Getting Down to Basics
Richard Cerione's molecular research unravels the mysteries of life itself
By Clare Ulrich
Thirteen years ago, before most of us ever heard the word genome, Richard Cerione made a breakthrough discovery that holds important clues to the molecular basis of how cells live and die. He and a team of colleagues discovered the human Cdc42 protein, which, at the time, Cerione thought of as a switch that turned cell growth on and off. After sequencing the DNA that encodes the human protein, they realized that it was extremely similar to an essential gene in yeast cells.
"When you see that rigorous similarity, it usually tells you that this has to be fundamentally important because it has been conserved through evolution," explains Cerione, who holds a dual appointment in the Departments of Molecular Medicine and Chemistry and Chemical Biology. "Of course you find differences, too, because we don't really look like yeast."
Further investigation revealed that Cdc42 was more complicated than Cerione originally thought. It turns out that three different regulators switch Cdc42 on or off. Once Cdc42 is on, it communicates to a whole array of proteins that affect virtually everything a cell does. And this happens in every human cell.
"You have this synchrony going on that, on the one hand, is really quite elegant, and on the other hand, is hopelessly complex," Cerione marvels. "It's amazing that it works at all-that cells function, that all these things are turned on at just the right time. So understanding this process in some molecular detail became pretty consuming."
That led to collaboration. Among the Cornell researchers Cerione works with are yeast geneticist Ruth Collins, molecular biologist Jun-Lin Guan, chemical engineer Kelvin Lee, and physicist James Sethna. He is also affiliated with the Tri-institutional Research Program partnership of Weill Cornell Medical College, Memorial Sloan Kettering Cancer Center, and The Rockefeller University. The three institutions create and share facilities for high-performance computing, physical analysis of molecular structure, light and electron microscopy, DNA sequencing, and other tools and techniques for genetic analysis.
Cerione also relies on the Cornell High Energy Synchroton Source and computer scientists to create three-dimensional models of Cdc42, its regulators, and its targets through x-ray crystallography. The process entails firing a beam of x-rays through a crystallized protein sample, which scatters the beam into a pattern that reflects the arrangement of atoms in the crystal. By decoding that pattern, experts can discern the shape of the protein molecule.
This is important because "understanding how Cdc42 orchestrates a number of different target proteins to trigger a range of cellular functions isn't something we can easily conceptualize anymore," Cerione explains. "And it's often counterintuitive. To really understand how Cdc42 is turned on and how it talks to its targets, you have to be able to see how it binds to its regulators and targets in three dimensions. Until you do that, all you basically know about a protein is its amino acid sequence-which amino acid comes first, second, third, and all that, but not how those amino acids work together to enable a protein to function in a particular way."
The structural information gained from x-ray crystallography has enabled Cerione to manipulate cellular activity by mutating either Cdc42 or its regulators to see what happens to cell growth. He has found that when one of the regulators causes Cdc42 to become hyperactive, cells grow wildly. That causes cancer.
"Some of the same molecules and proteins that are important to how cells grow, and which have relevance to cancer when cells are growing wildly, do entirely different things in a different context, such as allowing neurotransmission to occur, helping in memory, or influencing senescence," says Cerione. "So the things we're doing have application to cancer, but shortly there may be application to understanding how the brain works or why we grow old.
"The difference between what we knew about how cells grow and why they become cancerous when I started graduate school in the mid-seventies and what we know now is just staggering. We have come a tremendous way. I think there really is light at the end of the tunnel in terms of being able to translate all that information into application. A lot of exciting things are going to happen over the next five or ten years, and I think we're going to see really significant progress with regard to cancer."
Cerione was recently awarded a National Institutes of Health grant to study how Cdc42 influences human stem cell behavior. He says there are currently three or four laboratories authorized to distribute human stem cells, and researchers have to go through a rigorous process to request them. It will take about a year before he and his team have the materials and training to begin their research. He's well aware of the controversy.
"There are so many misconceptions and misapprehensions about stem cell research," says Cerione. "These are cells that are essentially immortal but also have the potential, upon receiving specific cues, to differentiate into virtually every specialized cell type (i.e., heart cells, nerve cells, etc.). If we could tap into understanding how they can do that, there would be so much we could do for disease and for understanding aging. There is some fundamental key to life itself that they hold the clue to, and right now we need more information. The minute we start to pull the shutters down and become fearful of gaining fundamental information about how we live and die, that's when we're making a mistake. But I think scientists haven't done a particularly good job communicating to the public."
That's beginning to change. Last spring Cornell faculty members affiliated with the New Life Sciences Initiative participated in a series of four forums held in the Northeast and California to increase public awareness of specific research and to discuss ethical issues. The annual Cornell Silicon Valley Program scheduled for next spring will continue to cover life sciences-related topics.
Cerione is optimistic about how the initiative will impact research. "I see the New Life Sciences Initiative as trying to position us to reach our full potential. The sky's the limit in terms of the breakthroughs that could happen at Cornell."