AWARDEE: Joseph G. Gall

FEDERAL FUNDING AGENCIES: National Institutes of Health, National Science Foundation

In every generation, there are people with a lifelong passion for the wonders of nature: they explore their surroundings from a young age, and then they carry that curiosity into a career – often in science. Perhaps no one exemplifies this more than Joseph Gall. Gall, often called the “father of modern cell biology,” was a consummate naturalist, and it was this knowledge of the natural world that guided his many contributions to the field of cell biology, including the development of a technique widely used to visualize genes that changed the field of cell biology and helps diagnose diseases. Arguably, an even bigger impact came from the way he ran his lab for more than 70 years: By treating everyone as equals. Indeed, his mentorship was renowned, and several highly accomplished, award-winning scientists have studied and worked with him, making their own important scientific contributions.

“Always the perfect cells, the perfect experiment, and at the perfect time … to even attempt to describe Gall’s scientific contributions is daunting, so many and diverse as they were,” wrote Thoru Pederson, a longtime friend, in a remembrance after Gall’s passing last year at the age of 96. “He was someone of sterling integrity, empowered by tremendous gifts of intelligence and a civility that set a tone for how we all should conduct ourselves in academia and in life.”

How to Raise a Scientist

Gall grew up running around his home and family farm in Northern Virginia. Supported by his parents, he collected insects, raised his own frogs, and acquired his first microscope, turning his bedroom into his own laboratory where he could study the natural world, said his wife, Diane Dwyer.

Gall was also an avid reader, devouring books like E.B. Wilson’s The Cell in Development and Heredity. Using the text as a jumping off point, he learned to test some of the ideas presented by searching for similar species and studying them for himself. When he went away to boarding school, his microscope and microtome, a tool that cuts samples for observation, went with him. The slides he made even as a teen were of “enviable quality,” remaining pristine for decades, wrote Allan Spradling of Carnegie Science and Dwyer.

By the time he was enrolled as an undergrad at Yale University, he developed an interest in chromosomes, structures found inside the nucleus (control center) of a cell. Chromosomes are made up of DNA molecules organized into genes, which serve as the body’s instruction manuals for physical traits and development. This interest became a major throughline in his career. By chance, he spotted a textbook photograph showing that newt oocytes (egg cells) contained “lampbrush” chromosomes, so named in the late 1800s because they resembled the brushes used to clean oil-burning lamps. These chromosomes were particularly large, and Gall thought that studying them with modern microscopy could reveal new information about chromosome structure and function. With help from his uncle, Gall constructed a microscope specifically optimized to investigate this idea for his Ph.D. thesis. It was just the beginning of his fascination with these chromosomes.

Knowledge of Nature’s Oddities Leads to Discovery

In 1952, Gall joined the zoology faculty at the University of Minnesota, where he continued mapping out the structure of the lampbrush chromosomes with early support from the National Science Foundation. There, his reputation began to grow as he figured out new ways to explore and strengthen scientific understanding of chromosomes. The lampbrush chromosomes were large enough for manipulations and observations that would have been difficult in smaller ones. Gall showed that these chromosomes are built around a single DNA double helix stretching from end to end, and his research provided insights into some of their fundamental features.

Gall’s knowledge of the animal kingdom informed his approach. “This depth of understanding enabled Joe to choose a particular species that is ideally suited to investigating a specific problem. He probably published important findings using more different organisms than any of his contemporaries, and in this respect was far ahead of his time,” wrote Spradling in a Carnegie Science tribute. Over the years, Gall worked with species as wide-ranging as newt, grasshopper, ciliated protozoan, mouse, snail, fern, water beetle, fly, toad, coelacanth, hydra, bullfrog, giant panda, marsupial frog, cricket, and damselfly, according to a presentation by former mentee Joan Steitz.

In 1961, Gall joined the nascent American Society for Cell Biology (ASCB) as one of its earliest members, later becoming its 7th president. Three years later, he returned to Yale, this time as a professor.

