Thursday, 21 March 2013 20:00

Frank Ruddle, Pioneer in Human Gene Mapping and Former ASCB President

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Francis Hugh Ruddle Francis Hugh Ruddle

Francis Hugh Ruddle, a former ASCB President and a pioneer at Yale University in mapping the human genome and creating the first transgenic mouse, died March 10 in New Haven. He was 83.

Ruddle coined the word "transgenic" in 1981, after startling the world the year before with a mouse born with heritable viral genetic material that had been inserted into newly fertilized mouse eggs.


Working with Jon W. Gordon, Ruddle soon after created a line of transgenic mice carrying a human gene, demonstrating in principle a technology that would revolutionize genetic and medical research. With William McGinnis, Ruddle was also the first to find human homologs for the newly discovered Drosophila homeotic or "master control" genes that dictate the dimensions of embryonic morphogenesis, the first evidence that homeobox genes were widely conserved across animals, plants, and fungi.

Raju Kucherlapati, now at Harvard Medical School was in the Ruddle lab during its gene-mapping heyday. "At the beginning of the 1970s, human genetics was just emerging as an important field," says Kucherlapati. "A large number of human (genetic) diseases had been identified but the causes were not understood. Frank was a pioneer in bringing together diverse approaches to attack that problem by mapping the human genome." Ruddle began promoting a comprehensive effort in 1973 with a Human Gene Mapping Workshop each year at Yale. The 1973 workshop cited 100 human genes in its report. The last Yale gene-mapping workshop in 1989 reported 2,000. "All of the work that Frank did and all of his efforts to bring together people from around the world who were interested in gene mapping were really the predecessor of the Human Genome Project," says Kucherlapati.

Ruddle's original breakthrough technology, "somatic cell hybrids," was still labor intensive and time consuming. To build scale, Ruddle assembled one of the largest labs of its day, occupying the entire 10th floor and half of the 11th in the Kline Biology Tower. Leslie Leinwand, now at the University of Colorado, Boulder, was a Ruddle graduate student in that era. "The lab was huge," Leinwand recalls. "At one point, there must have been 40-50 people there. It was massive."

She continues, "We used to joke with him. We'd say, 'Frank, can you remember everybody's name?' But when a new person joined the group, he would go around the table and introduce everybody. We were amazed." The sheer size of the lab was a big reason Leinwand chose Ruddle as her mentor. Scaling up a new technology with a large workforce yielded tremendous productivity, she recalls. "I actually liked that it was a large lab. I was extremely productive as a graduate student," Leinwand recalls. "I chose an equally large lab for my postdoc and I have a huge lab now."

Ruddle's transgenic mouse was the proof in principle of a technology that set off a new age in research biology. This SCID (severe combined immunodeficiency ) mouse shows how far the transgenic revolution has come. Photo courtesy of the National Cancer Institute, NIH.

Ruddle's secret, says Leinwand, was leaving day-to-day mentoring of students to a large cohort of talented postdocs who ran their own experiments. Ruddle himself was always around, day and very late at night. "Frank was literally larger than life," she explains. "I think he was almost 6' 8". He was a gentle giant, a supportive and gentle giant." His height was simply part of his worldview, says Leinwand. When a suite of tissue culture rooms was installed, Ruddle had the observation windows set at his eye level. The wall-mounted pencil sharpeners were at tiptoe level, she recalls with a laugh. "But Frank really made a huge contribution to human genetics but I think one of the important things to convey is that Frank created a laboratory environment that fostered collegiality and friendship. I'm still in touch with a number of people I met in Frank's lab who became colleagues and friends. That is not always the case in big labs."

In the midst of this work on gene maps and transgenic animals, Ruddle took a 1982 sabbatical at the University of Basel, Switzerland. He arrived in the Biozentrum lab of Walter Gehring, a former Yale colleague, just as Gehring identified the first homeobox or "master control" genes in Drosophila that lay out the dimensions and order of embryonic development. Convinced that a highly conserved homeobox sequence also existed in mammals, Ruddle and McGinnis identified the human homologs of Gehring's homeotic genes.

