Chemical-only Cell Reprogramming Transforms Human and Mouse Skin Cells into Neurons

Chemical-only Cell Reprogramming Transforms Human and Mouse Skin Cells into Neurons

Friday, 07 August 2015

Two labs in China have independently succeeded in transforming skin cells into neurons using only a cocktail of chemicals, with one group using human cells from healthy individuals and Alzheimer's patients, and the other group using cells from mice. The two studies reinforce the idea that a purely chemical approach is a promising way to scale up cell reprogramming research that may avoid the technical challenges and safety concerns associated with the more popular method of using transcription factors. Both papers appear on August 6 in the journal Cell Stem Cell.

One of the challenges of forcing cells to change identity is that the cells you end up with may look normal but have different internal activities than their naturally forming counterparts. The two papers provide evidence that similar gene expression, action potentials, and synapse formation can be detected in transcription-factor-induced neurons as those generated from the chemical cocktails. (Both groups used mixtures of seven small molecules, but different recipes – outlined in detail in the supplemental information section of each paper – because they focused on different species.)

This is an image of mouse chemical-induced

neurons. Credit: Courtesy of Hongkui Deng.

"We found that the conversion process induced by our chemical strategy is accompanied by the down-regulation of [skin-cell] specific genes and the increased expression of neuronal transcription factors," said human study co-author Jian Zhao, of the Shanghai Institutes for Biological Sciences and Tongji University.

"By coordinating multiple signalling pathways, these small molecules modulate neuronal transcription factor gene expression and thereby promote the neuronal cell transition."

The authors add that the direct conversion bypasses a proliferative intermediate progenitor stage, which circumvents safety issues posed by other reprogramming methods.

This is an image of human chemical induced

neurons. Credit: Courtesy of Gang Pei and

Jian Zhao.

Zhao's paper, co-led with cell biologist Gang Pei, also shows that the pure chemical protocol can be used to make neurons from the skins cells of Alzheimer's patients. Most of the work using patient stem cells has been done by using transcription factors – molecules that affect which genes are expressed in a cell – to create induced pluripotent stem cells. Chemical cell reprogramming is seen as an alternative for disease modelling or even potential cell replacement therapy of neurological disorders, but the "proof-of-concept" is still emerging.

"In comparison with using transgenic reprogramming factors, the small molecules that are used in this chemical approach are cell permeable; cost-effective; and easy to synthesize, preserve, and standardize; and their effects can be reversible," says mouse study co-author Hongkui Deng of the Peking University Stem Cell Research Center.

"In addition, the use of small molecules can be fine-tuned by adjusting their concentrations and duration, and the approach bypasses the technical challenges and safety concerns of genetic manipulations, which may be promising in their future applications."

Deng worked for four years with Zhen Chai and Yang Zhao, also of Peking University, to identify the small molecules that could create chemically induced mouse neurons. Researchers had been close for years, but a transcription factor was always necessary to complete the transformation. Through many chemical screens they identified the key ingredient, I-BET151, which works to suppress transcription in skin cells. They then found the right steps and conditions to mature the neurons post-transformation.

The authors of both papers aim to learn more about the biology behind chemically induced reprogramming and to make the protocols more efficient. While their success is promising, there are still a number of hurdles to overcome.

"We hope in the future that the chemical approaches would be more robust in inducing functional mature neurons," Deng says.

"In addition, we are attempting to generate specific neuronal subtypes and patient-specific functional neurons for translational medicine by using pure chemicals."

Jian Zhao, of the human study, says:

"It should be possible to generate different subtypes of neurons with a similar chemical approach but using slightly modified chemical cocktails."

"It also needs to be explored whether functional neurons could be induced by chemical cocktails in living organisms with neurological diseases or injury," she adds.

