Medicine and Translational Research, Neuroscience
University of California, San Diego
Dr. Tsien is also a professor of pharmacology at the University of California, San Diego, School of Medicine and a professor of chemistry and biochemistry at the University of California, San Diego.
Molecules in Living Color, Against Cancer, or For Long-Term Memory
Dr. Tsien is best known for designing and building molecules that either report or perturb signal transduction inside living cells. These molecules, created by organic synthesis or by engineering naturally fluorescent proteins, have enabled many new insights into signaling. Extension of these methods to electron microscopy aims to reveal biochemistry at nanometer resolution. At mm-cm scales, Tsien is exploiting new ways to target contrast agents and therapeutic agents to tumors and sites of inflammation based on their expression of extracellular proteases, and to highlight peripheral nerves to aid surgery. He is also testing the hypothesis that life-long memories are stored as the pattern of holes in the perineuronal net, a specialized form of extracellular matrix deposited around neurons during critical periods of brain development.
This work is supported by HHMI and grants from the National Institutes of Health.
Roger Tsien's fascination with colors has revolutionized the fields of cell biology and neurobiology by allowing scientists to peer inside living cells and watch the behavior of molecules in real time. He is renowned for developing colorful dyes to track the movement of calcium within cells and has genetically modified molecules that make jellyfish and corals glow, creating fluorescent colors in a dazzling variety of hues. These multicolored fluorescent proteins have been used by scientists worldwide to track where and when certain genes are expressed in cells or in whole organisms. Now, Tsien is building on his fluorescent protein work to develop a novel way to image and possibly even deliver specially targeted drugs to cancer tumors.
Tsien has always been drawn to pretty colors. "Your science should ideally feed the deeper parts of your personality, to provide some intrinsic pleasure to tie you over the inevitable periods of discouragement," he says. Tsien grew up among a number of engineers in his extended family, and even from a young age he seemed destined for a career in science. Childhood asthma often kept Tsien indoors, where he spent hours conducting chemistry experiments in his basement laboratory and was first exposed to the chemistry of pretty colors. At 16, he won top prize in the nationwide Westinghouse Talent Search. He later attended Harvard College on a National Merit Scholarship, graduating at age 20 with a degree in chemistry and physics.
As a graduate student at the University of Cambridge, Tsien worked to develop a better dye to track inside cells the levels of calcium, which plays a critical role in numerous physiological processes, including the regulation of nerve impulses, muscle contraction, and fertilization. At that time, measuring intracellular calcium was a laborious process and typically involved injecting a calcium-binding protein through the cell membrane, a technique that often damaged the very cells being studied. Using techniques of chemistry, Tsien developed organic dyes that twist when they bind calcium, dramatically changing the dyes' fluorescence, and he found a way to masquerade the dyes so they could pass through the cell membrane without having to be injected.
In the early 1990s, Tsien borrowed from jellyfish a molecule that glows, green fluorescent protein, and reengineered it to emit colors ranging from blue to yellow. The fluorescent proteins can be tagged to certain genes or specific proteins of interest. Using a light microscope, scientists can easily determine by their glow when and where the genes are activated or the proteins are expressed. Over the years, Tsien has expanded the color palette of fluorescent proteins to include oranges, reds, and purples. He has also developed a way to monitor the interactions of two proteins, each tagged with different hues of fluorescent proteins. "As a whole, fluorescent proteins have had a huge impact on many areas of biological sciences because they gave [scientists] a direct link from genes and DNA to something you can see inside a cell or inside any organism," Tsien says, while also acknowledging that other scientists initially discovered and cloned fluorescent proteins.
Tsien recently has set his sights on the imaging and treatment of cancer. He and his colleagues have built U-shaped peptide molecules to carry a payload—an imaging molecule or chemotherapy drug. The peptides are substrates for certain proteases, protein-cleaving enzymes that are exuded from tumor cells but rarely appear on normal cells. When the protease cleaves the bottom of the U, the two arms of the U are separated, unleashing one arm to drag the payload portion of the peptide into a neighboring cancer cell. "I've always wanted to do something clinically relevant in my career, if possible, and cancer is the ultimate challenge," Tsien says.