Jellyfish protein spawns revolution in biology
And last week, it won him and two other scientists the 2008 Nobel Prize in chemistry.
Shimomura discovered green fluorescent protein, or GFP, in 1962, and no one understood its potential. But today scientists studying everything from cancer to Alzheimer's disease are using GFP to light up and look into living things as no one had done before.
Before GFP, "we really didn't have a way of studying cells without killing them first," said Fabrice Roegiers, a researcher at Fox Chase. They could soak cells in formaldehyde to preserve them and use various dyes and stains, he said. "But it was always done on dead tissue."
Now, thanks to what Roegiers calls the GFP revolution, "you can watch what's going on in cells living within an organism."
That has made GFP an essential tool for biochemists, geneticists, and medical researchers in dozens of fields.
"If you open any major research journal - Cell, Neuron - probably a third to a half of the papers use these techniques," said James Heber, a biochemist at Brandeis University.
The Japan-born Shimomura, now 80, was a chemist at Princeton University when he made the finding. He said his bosses assigned him the task of deconstructing the jellyfish glow. In 1962, he found the key - a protein molecule that looked green and glowed under fluorescent lights.
"It was a very beautiful protein," Shimomura said from his home near the Marine Biological Laboratory in Woods Hole, Mass., where he is a scientist emeritus. But back then, nobody imagined the glow could be transferred to other living things, he said. "There was no use for it at the time."
That all changed in the 1990s when Nobel cowinner Martin Chalfie of Columbia University transferred the fluorescent protein's genetic code to E. coli bacteria, and then to a worm known as C. elegans. Soon scientists were making not just glowing worms but glowing yeast cells, flies, fish, mice and even pigs.
They do this by isolating the gene that holds the code for green fluorescent protein, copying it, and splicing it into the DNA of various organisms or cells. But they can refine this to only light up one kind of cell. If they want to study muscle cells, for example, they can splice the jellyfish gene into part of the DNA that's only activated in muscle cells but turned off in other cells.
Later in the 1990s, the other cowinner, Roger Tsien of University of California-San Diego, found a way to alter the GFP gene to make red, yellow and blue fluorescent proteins.
Fox Chase's Roegiers, who crossed paths with Shimomura on a previous job at the Woods Hole lab, said the story showed how even an arcane pursuit could lead to great things. "He was just trying to understand a simple problem that fascinated him, and it turned out to cause a revolution in biology," he said.
For his own research, Roegiers adds a glow to fruit flies to study the way cells make decisions and how those decisions can go wrong in cancer. During development, cells have to proliferate to make, say, a liver, he said, but at some point that process has to stop. Cancer cells can hijack those proliferation mechanisms to grow out of control.
In flies, he said, scientists have tagged muscle cells so they can watch how the muscles contract. He's working on tagging cells in the brain called progenitors, which give rise to other brain cells.
The jellyfish protein's usefulness goes to the heart of biological sciences, said James Eberwine, a professor of pharmacology at the University of Pennsylvania. "The key to the biological sciences - our history and our legacy - is observation," he said.
He and other neuroscientists use GFP to see neurons inside animal brains. Neurons can be connected halfway across the brain with long, slender appendages called axons and dendrites, he said. Even a mouse brain is a complex tangle..
With a whole palette of colorful fluorescent proteins, he said, neuroscientists can map connections in the brain in a way that would otherwise be impossible.
At Penn's Abramson Cancer Center, researcher Wafik El-Deiry said he used GFP to monitor the way cancer cells were behaving in living mice.
"It's not just cool," he said. "It's amazingly cool." Some studies make the whole mouse green under fluorescent light; others use it to track cells transplanted from one mouse to another. "You can do bone-marrow transplants with green bone marrow and see just where the cells go."
For him, GFP is increasingly important for testing the effects of potential cancer drugs in animals. He said scientists were starting to use GFP to observe what are called cancer stem cells, which can sometimes survive treatment and cause cancer to recur. "It's just opened up so many possibilities," he said.
The jellyfish GFP can track not only individual cells, said Penn chemist Barry Cooperman, but it can also track individual molecules inside those cells. "It allows you to visualize what proteins are doing in the context of a living cell," he said. Proteins are large molecules that run the mechanical processes of life. The instructions for constructing proteins are encoded in genes, and by splicing the genes for the GFP next to the genes for other proteins, he said, he can tag individual ones and watch them in action, thanks also to leaps in microscope technology.
That allows him to watch the critical processes of life - including the transcription of DNA into proteins inside cells. With video, he said, they can watch various proteins being made in real time.
The technology allows scientists to get away from reductionism - taking things apart to see how individual components work. Now they can watch the whole mechanism in action.
Fox Chase's Roegiers said it's hard to imagine Shimomura getting funding for his obscure jellyfish quest today. "Never in a million years did anyone imagine it would have led to all this."
Contact staff writer Faye Flam
at 215-854-4977 or fflam@phillynews.com.


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