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A New Generation of Ca2+ Indicators with Greatly Improved Fluorescence Properties (Grynkiewicz, G., Poenie, M., and Tsien, R. Y. (1985) J. Biol. Chem. 260, 3440–3450)
Born in New York, in 1952, Roger Yonchien Tsien grew up in Livingston, New Jersey. He had a number of engineers in his extended family, including his father who was a mechanical engineer and his mother's brothers who were engineering professors at the Massachusetts Institute of Technology. Tsien, who calls his own work molecular engineering, once said, “I'm doomed by heredity to do this kind of work (
Due to childhood asthma, Tsien was often indoors, where he spent hours conducting chemistry experiments in his basement laboratory. At age 16, Tsien won first prize in the nationwide Westinghouse talent search with a project investigating how metals bind to thiocyanate. He later attended Harvard College on a National Merit Scholarship and graduated at age 20 with a degree in chemistry and physics.
Tsien went on to the University of Cambridge with a Marshall Scholarship and earned a Ph.D. in physiology in 1977. As a graduate student Tsien worked on developing a better dye to track cellular calcium levels. At that time, measuring intracellular calcium was a laborious process that involved using microelectrodes or injecting the luminescent calcium-binding jellyfish protein, aequorin, through the cell membrane, a technique that often damaged the cells. Tsien designed a calcium-binding indicator called “quin2” that could be loaded into intact cells by incubating them with a membrane-permeant ester derivative (
). Cytosolic esterases would then split off the ester groups and leave the membrane-impermeant quin2 tetraanion trapped in the cytosol. Increases in quin2 fluorescence indicated increased calcium concentration.
Tsien remained at Cambridge to complete a postdoctoral fellowship and then took a position at the University of California, Berkeley in 1981, becoming a professor during his 8 years there. He spent his time at Berkeley developing and applying better dyes for calcium and other ions.
The Journal of Biological Chemistry (JBC) Classic reprinted here reports on a new generation of calcium indicators that Tsien designed to replace quin2. The older indicator had many limitations. For example, quin2 signaled calcium by increasing its fluorescence intensity rather than its excitation or emission wavelengths. Because fluorescence intensity is dependent on many factors, the method was unreliable. Quin2 also bound to Mg2+ and gave falsely low readings of calcium concentration when high levels of exchangeable heavy metals were present.
Tsien's new family of fluorescent indicators combined an 8-coordinate tetracarboxylate chelating site with stilbene chromophores. The new chelators offered “up to 30-fold brighter fluorescence, major changes in wavelength not just intensity upon Ca2+ binding, slightly lower affinities for Ca2+, slightly longer wavelengths of excitation, and considerably improved selectivity for Ca2+ over other divalent cations.” This Classic article by Tsien is the sixth all-time most cited article in the JBC.
In 1989 Tsien moved his laboratory to the University of California, San Diego and started working on cyclic AMP. Collaborating with Susan S. Taylor, he developed a molecular sensor for cyclic AMP by attaching a fluorescent dye to cyclic AMP-dependent protein kinase (PKA). In the mid-1990s Tsien turned his focus to developing genetically encoded macromolecular indicators. By modifying the sequence of green fluorescent protein (GFP), Tsien, along with Roger Heim, was able to produce mutants with brighter fluorescence. They also created blue- and cyan-emitting mutants, BFPs and CFPs, respectively. Most applications of fluorescent proteins now use versions pioneered by the Tsien lab.
Currently, Tsien is Professor of Pharmacology at the University of California, San Diego, School of Medicine and Professor of Chemistry and Biochemistry at the University of California, San Diego. He became an investigator with the Howard Hughes Medical Institute in 1989. In 1996 he was a scientific co-founder of Aurora Biosciences Corporation, which went public in 1997 and was acquired by Vertex Pharmaceuticals in 2001. In 1999 he was a scientific co-founder of Senomyx, Inc.
Tsien has received many honors for his work including the Young Scientist Award from the Passano Foundation (1991), the Artois-Baillet-Latour Health Prize from Belgium (1995), the Gairdner Foundation International Award (1995), the Basic Research Prize from the American Heart Association (1995), the American Chemical Society Award for Creative Invention (2002), the Heineken Prize for Biochemistry and Biophysics from the Royal Netherlands Academy of Sciences (2002), and the Christian B. Anfinsen Award from the Protein Society (2002). Tsien also received the Herbert Sober Lectureship from the American Society for Biochemistry and Molecular Biology in 2000. In 1995, Tsien was elected to the Institute of Medicine, and he was elected to both the American Academy of Arts and Sciences and the National Academy of Sciences in 1998.