THE 2004 WOLF FOUNDATION PRIZE IN MEDICINE
The Prize Committee for Medicine has unanimously decided that the 2004 Wolf Prize be jointly awarded to
Roger Y. Tsien
Howard Hughes Medical Institute
University of California San Diego
La Jolla, California, USA
for his seminal contribution to the design and biological application of novel fluorescent and photolabile molecules to analyze and perturb cell signal transduction.
Robert A. Weinberg
Whitehead Institute for Biomedical Research, and
MIT – Massachusetts Institute of Technology
Cambridge, Massachusetts, USA
for his discovery that cancer cells including human tumor cells, carry somatically mutated genes-oncogenes that operate to drive their malignant proliferation
In the 1970’s, it was widely believed that infection of normal cells, including cells in human tissues, by a variety of tumor viruses led to their transformation into cancer cells. Indeed, Dr. Weinberg’s research in the 1970’s focused on viral oncogenes and the role they play in cell transformation. However, in the late 1970’s it became increasingly apparent that many types of human cancer cells lack any trace of tumor viral infections or viral oncogenes. This suggested an alternative mechanistic explanation for cancer pathogenesis: that carcinogenic agents including mutagens inflict somatic mutations on cells in target tissues, leading in turn to the creation of mutant genes that subsequently function to provoke cell transformation and to drive the malignant proliferation of the mutant cells. However, evidence was lacking that tumor cells, including those derived from human tumors, carried such transforming, cancer-inducing genes.
In 1979, Dr. Weinberg’s lab reported that they were able to detect the presence of such transforming oncogenes in the DNA’s of chemically transformed rodent cells. This discovery depended upon exploitation of the gene transfer (transfection) technique, to introduce DNA from tumor cells into untransformed mouse NIH3T3 cells. This gene transfer resulted in the transformation of the recipient NIH3T3 cells, and thus proved that the DNA extracts from the tumor cells carried transforming sequences. In the following year, the Weinberg lab extended this observation to human tumor DNA’s, including one initially prepared from a human bladder carcinoma. The Weinberg lab then demonstrated that the transforming genes (i.e. oncogenes) from four independently transformed mouse sarcoma cell lines were all related in sequence structure, indicating that they all derived from a common precursor gene residing in the normal cell genome.
In 1982, Dr. Weinberg’s group reported the isolation by molecular cloning of the first human oncogene, derived from the DNA of the human bladder carcinoma. The Weinberg group soon reported that this gene was closely related to the ras oncogenes known to be transduced by acutely transforming rodent retroviruses. This led to the realization that a common repertoire of normal mammalian growth-regulating genes (proto-oncogenes) could be converted into active oncogenes, either by intervention of a transducing retrovirus, or by somatic mutations. Shortly thereafter, the Weinberg group elucidated on the nature of the somatic mutation leading to the creation of the human bladder carcinoma oncogene. They found that a single-base substitution
(point mutation) was responsible for the conversion of a normal ras proto-oncogene into an active oncogene. In the subsequent decade, a number of research groups found that similarly mutated ras oncogenes were present in about 25 percent of all human tumors, from a variety of tissue sites. The finding of a point mutation was the first documentation of a mutant cancer-promoting gene in the genome of a human tumor cell.
In 1999, Dr. Weinberg’s group reported the creation, for the first time, of genetically defined human tumor cells. Until this advance, all experimentally manipulated human tumor cells derived from human tumor biopsies and were thus, of unknown genetic constitution.
Professor Roger Y. Tsien has made unique contributions to two major areas of research, biomolecular engineering and signal transduction. Biomolecular engineering is the rational design, synthesis, and improvement of artificial molecules to interact with or modify biological systems in a controlled manner. Tsien’s contributions began with the rational design and synthesis of extremely useful calcium chelators and indicators for intracellular applications. His group pioneered, or improved, biologically useful indicators for sodium and for cAMP, membrane potential indicators, chelators that release or take up Ca2+ upon photoactivation, organic molecules to release nitric oxide intracellularly upon photoactivation, a general approach to making membrane-permeant, extracellularly-effective derivatives of phosphate-containing intracellular messengers and caged molecules that can perturb signal transduction with unprecedented three-dimensional spatial resolution.
He is also a leader in protein engineering, particularly in understanding and improving the Green Fluorescent Protein (GFP), a remarkable macromolecule that spontaneously synthesizes a fluorophore inside itself and thus enables strong visible fluorescence to be encoded genetically. Most of the huge number of applications of GFP in cell biology use mutations discovered in Prof. Tsien’s lab, to confer improved spectral properties, or altered colors. His group has used pairs of differently colored GFPs to build transfectable fluorescent indicators of cytosolic and organellar Ca2+ and to monitor dynamic protein-protein interactions in individual live cells. Prof. Tsien’s fluorescent indicators enable ultra-high-throughput the screening of large numbers of candidate compounds on mammalian cells. These are revolutionizing the pharmaceutical drug discovery process.
Tsien is also a leader in the cell biology signal transduction. His major accomplishments in this area include: the first direct measurements of the important increase in cytosolic free Ca2+ associated with immune cell activation secretion and the cell cycle; pioneer investigations on the occurrence and mechanism of Ca2+ oscillations; evidence that a major function of such oscillations may be to optimize gene expression; the discovery that intracellular Ca2+ gradients (and perhaps localized protein kinase C activation) may predict and control the directionality of toxin secretion from cytotoxic T lymphocytes. Elucidation of primary intracellular signaling pathways, involving synergism between nitric oxide, cGMP and Ca2+ for the induction of cerebellar long-term depression, one of the most important cellular models for mammalian synaptic plasticity.