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At the Bench and the Bedside


Sandro Santagata
Title: Visiting Scientist, Whitehead Institute for Biomedical Research,
MIT; Instructor, Harvard Medical School
Education: MD and PhD, Mount Sinai School of Medicine, 2002
Recommended by: Susan Lindquist

Sandro Santagata is that rare breed of physician and researcher who has one foot at the bedside and the other at the bench. Needless to say, this long and arduous path is not for the faint of heart, but for Santagata, the two naturally fit together, as one informs the other. As a neuro-pathologist, he sees a lot of severe and devastating diseases, whether it's surgical neuropathology where he diagnoses highly malignant brain tumors or during an autopsy. "I'm very research-oriented, and maintaining the clinical link constantly maintains the focus on how important all of our research is in terms of how to treat disease," Santagata says. "It's hard to go to the hospital and do frozen sections on people that are dying from brain tumors and come back to the lab and try not to do something that's relevant. It's a daily reminder that things need to improve and I've been inspired to find ways to target both cancer and neurodegeneration stemming from my clinical work."

Santagata is focused on trying to find ways to modulate small molecules and he uses genetic tools to find transcriptional responses for the treatment of neurodegenerative diseases. As a visiting scientist in Susan Lindquist's lab at the Whitehead Institute, he is exploring ways to use the heat shock response of cells as a sensor for bioactive molecules that can be used to treat brain tumors. Primarily, they are interested in better understanding protein homeostasis and are using high-throughput screening to identify small molecules that disrupt proteostasis in order to trigger a heat shock transcriptional response as an adaptive mechanism.

Ultimately, the goal of his research is to generally target transcription to find effective treatments that can be brought to his patients. To do this, Santagata looks at transcription in a slightly different way than most of his colleagues do. "I want to find drugs that will target important transcriptional responses to invoke defense responses that are innate to human beings as well as to inhibit transcriptional responses that are important for tumor cell survival," he says. "Traditionally, transcription hasn't been an easily targetable field but we're not, per se, trying to target the transcription factors directly, we're trying to influence the responses, so the transcription response is our readout."

Looking ahead

He says that this research would be greatly accelerated if he could have access to a tool capable of readily determining the transcriptional signatures of all microarrays in a dataset, find the signatures, correlate them immediately with small molecules that have similar signatures, and then determine which transcription factors one would be able to target to verify those questions.

Santagata's current area of focus also marks a major change from his earlier research efforts, which dealt mostly with DNA recombination and mutations in the V(D)J recombinase.To help make the transition as easy as possible, not to mention to get caught up with his colleagues in the Lindquist lab, Santagata is currently involved in a mentor/clinical/scientist position where he is taking five years to wipe the slate clean and take a jump in a new direction. "That's why I've come here to the Whitehead — so I have a break from my past work, which is the sort of courageous part of what I'm trying to do at least," he says. "It's challenging mostly because I'm trying to do clinical work, have a happy family, and be able to take these new steps. As a pathologist, I've been trained to use my eyes and to look at slides, but this is a big attempt to do something beyond tissue-based research."

And the Nobel goes to..

For the Nobel, Santagata says it would have to be for developing an effective treatment approach for curing glioblastoma multiforme.

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