Dalla-Favera’s Research Sets Stage for Lymphoma Advances

Riccardo Dalla-Favera, MD

The race began in 1976, right after Harold Varmus, MD, and J. Michael Bishop, MD, showed that normal cellular DNA from several bird species contained sequences similar to the SRC oncogene from the Rous sarcoma virus. Eminent scientists from around the world set off to claim a place in history by finding similar sequences, called proto-oncogenes, amid normal human DNA, but they all lost out to a junior researcher who had just begun a fellowship at the National Cancer Institute (NCI).

Analyzing Mutation Puzzle

Riccardo Dalla-Favera, MD, still ranks that first breakthrough among his best work, but it has plenty of competition. He has since helped to discover a good portion of everything that’s known about the genetics of lymphoma. The longtime leader of the Institute for Cancer Genetics at Columbia University, Dalla-Favera has helped improve the diagnosis of lymphoma with discoveries that hold the potential to influence the treatment of the disease, the most common of all hematologic malignancies. In 2014, his colleagues in the oncology field honored Dalla-Favera with a Giants of Cancer Care award in Lymphoma.“Even before the discovery of that first oncogene, it was pretty clear that a condition like lymphoma would only occur after mutations in many different genes, so I never saw the challenge as finding only one mutated gene,” Dalla-Favera recalled in an interview. “I saw the challenge as finding them all and figuring out how together they drove the disease.”

Dalla-Favera started at the NCI two years after Varmus and Bishop published their landmark paper. Like many other researchers, he figured that if healthy bird genomes contained Src homologs, then healthy human DNA might also contain proto-oncogenes, long sections of code a mutation or two away from genes found in tumors.

Capitalizing on Technology

Confirming this hypothesis amid the entire human genome would obviously be impossible, but Dalla-Favera knew how he could narrow the search. Earlier research had already demonstrated that the few genes of any virus would pair with whatever human genes were the closest match. Therefore, Dalla-Favera figured, an oncogene inside a virus would likely pair with the most similar proto-oncogene inside human cells.Dalla-Favera’s timing was fortuitous. The first technology capable of testing his idea had just arrived at research facilities, and Dalla-Favera had just gone to work in a laboratory that stored many cancer-causing viruses.

He requisitioned everything he needed and, within a few months, discovered human cellular sequences that are homologous to the v-Myc oncogene in the avian myelocytomatosis virus. He then followed up with research that showed where the gene localized and demonstrated that it sometimes translocated to other chromosomes. Dalla-Favera’s work was a key step in confirming the hypothesis that Varmus and Bishop put forward years earlier and in creating the modern understanding of how cancer develops.

Indeed, the discovery of proto-oncogenes helped solve mysteries—some decades old, some even centuries old—such as why carcinogens and viruses trigger cancer in some people but not others, why the propensity to some cancers is hereditary, and why the risk of developing cancer increases with age.

And for Dalla-Favera, it was a sign of things to come.

“Riccardo was exceptional even by the standards of people who do research at NCI,” said Robert C. Gallo, MD, who ran the NCI’s Laboratory of Tumor Cell Biology during Dalla-Favera’s fellowship.

“He had a natural gift for conceptual science that made him insightful, but his biggest gift was his focus. When he set his mind on a goal, he worked relentlessly toward it. Each time he took a step forward, he immediately identified the next step and focused on that,” Gallo said. Research Beckons Dalla-Favera was born in 1951 and raised in Milan, Italy, where his father and several other family members practiced medicine. Their influence inspired him to enroll in medical school, but he never planned to follow them into the clinic. The research laboratory was already beckoning.

Dalla-Favera chose to concentrate on lymphoma for largely pragmatic reasons. Italy’s hematology departments received substantial funds from a government that shortchanged other research areas. That money allowed those departments to do some of the only world-class research in all of Italy, and most of the cash naturally went to study hematologic cancers.

Still, despite the relative strength of Italy’s hematology programs, Dalla-Favera set off for the United States after completing his residency at the University of Milan. Americans spent more on science than did Italy, and they clearly led the world in cancer research. Dalla-Favera figured he’d spend a few years studying with the masters in America and using the technology before he returned home for good.

That was 38 years ago.