Source: Cell Press

Contact: Joseph Caputo

References:

Small-Molecule-Driven Direct Reprogramming of Mouse Fibroblasts into Functional Neurons

Xiang Li, Xiaohan Zuo, Junzhan Jing, Yantao Ma, Jiaming Wang, Defang Liu, Jialiang Zhu, Xiaomin Du, Liang Xiong, Yuanyuan Du, Jun Xu, Xiong Xiao, Jinlin Wang, Zhen Chai, Yang Zhao, Hongkui Deng

Cell Stem Cell Volume 17, Issue 2, p195–203, 6 August 2015

Direct Conversion of Normal and Alzheimer's Disease Human Fibroblasts into Neuronal Cells by Small Molecules

Wenxiang Hu, Binlong Qiu, Wuqiang Guan, Qinying Wang, Min Wang, Wei Li, Longfei Gao, Lu Shen, Yin Huang, Gangcai Xie, Hanzhi Zhao, Ying Jin, Beisha Tang, Yongchun Yu, Jian Zhao, Gang Pei

Cell Stem Cell Volume 17, Issue 2, p204–212, 6 August 2015

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Tiny Tweezers Allow Precision Control of Enzymes

Tiny Tweezers Allow Precision Control of Enzymes

Wednesday, 03 July 2013

Tweezers are a handy instrument when it comes to removing a splinter or plucking an eyebrow.

In new research, Hao Yan and his colleagues at Arizona State University's Biodesign Institute describe a pair of tweezers shrunk down to an astonishingly tiny scale. When the jaws of these tools are in the open position, the distance between the two arms is about 16 nanometres — over 30,000 times smaller than a single grain of sand.

The group demonstrated that the nano-tweezers, fabricated by means of the base-pairing properties of DNA, could be used to keep biological molecules spatially separated or to bring them together as chemical reactants, depending on the open or closed state of the tweezers.

In a series of experiments, regulatory enzymes — central components in a host of living processes — are tightly controlled with the tweezers, which can switch reactions on or off depending on their open or closed condition.

"The work has important implications for regulating enzymatic function and may help usher in a new generation of nanoscale diagnostic devices as well as aid in the synthesis of valuable chemicals and smart materials", said Yan.

Results of the new research appear in the current issue of the journal Nature Communications. Minghui Liu, a researcher in Biodesign's Center for Single Molecule Biophysics and the Department of Chemistry and Biochemistry at ASU is the paper's lead author. Other authors include Jinglin Fu, Yan Liu, Neal Woodbury from ASU and Christian Hejesen and Kurt Gothelf from Aarhus University, Denmark.

The left panel shows tweezers in the open position,
with the enzyme (green) on the upper arm and the
co-factor (gold) on the lower arm. Supplying a
complementary fuel strand causes the tweezers to
close, producing the reaction of the enzyme-cofactor
pair. (Right panel) while a set strand restores the
tweezers to their open position. Credit: The Biodesign
Institute/Nature Communications.

Enzymes are large molecules responsible for thousands of chemical interactions essential to life. A primary role for enzymes is to accelerate or catalyse myriad chemical reactions involved in processes ranging from digestion to DNA synthesis. To do this, enzymes lower the activation energy — the minimum energy needed for chemical reactions to occur — thereby speeding up the rate of such reactions. Enzymes are critical factors for health and disease, helping cells maintain their delicate homeostasis. When mutations lead to over- or under-production in certain key enzymes, severe genetic diseases — some of them, lethal — can result.

Because of the central importance of enzymes for biological systems, researchers want to gain a better understanding of how normal enzymatic reactions occur and how they may go awry. Such knowledge may encourage the development of techniques to mimic cellular processes involved in enzyme regulation.

In the current study, the authors create a nanoscale tool designed to manipulate enzymatic reactions with fine-grained control. The group dubs their device a tweezer-actuated enzyme nanoreactor.

This is lead author Minghui Liu. Credit: The
Biodesign Institute at Arizona State University.

The clever design separates an enzyme and a cofactor essential for successful reactions on separate arms of the tweezer-like instrument (See Figure 1). Enzyme function is inhibited when the tweezers are in their open position and the two molecules are held apart. Enzyme activation takes place when the tweezer prongs close, bringing enzyme and cofactor in contact. (The closing of the tweezers occurs when a specific DNA sequence is added, altering the thermodynamics of the system and causing a conformational change in the structure.)