A Game-Changing Technique

By the mid-60s, Gall began to work on his longtime dream of visualizing specific genes on chromosomes. Genes produce RNA molecules, cousins of DNA that are essential for many biological functions, and the idea was to locate RNA on the chromosome to infer the position of the gene. While he was far from the only one with this interest, according to Pederson, it was his knowledge of the right biological system to employ that made a difference. Thus, he was among the first to uncover gene amplification in frog oocytes, which generate large quantities of extra copies of certain types of genes.

Later, again using frog oocytes, he worked with one of his students, Mary-Lou Pardue, to develop a technique that allowed them to visualize these amplified DNA sequences. The technique was called “in situ hybridization” and changed the field of cell biology, allowing researchers to locate and map genes with a microscope.

Gall and Pardue’s technique found wide applications in scientific research, and as time went on, others enhanced the technique further by using fluorescent probes and signal enhancement techniques. “In situ hybridization became the gold standard for linking sequences to chromosome rearrangements associated with cancer and also helped identify disease genes,” wrote Spradling and Dwyer.

The in situ hybridization technique has fostered new discoveries in cell biology and has also had significant clinical applications. “It was a basic science discovery, where it was thought it would benefit basic science, but the medical applications that happened subsequently have been of great importance,” said Susan Gerbi, who worked on developing the technique as a student in Gall’s lab.

For Gerbi, the in situ hybridization technique even touched her on a personal level, when she learned she had breast cancer in 2006. Her medical care team used the technique to get a better read on her diagnosis and find the proper treatment. “Joe didn’t patent it,” she pointed out, “so it was readily available for translation by others into future medical applications of benefit to the public whose taxpayer dollars had funded his studies.”

Tetrahymena under the microscope (Protist Information Server)

The Power of Pond Scum

One of Gall’s many wildlife adventures as a youth involved collecting pond water and looking into his microscope to see what living things he could find in it. Thus, it’s no surprise that Gall’s familiarity with a single-celled ciliated protozoan found in “pond scum,” Tetrahymena, would come into play in his scientific work as well. Gall’s lab demonstrated that Tetrahymena generates many copies of certain types of genes, similar to the frog oocytes.

“I had never heard of Tetrahymena, and I think most people hadn’t heard of it either,” recalled Kathleen Karrer, one of the students who worked on this single-celled critter in Gall’s lab and continued to work with it throughout her career. “It was unique that his lab worked on all kinds of different organisms.”

Another student who worked on Tetrahymena was Elizabeth Blackburn, who came to Gall’s lab with DNA sequencing know-how after getting a Ph.D. in Fred Sanger’s famous molecular biology lab in England. With Joe’s insight and encouragement, she opted to conduct experiments using Tetrahymena and worked to unlock the mysteries of telomeres. She discovered that telomeres are made of repetitive DNA sequences at the ends of chromosomes. They are often compared to the piece of plastic that protects the end of a shoelace. Telomeres protect genetic material from damage, and they become shorter as we age.

Carol Greider, Joe Gall, and Elizabeth Blackburn (Gall Family)

Later, Blackburn moved on to her own lab at UC Berkeley, where she and student Carol Greider discovered the enzyme telomerase; this enzyme can replenish the length of telomeres. In 2009, Blackburn, Greider and Jack Szostak shared the Nobel Prize in Physiology or Medicine for their telomere research. Gall and Dwyer were guests at the ceremony. In her acceptance speech, Blackburn said, “If we had not been able to use these seemingly oddball organisms because of the advantages they offered as experimental systems for biological research, I don't know when we would have learned about telomeres and telomerase.”

(Fun fact: Tetrahymena has contributed to two Nobel Prizes. Tom Cech, who did a postdoc with Mary-Lou Pardue, also used the organism for research on self-splicing RNA, for which he won the Nobel Prize in Chemistry in 1989.)

The discovery of telomerase made a splash in biomedical science and has strongly influenced research into cancer and aging. Studies are investigating whether telomerase can be inhibited to curb cancer cell growth.

