Dalla-Favera’s Research Sets Stage for Lymphoma Advances

Published: Tuesday, May 03, 2016
Riccardo Dalla-Favera, MD

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).

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.

Analyzing Mutation Puzzle

“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.

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.

Capitalizing on Technology

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.

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