The current study explores reactions in regulatory enzymes — multitasking entities that are important for modulating biochemical pathways. Regulatory enzymes, which can catalyse reactions over and over again, accomplish their feats by binding with biomolecular cofactors. (Hormone production and regulation are just one example of regulatory enzyme activity.)

In a series of experiments, the group was able to externally control the inhibition and activation of the enzyme through successive cycles. The authors stress that the nanoreactor tweezers could be used to regulate other types of enzymes and their control could be further refined by means of feedback and feed forward loops.

Hao Yan is a researcher in the Biodesign Institute's
Center for Single-Molecule Biophysics and holds
the Milton D. Glick Distinguished Chair in Chemistry
and Biochemistry at ASU. Credit: The Biodesign
Institute at Arizona State University. 

Engineering nanostructures from the bottom up, using DNA as a construction material, affords researchers exacting control over the resulting geometry. Previously, Yan has created nanostructures in two and three-dimensions, ranging from flat shapes to bowls, baskets, cages, Möbius strips and a spider-like autonomous walker.

In the tweezer design, a pair of 14 nm arms is connected at their ends by means of a 25 nucleotide single strand of DNA. This strand controls the opening and pinching of the tweezers, much the way a spring acts in a pair of gardening shears.

Two types of complementary sequence strand interact with this component, either forming a rigid DNA double helix, which supports the tweezers in their open position (set strands) or disabling the structural support and closing the tweezers, (fuel strands).

Two techniques were used to measure and analyse the resulting structures with nanoscale precision: Fluorescence Resonance Energy Transfer (FRET) and Atomic Force Microscopy (AFM). Experiments demonstrated a high yield for enzyme-bound tweezers, and successful switching between open and closed states was observed. The use of FRET allowed the process to be monitored in real time.

Lengthening the cofactor linker dangling from one of the tweezers’ arms enhanced successful opening and closing of the enzyme tweezers. Analysis revealed a 5-fold increase in enzymatic activity in the closed state compared with the open state. The study also demonstrated durability in the tweezers, which were able to cycle between the open and closed positions 9 times without losing structural integrity. The process was only limited by the accumulation of set strands and fuel strands.

Future work will explore similar responsive enzyme nano-devices capable of selective chemical amplification, with potentially broad impacts for medical diagnostics. Nanoreactors may also be applied as precision biocatalysts for the production of useful chemicals and smart materials.

Source: Arizona State University 

Contact: Joseph Caspermeyer

Written by: Richard Harth 

Reference:

A DNA tweezer-actuated enzyme nanoreactor

Minghui Liu, Jinglin Fu, Christian Hejesen, Yuhe Yang, Neal W. Woodbury, Kurt Gothelf, Yan Liu, Hao Yan

Nature Communications 03 Jul 2013, doi: 10.1038/ncomms3127

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Scientists Home in on Chemicals Needed to Reprogram Cells

Groundbreaking discovery moves field closer to therapeutic applications
Friday, 03 December 2010

Scripps Research Institute scientists have made a significant leap forward in the drive to find a way to safely reprogram mature human cells and turn them into stem cells, which can then change into other cell types, such as nerve, heart, and liver cells. The ability to transform fully mature adult cells such as skin cells into stem cells has potentially profound implications for treating many diseases.

Scripps Research Associate Professor

Sheng Ding.

In research published in the December 3, 2010 issue of Cell Stem Cell, Scripps Research Associate Professor Sheng Ding, PhD, reports a novel cocktail of drug-like small molecules that, with the assistance of a gene called Oct4, enables reprogramming of human skin cells into stem cells.

"Our ultimate goal is to generate induced pluripotent stem cells with defined small molecules," Ding said.

"This would offer a fundamentally new method and significant advantages over previous methods, such as genetic manipulation or more difficult-to-manufacture biologics."

Using small-molecule compounds to reprogram adult human cells back to their pluripotent state — able to change into all other cell types — avoid the ethical controversy around embryonic stem cell research, and pave the way for the large-scale production of stem cells that could be used inexpensively and consistently in drug development. Cures for Alzheimer's, Parkinson's, and many other diseases might be possible if new cells could be created from a patient's own cells to replace those that have succumbed to disease or injury.

