Feature

Life Lit by a Jellyfish

The green glow of a special jellyfish has shone a light on a whole host of life functions.

Dr Martin Kennedy

They glow bright green in the night water -- shimmering, ephemeral galaxies drifting across a dark marine universe. No ordinary jellyfish these, their eerie, ghost-like parasols bathed in some alien inner light. Aequorea victoria; a beautiful name for an elegant and mysterious creature that has provided science with a remarkable gift.

This luminescent jellyfish has fascinated biochemists for over 20 years. The molecules that give A .victoria its green fluorescent soul were long ago isolated and subjected to chemical analysis, but this knowledge proved of limited use. Despite its intrigue, A. victoria remained a biological curiosity.

Now all of this has changed. Five years ago a group of molecular biologists studying the jellyfish distilled the essence of its beauty. In so doing they changed the face of biology. By tracking down and isolating the gene from A. victoria which produces green fluorescent protein (GFP for short), the secret of this surreal beauty was harnessed to cast light on nature's secrets. Like the genie from the lamp, this short length of DNA has made biologists' wishes come true. Unlike the genie, the jellyfish gene goes on granting wishes, and it has staggered the research community with its magic.

In 1992, when Massachusetts biologist Douglas Prasher and colleagues isolated the GFP gene from A. victoria specimens found in Friday Harbor, Washington, they were more interested in evolutionary relationships, and in understanding how the protein was put together and how it worked. Once Prasher teamed up with Martin Chalfie, of Columbia University, he must have quickly sensed the impending gold rush, because by February 1994 this team had taken GFP and A. victoria from the depths of Friday Harbor and elevated them to the cover of Science magazine.

However, along the way these genetic alchemists carried out a remarkable transformation -- the creature gracing the cover of Science was not a jellyfish, but a simple worm. The primitive nervous system of this worm was illuminated with precisely the same, beautiful green glow that makes A. victoria so special.

By transferring the jellyfish gene to a worm, Chalfie and Prasher showed the world that GFP would work harmlessly in animals other than the jellyfish. For the first time in biology, here was a tool that opened up the world of the living cell and showed us things we'd never seen before.

Once GFP became famous, biologists all over the world quickly realised that it was exactly the tool they needed. GFP was embraced by the research community, and in four years it has become a much loved pet. Already, over 400 scientific papers have been published involving application of GFP, and it still seems to be learning new tricks.

Lighting Up Cells

The key to using GFP is remarkably simple. The GFP protein is added, like a molecular lamp, onto the protein of interest. This is done in the laboratory by inserting the short piece of GFP DNA into the gene for the protein under scrutiny. Once the newly engineered gene is introduced back into a cell it behaves like any other, and instructs the cell to make a protein which now has a GFP tag. With careful placement, the GFP tag doesn't usually affect the tagged protein, but it does make it glow so that it can be seen clearly through a microscope.

The simplest and most effective use of GFP is to study the way that proteins are targeted to different locations within cells. Many proteins have homing signals that guide them to specific sites. The "residential address" of a protein in the sprawling three-dimensional city of the cell, often gives us vital clues about its function. If the protein jumps on a tram bound for the nucleus, it is probably heading to work at the chromosomal switchboard; if it makes its way to a mitochondrion, it is probably an employee of this power plant; a protein that buys a ticket on the underground system, the labyrinthine endoplasmic reticulum, may be leaving to see the world beyond the cell.

This approach has shown us ways that signalling proteins -- the cycle couriers of the cell -- carry messages from place to place; and how a highly ordered transport and communication network forms inside the cell, along which various small sacs, protein complexes, and organelles are driven, like jiggers and trains running on railway tracks.

Before GFP was discovered, one of the best tools for glimpsing order at this level was the electron microscope. The electron microscope, however, can only show us images of dead things that have been spray-painted with metal.

In contrast, GFP-tagged proteins execute their delicate and sometimes flamboyant dances in live theatre, before an eager and appreciative audience, bringing clarity to processes that were either unknown or never previously appreciated. Movements of microbes through plants and animals, the dynamics of chromosomes, intricate webs of tiny fibres that alter cell shapes, and even the release of brain chemicals from nerves, have all been played out in green on a microscopic stage.

Not only can GFP show us where cellular molecules live and how they get there, but once a tagged protein makes its way home it acts like a lamp in a tent, lighting up the tiny organelles and other structures that inhabit the interior of a cell. In this way, scientist voyeurs may gaze at their shapes, movements and relationships with other components in the cell. Glowing GF- illuminated organelles turn the cell into a microscopic lava lamp; tiny membranous sacs form, grow in size, drift about, bump into and merge with one another, performing the vital functions of our lives without us ever being aware of it. That is, until GFP came along.

Early forays with GFP were in microbes, worms, insects and then plants. Now, attention has turned to higher animals. The first green mice were developed by a Japanese group to simplify transplantation experiments, though the mere thought of a green glowing mouse must have been alluring. In a more sophisticated study, Cambridge scientist Martin Evans and colleagues introduced the GFP gene into early embryonic cells, allowing the patterns of cell division, growth and movement to be tracked throughout the developing animal. Already, the first use of GFP in humans is being considered -- to follow blood cells in the body after bone marrow transplantation.

If the success of an organism is measured by the spread of its genes, then in a curious way the green glowing jellyfish is very successful indeed. Its remarkable protein may even make its mark beyond biology. A recent study, published in Nature, showed that individual GFP molecules blink on and off every few seconds. Each blinking molecule eventually enters a dark state, but exposure to light triggers the blinking process again. The authors of this study envisage using GFP molecules as optical switches or storage elements in microscopic supercomputers of the future.

What other marvellous tools like GFP lie awaiting discovery in Earth's myriad unusual life forms? Unless we continue looking, we will never know. But, ironically, the kind of research that gave the world GFP is most vulnerable to cost cutting by myopic politicians and science administrators. It is precisely the kind of work that led Nobel laureate Joshua Lederberg, one of the founders of molecular biology, to state "the best way to achieve scientific progress is to resist the temptation to control it".

Time and again, we see the most important discoveries come from the most unexpected and unpredictable places. From the jellyfish of Friday Harbor came a green, glowing revolution that has enveloped the biologists world. That is science at its most wonderful. Hail Aequorea victoria!

Dr Martin Kennedy works in the Cytogenetics and Molecular Oncology Unit, Christchurch School of Medicine.