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Dulbecco

Jonas Salk and Renato Dulbecco in the courtyard, 1967

To understand how the Salk Institute became one of the preeminent cancer research institutions in the world, look no further than the life and work of Nobel laureate Renato Dulbecco. Dulbecco, who died February 19 at age 97, pioneered the field of tumor biology, and his interest and talent in mentoring young investigators greatly influenced the direction that cancer research has since taken at the Salk and in other world laboratories.

Dulbecco, a Founding Fellow of Salk, was awarded the Nobel Prize in 1975, along with Howard Temin and David Baltimore, who worked with Dulbecco at different times, for their discoveries illuminating how tumor viruses interact with the genetic material within a cell. Dulbecco demonstrated how a virus could insert its own genes into the DNA of the cell it infects, sparking cancer growth. In essence, his work helped uncover some of the molecular pathways that define cancer growth however it occurs, providing the conceptual breakthrough that has guided the field ever since.

Dulbecco's story is one of a remarkable scientist, and it is also a story of an enduring scientific legacy that carries on to this day. Over the course of his career, Dulbecco trained and collaborated with some of the leading biologists in the world, and his life and work charted a course for many young cancer researchers.

"He had a broader vision of science than most and a keen instinct for important problems to solve," says Tony Hunter, a professor in the Molecular and Cell Biology Laboratory and director of the Salk Institute Cancer Center. "His work drew outstanding young investigators to Salk and influenced a whole generation of biologists."

Brilliant Minds

Dulbecco was born in Catanzaro, Italy, in 1914. When he was a student at the University of Torino in Italy—an institution he attended at age 16—he met scientists who would strongly influence his life. There, in the laboratory of Giuseppe Levi, a professor of anatomy, he met students Salvador Luria and Rita Levi-Montalcini, both of whom would also go on to win Nobel Prizes.

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Marguerite Vogt

Before and during the Second World War, Dulbecco served forced stints as a medical officer in Italy's military, both on the French front and the Russian front, where he was wounded. He later joined the resistance and served as a village physician near Torino. After the war, he and Levi- Montalcini left Italy for the United States. In 1947, Dulbecco joined Luria at Indiana University—the university awarded Dulbecco the President's Medal for Excellence in 2011—and together they worked on viruses that infect bacteria. Luria and Dulbecco shared a small lab, and James Watson, another future Nobel Prize winner, soon joined them, as Luria was Watson's doctoral advisor.

While at Indiana, Dulbecco attracted the interest of Max Delbru?ck, who in 1949 offered Dulbecco a job at Caltech as a research fellow. Delbru?ck later won a Nobel Prize for discovering that bacteria become resistant to viruses as a result of genetic mutations.

At Caltech, Dulbecco met Marguerite Vogt, another European immigrant, who would become his longtime scientific collaborator. Together they first described how the poliovirus forms plaques in cell cultures— work that transformed virology from a descriptive to a quantitative science.

In 1963, Dulbecco left Caltech to become one of the first Fellows of the Salk Institute, (a position equivalent to a full professor in a regular faculty) which had been founded three years earlier by polio vaccine pioneer Jonas Salk—a move that would establish Salk as a beacon for talented cancer scientists.

Shared purpose

Vogt joined Dulbecco at Salk, where they worked on tumor viruses. They studied Simian vacuolating virus 40 (SV40) and mouse polyomavirus, a related virus that can cause cancer in rodents. Their work showed that SV40 inserted its genes into the cells it infects, causing the cells to grow uncontrollably. This definitively proved the essential role of SV40 genes in transforming cells into cancers and, more fundamentally, provided the first clear evidence that genetic mutations cause cancer.

At Salk, Dulbecco had the opportunity to cultivate the next generation of scientists through his mentorship. He wrote that the daily interaction through the years with a continuously changing group of young investigators shaped his work. "For although I had general goals, the actual path followed by my research was pragmatically determined by what could be done at any given time, and my young collaborators were an essential part of this process," he wrote.

Walter Eckhart, now professor emeritus in Salk's Molecular and Cell Biology Laboratory, remembers the intellectual pull that Dulbecco had on him. He began working with Dulbecco in 1965 as a postdoctoral fellow and was later appointed to the Institute's faculty. Eckhart and other young scientists at the Salk focused on the regulation of cell growth and what happens when cancer disrupts that regulation and forces cells to run amok.

"It was exciting to work around the clock and to be part of experiments that solidified the idea that genes could be instrumental in provoking cancer," Eckhart says. "At the time, a lot of us didn't quite appreciate the magnitude of what we were living. There was a lot to know and to discover. Dulbecco was a wonderful mentor."

The Salk Cancer Center's focus on the genetics of cancer and cellular processes began with Dulbecco, Eckhart says. "He was always ahead of his time," he says. "He had the big picture in mind."

