Harold Weintraub (1945–1995)

Acreative intellect, he contributed profoundly to our understanding of the molecular biology of development. From his early work on the structure of the eucaryotic chromosome to the recent identification of genes capable of etic-iting an entire program of cellular differentiation, Hal repeatedly identified important problems in biology and solved them in an elegant fashion. For those fortunate enough to have shared Hal's enthusiasm for science or to have been touched by his humanity, his premature death is an immeasurable loss. Hal Weintraub grew up playing baseball and basketball on the streets of Newark. He began his training in science as an undergraduate at Harvard College and received M.D. and Ph.D. degrees from the University of Pennsylva-nia, working in the laboratory of Howard Holtzer. As a Ph.D. student in the early 1970s, Hal became intrigued by the problem of how the regulation of gene expression during development leads to the differentiation of specific cell types. Insight into the molecular mechanisms of gene control had only recently emerged for a few phage and bacterial genes. Despite the complexity of mammalian development , Hal initiated a bold effort to understand the relationship between the structure of eukaryotic genes in the chromosome and the regulation of their expression during development. Experiments initiated at the Medical Research Council in Cambridge, England, when Hal was a fellow with Sidney Brenner and Francis Crick, showed that nucleosomes reside on active genes in the chromosome, but that the nucleosomal structure is altered when the gene is transcribed. At Princeton University and later at the Fred Hutchinson Cancer Center, Hal used the globin gene clusters as a model system to define the concept of a transcrip-tionally active chromosomal domain. The globin gene domains contain the cluster of developmentally regulated globin genes and tens of thousands of base pairs of DNA on either side. The entire domain exhibited enhanced sensitivity to nuclease in erythroid cells, and discrete sites of hypersensitivity appeared adjacent to the individual genes as they were sequentially activated during development. This work established an important relationship between gene activity and chromosome structure. In the early 1980s Hal began to think about the problem of identifying genes central to embryonic development in vertebrates. Recognizing the difficulty in obtaining useful developmental mutants in vertebrates, Hal introduced the idea of using antisense RNA to elicit specific mutant phenotypes. This approach, in which a complementary strand of mRNA is expressed in …