Robert A. Weinberg
Wolf Prize Laureate in Medicine 2004
Robert A. Weinberg
Affiliation at the time of the award:
Whitehead Institute for Biomedical Research, Massachusetts Institute of Technology (MIT), 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.