How About Glow-in-the-Dark Birthday Cake?

Steven Levingston

Jellyfish Gene Leaps From the Test Tube to Tickle Entrepreneurs' Imagination

PARIS Martin Chalfie, a professor of biology at Columbia University, had studied the tiny worm
Caenorhabditis elegans for nearly two decades - "far too many years," he muses - when his big
breakthrough finally came.

In 1994, he and his team inserted the fluorescence gene of a jellyfish into his favorite creepy
crawly with glowing results: the worm's nerve cells shone bright green.

Mr. Chalfie's triumph launched a scientific mad dash to set the world aglow. Now researchers are
lighting up so many parts of life that bioluminescence has emerged as one of the hottest tools
in genetics.

Today, things glow that were never intended to glow: cancer cells, zebrafish, potatoes, bunnies.
In the latest feat, scientists announced last week that they had used the jellyfish gene in an
attempt to create a glowing monkey.

The fluorescence-driven research is primarily aimed at shedding light on biological processes. A
jellyfish gene inserted into an organism triggers a green glow to alert scientists of a particular
cellular activity. What was once invisible is now witnessed in real time, allowing researchers to
peer inside live cells and track the development of disease.

In the case of the monkey, scientists inserted the fluorescence gene as a first step toward
creation of primates with human diseases in order to test therapies. If the monkey glows green
under blue light, which is needed to activate bioluminescence, then scientists will know the gene
transfer worked.

Success would raise the possibility of producing families of genetically modified monkeys with
Alzheimer's, hereditary blindness and other diseases. So far, researchers have proof that the
gene has entered the monkey's cells but they have not detected a glow.

Experimentation with the jellyfish gene is so popular that researchers have trouble keeping track
of all the projects. "If it were something bad, you'd say it was an international plague - it's
everywhere," says William Ward, a professor of biochemistry at Rutgers University.

Scientists now hope the fluorescence gene will serve as an aid in cleaning polluted waters,
discovering how food poisoning spreads, perhaps even in creating Christmas trees that light up
on their own. Already the business world is racing to cash in with production of luminous makeup
and toy pistols that shoot glow-in-the dark liquid. Jokesters have discovered the humor of a
man-made glow, and artists are attracted to the gene as a tool to expand the boundaries of their
craft.

Such wide and novel use has ignited fears among ethicists and some scientists and has drawn
the jellyfish gene into the long-running battle over biogenetic modification. The rancorous debate
is widening to include, among other things, a cloned sheep named Dolly, genetically engineered
corn containing a possible human allergen and now a monkey named ANDi that may glow green.

The ocean brims with creatures that glow. For 650 million years, jellyfish have lighted up the
briny deep, and tiny plankton have turned swaths of the sea surface to glittering blankets. There
are many luminous shrimp and squid and a luminous octopus, in Japan, and there is the aptly
named flashlight fish in Indonesia that has large light organs below its eyes.

Scientists say that the light show beneath the waves may represent the most common form of
communication in the natural world. Marine creatures recognize members of their own species by
their glow, play luminous mating games, lure prey by flashing, and confuse attackers by
squirting a cloud of light.

Things that glow have fascinated humans ever since the first clans stared into a fire or gazed up
at the stars. A flickering candle can mesmerize the eye and the flash of the firefly delight the
soul. In art and film, angels soar in radiant halos and ghosts drift in luminous bodies. "A glow
has a beatific aspect," says Stuart Newman, professor of cell biology and anatomy at New York
Medical College. "Something that emits its own light appears to have some kind of intrinsic
virtue to it."

Nearly 2,000 years ago, the Roman naturalist Pliny the Elder was dazzled by a clam that spit
phosphorescent green slime when frightened. Even more intriguing, he found, was that anyone
who ate the bizarre mollusk was left with luminescent lips. The culinary novelty set off a
first-century fad: Romans threw clam feasts in the dark and frolicked with glowing green mouths.

