Obituary
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《核酸研究医学期刊》
Robert Simpson, a molecular biologist with a long history of fundamental contributions to our understanding of chromatin chemistry and biology, died on April 21, 2004. Bob received his M.D. and Ph.D. degrees at Harvard, where he worked with Bert Vallee on the physical chemistry of metalloproteins. In 1969 he came to NIH, where he was to spend the next 25 years, and began almost at once to address problems of histone–DNA interactions and their role in organizing chromatin structure. He explored chemical acetylation of histones, comparisons of the protein content and properties of extended and condensed chromatin, and methods of fractionation. When the nucleosome, the fundamental subunit of chromatin, was discovered, Bob’s background in physical chemistry gave him a great advantage. He used it to devise experiments that were crucial in defining the nucleosome and its physical and chemical properties. These were classic experiments. He studied the way in which DNA could be reversibly displaced from the ends of nucleosome core particles under mild conditions of thermal denaturation, providing an early insight into the way in which nucleosomes could be perturbed as part of their biological function. Bob was among the first to establish that nucleosomes could occupy specific positions on DNA, determined by the nucleotide sequence. He was deeply interested in the forces that controlled positioning of nucleosomes, and that might determine the spacing between them. This led to his investigation of the association of histone H1 with the linker region DNA between nucleosomes, and ultimately to his redefinition of the repeating subunit as an entity with a histone octamer, two full superhelical turns of DNA, and a molecule of histone H1; he named this the chromatosome. In another critical study he showed that cross-linking the proteins of the histone octamer did not prevent them from forming nucleosome-like particles when DNA was added. This elegant experiment told us a lot about the topology of the nucleosome at a time when structural studies were just beginning.1
Robert Simpson (1938-2004)
During the next decade Bob turned to the study of naturally occurring chromatin structures, notably in Saccharomyces cerevisiae. He constructed a plasmid containing the TRP1 gene and an ARS1 element important for autonomous replication, and devised a method for purifying it from yeast as an intact chromatin complex. This became one of his most important tools: In a typically incisive experiment, he used it to show that nucleosome positioning could affect the activity of a cis-acting element in vivo. This first demonstration of an in vivo effect of positioning called attention to the importance of understanding what controlled nucleosome placement and structure. He and his associates employed the TRP1/ARS1 plasmid in conjunction with the yeast alpha 2 repressor to explore the role of the repressor in nucleosome positioning, the response of positioning to transcriptional activation, and the role of histone tails in controlling these events. This led in turn to studies of the role of the regulatory proteins TUP1 and SSN6 in alpha2 repression, an interest that remained strong at the time of his death.
The continuity of Bob’s interests from his earliest to his most recent work was consistent with his character. He was inventive as well as deliberate, thoughtful and thorough. In a field as amorphous (at least at its beginnings) as the one in which he chose to work, he was someone whose results could be depended upon for absolute reliability. That attribute, coupled with his originality, explains why his experiments and conclusions are just as important today as they were when he first published them. Bob was a very calm, dependable and kind colleague. Like many who choose to stay at NIH for long periods, he enjoyed working in the laboratory, and his papers describe many of his own experiments. He moved from the NIH in 1995 to accept the Verne Willaman Chair in Biochemistry and Molecular Biology at Penn State, where he was instrumental in turning his department into a major center for research in gene expression and chromatin structure. As he had while he was in Bethesda, he continued to attract outstanding young investigators to his laboratory; the influence of his training can be seen in the quality of the work that they continue to produce as independent investigators. Although I and many others regretted his departure from NIH, it was a pleasure to see him succeed so well in his new job and his many talents put to such good use. He was a deeply respected and admired member of our community, and all of us will greatly miss him as a colleague and friend.
Contributed by Gary Felsenfeld
Editor’s note
Bob served with distinction as an Executive Editor of Nucleic Acids Research from 1992–1999 and continued as a valued member of its editorial board from 2000 until his untimely death earlier this year.
Gary Felsenfeld(Editor)
Robert Simpson (1938-2004)
During the next decade Bob turned to the study of naturally occurring chromatin structures, notably in Saccharomyces cerevisiae. He constructed a plasmid containing the TRP1 gene and an ARS1 element important for autonomous replication, and devised a method for purifying it from yeast as an intact chromatin complex. This became one of his most important tools: In a typically incisive experiment, he used it to show that nucleosome positioning could affect the activity of a cis-acting element in vivo. This first demonstration of an in vivo effect of positioning called attention to the importance of understanding what controlled nucleosome placement and structure. He and his associates employed the TRP1/ARS1 plasmid in conjunction with the yeast alpha 2 repressor to explore the role of the repressor in nucleosome positioning, the response of positioning to transcriptional activation, and the role of histone tails in controlling these events. This led in turn to studies of the role of the regulatory proteins TUP1 and SSN6 in alpha2 repression, an interest that remained strong at the time of his death.
The continuity of Bob’s interests from his earliest to his most recent work was consistent with his character. He was inventive as well as deliberate, thoughtful and thorough. In a field as amorphous (at least at its beginnings) as the one in which he chose to work, he was someone whose results could be depended upon for absolute reliability. That attribute, coupled with his originality, explains why his experiments and conclusions are just as important today as they were when he first published them. Bob was a very calm, dependable and kind colleague. Like many who choose to stay at NIH for long periods, he enjoyed working in the laboratory, and his papers describe many of his own experiments. He moved from the NIH in 1995 to accept the Verne Willaman Chair in Biochemistry and Molecular Biology at Penn State, where he was instrumental in turning his department into a major center for research in gene expression and chromatin structure. As he had while he was in Bethesda, he continued to attract outstanding young investigators to his laboratory; the influence of his training can be seen in the quality of the work that they continue to produce as independent investigators. Although I and many others regretted his departure from NIH, it was a pleasure to see him succeed so well in his new job and his many talents put to such good use. He was a deeply respected and admired member of our community, and all of us will greatly miss him as a colleague and friend.
Contributed by Gary Felsenfeld
Editor’s note
Bob served with distinction as an Executive Editor of Nucleic Acids Research from 1992–1999 and continued as a valued member of its editorial board from 2000 until his untimely death earlier this year.
Gary Felsenfeld(Editor)