Substituting Chemicals for Genes
Scientists discovered in 2007 that fully differentiated mature cells, such as skin cells, could be "reprogrammed" to become pluripotent by using four transcription genes. One problem with this technique is that these genes, once inserted into a cell, permanently alter the host cell's DNA.

"There are many concerns when the host cell's genome is manipulated," Ding says.

"One major worry is that since the four genes are [cancer-causing] oncogenes, they could induce tumours or interrupt functions of other normal genes."

Because of this danger, scientists have been searching for methods that could induce reprogramming without the use of these cancer-causing genes. The method the Ding lab has been pioneering — using small, synthetic molecules — represents a fundamentally different approach from the previous methods.

"We are working toward creating drugs that are totally chemically defined, where we know every single component and precisely what it does, without causing genetic damage," Ding says.

Breaking New Ground
Scientists have known for at least 50 years that a cell's identity is reversible if given the right signal — cells go forward to become mature, functional cells or they can go backward to become primitive cells. In order for cellular reprogramming to be safe and practical enough to use in cell therapy, researchers have sought an efficient, reliable way to trigger the reprogramming process.

In 2008, the Ding lab reported finding small molecules that could replace two of the required four genes. Now, two years later, through extraordinary effort and unique screening strategy, the lab made a major leap forward by finding a way to replace three out of the four genes.

"We are only one step away from the ultimate goal, which would represent a revolutionary technology," Ding says.

The new study also revealed that the novel compound facilitates a novel mechanism in reprogramming: the metabolic switch from mitochondrial respiration to glycolysis, an important mechanism for tissue regeneration. The small molecules Ding and his colleagues found promote reprogramming by facilitating such metabolic switching — an entirely new understanding of reprogramming.

A future goal is to replace Oct4, a master regulator of pluripotency, in the chemical cocktail.

"That would be the last step toward achieving the Holy Grail," Ding says.

"Our latest discovery brings us one step closer to this dream."

Source: Scripps Research Institute
Contact: Mika Ono

Reference:
Reprogramming of Human Primary Somatic Cells by OCT4 and Chemical Compounds
Saiyong Zhu, Wenlin Li, Hongyan Zhou, Wanguo Wei, Rajesh Ambasudhan, Tongxiang Lin, Janghwan Kim, Kang Zhang, Sheng Ding
Cell Stem Cell, Volume 7, Issue 6, 651-655, 3 December 2010, doi:10.1016/j.stem.2010.11.015
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China Stakes Claim as Global Centre for Scientific Research

China Stakes Claim as Global Centre for Scientific Research Thursday, 14 January 2010 Contrary to popular belief, China is doing much more than exporting clothing, toys, electronics, and other popular consumer goods. The country is on a scientific roll, to the point where it could conceivably be regarded as the emerging global centre for scientific research, a new report indicates. It describes an amazing growth in chemical patenting and publishing that could bring new and innovative products to the world market ranging from pharmaceuticals to microchips, according to an article in the current issue of Chemical & Engineering News, (C&EN) ACS' weekly newsmagazine. C&EN Senior Editor Sophie L. Rovner reports that China in 2009 became the world leader in the number of chemistry patent applications published annually. China published 67,000 patent applications in 2009, compared to 52,000 for Japan and 41,000 for the United States. Publication of scientific papers originating in China increased faster than any other nation during the last 10 years. The output of papers with Chinese authors more than quadrupled — from 20,000 papers in 1998 to more than 112,000 in 2008. The publication of U.S. scientific papers rose by barely 30 percent during that period. In achieving this growth, scientists in China are embracing collaborators in the U.S. and other countries. It is becoming increasingly clear that the country is changing the "world map of research," with China conceivably at its centre, the article suggests. This story is available at China Ascendant. ......... ZenMaster

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Biological Reaction Essential to Life Takes 2.3B Years Without Enzyme

