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The Rise and Fall of Oncogenes

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  • Title: Assistant Professor of Pathology and Pediatrics, Columbia University
  • Education: PhD, University of Oviedo, 1999; MD, University of Oviedo, 1994; Postdoc, Dana-Farber Cancer Institute
  • Recommended by: Andrea Califano

Adolfo Ferrando has a mission to understand and eventually subvert the mechanisms of malignant leukemias. It's an ambitious undertaking, but it's one for which the physician-scientist seems well equipped — both in terms of clinical expertise and technological savvy.

Ferrando's two-year-old lab at Columbia University is primarily engaged in teasing apart the cellular and molecular biology of aggressive malignant leukemias through the use of a variety of genomic tools, including expression arrays and ChIP-on-chip technology. Ferrando started work on this topic as a postdoc in Thomas Look's lab at Dana-Farber. While in Boston, he also picked up powerful gene analysis techniques through collaborations with Todd Golub's MIT lab. Ferrando is now interested in building on his postdoc work by “trying to decipher the actual effectors of the oncogenic program” in lymphoblastic leukemias, he says.

His team has found that a limited amount of oncogenic factors can turn on the program for human T-cell leukemia. The oncogenes operate by controlling the development of immune system progenitor cells, so it was a natural step to look into the activation of one gene in particular: Notch1, which is crucial for immune system formation. At Look's lab, Ferrando's research helped establish that Notch1 mutations were indeed involved in a high proportion of tumors. At this point, Ferrando's team has “identified that Notch1 appears to be working as a key regulator of cell growth in T-cell development and T-cell leukemias.” The next step will be to fine-tune the extent of this role, with the ultimate goal of translating such a finding into clinical use.

To that end, Ferrando is at work on getting his new lab off the ground while generating data to support his research goals. These objectives may hinge on integrated analysis techniques, especially for expression and ChIP-on-chip data, which Ferrando cites as one of the field’s  bottlenecks.

Looking ahead

Ferrando sees the field moving rapidly toward a point where the consolidation of data from disparate origins will help researchers investigate the functions of genes at the level of whole organisms, rather than only at the cellular level. It's just what the doctors are ordering. “We need to understand how genes work, how tissues work, how organisms work — ultimately that will give us an amazing understanding of how to intervene and provide therapy for cancer and other diseases, Ferrando says.

Publications of note

Ferrando's postdoctoral work on the Notch1 gene helped establish that its mutations are involved in more than half of all T-cell acute lymphoblastic leukemias, as was reported in a Science paper entitled “Activating mutations in Notch1 in acute myeloid leukemia and lineage switch leukemias.” Ferrando went on to collaborate with Todd Golub's group on a systematic expression analysis of several human cancers. This work, published in Nature last year, showed how microRNA profiling can be used for understanding molecular pathology and improving cancer diagnosis. Together these findings opened up a raft of new questions as to the mechanisms of Notch1 activation, as well as how to harness gene signaling inhibitors for therapeutic use. These are a couple of the directions Ferrando's own lab is now pursuing.

The Nobel goes to…

Ferrando notes that although the Nobel is awarded for very basic science, his ideal findings “would have a very direct impact on global human health.” In his view, “the best Nobel Prize you could win would be the one where they wouldn't know whether they were giving it to you on the science side, the medicine side, or on the peace side. That would be really amazing.”

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