Ruddle devoted much of the latter part of his career to tracking the homeobox sequence across a worldwide DNA zoo to see how this small number of highly conserved homeotic genes could yield so much morphological difference across so many species. Cooduvalli Shashikant, who is now at Pennsylvania State University, collaborated on homeobox studies of more than 30 species. The study moved from mice to hagfish to sharks to elephants to the largest living animals on the modern earth, the baleen or humpback whales. Marc Borbély, an undergraduate working in the Ruddle lab, found a single four base-pair deletion unique to baleen whales in the Hoxc8 gene. This small change in a Hox regulatory element radically shortened the axial morphology of the baleen rib cage, says Shashikant. "Frank gave us a great deal of freedom to follow the story. We started this at first only in mammals but then we spread around because we were trying to figure out small differences between closely related species." That led them to the whales, the sperm, the bowhead, and the baleen. "Frank wrote to people all over the world to get (DNA) samples plus he had the patience to wait for us to make a good story."

Ruddle was born in West New York, New Jersey, in 1929 but grew up outside Cincinnati in the suburb of Mariemont. He described himself as an indifferent student and dropped out of high school in 1946 to enlist in the U.S. Army Air Forces. After service in postwar Japan, he earned his Bachelor's in 1953 and his Master's in 1955 at Wayne State University. He completed his doctorate in Zoology at the University of California, Berkeley, in 1961. After a postdoc at the University of Glasgow in Scotland, Ruddle joined the Yale faculty where he retired as Sterling Professor of Molecular, Cell, and Developmental Biology in 2007.

Ruddle led the ASCB in 1987, one of three major scientific societies he served as president including the American Society of Human Genetics and the Society for Developmental Biology. This alone marks the man and his era, says Kucherlapati. "It would be unthinkable today that anyone would have that kind of breadth and versatility."

The Ruddle lab pursued the homeobox or "master control" genes that set embryonic morphology across the genomes of 30 species. In the baleen or humpback whale, a tiny deletion in Hoxc8 made a huge difference. Photo from the National Oceanic and Atmospheric Administration.

Ruddle was married for 48 years to Nancy Ruddle, a renowned immunologist in her own right who is now emeritus at the Yale School of Public Health. They had two daughters, Kathlyn and Amy. The Ruddle house in New Haven was known for its good food and open doors, especially on holidays. Leinwand remembers being invited as a new graduate student for Thanksgiving "probably because I didn't have family anywhere nearby." It was a lively and very long party, she recalls, after it was discovered that the turkey had gone into an unlit oven.

Ruddle was also known as a passionate sailor, often commuting from New Haven to the Ruddle house on Block Island on his 18-foot sloop, Shamrock. Kucherlapati went sailing once with Ruddle. That was enough, he says, especially after hearing the tale of a subsequent Ruddle sailing voyage from New Haven to a seminar at the Cold Spring Harbor Laboratory on Long Island. The trip out was fine but homeward bound, Ruddle and a postdoc serving as crew were caught in a violent squall on Long Island Sound. Disoriented and shaken, Ruddle managed to reach safe harbor at Bridgeport. "They had to take a taxi from Bridgeport to Yale," Kucherlapati recalls, "where they arrived wet, hungry, and cold."

Thomas Lo was a Yale undergraduate in 1998 when he applied for a place in the Ruddle lab. On his application, Lo said that in high school he'd worked in a Buffalo bakery. Ruddle took note, asking about Lo's interest in cooking. The cooking Lo did in the lab centered on Hox gene experiments, but talking about food with Ruddle continued for the next three years.

In the summer of his junior year, Ruddle ended a lab meeting by pulling Lo aside. "Hey, Tom. I've got to talk to you about a possible collaboration." The subject was a wedding cake for his daughter Amy. They designed an enormous four-tier carrot cake in Ruddle's well-equipped kitchen in New Haven. "Frank was always about life and food and cooking," Lo remembers. "He also had great equipment." With Ruddle watching closely, Lo baked a test cake. Just before the wedding, Ruddle baked the full-scale cake himself. They transported the layers to the Block Island house for assembly and for butter-cream cheese icing. It was decorated in rose petals harvested on the island.

At the reception, Ruddle hauled Lo up to the head table, telling the crowd that here was the student who had shown him how to bake a cake. "This week he was my mentor," Ruddle said, "but I'm still his mentor." The guests roared. It was true, says Lo, who after a short career as a sous chef went back to medical school and is now in private practice as an anesthesiologist in the New York City area. "Frank was a renowned scientist whose contributions to science were immeasurable and whose accolades would fill countless pages. He was my mentor who guided me throughout my career, but more importantly, he was a friend. We shared an interest for not only science, but also for the love of food. He will be missed," says Lo.

John Fleischman

John is ASCB Senior Science Writer and the author among other things of two nonfiction books for older children, "Phineas Gage: A Gruesome But True Story About Brain Science" and "Black & White Airmen," both from Houghton-Mifflin-Harcourt, Boston.

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