Biological Reaction Essential to Life Takes 2.3B Years Without Enzyme Tuesday, 11 November 2008 All biological reactions within human cells depend on enzymes. Their power as catalysts enables biological reactions to occur usually in milliseconds. But how slowly would these reactions proceed spontaneously, in the absence of enzymes – minutes, hours, days? And why even pose the question? One scientist who studies these issues is Richard Wolfenden, Ph.D., Alumni Distinguished Professor Biochemistry and Biophysics and Chemistry at the University of North Carolina at Chapel Hill. Wolfenden holds posts in both the School of Medicine and in the College of Arts and Sciences and is a member of the National Academy of Sciences. In 1995, Wolfenden reported that without a particular enzyme, a biological transformation he deemed "absolutely essential" in creating the building blocks of DNA and RNA would take 78 million years. "Now we've found a reaction that – again, in the absence of an enzyme – is almost 30 times slower than that," Wolfenden said. "Its half-life – the time it takes for half the substance to be consumed – is 2.3 billion years, about half the age of the Earth. Enzymes can make that reaction happen in milliseconds." With co-author Charles A. Lewis, Ph.D., a postdoctoral scientist in his lab, Wolfenden published a report of their new findings recently in the online early edition of the Proceedings of the National Academy of Science. The study is also due to appear in the Nov. 11 print edition. The reaction in question is essential for the biosynthesis of haemoglobin and chlorophyll, Wolfenden noted. But when catalyzed by the enzyme uroporphyrinogen decarboxylase, the rate of chlorophyll and haemoglobin production in cells "is increased by a staggering factor, one that's equivalent to the difference between the diameter of a bacterial cell and the distance from the Earth to the sun." "This enzyme is essential for both plant and animal life on the planet," Wolfenden said. "What we're defining here is what evolution had to overcome, that the enzyme is surmounting a tremendous obstacle, a reaction half-life of 2.3 billion years." Knowing how long reactions would take without enzymes allows biologists to appreciate their evolution as prolific catalysts, Wolfenden said. It also enables scientists to compare enzymes with artificial catalysts produced in the laboratory. "Without catalysts, there would be no life at all, from microbes to humans," he said. "It makes you wonder how natural selection operated in such a way as to produce a protein that got off the ground as a primitive catalyst for such an extraordinarily slow reaction." Experimental methods for observing very slow reactions can also generate important information for rational drug design based on cellular molecular studies. "Enzymes that do a prodigious job of catalysis are, hands-down, the most sensitive targets for drug development," Wolfenden said. "The enzymes we study are fascinating because they exceed all other known enzymes in their power as catalysts." Wolfenden has carried out extensive research on enzyme mechanisms and water affinities of biological compound. His work has also influenced rational drug design, and findings from his laboratory helped spur development of ACE inhibitor drugs, now widely used to treat hypertension and stroke. Research on enzymes as proficient catalysts also led to the design of protease inhibitors that are used to treat HIV infection. "We've only begun to understand how to speed up reactions with chemical catalysts, and no one has even come within shouting distance of producing, or predicting the magnitude of, their catalytic power," Wolfenden said. Reference: Uroporphyrinogen decarboxylation as a benchmark for the catalytic proficiency of enzymes Charles A. Lewis, Jr. and Richard Wolfenden PNAS, November 6, 2008, doi: 10.1073/pnas.0809838105 ......... ZenMaster

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Scientists Improve iPS Cell Method

Scientists Improve iPS Cell Method Thursday, 06 November 2008 Scientists from the Scripps Research Institute have identified a combination of drugs that can be used to reprogram cells from human tissue to become similar to embryonic stem cells so that they may develop into all the cell types in the body. The Scripps method, documented in a story published Thursday in the journal Cell Stem Cell, improves upon a process that until now involved using genes and viruses to coax human cells backward down the development pathway until they are pluripotent, meaning they can become many different cell types. One of the genes used, known as Sox2, had previously been regarded as essential for the reprogramming process. In June, the Scripps team, led by Sheng Ding, associate professor in the Department of Chemistry at The Scripps Research Institute, showed that it could use drugs to create pluripotent cells from the brain cells of mice. This recent Scripps study appears to be the first published showing success with an alternative method for creating human pluripotent cells. Ding said the work of his team, which included scientists from the Max Planck Institute for Molecular Biomedicine in Germany, could be used to identify other drugs and small molecules that might also be used in the process for different results.

