For the first time, researchers can see and reliably measure how genes turn on and off in individual cells in a living animal — and they can track that gene activity through the animal’s entire life.
This new technique, described in a paper published Wednesday in the journal PLOS ONE, will allow researchers to explore heretofore unanswered questions about the role of random variation in disease and aging, said Fred Hutchinson Cancer Research Center molecular biologist Dr. Roger Brent, who led the study.
Brent, Fred Hutch postdoctoral fellow Dr. Alexander Mendenhall and their colleagues developed a method that uses a fluorescent protein to visualize activity of single genes in every cell of the intestinal tract of the microscopic roundworm Caenorhabditis elegans. This is the first time a gene’s activity has been reproducibly measured in individual cells in a living adult animal, and now that the researchers have demonstrated their technique, it can be used for other genes or other organs, Mendenhall said.
That technological feat may open doors to new understanding of the causes of cancer, Brent said.
For many diseases, researchers study how an individual’s genes or environs — or the interplay between the two — affect their chances of developing that illness. That focus is especially true in cancer research. But it turns out that’s not the whole story.
“You’re born with some genetic constellation, and then things that happen to you during your life due to the influence of your environment also predispose you to cancer – or not,” Brent said. “And there’s this other stuff. Even [animals] that are genetically identical in the exact same environment come out differently. It’s that third component that this work is aimed at.”
Think of it as nature, nurture or neither. That third, "neither," aspect might be due, for example, to “random collisions of molecules,” Brent said, and researchers have only recently begun to appreciate that such variation among identical creatures exists, let alone understand why it happens or what its consequences are.
Random chance may explain why identical twins raised together might end up with differences in physical strength or life span, or why genetically indistinguishable mice raised under the same laboratory conditions can have different amounts of hair, variable sized organs, or even different chances of getting cancer.
Mendenhall is interested in how those variations affect an animal’s longevity. In a previous fellowship at the University of Colorado Boulder, he studied how roundworms age. It’s long been appreciated that identical worms raised in the same petri dish in the lab can have very different life spans, Mendenhall said, but the reason for that variation was not understood.
Mendenhall found that identical animals activate their genes differently — and those that are better at turning genes on overall tend to live longer. That was an interesting finding, but to explore it further he needed a research tool that didn’t yet exist: the ability to track how genes behave in worms’ cells over their entire lifetime.
“We want to observe the living system as it is, intact,” Mendenhall said.
So he joined Brent, who previously developed the tools and concepts to look at differences in gene activity in single-celled yeast, to attack that technical challenge. Perfecting the microscopy, genetic and statistical aspects of their technique took several years, but now that the method is up and running, the researchers are excited to see what they can learn about why and how animals age.
“Only now do we have the tools and the capability to understand this third kind of variation inside an animal's cells,” Mendenhall said. “We get to measure what’s going on while it’s going on.”
The researchers are also using their technique to understand why some animals (or people) get cancer while some don’t — even when their genes and surroundings are the same. For example, even women with cancer-associated mutations in the so-called breast cancer genes BRCA1 and BRCA2 aren’t guaranteed to get the disease.
That third “something” other than nature or nurture, genes or environment, which the researchers refer to as “differences in physiology,” may be at play here.
“Differences in physiology may affect how powerfully cancer genes act,” Brent said.
The researchers may even be able to understand something about cancer from worms. Although C. elegans don’t get cancer (unlike those of humans, adult worm cells don’t divide), there are laboratory tricks that cause cancer-like growths in these roundworms.
Brent and Mendenhall are now using their tool to look at how random changes in gene activity among identical worms affects whether those pseudo-cancers develop. Understanding what drives those differences could have implications for cancer prevention and treatment, Mendenhall said.
“If you understand what physiology makes someone or some cell more disposed to becoming cancerous, you might be able to devise interventions to change that physiology,” he said.
Rachel Tompa is a former staff writer at Fred Hutchinson Cancer Research Center. She has a Ph.D. in molecular biology from the University of California, San Francisco and a certificate in science writing from the University of California, Santa Cruz. Follow her on Twitter @Rachel_Tompa.