Joseph Grafton Gall (1928–2024)

Joseph Grafton Gall researched and taught cell biology for over seventy years in the late twentieth and early twenty-first centuries in the United States. Much of his early work revolved around the structure and function of chromosomes, which are structures made of DNA and protein found in cells. As a professor at Yale University in New Haven, Connecticut, Gall and his graduate student Mary-Lou Pardue developed in situ hybridization, a technique that uses probes to identify the location of specific DNA sequences along a chromosome. With another graduate student, Elizabeth Blackburn, he also performed research on the structure of telomeres, which are the ends of chromosomes. Gall was an early advocate for women in STEM and trained many female scientists, many of whom became successful in their fields. Gall studied the structure and function of different forms of genetic information, namely DNA and RNA, helping to expand the understanding of how those molecules replicate within cells. 

Gall was born on 14 April 1928 in Washington, DC, to Elsie Grafton Rosenberger and John Christian Gall, a lawyer. He had two brothers, John Christian Gall, Jr., and Howard Smyer Gall. His family later moved to a farm in Virginia when he was fourteen years old.

According to an obituary published by the Carnegie Institution for Science, a research institute in Washington, D.C., Gall credited his mother, who had a degree in mathematics, for cultivating his interest in science and the natural world. His mother provided Gall with handmade butterfly nets and guidebooks, which he used to catch insects when he spent his summers on a farm in Northern Virginia. According to biographers, Gall’s interest in biological research emerged in his childhood. Allen Spradling, a scientist at the Carnegie Institution for Science and a longtime colleague of Gall’s, and Diane Dwyer, Gall’s wife, both write that, in Gall’s teenage years, he turned his bedroom into a makeshift lab complete with a microtome, which is an instrument to make very thin tissue slices for the purpose of slide preparation, and a microscope to inspect the slides. According to Spradling and Dwyer, his slides, containing the tissues of small animals and plants found on the family farm, were at an expert level. When Gall was a teenager, his brother John sent him Edmund Beecher Wilson’s 1925 book The Cell in Development and Heredity. Gall also read Lester Sharp’s 1921 book The Principles of Cytology. Wilson and Sharp were both early researchers in cytology, which is the scientific study of cells. Those texts taught Gall the core principles of biology, including that variation in cell types is the source of the physical properties of animals and plants. Additionally, according to Gall’s former trainees Susan Gerbi, Virginia Zakian, and Blackburn, both texts played a significant role in cultivating his interest in the history of science and they were amongst the first manuscripts added to what became his extensive collection of historical and scientific books.

For high school, Gall went to Woodberry Forest School, a private boarding school in Charlottesville, Virginia. According to Spradling and Dwyer, during high school, Gall often tried to validate or further explore the ideas about cells in Wilson’s book by studying the phenomena himself using the microscope he had brought from home. He also built a telescope with the help of his brother John, which helped him gain an understanding of the mechanics of optical instruments.

In 1945, Gall matriculated to Yale University in New Haven, Connecticut, where he majored in zoology. After finishing his bachelor’s degree in 1949, with the help of one of his undergraduate biology professors, Donald Poulson, he transitioned into a doctoral program in zoology at Yale and joined Poulson’s lab. Poulson, a geneticist who studied fruit flies, taught Gall how to prepare and analyze polytene chromosomes, which are massive, multistranded chromosomes found in the salivary glands of larvae of the fruit fly Drosophila melanogaster. Polytene chromosomes are so large because, unlike other types of chromosomes, they replicate multiple times without the cell dividing and breaking up the chromosome into the resulting daughter cells. Their large size makes it easier for scientists to study how chromosomes replicate. However, since researchers had already been studying them for about ten years at that time, according to Spradling and Dwyer, Gall decided not to take on that research because he thought that any further progress in the topic might be slow. Instead, he chose to work on a different giant chromosome. 

During his doctoral studies, while flipping through biologist Conrad Hal Waddington’s 1939 book Introduction to Modern Genetics, Gall came across a type of giant chromosome found in the egg cells of salamanders. Called a lampbrush chromosome, its structure is full of loops and looks like the brushes that people use to clean oil lamps. Since researchers had not extensively studied those chromosomes using microscopic techniques at the time, Gall decided to make them the focus of his doctoral research, especially considering that the large size of the chromosome made it easy to observe them. Yale did not have the appropriate type of microscope, however, so with his uncle’s help, Gall built an inverted microscope to study the chromosomal structure. He completed his dissertation on lampbrush chromosomes three years later in 1952.

In 1952, at age twenty-four, Gall accepted his first faculty position in the Zoology Department of the University of Minnesota in Minneapolis, Minnesota. He had no post-doctoral training or published work at that point, but according to Spradling and Dwyer, he was well-known to his peers because of his microscopic skills. In 1954, Gall published his observations using an electron microscopy of the pores found on nuclear membranes, which are thin coverings around a part of the cell called the nucleus, in amphibian cells. An electron microscope uses a beam of electrons instead of light to produce magnified images of very small objects. Gall also used an electron microscope to study how centrioles, which are small, tube-shaped structures that help the cell split in half during cell division, replicate during the formation of sperm cells in a species of snail. He published an article in 1961 describing that centrioles duplicate by forming daughter centrioles at right angles to existing ones and dividing evenly such that each sperm cell gets the right number of centrioles. Concurrently to that research, Gall, due to his extensive experience with electron microscopy, helped to found the American Society of Cell Biology, or ASCB, in 1961.

