Albert Lasker Award
for Special Achievement in Medical Science

Award Presentation by Joan A. Steitz

I was a freshly minted graduate of a small Midwestern liberal arts college when I first set foot in Joe Gall's lab in the summer of 1963. It was located in the century-old Zoology Building on the Minneapolis campus of the University of Minnesota. I was slated to begin Harvard Medical School in the fall, and had wanted to spend the summer beforehand at home with my parents. As an undergraduate, I had been extremely fortunate to have been introduced to the brand new field of molecular biology because of my school's work-study program. I had therefore interviewed for several summer research positions at the University of Minnesota, but Joe was the only one who offered me a job.

I knew that even though he was relatively young, Professor Gall had made already important contributions to understanding the relationship between DNA and chromosomes. What I did not know was that the privilege of working with Joe Gall that summer would change my future.

Joe set me to growing the same pond organism (Tetrahymena) that Liz Blackburn and Carol Greider used so productively to study telomeres. My project was to analyze the little bodies at the bases of their cilia (the cellular projections that enable them to swim) for DNA and RNA; this was a salient question since the presence of DNA in parts of the cell other than in the chromosomes of the nucleus had recently been established. Meanwhile, Joe was busy packing up the lab for his impending move to Yale, where he would spend the next 20 years on the faculty. When he was present, his fascination with all scientific questions was evident. I recall his setting the brain-teaser of calculating whether you would stay drier in a rainstorm by walking slowly, so that the drops fell only on your head, or by running and encountering drops sideways but for a shorter period of time. My facility with differential equations was not on a par with Joe's; only he could calculate the answer. Also, during a partial eclipse of the sun, Joe grabbed his camera and rushed outdoors to snap pictures of the myriad crescent-shapes thrown by the sunlight filtering through the leaves of a tree. By August 1, I decided that I had missed my calling—research rather than medicine was my true passion—and (with Joe's help in switching programs) I enrolled instead in graduate school at Harvard in the fall. Otherwise, I probably would never have become a molecular biologist; Joe Gall was one of the best things that ever happened to me. And I am not alone, as will become evident later.

I have already alluded to the elegant experiments that Joe did to demonstrate for the first time that each chromosome consists of a single DNA double helix. These exploited one of Joe's favorite experimental systems, so-called lampbrush chromosomes from the eggs of newts. Lampbrush chromosomes are giant structures where the DNA extends in loops from the axis and becomes easily observable in the light microscope. Joe also used them to show that newly synthesized RNA appeared on the loops, one of the first demonstrations of the central dogma of molecular biology—that DNA makes RNA (and RNA then goes on to make protein). By examining the nuclear membrane of the same cells in the electron microscope, Joe observed—also for the first time—the beautiful eight-fold symmetry of pores that enable molecules to move in and out of a cell's nuclear compartment. After moving to Yale, Joe began to study the genes for ribosomal RNA and discovered that these genes are able to leave their location in the chromosome and multiply independently during the early stages of egg formation. This enables prodigious amounts of ribosomes to be made and stored for development after fertilization. It was the study of ribosomal RNA genes that later led to Liz Blackburn's pioneering work on telomeres, about which you have already heard.

Another blockbuster of the late 1960s was when Joe and graduate student Mary Lou Pardue devised a technique called in situ hybridization. This was ingeniously simple, but has had immense impact not only on basic research but on the development of diagnostic approaches, such as detecting the presence of bacteria or viruses in tissues or of chromosomal rearrangements in prenatal diagnosis. You all know that a cell growing on a surface looks something like a fried egg, with the yolk being the nucleus containing the DNA and the white corresponding to the cytoplasm where proteins are made and act. What if you want to know where in a cell a particular DNA or RNA is located? As Joe and Mary Lou figured out, all you need to do is use enzymes to make radioactive RNA copies of the DNA or RNA sequence you care about, incubate the copies with fried-egg-like cells under conditions where base pairs can form, wash away what doesn't "hybridize" and then make an autoradiogram to see where the radioactivity has stuck. Since the two strands of DNA, or of DNA and RNA, are held together by a specific sequence of base pairs, this method precisely locates the molecules you are looking for inside the cell.

Joe and his students and postdocs used this technique to identify the sequences that hold the pairs of daughter chromosomes together just before a cell divides. It was also invaluable for showing that telomeric sequences are indeed located at the ends of chromosomes. Joe never patented in situ hybridization and clearly lost his chance to become a millionaire. The procedure has subsequently been modified for hundreds of different applications. Today, Google lists more than 5,230,000 hits for "in situ hybridization"!