Reference: Induction of Pluripotent Stem Cells from Mouse Embryonic Fibroblasts by Oct4 and Klf4 with Small-Molecule Compounds Yan Shi, Caroline Desponts, Jeong Tae Do, Heung Sik Hahm, Hans R. Schöler and Sheng Ding Cell Stem Cell, Volume 3, Issue 5, 568-574, 6 November 2008, doi:10.1016/j.stem.2008.10.004 See also: Embryo-free Stem Cell Research Gets an Advance CellNEWS - Thursday, 05 June 2008 Scientists Identify Synthetic Compound that Keeps Stem Cells Young CellNEWS - Wednesday, 08 November 2006 ......... ZenMaster

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Living Cells as Nanotechnology Factories

Bacteria used as factories to make complex DNA based nanostructures Thursday, 09 October 2008 In the tiny realm of nanotechnology, scientists have used a wide variety of materials to build atomic scale structures. But just as in the construction business, nanotechnology researchers can often be limited by the amount of raw materials. Now, Biodesign Institute at Arizona State University researcher Hao Yan has avoided these pitfalls by using cells as factories to make DNA based nanostructures inside a living cell. Yan specializes in a fast-growing field within nanotechnology — commonly known as structural DNA nanotechnology — that uses the basic chemical units of DNA, abbreviated as C, T, A, or G, to self-fold into a number of different building blocks that can further self-assemble into patterned structures. "This is a good example of artificial nanostructures that can be replicated using the machineries in live cells" said Yan. "Cells are really good at making copies of double stranded DNA and we have used the cell like a copier machine to produce many, many copies of complex DNA nanostructures." DNA nanotechnologists have made some very exciting achievements during the past five to 10 years. Nevertheless, DNA nanotechnology has been limited by the need to chemically synthesize all of the material from scratch. To date, it has strictly been a test tube science, where researchers have developed many toolboxes for making different DNA nanostructures to attach and organize other molecules including nanoparticles and other biomolecules. "If you need to make a single gram of a DNA nanostructure, you need to order one gram of the starting DNA materials. Scientists have previously used chemical methods to copy branched DNA structures, and there has also been significant work in using long-stranded DNA sequences replicated from cells or phage viruses to scaffold short helper DNA sequences to form 2-D or 3-D objects," said Yan, who is a professor in the Department of Chemistry and Biochemistry at ASU. "We have always dreamed of scaling up DNA nanotechnology. One way to scale it up is to use the cellular system because simple DNA can be replicated inside the cell. We wanted to know if the cell's copy machine could tolerate single stranded DNA nanostructures that contain complicated secondary structures." Yan and his fellow researchers, Chenxiang Lin, Sherri Rinker and Yan Liu at ASU and their collaborators Ned Seeman and Xing Wang at New York University, wanted to test the nanoscale manufacturing capabilities of cells. They went back to reproducing the very first branched nanostructure made up of DNA — a cross-shaped, four-arm DNA junction. Another DNA junction structure containing a different crossover topology was also tested. To copy these branched DNA nanostructures inside a living cell, the ASU and NYU research team first shipped the cargo inside a bacterial cell. They cut and pasted the DNA necessary to make these structures into a phagemid, a virus-like particle that infects a bacterial cell. Once inside the cell, the phagemid used the cell just like a photocopier machine to reproduce millions of copies of the DNA. By theoretically starting with just a single phagemid infection, and a single millilitre of cultured cells, Yan found that the cells could churn out trillions of the DNA junction nanostructures. The DNA nanostructures produced in the cells were also found to fold correctly, just like the previously built test tube structures. According to Yan, the results proved the key existence of the DNA nanostructures during the cell's routine DNA replication and division cycles. "When a DNA nanostructure gets replicated, it does exist and can survive the complicated cellular machinery. And it looks like the cell can tolerate this kind of structure and still do its job. It's amazing," Yan said. Yan acknowledges that this is just the first step, but foresees there are many interesting DNA variations to consider next. "The fact that the natural cellular machinery can tolerate artificial DNA objects is quite intriguing, and we don't know what the limit is yet." Yan's group may be able to change and evolve DNA nanostructures and devices using the cellular system and the technology may also open up some possibilities for synthetic biology applications. "I'm very excited about the future of DNA nanotechnology, but there is a lot of work to be done. An interesting research topic to pursue is the interface of DNA nanostructures with live cells; it is full of opportunities," said Yan. The results were published in the early online edition of the Proceedings of the National Academy of Sciences. ......... ZenMaster

