Jellyfish, worms and research revolutions

At first glance the jellyfish Aequorea victoria seems an unlikely candidate to spark a revolution in medical research, but thanks to the work of the marine biologist Osamu Shimomura that’s exactly what it did.  In their decision to award the Nobel Prize in Chemistry to Osamu Shimomura, Martin Chalfie and Roger Y. Tsien for their work on the Green Fluorescent Protein (GFP) the Nobel  Foundation has recognized how research in apparently esoteric areas of biology can ultimately transform the biomedical research.

This revolution began in the early 1960′s when Osamu Shimomura and Frank Johnson at the University of Princeton, intrigued by the ability of Aequorea victoria to glow green when disturbed, set out to isolate the proteins responsible.  They succeeded in isolation two proteins, a blue luminescent protein they named aequorin and another green protein that glowed when exposed to UV light.  In the 1970′s Osamu Shimomura studied the green protein, later known as GFP, and found that unlike aequorin GFP did not need a supply of energy to glow, a useful property for a molecule being used to label proteins in a cell.

GFP was clearly a very interesting protein but there was a problem, it could only be obtained from jellyfish, so obtaining useful quantities of it was next to impossible.  A scientist named Douglas Prasher working for the National Cancer institute had the answer, if the gene for GFP could be identified and cloned it could be inserted next to a gene that scientists wished to study so that the protein produced by that gene would be labeled by a GFP molecule.  This label would then allow the scientists to follow what that protein was doing in a cell or organism.  With this in mind Douglas Prasher identified and sequenced the gene encoding GFP, publishing his results in 1992.  Unfortunately at this point his funding ran out, but he did send copies of the gene to several researchers, including Martin Chalfie at Colombia University.

Martin Chalfie’s research concerned the development of the nematode worm Caenorhabditis elegans, and he was excited by the possibility that bioluminescent proteins could be used to follow twhat proteins and cells were doing and where they were doing it.  C.elegans is an organism favoured by many scientists who study animal development and genetics, and has played a decisive role in research leading to two other recent Nobel Prizes, that awarded to Sidney Brenner, John Sulston and Robert Horvitz in 2002 for their discoveries concerning genetic regulation of organ development and programmed cell death, and  that awarded to Andrew Fire and Craig Mello in 2006 for their discovery of RNA interference.  Martin Chalfie himself worked with Sidney Brenner and John Sulston while at the Laboratory of molecular Biology in Cambridge a few years earlier.  What Martin Chalfie and his colleagues did was to prove that GFP could be expressed in the bacteria E. coli and in  C.elegans, and then to place the GFP gene under the control of a gene that is active in only six nerve cells in the worm.  The resulting worm with six cells that glowed green under UV light caused a sensation when it was published in the journal Science (1) in 1994, if GFP could be function in organisms as diverse as bacteria, jellyfish and nematode worms why shouldn’t it work for other species?

While scientists around the world started to employ GFP in their research its versatility was greatly increased by the work of Roger Tsien who used the techniques of molecular biology to increase the numbers of colours available to scientists from just one colour, green, to a palette that covers the visible spectrum.  A dramatic demonstration of the potential of the expanded palette of GFP proteins cane in 2007 with the publication of a paper that used different colour GFP labels to enable scientists to follow the fates of thousands of cells simultaneously in a portion of the mouse brain (2), a technique quickly dubbed the brainbow. Just this week another paper in Science described how scientists at the European Molecular Biology Laboratory used GFT labeling to track all the cells in the zebrafish embryo during the first 24 hours and use this information to construct a digital 3D model, allowing early embryonic development in vertebrates to be studied in unprecedented detail (3).

Scientists now use GFP widely in the laboratory, and its uses are as diverse as determining when and how proteins bind to each other in cells in vitro to following the fate of individual nerve cells in the developing brain of living organisms. The importance of GFP to biological and medical research today cannot be overstated.

We salute the winners of the 2008Nobel Prize in Chemistry on their magnificent achievements.

Paul Browne
1)Chalfie M., Tu Y., Euskirchen G., Ward W.W., and Prasher D.C. “Green
fluorescent protein as a marker for gene expression.” Science Volume 263,
pages 802-805 (1994).

2)Livet J., Weissman T.A., Kang H., Draft R.W., Lu J, Bennis R.A., Sanes
J.R., Lichtman J.W. “Transgenic strategies for combinatorial expression of
fluorescent proteins in the nervous system.” Nature Volume 450(7166) pages
56-62 (2007).

3) Keller P.J., Schmidt A.D., Wittbrodt J., Stelzer E.H.K. “Reconstruction of Zebrafish Early Embryonic Development by Scanned Light Sheet Microscopy ” Science, Published Online October 9 2008, DOI: 10.1126/science.1162493

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