“I was probably naïve in thinking that I’d return, given how much I wanted to do research and how much better the opportunities were here,” Dalla-Favera said. “I missed my family and friends. I missed my native culture. I missed my soccer team. I still do. But I’d have probably been willing to move to Antarctica if that had been the best place to do research. I’m very lucky that I ended up someplace as nice as New York.”

Discovering Oncogenes

Dalla-Favera arrived in the city in 1983, when he took a job at New York University, and his only move since then has been uptown, to Columbia University.When he began his work, Dalla-Favera found oncogenes by looking at chromosomes under the microscope, trying to detect minute differences between cancerous and healthy cells.

It may sound primitive to modern ears, but the technique proved surprisingly productive. Dalla-Favera kept making significant discoveries throughout the 1980s, about how oncogenes mutated and how different mutations produced different results.

He collaborated, for example, on a number of papers about the genetics of Burkitt lymphoma. His work explored topics such as how c-MYC mutations differed in the endemic and sporadic forms of the disease and how the expression of a c-MYC oncogene causes the tumorigenic conversion of human B-lymphoblasts infected by Epstein-Barr virus.

The same period saw him contribute to a number of papers that explored the relationship between viruses—particularly the AIDS virus— and various forms of lymphoma.

The steady production helped him rise through the ranks, from assistant professor to associate professor to full professor. During that time, he kept distractions to a minimum. He saw no patients. He ran no drug trials. He did no administration.

In 1992, life became more complicated. Columbia awarded Dalla-Favera an endowed chair, put him in charge of the Division of Oncology in the Department of Pathology & Cell Biology, and made him a deputy director of the Columbia- Presbyterian Cancer Center. In 1999, Columbia made him director of its Institute for Cancer Genetics, a title he still holds.

Dalla-Favera now oversees the work at 15 separate research laboratories, but he has always maintained a team of his own and managed to devote most of his professional life to its efforts. (He still doesn’t see patients or run drug trials.) “The thing that really illustrates his commitment to lymphoma research is his willingness to let go of promising discoveries if their potential importance lies with other diseases.

Cited Extensively

He has repeatedly allowed his team members and others to take things out of his lab rather than working on them in-house and diffusing his team’s concentration,” said Michael L. Shelanski, MD, PhD, a senior vice dean for research and the Delafield Professor of Pathology and Cell Biology at Columbia University.Dalla-Favera’s research has always won space in the most prestigious journals and respect from colleagues who understand its true importance. Dalla-Favera’s scholarly works have already been cited more than 39,000 times, and the rate of citation keeps increasing as the implications of his discoveries emerge.

Moreover, time has begun to reveal practical applications for the work. For example, some antibody tests that provide specifics about each patient’s cancer trace their origins back to discoveries that Dalla-Favera and colleagues made about B-cell lymphoma 6 protein.

Such advances have already improved the diagnosis of lymphoma, but Dalla-Favera believes the future holds much more important applications.

“We’ve finally reached the point where we know most of the genes that are responsible for producing different types of lymphoma. Now we want to learn more about the importance of each and group them by functions such as cell reproduction or cell suicide,” Dalla-Favera said.

Further information in those very basic areas may help others create rational ways to determine which medications, among the dozens that are currently approved, will work best for different tumor types in general and individual patients in particular.

Passionate About Biology

It may even underlie the development of treatments that can reverse a few of the most important genetic mutations and cause tumors to collapse.But Dalla-Favera and the team he leads won’t be doing any of the development work, and they certainly won’t be doing clinical trials. “The skills needed to perform biological research and to develop new treatments appear completely different to me. I have spent decades developing my skills in the first area, so I can be much more productive by concentrating my efforts there and leaving drug development to the experts,” said Dalla-Favera, who added that he feels much more passion for biology than for chemical engineering.

“There’s no way to do good work over any period of years without true passion. Research is frustrating. Many days—perhaps even most days—are entirely unproductive. You need passion to work at problems long enough to solve them,” Dalla-Favera explained.

Looking back, he counts himself lucky to have had so many opportunities, but he does not look back often. There are still so many questions he wants to answer.

“Those early years were golden years because new technology gave you the opportunity to do things that no one else had ever done before,” he said. “But the same is true today. We can now do more of some kinds of work in a day than we once could do in a year, and that opens up incredible possibilities.”