Kevin Morris Romances the Genome

By Eric Sauter

Kevin Morris makes his niche clear on his laboratory's website: pro-knowledge, not-for-profit lab dedicated to understanding the essence of life.

"I'm an academic investigator fundamentally motivated by understanding things," said Morris, an assistant professor at The Scripps Research Institute campus in La Jolla, CA.

The Morris lab is specifically interested in non-coding RNAs, molecules that do not produce proteins and were once thought of as little more than evolutionary leftovers that littered the genome but did nothing of any real importance. As it turns out, non-coding RNAs now are seen as central players in maintaining tighter control over the genome.

The study of these admittedly odd pieces of genetic material is contributing to a growing body of evidence that the central dogma of genetics—that chromosomal DNA is transcribed into RNA, then translated by the cell into proteins—is, while perhaps not wrong, at the very least incomplete.

Morris wants to find out more about RNA, which he sees as so much more than an ad infinitum copy machine.

"[RNAs] may be the molecules that actually govern the natural selection process as it plays out in humans," Morris said. "They appear to be able to change gene expression from the outside in, and quite possibly, this is driven by environmental stimuli. We just haven't been able to connect the entire picture together just yet."

A Gray Switch

Morris's research into the formidable powers of non-coding RNA actually started when he was a postdoctoral fellow at the University of California, San Diego, where he published a groundbreaking study showing that standard RNA could significantly inhibit transcription in human cells, something that seemed at odds with the conventional wisdom that said RNA never accomplished gene silencing through transcription.

And that was only the beginning, Morris said.

"There are a lot of different functions for these non-coding RNAs," he said. "They have target-recognizing capabilities. There's more power in non-coding RNA because it can shepherd different helper proteins to various cell sites to produce changes in gene expression. This isn't completely an on-or-off switch, it's more like a gray switch."

Interestingly, many genes with these non-coding RNAs are tumor-suppressor genes. Studies have shown that, in cancer, these tumor-suppressor genes are shut down epigenetically to some extent by the action of non-coding RNAs. Morris knows this because he has learned how to turn the tumor-suppressor genes back on.

His laboratory has developed state-of-the-art algorithms that can predict which genes can be turned on and off epigenetically (outside of the underlying DNA sequence) using the very same non-coding RNA-mediated pathway by which tumor suppressor genes become epigenetically silenced. With this algorithm, the team can identify targets and create small-molecule non-coding RNAs that, when thrown into cells, turn those target genes off or on as desired.

"If we hit a gene promoter target with about a 20-fold excess of small-molecule non-coding RNA, it can stay knocked down by 80 percent—permanently," he said. "This is because we are specifically targeting epigenetic changes within the genome."

Rebuilding the Model

This relatively new area of science still has many skeptics, despite studies that have confirmed Morris's initial findings. But the skeptics haven't stopped Morris.

"This gene-silencing function was never even considered ten years ago," he said. "Nobody ever stopped to wonder how certain genes behaved the way they did or the possibility that non-coding RNAs are actually in charge for some genes. There's a huge amount of work that these RNAs are doing in different and mysterious forms."

Morris isn't certain what evolutionary advantage non-coding RNAs offer humans (or mice; they have them as well) except that they may allow for subtle and graded genetic changes to occur. For those familiar with biochemistry, these regulatory changes are first observed in the epigenetic state of the targeted loci, which can, when reinforced, become selected for and instilled in the genome via RNA-targeted DNA methylation (the addition of a methyl group). Such methylation has the ability to lead to deamination, i.e., changing a cytosine to a thymine in the context of the DNA. Nonetheless, being able to turn genes off, Morris said, also means scientists could turn genes on if they know the right non-coding RNA involved.

"The beauty is you can take any gene and do it—drop it into our algorithm and you're good to go—experimentally. Beyond that, we still have a long way to go. Nothing we've done so far has gone anywhere beyond the laboratory," Morris noted.

But it certainly has that potential. Right now, relatively little is known about non-coding RNAs. But, as Morris pointed out, since more than 95 percent of the genome consists of non-coding RNAs, the implication is something massive is going on. Even HIV—a virus in which Morris's laboratory is interested—has a non-coding RNA; in fact, it needs it to survive.

"It wouldn't be there if it didn't have a serious purpose," he said.

Morris's approach to science is a blend of romantic skepticism (he originally came to California to surf and play in a rock and roll band) and damn-the-torpedoes, full-speed-ahead-determination that has served both him and science well.

"I have an ability to be creative and ask questions, and I don't have preconceived notions that things are suppose to work a certain way," he said. "I ask for experiments that go against what we learned in school, but that's because I actually forget what we learned in school and that we're supposed to know something only goes a certain way. People get stuck on these models and they think that's the way it is, but it's not. Models are simply a scaffolding to rip down and rebuild. We seem to think the model is built in stone, but every time we build it up again, we get a version that is more true to the essence of the cell."

Send comments to: mikaono[at]scripps.edu

"There's a huge amount of work that these RNAs are doing in different and mysterious forms," says Assistant Professor Kevin Morris. (Photo by Kevin Fung.)