small world of Scottish proteomics, the UK government-funded Biotechnology and Biological Sciences Research Council last week awarded £11.5 million ($20.9 million) to two Scottish-led consortia as part of its £14 million, five-year Structural Proteomics of Rational Targets initiative.
Of this funding, £6.8 million was earmarked for a newly formed group called the Membrane Protein Structure Initiative, led by Neil Isaacs, a professor of chemistry at the University of Glasgow; and around £4.7 million was allocated to the 1-year-old Scottish Structural Proteomics Facility, jointly led by James Naismith and Malcolm White at the University of St. Andrews, and by Bill Hunter at the University of Dundee.
Another £2.5 million of the SPORT money has yet to be awarded. “There were one or two components of applications which at the time were felt to be reasonably good quality, but not in sufficient state to be able to fund. So what we have done is ask people to redraft these applications,” Debbie Harding, program manager in biomolecular sciences at BBSRC, told ProteoMonitor. Harding expects those projects will be funded once they go through “the next phase of peer review.”
BBSRC conceived of SPORT — which Harding called “a major departure” for the organization — when it received £49 million for proteomics initiatives as part of its 2002 budget from the UK government. At that time, “members of the protein crystallography community in the UK got together, and they put a proposal to BBSRC to basically say, ‘we should be making heavy investments for long-time support for high quality groups in protein crystallography so that they can invest in high-throughput technologies,’” Harding said. BBSRC agreed, and established SPORT — which is geared toward providing a few groups with substantial blocks of funding over a five-year period, rather than the usual smaller levels of funding over three-year periods. “In certain things like trying to get crystal robots and the high throughput apparatus for structural biology into labs, you couldn’t do that in a series of small research grants — you really need a large-scale commitment to even start doing that,” Harding said. BBSRC is sponsoring some other large proteomics initiatives with its 2002 funds — including a Proteomics and Cell Function Initiative for £24 million, and a stake in a £10 million Interdisciplinary Research Collaboration in Proteomic Technologies in conjunction with two other UK research councils — that have yet to be awarded (see PM 1-30-04).
The ultimate goal of SPORT, Harding said, is to take labs “into the next phase in structural biology,” by providing high throughput technologies that would be on par with US structural proteomics initiatives (see PM 2-13-04). But in terms of biology, this program is more targeted than many comparable initiatives, Harding said. “We don’t want to go through the structural genomics approach, where you just try to get all of the proteins involved in a particular genome,” she said. Instead, SPORT institutions only study structures with specified functions, with the Isaacs group focusing on membrane proteins and the Naismith group zeroing in on microbial proteins.
All Membranes, All the Time
Isaac’s group at Glasgow established the MPSI last year directly in response to the SPORT funding call. Isaacs and his colleagues at his partnering schools — University of Leeds, University of Sheffield, Oxford University, Imperial College London, Manchester Institute of Science and Technology, CCLRC Daresbury, and Birkbeck College — were all membrane protein scientists, but none of them had made the transition into proteomics at the time of the call. With the funding, Isaacs said the institutions aim to pool their expertise to “develop [high throughput] techniques that people can build on to produce the protein that’s needed and crystallize the protein.” In the process, “it would be nice to get a number of structures at the end of the program,” he said. Specifically, by the end of five years, Isaacs said the MPSI hopes to express 200 proteins, purify 100 in milligram quantities, crystallize 25, solve the structures of 20, and build models for a total of 500 structures based on homologies.
To accomplish this goal, Isaacs said that each institution would work on the same structures, but that each would also use its expertise in one area of membrane protein science. Sheffield, for example, focuses on electron microscopy and 2D structure techniques, while Oxford works on computational modeling and dynamics. Leeds, which has particular strength in expressing membrane proteins in bacterial systems, will express the proteins from a central list of targets — mostly consisting of transporters and ion channels — and then all the institutions will work on them. “If one group’s not making headway on a problem, we’ll move it off to another center and let them have a crack at it,” Isaacs said.
In addition to its BBSRC funding, MPSI will seek “sponsorship or support from industrial sources,” but talks on this end have so far been informal. “We really wanted to get our own house in order … before we approach others for support,” Isaacs said.
Solving Structures in Scotland
Naismith and his colleagues established the SSPF a year ago with £1.3 million from a Scottish state government program that aims to “establish international-class facilities in Scotland so it can compete effectively for federal funding,” Naismith said. The Scottish program provides for infrastructure development only, with the expectation that specific biological projects will be funded by the UK government. With the Scottish money, Naismith and his colleagues spent the last year “designing and implementing robotics for automating crystallization, protein purification, and cloning,” and will use the BBSRC money to move on to the next phase: studying the structures of enzymes involved in microbial pathways. Particular microbes of interest will include those involved in malaria and sleeping sickness, as well as archaea and multi-resistant bacteria.
The two main SSPF sites, Dundee and St. Andrews, will split up the work involved in the structure determination pipeline, based on the particular skills of each institution. St. Andrews will specialize in crystallization and cell-free work, while Dundee will work on structure determination and novel expression systems. Each site will also focus its work in particular areas of the involved biology. “There will be a single target database that both universities will feed into, and then [work will go] between the institutions when a particular piece needs to be done,” Naismith said.
The SSPF initiative also includes some participants from the University of Glasgow and the University of Warwick.
The five-year goal for the SSPF is to solve 50 structures, and ultimately, “If we can find some interesting targets, we would like to put them in high-throughput screening and see if we can’t identify inhibitors,” Naismith said.
SSPF will seek additional funding from broader European structural proteomics initiatives, and Naismith said that SSPF will join the Structural Proteomics in Europe consortium as an observer. “We don’t get any money, but we share all the data and explain what we’re doing,” he said.
A New Scottish Powerhouse?
Considering the small size of Scotland — and England’s relative prominence on the UK science scene — Harding acknowledged that it may seem unusual that Scottish institutions are leading both of the winning SPORT efforts. But she insisted that this was a coincidence. “It wasn’t a deliberate [move] to put funds into Scotland, it just happened to be that those came out highest in the peer review,” Harding said.
Isaacs said the awards were a reflection of a previously ignored strength in the North. “I think there’s a general perception that all of the big science goes on in the ‘golden triangle’ in London, Oxford and Cambridge,” he said. “But in fact, up here in Scotland, there is very high quality science, and … we hope that it will lead to further investment up here.”
But if Scotland is to become a proteomics powerhouse, it will need more than just funds, Naismith said. The funding “is good for Scotland,” he said. “It would be even better if we could attract post-docs to come. Recruitment is the big challenge.”