With advances in genetics, things that glow moved from the natural world into the lab. At the
heart of the research is the jellyfish Aequorea victoria, whose genes instruct cells to produce a
green fluorescent protein that is responsible for the glow. Insert the jellyfish gene successfully
into another organism and its cells will produce the protein that stimulates the glow.

Efficient and time-saving, the revolutionary process has given life to several dozen genetically
altered small minnows, called golden longfin zebrafish, that shine in polluted waters. Scientists at
the University of Cincinnati hope that large numbers of the fish can be bred to flash early
warnings of toxic chemicals in rivers and lakes.

Some researchers dream in rainbow colors. New genes have recently been discovered that offer
the hope of a red protein and a blue one.

In a competition sponsored last year by the British Biotechnology and Biological Society
Research Council, a team of postgraduate students at Hertfordshire University proposed the
creation of a Christmas tree that lighted up on its own. They described how to genetically modify
a Douglas Spruce and included a business plan for a company to produce and market the
glowing tree.

Deri Morgan, one of the students, believes it would be possible to go beyond creating a
Christmas tree that merely shines green, blue and red. Eventually, he says, the tree could be
genetically instructed to glow just at its tips. The project was among the eight finalists in the
competition but failed to garner the top prize. The team did attract some criticism, however.
"Some people thought we were trying to take God into our own hands," Mr. Morgan said.

Biogenetics raises such delicate issues that many observers find it hard to accept even the
most serious medical efforts, much less have any sense of humor about the most bizarre
prospects.

Not so at Australasian Science, a popular science magazine in Australia. Its April issue last
year carried a story about a brewer who planned to introduce a genetically altered beer that
caused the faces of heavy drinkers to glow green. The article described how the yeast to brew
beer had been engineered with the green fluorescent protein in a bid to help police identify drunk
drivers.

Understandably, the piece set off a storm of concern and anger. But those who read the article
carefully would have been tipped off to a ruse. The last sentence instructed readers to look at
the first letter in each paragraph, which spelled out April Fool. "People killed themselves laughing
when they realized it was a hoax," says Guy Nolch, editor of Australasian Science.

Few people were laughing when a Chicago artist, Eduardo Kac, persuaded the National Institute
of Agronomic Research near Paris to create a genetically modified bunny for display at an
exhibit in Avignon.

The institute had created 10 bunnies with the green fluorescent protein as part of program aimed
at cloning rabbits for research into cystic fibrosis. Louis-Marie Houdebine at the institute says
that, viewed through special glasses under ultraviolent light, the bunnies glow green mainly at
the eyes, and also at the ears, nose and hair roots. Mr. Kac wanted to create one bunny to
inaugurate what he called a new era of transgenic art. The uproar was deafening as genetic
ethicists howled that Mr. Kac had crossed a dangerous line by proposing to use altered life
forms for artistic purposes.

Mr. Kac offered that he hoped the exhibit would spark meaningful discussion on all issues of
biogenetics. In the end, the institute demurred, and the bunny was a no-show at the Avignon
exhibition. Still, Mr. Kac is pushing forward with his dreams of transgenic art and hopes one day
to put on exhibit a glowing dog.

In the world of bioluminescence, the serious and the frivolous merge at Prolume Ltd., a start-up
company in Pittsburgh. Prolume, founded by a surgeon and an oncologist, does
bioluminescence-based cancer research. In its bid for funding, the company also is working on
glowing foods, beverages and cosmetics. Among its projects: cake frosting that will glow Happy
Birthday after the candles are blown out. The company already has marketed a glow in-the-dark
water pistol. George Finley, an oncologist and chief executive officer of Prolume, recognizes that
critics may believe it is wrong to commercialize genetics research. "One could construe what we
do as frivolous," he says. "But we don't think there's any harm in creating a revenue model to
fund basic science. Bioluminescence is a great venue to introduce biotechnology to consumers.
Our products are very compelling, really 21st-century in appeal, novelty and fun value."

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