Good Mentoring

As some of his career highlights illustrate, Gall’s mentorship inspired scores of scientists and had ripple effects throughout the scientific community, as students and trainees in his lab went on to have their own productive careers. A 2009 book called Good Mentoring by J. Nakamura and D.J. Shernoff even devoted its entire second chapter to Gall and his approach.

An article by Gerbi, Blackburn, and fellow Gall mentee Virginia Zakian elaborated on how women in particular thrived in his lab at a time when that wasn’t the norm: “When the authors were in Joe’s lab, women were hardly visible in academia. Given this paucity, it is remarkable that virtually all of the female trainees in the Gall lab saw themselves as destined for faculty positions, and many achieved this goal. Female trainees from the Gall lab have succeeded at the highest levels, including four members of the National Academy of Sciences, three ASCB Presidents, a co-founder of the RNA Society, president of the Genetics Society of America, president of the American Association of Cancer Research, and a Nobel laureate.”

Steitz, one of Gall’s trainees, gave the introductory talk when Gall won the prestigious Lasker Special Achievement Award in Medical Science in 2006. “Joe Gall was one of the best things that ever happened to me,” she said, because he had inspired and helped her to pursue research as a career. Steitz won her own Lasker Special Achievement Award in 2018 for her work in RNA biology.

Gerbi, who joined Gall’s team as a graduate student in 1965, wanted to do her Ph.D. thesis with him specifically; she saw him as the emerging leader using molecular methods for chromosome research. “Originally, I was going to apply to Minnesota,” she said. “But then I found out he was moving to Yale, so I applied there.” Gall’s approach was simple: He wasn’t necessarily “going out of his way to be a mentor,” she said, “rather, he simply treated everybody as equals.” At the time, that in itself stood out. Karrer agreed, “You couldn’t ask for a better advisor.”

Zehra Nizami joined Gall’s lab as a grad student when Gall was in his mid-70s, an age when many scientists would be well into retirement. But Gall was “going strong,” working on new scientific inquiries, such as those involving small structures within the cell nucleus called “Cajal bodies.” Nizami recalls him fondly as a highly skilled problem solver who was “even keeled” and at the same time “massively fun.” She worked with Gall for 12 years.

A Naturalist’s Legacy

“The one thing that he always did was credit the NIH system of funding,” Dwyer noted. National Institutes of Health grants were the central force in supporting his career, enabling the many developments in his lab over a span of decades. They paved the way for Gall to use his skills as a naturalist to revolutionize cell biology, which ultimately advanced disease diagnostics and treatments. Additionally, his students were often funded through NIH Training Grants. Gall gave back to the agency by serving throughout his career on numerous NIH peer review panels to evaluate grant applications.

In 1983, Gall joined the Carnegie Institution of Washington (now known simply as Carnegie Science), and it’s where he spent the remainder of his career until his retirement in 2020. The lampbrush chromosomes continued to fascinate him, and he worked on characterizing other components of amphibian oocytes.

The combination of Gall’s scientific outputs and his talents as a mentor resulted in several recognitions beyond the Lasker Award, including the ASCB’s E.B. Wilson Medal and senior leadership award for promoting women in science, the Louisa Gross Horwitz Prize, and AAAS’s Lifetime Mentor Award. He was also known for his research papers and books, as both an author – including of a volume illustrating the history of cell biology – and as an avid rare book collector. Gall passed away on September 12, 2024. In addition to Dwyer, he is survived by two children, Larry, the senior entomology collections manager at Yale’s Peabody Museum, and Barbara, a veterinarian.

Accolades for Gall abound: His family, friends and colleagues remember him as kind, intelligent, humble, thoughtful, respected, and committed to science and to his mentees. And his impact on science – and scientists – is clear. “Joe’s instincts as a naturalist, his knowledge of earlier findings, understanding of model systems, and choice of the right one for the experiment at hand ultimately led to fundamental discoveries,” said Gerbi. “This is the reason to support basic science,” added Karrer. “Something that doesn’t sound ‘translational’ can turn out to be a huge finding.”

By Erin Heath