A Hidden Gene: An accidental discovery leads to new avenues of research
It was all an accident, really. But that’s often the way it is with scientific discovery. For Zhi-Chun Lai, professor of biology and of biochemistry and molecular biology, it happened in the mid 1990s. He was investigating the development of photoreceptor neurons using fruit flies when he began to notice massive tumors on the bodies of a line of his flies.
“That surprised us,” said Lai. “We thought we should do something about it, so we made a lot of effort and eventually identified a major mutation to a specific gene.”
The gene that Lai and his team discovered—which they named the “Mob as tumor suppressor,” or “Mats” gene—turned out to be part of the Hippo signaling pathway. The pathway plays a major role in signaling to the body when an organ should stop growing. Specifically, the pathway restrains cell division within organs and promotes cell death, or apoptosis. Problems that arise within the pathway can lead to the types of tumors that are caused by unchecked cell division.
“We discovered a major component in this pathway,” said Lai. “The Mats gene has a dramatic impact. When you knock this gene out in fruit flies you see tumor development. That’s why we called it a tumor suppressor gene.”
The team decided to sequence the mutant fly genome and found that the mutation was caused by a piece of DNA, known as a transposable element, that can jump around inside the genome. According to Lai, in his flies the transposable element jumped into the Mats gene and then jumped back out again, leaving behind a disruption in the gene, which led to tumor development.
To be sure they had the right gene, Lai and his group took an intact, normal fly Mats gene and put it back into a mutant fly to see if the tumors would disappear. Indeed, everything returned to normal. “The tumors disappeared and did not come back,” said Lai. “By doing this, we proved that disruption of the Mats gene was the culprit behind the mutant phenotype.”
Once Lai was satisfied with the identification of the gene, he began to look beyond the fly to see what other animals might possess the gene. For example, he looked at zebrafish, mice, and humans. “We found that Mats is a highly conserved gene all the way up to us,” said Lai. “We actually have two of them. We put one of those two human genes into the fly genome and saw exactly the same thing that we did in flies. That was evidence for functional equivalence. In humans it does the same job as it does in flies, at least at the molecular level.” Lai published his first paper about the work in 2005 in the journal Cell.
Lai currently is pursuing studies using publicly available sequence data from human cancer patients. According to him, the applications of his findings to human health are exciting. “I would be very happy to know that my research helped people,” he said. “One thing we know for sure is that the Mats gene, or the equivalent genes in humans, have something to do with cancer. We are now investigating the detailed mechanisms of how the genes work and what might be done to counteract issues with mutations. The pharmaceutical companies are already very interested in this.”
But it’s more than just the possibility of saving lives that drives Lai; he’s also fascinated by the biology itself. “I want to make progress in understanding basic science,” he said. “Ten to 15 years ago, nobody knew that the Hippo signaling pathway existed. Now we know how important it is for animal development. One of the things I do in class is remind students that basic science is important. You never know where it will lead.”