Kingdom-crossing research pinpoints new genes possibly implicated in cancer and disease


What do plants and worms and humans have in common, and how can they help humans?

To address that deceptively simple question, Professors Anne Britt of Plant Biology and JoAnne Engebrecht of Molecular and Cellular Biology are collaborating through the first-ever CBS Kingdom-Crossing grant to identify genes shared by plants and worms that are involved in DNA metabolism.

Their work may ultimately pinpoint new genes that are key to genome stability and that, when malfunctioning, cause disease.

"Understanding how our genomes are maintained, whether in plants or worms or humans, is critical in diseases like cancer," Engebrecht said. "Everyone has someone who has been affected by cancer in their lives and the disease is clearly a consequence of genome instability."

She added that they are trying to understand how that process works with the ultimate goal of providing either diagnostics or chemotherapy agents.

"Anne and JoAnne's collaboration exemplifies the spirit of our Kingdom-Crossing grants," Dean James E. K. Hildreth said. "They are reaching beyond their own areas of expertise to find the commonalities between life forms. This type of research will hopefully contribute to real-world solutions for major problems in the areas of health, food and the environment."

The project idea took seed in Britt's lab.

"I work in Arabidopsis and what we found is that when we expose the plant to ionizing radiation, Arabidopsis switches on hundreds of genes in response," Britt said.

The Britt lab found that plants, unlike animals, strongly upregulate hundreds of genes in response to DNA damage. The most overrepresented category of those genes were ones involved in DNA metabolism, which includes repair, recombination and synthesis. And, in fact, at the top of the list was the breast cancer gene, BRCA1.

Britt began looking for a way to find out whether those same genes would be conserved in all eukaryotes or if they are plant-specific.

"Given the importance of BRCA1, there might be other transcripts in the group that are incredibly important for genome stability and maybe even cancer biology. In which case it would be great to look for them in animal systems," Britt said.

So Britt approached Engebrecht, who works with Caenorhabditis elegans, thinking the worms might be an ideal intermediary between her plant gene list and the animal kingdom.

Through the Kingdom-Crossing grant, which fosters collaboration between experts in different life systems, the professors were able to hire researcher Kayla Aung to bridge the work between their labs.

Aung spearheaded the project, setting to work with Britt's Arabidopsis gene list and generating a new one of orthologous genes in C. elegans. She then developed an assay to explore whether, when she inactivates these orthologous genes in worms and then exposes them to radiation, the worms show sensitivity to the radiation.

Sensitive genes go on a short list of good candidates for those involved in genome stability of both plant and animal systems.

"I've found some interesting candidates for further investigation," Aung says, "And there are still many more to assay."

Britt added that the technique is a novel one, and that Arabidopsis and C. elegans are actually ideal organisms for the hunt for genes involved in disease.

"People did look for upregulated genes in animals and fungi but they found that the effects were small and therefore hard to observe reproducibly," she said.

She added that looking for cancer genes by knocking out various genes and then looking for sensitivity to radiation would kill the cell line in those systems, whereas both plants and worms are perfectly fine. They mature into viable organisms despite the gene inactivation and radiation.

The researchers said the project is a good proof-of-concept endeavor for this method of gene-function discovery, adding that their collaboration has enriched their own research.

"It's been fun to interact with Anne and think a little bit outside of what my normal sphere of science is," Engebrecht said. "We try to think in larger terms when we're discussing and I learn things I wouldn't with specialists from my own lab."

"For every scientist on campus you chat with regularly, they chat with other scientists, and it creates new connections not just with two people, but dozens," Britt added.