Ames, Iowa, USA
April 8, 2011
An improved molecular tool for precisely modifying DNA in living cells could allow researchers to better introduce genes for disease resistance in crops or develop safer gene therapies to treat human diseases.
Technology co-developed by researchers at Iowa State University and the University of Minnesota now makes these kinds of advances possible. The technology, called TAL effector nucleases, removes the guesswork from DNA targeting, allowing researchers to make modifications at virtually any place in a genome.
A Paris-based biotechnology company, Cellectis, recently signed an exclusive license agreement with University of Minnesota and Iowa State granting the company worldwide rights to use and market TAL effector nucleases. Scientists at Minnesota and Iowa State have a patent pending on the technology.
“TAL effector nucleases are like scissors that find and cut specific DNA sequences,” said Adam Bogdanove, associate professor in plant pathology, and co-inventor. “We can build these scissors to recognize any DNA sequence we want, allowing us to target very specifically.”
Bodganove said this specificity is important because most of the genome engineering techniques scientists have relied on to date — to introduce a new gene into a crop, for instance, or mutate a gene to study its function — have been random with respect to where the mutation takes place or the new gene goes in the genome. TAL effector nucleases, however, remove this randomness.
“This new tool for genome engineering could impact agriculture and human health in pretty astounding ways,” he said. “Precise targeting could drastically reduce the time needed to develop a transgenic crop with improved traits, and would remove the potential for unexpected changes in the genome due to random insertion of a transgene.”
For human health, Bogdanove said an important application is in cell therapy to treat genetic disorders, where better targeting would allow correction of defects in a patient’s own stem cells.
“That would make it unnecessary to use cells from a donor, which might be rejected by the patient’s immune system,” he said.
Earlier research by Bogdanove helped pave the way for these advances. TAL effectors are a class of proteins that pathogenic bacteria inject into plant cells, where they attach to the host’s DNA at specific locations and turn on genes within the plant that allow infection to take place.
Seeking to understand how these proteins find their targets, Bogdanove stumbled on what turned out to be a clear-cut coding mechanism that matches amino acid pairs in the protein with individual units in the DNA.
“It was like the holy grail for genome engineers,” Bogdanove said. “So I contacted an expert in the area and asked if he wanted to work together.”
That expert was Dan Voytas, a former Iowa State professor who’s now director of the Center for Genome Engineering at the University of Minnesota.
In 2010, Bogdanove and Voytas published a paper in the journal “Genetics” describing their discovery that TAL effector proteins, which bind DNA, could be hooked to a nuclease, which cleaves it — yielding the precise scissors that are needed for genome editing.
A manuscript showing similar results was published at almost the same time by another Iowa State researcher, Bing Yang, and colleagues. Yang is assistant professor of genetics development and cell biology at Iowa State and had also been studying TAL effectors. A number of other labs have since adopted the technology.
Bogdanove said that genome engineering with existing tools had been frustrated by the difficulty of consistently designing proteins with the specificities required to target sequences of interest.
“With TAL effectors, however, the parts of the protein that specify bases in the DNA are modular, so there’s no guesswork,” Bogdanove said. “We can move them around and create TAL effectors or TAL effector nucleases that target whatever DNA sequence we need to.”
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