At the University of Minnesota, Gall also collaborated with other researchers working on lampbrush chromosomes, including Harold Garret Callan, who also studied zoology. Together, Gall and his collaborators studied the structure and molecular processes of lampbrush chromosomes by observing them under a microscope while the chromosomes were unfolding in real time in living cells. In 1962, they published their findings in an article titled “H³ Uridine Incorporation in Lampbrush Chromosomes,” describing that RNA synthesis on lampbrush chromosome loops proceeds in a directional fashion, while protein synthesis occurs without a discernable pattern.

In 1962, Gall returned to Yale University for a sabbatical and stayed there after being offered a tenured position as the Ross Harrison professorship of biology in 1963. Prior to officially starting his new position at Yale, Gall published an article in 1963 which described his study of the speed and pattern of lampbrush chromosome breakdown by an enzyme called DNase. DNase breaks down DNA by cleaving the bonds between nucleotides, which are the basic structural units of nucleic acids like DNA or RNA. He measured how quickly visible breaks appeared in each half of the duplicated chromosome, which are called chromatids, when exposed to DNase. He found that a chromatid broke in half when two nearby cuts occurred in the DNA, which is consistent with DNA being double-stranded. According to Gerbi, Zakian, and Blackburn, Gall’s experiment was amongst the first to demonstrate that each chromatid consists of one continuous piece of double-stranded DNA. 

In 1964, Gall officially started his position at Yale, where he started working more exclusively in molecular biology, which is a type of biology that studies biological molecules like DNA and RNA. He started studying how cells build the machinery needed to make proteins during the early stages of animal development. Since the mid-1800s, scientists had observed that small structures inside cells responsible for making ribosomes, called nucleoli, could multiply dramatically in egg cells that were about to grow massively in preparation to be fertilized with a sperm. Ribosomes are structures made of ribosomal RNA, or rRNA, and they are the locations where protein synthesis can take place in a cell. Ribosomal DNA or rDNA, undergoes a process called transcription to produce rRNA. At that time, the mechanism by which cells were making so many ribosomes during the rapid growth of egg cells was unclear. By comparing differences in DNA density between toad eggs and non-specialized cells in toads, Gall found that the eggs contained denser DNA with a higher percentage of the nucleotides guanine and cytosine, which is a known property of rDNA. Gall published a paper in 1968 showing that each nucleoli contained many copies of rDNA, a phenomenon which Gall referred to as gene amplification. That excess rDNA resulted in excess rRNA, which culminated in many ribosomes and prolific protein production in egg cells in preparation for cell growth. At roughly the same time as Gall but using different biochemical techniques, scientists Donald Brown and Igor Dawid identified the same findings, namely that rDNA genes in egg cells are amplified to support egg growth. 

According to Gerbi, Zakian, and Blackburn, Gall had aspired, at that time, to use microscopy to locate specific genes on chromosomes. In 1965, researchers David Gillespie and Sol Spiegelman had described a process called molecular hybridization, which is when two complementary DNA and RNA molecules hybridize, meaning that they bind together to form a double-stranded hybrid molecule. According to Spradling and Dwyer, since the release of Gillespie and Sol’s article, Gall had been trying to localize specific DNA sequences by performing hybridization in situ, meaning within the cell. He finally succeeded in 1969, when Gall and his graduate student Mary-Lou Pardue published a paper describing their use of molecular hybridization and Gall’s previous research on rDNA in frog egg cells to develop a technique called in situ hybridization. In this technique, Gall and Pardue used a piece of radioactively labeled rRNA called a probe to hybridize to its complementary rDNA sequence, therefore allowing researchers to find the exact location of specific DNA sequences directly in a particular cell. However, visualization of the probe was easier in egg cells compared to other cell types because Gall had already located where rDNA was massively amplified in a specific part of the egg cell’s nucleus, so the radioactive probe was clearly visible via autoradiography, a type of imaging that detects radioactive signals. Gall and Pardue detected strong signals in one precise location and proved the reliability of the in situ hybridization technique.

In their 1970 paper titled “Chromosomal Localization of Mouse Satellite DNA,” Gall and Pardue used in situ hybridization on mouse cells to locate satellite DNA, which is a stretch of repetitive nucleotide sequences near the center of chromosomes. The name satellite refers to how that specific type of DNA forms a distinct band when researchers spin the cell very quickly; that is because satellite DNA consists of different proportions of nucleotide bases, namely more adenine and thymine, than other types of DNA in the cell. To determine the location of satellite DNA, Gall and Pardue isolated the satellite DNA in order to made a radioactive complementary RNA probe from it and apply the rest of the in situ hybridization pipeline. They found that the mouse satellite DNA was concentrated mainly at the chromosome centromeres. The dense, tightly packed DNA in this region is called centromeric heterochromatin.

