Roundtable Review

Nobel Gold for Fluorescent Green
Posted 24 June '13

20X magnification of the somatosensory cortex of a mouse brain slice. These little guys have green flourescent protein (GFP) from a jelly-fish expressed in a subset of their neurons. Author: Robert Cudmore, Source: new_20x, Under: Creative Commons Attribution-Share Alike 2.0 Generic

Have you heard of GFP? Or rather, Green Fluorescent Protein?  Biologists certainly have, and more notably, they have seen it.  Whether as a biomarker for tumors, a biosensor of toxic metals, or a way to track HIV infection (just to name a few of thousands of examples), GFP literally sheds light on the otherwise invisible inner universe of living organisms.

True to its name, GFP is a protein, a small stable one that becomes green when exposed to UV or blue light.  Much of its use comes from the fact that normally proteins are too small to be observed even with the assistance of powerful microscopes.  To try to spot one is like trying to make out the needles in a haystack – in the dark.

Biotechnology allows a scientist to tether GFP to a protein of interest, and this fusion protein is ready to glow.  So now if the needles had a powerful green light attached, blasting through the haystack and locating them would become much easier. Since understanding proteins is key to understanding life, GFP opens up a vista for researchers to examine what they do, where they go, and when.  The now-ablaze protein under investigation may be one that is predominantly found in cancer cells, produced by a microorganism in response to the presence of an environmental toxin, or used by HIV to travel through infected cells.  The approximately 46,000 publications on GFP reflect the endless possibilities.  From plants, to yeast, to vertebrates – GFP is utterly pervasive in biological research.

For their work on GFP, Osamu Shimomura, Martin Chalfie, and Roger Tsien received the Nobel Prize in Chemistry in 2008 (We are made of chemicals, after all!).  They each played a crucial role in “lighting” up the lives and research of scientists worldwide. Shimomura was central in isolating and characterising GFP from its native source, a jellyfish off Washington State.  Martin Chalfie demonstrated the general applicability of GFP by lighting it up in a type of worm and a bacterium.  Roger Tsien was central to improving the properties of GFP, not only making it brighter but engineering mutants with visually arresting colors, from dazzling reds to alluring blues.  You can put these in different combinations in a cell to mark different proteins, and the image will seem to come from a Hollywood special effects crew.

Many other scientists contributed to the development of GFP, but the statutes of the Nobel Foundation dictate that the prize cannot be shared by more than three people.  That rule, unfortunately, may have stood in the way for Douglas Prasher, a scientist who was the first to clone (multiply) the jellyfish GFP gene in bacteria.  Obviously, the number of winners should be kept small to celebrate the few people who made truly outstanding achievements.  But to rigidly set the limit at the rather arbitrary total of three in some instances shuts the door on one or two more talented individuals who deserve appreciation.

Winner Roger Tsien has commercialised much of his research throughout his career.  He cofounded Aurora Biosciences Corporation in 1996, which was acquired by Vertex Pharmaceuticals in 2001.  He also helped establish Senomyx, where he is a member of the scientific advisory board, which develops flavour additives and has used GFP in the course of its research.  Indeed, the broad utility of GFP means that many companies use it in their basic research to develop products, such as drugs, that themselves are not related to GFP. Tsien also puts fluorescence into play with Avelas Biosciences.  One of the company’s projects is to enable surgeons to better ascertain the boundaries of cancerous tissue in a patient.  A surgeon neither wants to leave part of a tumor behind nor cut away healthy tissue.  To this end Avelas is developing fluorescent peptides that change color when they bathe in cancerous tissue.


A human mesenchymal stem cell expressing 1) microtubule associated protein fusion to GFP (green) and 2) histone 2b fusion to tagRFP (red) via BacMam gene delivery technology. Author: Ghanson. Under: Creative Commons Attribution-Share Alike 3.0 Unported

Roadblocks may hinder GFP-minded entrepreneurs.  The ever-growing multitude of GFP derivatives provides opportunities for research, but because there are so many derivatives to choose from, a commercial supplier may not have in its inventory the one that you want.  Also, patent protections, sometimes overly broad, impose restrictions.  On top of these issues, technical challenges can sometimes arise, including the fact that, despite its relatively small size, GFP adds on a lot of bulk to the protein it’s attached to, which may affect how that protein behaves.

Of course, technical challenges are a reality for most scientific projects, and GFP should certainly not signal a red flag.  Still, the slow pace of research sometimes gives investors cold feet.  Reportedly, one fluorescently-oriented company saw its investors pull out, hoping to gain a faster return instead from a business specialising in social media games.  Such a “show me the results before I commit” attitude is like refusing to water the lawn until grass begins to grow.  Instead, investors should decide whether they believe in the science or not and act accordingly.  Setbacks or delays should not be taken as signs that there must be a problem with the underlying premise.  In return, fledgling companies should do what they can to demonstrate to investors, many of who plead scientific ignorance, that the science is sound.  Receiving government grants or even just letters of support from leaders in the field may help soothe investor jitters.

All in all, it’s a safe bet that GFP will continue to be either part of the research program of many companies large and small, or a main component to the final product or service.  Successful applications of GFP will help move companies’ projects forward, let investors see some green of their own, and deliver some truly remarkable science for us all.

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