Louisa Gross Horwitz Prize - 2007

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Joseph G. Gall

Joseph G. Gall, Ph.D., received the B.S. degree in Zoology from Yale University in early 1949 then directly entered the graduate program there in the Zoology Department.  He completed his Ph.D. in 1952, working with the Drosophila geneticist and developmental biologist Donald F. Poulson.  He took a teaching position in the Zoology Department at the University of Minnesota, where he remained until 1963. In the fall of 1963 he returned to Yale as a visiting professor to what was then the Biology Department, after fusion of Zoology and Botany, and later became Professor of Biology with a joint appointment in Molecular Biophysics and Biochemistry.  He remained at Yale for 20 years, from 1963-1983; during the last few years he held the Ross G. Harrison Chair in Biology.  In 1983 he joined the Embryology Department of the Carnegie Institution in Baltimore as a Staff Member. In 1984 he was appointed American Cancer Society Professor of Developmental Genetics, a lifetime appointment.

He has been an active member of the American Society for Cell Biology (ASCB) since its inception in 1960, serving as president in 1967-68 and a member of its council and several committees at various times.

His long-term research interests have been in the structure and function of the cell, particularly the nucleus. His earliest studies involved the giant “lampbrush” chromosomes found in oocytes of frogs and salamanders. These are the largest known chromosomes and permit various observations and manipulations that are difficult or impossible with smaller chromosomes. Among his more important findings, made at a time when the site of  cellular RNA synthesis was still unclear (late 1950s, early 1960s), was that cellular RNA synthesis occurs on loops of DNA that extend out from the axis of the chromosome. Studies on the kinetics of DNase digestion demonstrated that the chromosome consists of a single extremely long DNA molecule. Electron microscopic studies he carried out at about the same time on the nuclear envelope established the existence of the nuclear pore complex and its eight-fold symmetry. Other studies on centrioles clarified aspects of their replication during the cell cycle.

After moving to Yale, Dr. Gall began studies on ribosomal RNA (rRNA) and the genes that code for it (rDNA). In 1967-68 by a combination of biochemical and cytological observations he demonstrated that these genes are able to leave the chromosome and replicate independently during the early stages of oocyte formation in amphibians and other animals. This phenomenon of gene amplification was independently discovered by Igor Dawid and Donald Brown of the Carnegie Institution. At about the same time, a former postdoctoral student of Dr. Gall’s, Oscar Miller, demonstrated the activity of the amplified genes in a set of electron microscopic observations.

The studies on gene amplification were followed almost immediately by development of the technique of in situ hybridization, in collaboration with Dr. Gall’s graduate students, Mary Lou Pardue and Susan Gerbi. This technique allowed the identification of specific DNA or RNA sequences at the cellular or subcellular level. Their original technique used radioactive probes. The procedure was later modified by others to use fluorescent probes, which permit even finer localization and simultaneous use of multiple probes. In situ hybridization is now one of the most widely used cytological techniques. It permits localization of genes to specific chromosome regions and of RNA sequences to specific cells or groups of cells.

Among several important observations Dr. Gall’s team made with the in situ hybridization technique was the demonstration that the heterochromatic regions of chromosomes consists of simple sequences called “satellite” DNA. They also showed how in situ hybridization could be used with the giant chromosomes of Diptera for precise gene localization. A few years later, gene cloning made numerous sequences available for mapping studies.

Dr. Gall’s interest in rDNA amplification during oocyte formation led him to investigate the similar phenomenon he discovered in the ciliated protozoan Tetrahymena. Work on this organism led to the demonstration that the rDNA genes exist as free molecules in the macronucleus. A postdoctoral fellow, Dr. Elizabeth Blackburn, found that the ends of these molecules had a unique structure consisting of a hexanucleotide repeat GGGGTT. Although they did not realize it at that time, later studies by Blackburn and others established that this repeat, or very similar ones, are found at the ends or telomeres of chromosomes from nearly every type of animal and plant investigated. The in situ hybridization technique was valuable in making this determination.

In recent years the focus of Dr. Gall’s research has been the organization of transcription in the nucleus. He has studied the small nuclear RNAs (snRNAs), which are known to play important roles in the processing of all types of messenger RNA (mRNA) and ribosomal RNA (rRNA). His lab is concentrating on several nuclear organelles that contain snRNAs, including the nucleolus, Cajal bodies, and the nuclear speckles. Their most recent studies suggest that Cajal bodies may be sites for preassembly and/or modification of macromoleuclar complexes that carry out nuclear transcription and RNA processing.

The research findings from Dr. Gall’s laboratory have been reported in 150 articles in various scientific journals. His research has been combined with his long-standing interest in the history of biology, particularly cell biology and microscopy. He has collected early books in these areas and in1996 published a book, “Views of the Cell: A Pictorial History,” published by the American Society for Cell Biology. The book brings together 60 historical images and their descriptions Dr. Gall prepared originally as covers for Molecular Biology of the Cell, the official journal of the American Society for Cell Biology. In 2001, Dr. Gall co-edited with J. Richard McIntosh a book of readings in cell biology titled “Landmark Papers in Cell Biology,” published jointly by the American Society for Cell Biology and Cold Spring Harbor Laboratory Press.