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Colouring the Biomedical Research gets the Nobel Prize in Chemistry 2008

Nobel Prize in Chemistry 2008 is lighting up biomedical research Wednesday, 08 October 2008 This years Nobel Prize in Chemistry goes to: Osamu Shimomura, Marine Biological Laboratory (MBL), Woods Hole, MA, USA, Martin Chalfie, Columbia University, New York, NY, USA, Roger Y. Tsien, University of California, San Diego, CA, USA "for the discovery and development of the green fluorescent protein, GFP"

for colouring the biomedical research!

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Zebra fish glowing green and red.

GloFish. Courtesy of www.glofish.com.

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Glowing proteins – a guiding star for biochemistry The remarkable brightly glowing green fluorescent protein, GFP, was first observed in the beautiful jellyfish, Aequorea victoria in 1962. Since then, this protein has become one of the most important tools used in contemporary bioscience. With the aid of GFP, researchers have developed ways to watch processes that were previously invisible, such as the development of nerve cells in the brain or how cancer cells spread. Tens of thousands of different proteins reside in a living organism, controlling important chemical processes in minute detail. If this protein machinery malfunctions, illness and disease often follow. That is why it has been imperative for bioscience to map the role of different proteins in the body. This year's Nobel Prize in Chemistry rewards the initial discovery of GFP and a series of important developments which have led to its use as a tagging tool in bioscience. By using DNA technology, researchers can now connect GFP to other interesting, but otherwise invisible, proteins. This glowing marker allows them to watch the movements, positions and interactions of the tagged proteins. Researchers can also follow the fate of various cells with the help of GFP: nerve cell damage during Alzheimer's disease or how insulin-producing beta cells are created in the pancreas of a growing embryo. In one spectacular experiment, researchers succeeded in tagging different nerve cells in the brain of a mouse with a kaleidoscope of colours. The story behind the discovery of GFP is one with the three Nobel Prize Laureates in the leading roles: Osamu Shimomura first isolated GFP from the jellyfish Aequorea victoria, which drifts with the currents off the west coast of North America. He discovered that this protein glowed bright green under ultraviolet light. Martin Chalfie demonstrated the value of GFP as a luminous genetic tag for various biological phenomena. In one of his first experiments, he coloured six individual cells in the transparent roundworm Caenorhabditis elegans with the aid of GFP.

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Roger Y. Tsien, Howard Hughes Medical Institute at the University of California, San Diego. Credit: Joe Toreno for HHMI.

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Roger Y. Tsien contributed to our general understanding of how GFP fluoresces. He also extended the colour palette beyond green allowing researchers to give various proteins and cells different colours. This enables scientists to follow several different biological processes at the same time. Osamu Shimomura, Japanese citizen. Born 1928 in Kyoto, Japan. Ph.D. in organic chemistry 1960 from Nagoya University, Japan. Professor emeritus at Marine Biological Laboratory (MBL), Woods Hole, MA, USA and Boston University Medical School, MA, USA. Martin Chalfie, US citizen. Born 1947, grew up in Chicago, IL, USA. Ph.D. in neurobiology 1977 from Harvard University. William R. Kenan, Jr. Professor of Biological Sciences at Columbia University, New York, NY, USA, since 1982. Roger Y. Tsien, US citizen. Born 1952 in New York, NY, USA. Ph.D. in physiology 1977 from Cambridge University, UK. Professor at University of California, San Diego, La Jolla, CA, USA, since 1989. ......... ZenMaster

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