In 1983, Joe "did the unthinkable"—in the words of his new boss, Don Brown, Director of the Carnegie Institution's Department of Embryology in Baltimore. He left Yale to reduce the size of his lab and be less encumbered with administration, so that he could work at the bench himself (which he continues to this day). Both at Yale and at the Carnegie, three features have distinguished Joe's lab as a terrific place to do science: the menagerie of organisms used for experiments, the versatility of techniques employed, and women. Let me say a few words about each.

Today, the vast majority of scientists are organismal chauvinists—they work on yeast, Drosophila, E.coli or human cells growing in Petri dishes. Not Joe. As a teenager, Joe collected and peered down the microscope at insects, amphibians and pond creatures. One of his great strengths as a biologist is selecting the best organism and system for extracting experimental answers. The titles in his publication list include the following array: newt, grasshopper, several species of ciliates (like Tetrahymena), mouse, snail, fern, water beetles, flies (both of the fruit and other sorts), toad, coelacanth, hydra, bullfrog, giant panda, marsupial frog, cricket, and damselfly. In one case, choosing the right organism enabled Joe to determine the sequence of 41 percent of a fly genome—decades before the advent of genome projects!

Versatility in approach is another of Joe's hallmarks as a scientist. He has always had a knack for developing new technologies based both on experimental fearlessness and an unusually broad knowledge of other all sciences—chemistry, physics, optics. A 1967 publication was entitled "The light microscope as an optical diffractometer," whereas a 2006 paper analyzes the density of various subcellular compartments, revealing how molecules are able to move around inside cells.

Women. Here I simply quote from letters of former graduate students, postdocs and colleagues supporting Joe's recognition by the AAAS Lifetime Mentor Award (l996) and the upcoming 2006 Women in Cell Biology Senior Award.

• Don Brown: "…he has been mentor to a remarkable diversity of graduate students, many of whom have become distinguished in their own right. I cannot think of anyone with the success rate of Joe Gall. What makes this even more unusual is the very large fraction of his students who have been women, and this was always the case."
• Liz Blackburn: "Most importantly, his mentoring style in non-scientific matters was crucial to my recognition that I could succeed as a scientist."
• Nancy Lane: "Joe Gall is a particularly splendid mentor to women, because he encourages women to stay in research by seeing no differences between men and women as regards their science. When his attention was drawn to the fact that at one time he had eight girls in his lab, as either graduate students or postdocs, he was genuinely startled to realize this and expressed surprise. He had simply accepted able candidates into his lab."
• Mary Lou Pardue: "It is possible to put some quantitative measures on Joe's success as a mentor. The year I was elected to the National Academy [of Sciences], there were two other women in the class and one of them [had also] worked with Joe…."
• Virginia Zakian: "The message was clear; we were in training for success."
• Susan Gerbi: "He has instilled in his students that the reason for being in this business is to enjoy the process of scientific discovery, and this is what keeps us going when times get tough…."
• Patricia Pukkila: "He minimized the negative aspects of scientific competition, saying that if you had a good reason to do a set of experiments, your contribution was bound to be unique."
• Sharyn Endow: "Joe's mentoring did not stop with our leaving his lab, rather he has continued to maintain an interest in our research and take pride in our accomplishments."

I think by now you have the flavor of why Joe Gall is being honored with the Lasker Special Achievement Award. In closing, let me say a few words about Joe as a historian of science. In 1992, the editors of the journal Molecular Biology of the Cell approached Joe to provide covers for their monthly issues because they knew that he had special interest in the history of cell biology, as well as a collection of early books on microscopy and related topics. The result was 60 unique covers that were later collected into a picture book that records the development of the light microscope and views of cellular architecture from the early 17th century to about 1950. Each plate is accompanied by Joe's brief description of the historical and biological context—a magnificent work. Meanwhile, he crusaded to rename certain particles in cell nuclei in honor of their discovery by Ramón y Cajal, 100 years ago. This is clearly out of step with current trends to give an object a new name, so that past work will be forgotten. But Joe, because of the immense respect he commands, convinced everyone to call them Cajal bodies.

There is a lesson in all this: whether it be as a historian, scientist, or mentor, you cannot go far wrong by striving to be like Joe Gall.