In 1971, Gall used in situ hybridization to determine the amount and location of satellite DNA in fruit fly cells. Because fruit flies have both normal and polytene chromosomes, which do not divide like other chromosomes, Gall was able to determine how much centromeric heterochromatin replicates during the process of creating polytene chromosomes. In the normal chromosomes, the probe strongly hybridized to the centromeric heterochromatin, indicating high concentration of that DNA type in those regions. Conversely, in the polytene chromosomes, the signal for heterochromatin was much weaker, indicating low concentration. That demonstrated that during the many cycles of chromosomal replication that form polytene chromosomes, heterochromatin does not replicate like the rest of the DNA. According to Gerbi, Zakian, and Blackburn, Gall’s application of in situ hybridization upon mice and fruit fly genomes suggested that satellite DNA and heterochromatin have a structural function in chromosome distribution when cells divide.

Through the late 1970s and early 1980s, Gall continued to research the structure and function of rDNA, often using a single-celled pond organism called Tetrahymena for his experiments. In 1976, Gall and his graduate student Kathleen Karrer published a paper describing how, in Tetrahymena, the amplified rDNA is structured as a palindrome, meaning that each rDNA unit consists of two identical sequences joined in an inverted, head-to-head orientation. Later, Blackburn, one of Gall’s postdoctoral students at that time, sequenced the ends of the amplified Tetrahymena rDNA, finding that each end contained many repeats of the same sequence of six nucleotides. She and Gall published their findings in 1978 in the Journal of Molecular Biology. According to Gerbi, Zakian, and Blackburn, Gall’s and Blackburn’s research greatly advanced scientific understanding at that time of telomeres, which are caps at the ends of chromosomes consisting of repetitive DNA sequences that stop the chromosome from being damaged. That was because other scientists later found that most multi-celled organisms also have many repeats of those simple nucleotide sequences at the ends of their rDNA molecules.

In 1983, Gall left Yale University because his administrative duties cut into his research time, according to Spradling and Dwyer. He began working at the Carnegie Institution for Science's Department of Embryology in Baltimore, Maryland, where he remained for the rest of his career. According to Gerbi, Zakian and Blackburn, Gall’s research at the Carnegie Institution for Science focused mainly on RNA. Spradling and Dwyer note that Gall and his team studied ribonucleoproteins, which are microscopic structures made of RNA and protein, to understand how they help process RNA. Gall remained at the Carnegie Institution for Science until his retirement in 2020.

In 1992, the ASCB hired Gall as a cover illustrator for their new journal at that time, Molecular Biology of the Cell. Every month for the next five years, he produced cover pages highlighting significant moments in the history of cell biology. He referenced images from publications that researchers in molecular biology considered highly influential and often added his own historical comments to the illustration. The ASCB published all of Gall’s illustrations as a book in 1996.

In an obituary published after Gall’s death in 2024, Gerbi, Zakian, and Blackburn state that throughout his scientific career, Gall coached many students, and he was highly supportive of female researchers. Gerbi and her colleagues assert that, at that time, there were few female scientists working in molecular biology, but Gall treated male and female researchers equally, and the welcoming environment caused his lab to have an unusually high proportion of women. They also report that there was no sexual harassment in his lab. Many of Gall’s female trainees went on to be highly successful, obtaining faculty positions and holding leadership in prestigious professional societies for scientists. According to his graduate student Gaëlle Talhouarne Talross, Gall had a unique teaching style. She states that he was a dedicated and inspiring mentor who encouraged exploration through shared curiosity and gave unwavering support to his students. In 1996, Gall received the American Association for the Advancement of Science Mentor Award for Lifetime Achievement in recognition of his mentorship efforts.

At the time of Gall’s death in 2024, he was survived by his second wife of forty-two years, Diane M. Dwyer; his first wife, Dolores Gall; his children, Lawrence F. Gall and Barbara G. Eidel; three granddaughters; and other close family members.

In 2006, Gall received the Albert Lasker Award for Special Achievement in Medical Science for working on chromosome structure and function and in situ hybridization, which according to the Lasker Foundation, transformed molecular biology. According to Spradling and Dwyer, in situ hybridization became the gold standard for identifying genes that cause diseases and chromosomal abnormalities that can contribute to the development of cancer. Spradling and Dwyer also assert that in situ hybridization led to the identification of G bands, which are striped patterns on chromosomes that can help scientists map genes and detect chromosomal abnormalities that can result in diseases.

In addition to the Albert Lasker Award, Gall received numerous awards and honors over the course of his life. He was a member of several scientific societies, including the American Academy of Arts and Sciences, the National Academy of Sciences, and the American Philosophical Society. In 1983, the ACSB awarded him their highest recognition, the E.B. Wilson Medal. Gall also shared the 2007 Louisa Gross Horwitz Prize from Columbia University in New York, New York, with Blackburn and another prominent telomere researcher, Carol Greider, for their work in determining the biochemical mechanisms of the cellular aging process through their work on telomeres.

Gall died of heart failure at his home in Baltimore on 12 September 2024 at the age of ninety-six.

Sources

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