Four of the investigators who trained or worked with Dulbecco at Salk were later awarded Nobel Prizes. Susumu Tonegawa, a 1987 winner, was a postdoctoral fellow with Dulbecco working on transcription by SV40. Lee Hartwell, also a postdoctoral fellow in Dulbecco's lab, eventually switched from working on polyomavirus to yeast, which led to his work on the genetics of cell division and his 2001 Nobel Prize. Paul Berg, a 1980 Nobel laureate, spent a year in Dulbecco's lab, conducting research that led to d eveloping SV40 as a vector for introducing new genes into mammalian cells using recombinant DNA techniques. David Baltimore, a Salk Non-Resident Fellow and president emeritus of the California Institute of Technology, who conducted research at Salk for three years, credits Dulbecco for his influence in setting the direction of Baltimore's later work on mammalian tumor viruses. Although the problem he worked on was separate from Dulbecco's investigation, Baltimore says he was clearly influenced by Dulbecco's clarity of thought.

Legacy of Discovery

The Salk Institute Cancer Center was established in 1970 under the direction of Robert Holley, who had received the Nobel Prize two years earlier, and in 1973, the National Cancer Institute designated the Salk center as one of the first seven basic cancer centers in the United States.

Dulbecco

Maureen and Rentao Dulbecco at the 2007 Salk International Council meeting in Austria

Dulbecco left Salk in 1972, moving to London with his wife, Maureen, and their young daughter, Fiona, to serve as deputy director of research at the Imperial Cancer Research Fund Laboratories. At Salk, four of the original faculty appointed to the Tumor Virology Laboratory set up in Dulbecco's previous research space—Walter Eckhart, Gernot Walter, Bertold Francke and Tony Hunter—and worked on polyomaviruses as a model for human cancer.

Their work spawned a number of key findings at Salk, including Hunter's discovery that tyrosine phosphorylation is a chemical "on-off" switch responsible for telling cells to become cancerous. Discovery of this important signaling mechanism, which proved to be the underlying cause of many types of human cancer, revolutionized cancer medicine and ultimately led to the development of several innovative cancer therapies, including the leukemia drug Gleevec.

Dulbecco returned to Salk in 1977 and launched a new research program focused on breast cancer. He used monoclonal antibody technology to identify proteins found on the surface of normal mammary cells. This provided important insights into the normal development of mammary glands and allowed him to study how mutagens might cause mammary cells to become cancerous.

Dulbecco closed his laboratory to serve as Salk's president from 1988–92. After winning the Nobel Prize in 1975, he used his influential voice to speak out for fundamental changes in the way that cancer research is conducted.

"Renato was a giant of cancer biology, and he did not shy away from making bold, visionary statements," says Inder Verma, a professor in Salk's Laboratory of Genetics.

One example was the two-page "Perspective" he wrote for Science magazine in 1986, in which he argued that the best way to understand cancer would be to sequence the entire human genome and that an international collaboration should be convened to tackle the project.

Geoffrey Wahl, a professor in Salk's Gene Expression Laboratory, says this assertion, which led to the Human Genome Project, completed in 2003, may have been Dulbecco's most transcendent contribution to science.

"Little could he have imagined that this suggestion would not only become a reality in his lifetime, but would transform all areas of biology," says Wahl.

Eckhart adds that at the time, many people felt the genome project was premature and was going to be very expensive, siphoning off a lot of National Institutes of Health money that could otherwise be spent on research.

In his Nobel Prize lecture, Dulbecco took the opportunity to warn that substances in the environment, such as tobacco smoke, can cause genetic mutations that lead to cancer. "While we spend our life asking questions about the nature of cancer and ways to prevent or cure it, society merrily produces oncogenic substances and permeates the environment with them," he told the audience. He urged governments to discourage use of tobacco and also to test chemicals for their ability to produce cancer-causing mutations.

"He was one of the first prominent people to stand up and take a very public position about the cancer risks of smoking," says Hunter. "It was daring—not what the committee expected to hear. We—all of us—owe a great deal to Renato Dulbecco. Many of us are in cancer biology because of the example he set for us."

Salk Cancer Research Milestones

1950s
Renato Dulbecco and Marguerite Vogt describe how a tumor virus can "turn on" the uncontrolled growth that is the hallmark of cancer, providing an important clue to the genetic nature of cancer.

1970
Salk Cancer Center is established under the direction of Nobel laureate Robert Holley. Salk professor Leslie Orgel discovers a straightforward way to synthesize cytosine arabinoside (Ara C), a compound that becomes one of today's most commonly used anti-cancer agents.

1972
The National Cancer Institute designates the Salk center as one of the first seven basic cancer centers in the United States.

1975
Dulbecco shares the Nobel Prize in Physiology and Medicine with Howard Temin and David Baltimore.

1979
Tony Hunter discovered a process called tyrosine phosphorylation turns out to be the underlying cause of many types of human cancer, a discovery that leads to the development of the leukemia drug Gleevec.

1983
Inder Verma pioneers the use of stripped-down versions of viruses to insert genes into cells throughout the body, paving the way for gene therapy trials in cancer patients.

1985
Ronald Evans identifies the first of a large family of molecules, named "nuclear receptors," which are primary targets in the treatment of breast cancer, prostate cancer and leukemia.

1992
Geoffrey Wahl and his lab identify the central player that stands guard over the stability of the genome, a protein called p53, which is often disarmed in cancer cells.

2012
Salk scientists continue Dulbecco's legacy, explaining how a popular class of chemotherapy drugs works, discovering a new target for lung cancer drugs and showing that stem cells in develop - ing organs may help us understand the genetic underpinnings of cancer.