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Proteomics Researchers Wait as FLEXGene Readies Cloning Consortium

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Having raised $500,000 and spent almost one year developing a protocol for building a library of sequence-verified, expression-ready clones of human genes, the FLEXGene Consortium seems poised to make protoemics researchers’ lives a whole lot easier. After all, who wouldn’t want to shave a month or two off the time it takes to clone a gene for expression, and still feel confident the protein is exactly what you think it is?

Josh LaBaer, the driving force behind the project and the director of the Institute of Proteomics at Harvard Medical School, is working busily to make that happen. He and the other members of the consortium’s scientific advisory panel — financial contributors whom he declines to name — are in the midst of completing experiments to test various commercial and academic gene expression technologies, and at the same time completing the business model for the non-profit consortium before heading out to solicit donations.

But still this is just the beginning. Although most researchers would agree on the need for a comprehensive repository of full-length cDNAs, the cost of carrying it out — most notably with respect to verifying that each cDNA has the correct sequence—is somewhat daunting. (LaBaer’s estimates hover around $53 million.) Furthermore, the logistics of the operation are somewhat complicated, given the challenge of keeping costs to a minimum while still maintaining a high quality service.

 

Competitive Cloning

 

One of the major challenges so far, LaBaer said, has involved selecting the technology for transforming the full-length cDNAs assembled by the consortium into expression-ready clones. So far, LaBaer and the members of his group at the Harvard Institute of Proteomics have evaluated three: those of Invitrogen and BD Biosciences, and a technique developed by Stephen Elledge of the Baylor College of Medicine in Houston.

FLEXGene hasn’t completed its experiments to test the competing systems, LaBaer said, but nor has the consortium ruled out using more than one. While the prospect of applying multiple technologies to create the clones is appealing because it would prevent FLEXGene from being locked in to one — potentially reducing competitive innovation — the cost of employing more than one would significantly increase, he said. Furthermore, FLEXGene should ideally promote a standard “operating system for biology,” he said, much as VHS has become the standard format for carrying motion pictures on cassettes.

The fundamental idea behind the project, LaBaer added, is to create master clones using one or more of the technologies FLEXGene is testing, and then allow researchers to transfer the cDNA by recombinational cloning to their vector of choice — be it for expression in yeast, mammalian, or insect cells — or to add a specific purification or epitope tag such as green fluorescent protein. Although there are companies that provide a variation on this service, LaBaer said only a public-sector project could make the long-term commitment to ensure that the resource would be available at a high standard in perpetuity.

 

FLEX Funding

 

Yet another question facing LaBaer and FLEXGene’s advisory board is how to distribute the clones once the consortium has collected them in its repository. “We all feel pretty strongly that it ought to be done in the most open possible way, and in a way that maintains commercial competition,” LaBaer said.

To that end, LaBaer said ideally scientists should be able to go through more than one distributor to access the clone of their choice, which would allow the scientist as a consumer to decide on the best balance between cost and quality. “But to be fair, that hasn’t been settled yet,” he said, “although it’s hard to imagine what could convince us to follow another course.”

Finding the money to pay for FLEXGene will also require effort. The consortium has decided to seek private as well as public funds to ensure that the end product — the expression-ready clone — is useful for both pure research as well as commercial purposes, LaBaer said. “If we had built a set of clones just for academic research purposes, we would have saved ourselves an immense amount of time and effort,” he said. “But we think that this is a project that’s going to benefit everybody, and we think everybody should pay for it.”

To collect the necessary $53 million, however, FLEXGene must first complete its business plan, which should settle some of the questions about distribution and management. With that in place, LaBaer said the next step is to go all out to solicit funds, to see whether the support exists to complete the project.

Because FLEXGene is modeled loosely after other successful public/private partnerships, such as the SNP or Mouse Consortium, companies or institutions that sign on at the beginning will have to make a commitment to fund the project until it is completed. “If FLEXGene is going to go it’ll be an all or none deal,” he said. “It’s not the kind of thing where you’re going to bring in a little bit of money, then bring in a little bit more money… it’s going to be, ‘here’s the plan: do you want to sign on or do you not want to sign on?’” Likewise, if FLEXGene doesn’t meet the milestones set at the outset, funding stops, LaBaer added.

As soon as the management structure is put in place, LaBaer hopes to start producing clones sometime this year, and in theory scientists should have access to the clones through distributors shortly thereafter.

As far as the final cost, LaBaer had this to say: “Although it is a lot of money, and I don’t want to belittle the amount of money because it is substantial, it’s a whole lot less than the Human Genome Project — by orders of magnitude.”

— JSM