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Robert Bradley: The Splice Effect

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Recommended by: Steve Henikoff, Fred Hutchinson Cancer Research Center

Splicing affects nearly every gene and when it goes awry, it can contribute to a number of diseases. "We know now for the first time that not only is splicing so ubiquitous that it affects almost every human gene, but for the first time, we have the tools to study it in a genomics manner, with high accuracy," says Robert Bradley from the Fred Hutchinson Cancer Research Center, adding that "there are all these examples now of human diseases, ranging from inherited genetic diseases to neoplasias and cancers, that are modulated or even driven entirely by dysregulation of splicing."

Bradley's lab, rather than specializing on one of those diseases, is setting its sights on splicing. "We study basically any disease where it appears that splicing plays an important and previously unappreciated role," he says.

Additionally, Bradley's lab combines computational and experimental work. Bradley says he saw the power of such an approach while a postdoc in Chris Burges' lab at MIT. "What was very influential was seeing in his laboratory how powerful it can be to begin with computation and then take those findings to the bench and really test them," he says. "That's definitely something that we've tried to emulate in all of our work."

Paper of note

While a postdoc, Bradley studied a form of splicing, called NAGNAG, in which a single codon is inserted or deleted as opposed to other forms of alternative splicing in which full exons are included or excluded. Because NAGNAG splicing causes such limited changes, researchers had thought it was not regulated and not an important form of splicing, Bradley says. But in a PLOS Biology paper published about a year ago, Bradley and his colleagues reported that NAGNAG splicing was indeed regulated. "It demonstrated that the spliceosome is capable of doing things that we hadn't realized, controlling these very subtle changes," he says.

Looking ahead

As the field advances, Bradley says he envisions that there will be more integration of functional genomics into studies. For example, he says that it will not only be important to characterize what splicing is occurring, but also to understand how that splicing affects cell function. "I think we are now prepared to take the next step, to move from just a characterization to functional tests," he adds.

And the Nobel goes to…

The premise of Bradley's work is that splicing plays an important role in a number of different diseases. If that turns out to be the case, the splicing machinery could be a possible target for therapeutics. If he were to win the Nobel Prize, he says "it would be for the demonstration that canonically nonrelated diseases — everything from a muscular dystrophy to a disorder of the blood — might be treatable by therapeutics that target similar processes involved in splicing."

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