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Spotlight - Andrea Ventura
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Cancer biologist Andrea Ventura became fascinated with the machinery of genetics as a student in Italy and focused on cancer genes during postdoctoral work at MIT. Now the incumbent of a Geoffrey Beene Junior Faculty Chair at SKI, he devotes his research to the nascent field of microRNA expression, seeking to understand how these small particles act on genes to promote or suppress cancer.
I first became interested in science growing up in a small village on the east coast of Sicily. As a teenager, I began watching this fantastic Italian TV show about science called Quark, which explained concepts in terms laymen could understand. They discussed genetic engineering, and I became captivated by DNA and how genetics worked. When I began learning about biology in high school, I found the topic to be awe-inspiring. The idea that you have a single cell, a fertilized egg, that somehow contains all the information required to make a human being — that to me was mind boggling. I decided there wasn't any better way to spend your life than trying to understand how this thing works.
Research Trumps Medicine
Following high school, I wanted to learn more about genetic engineering so I went to medical school. The educational system in Italy is different from the US; if you are interested in biology or medicine, you go to medical school for six years, rather than college first and then medical school. I went to Catholic University Medical School in Rome and got my degree — by that time planning on practicing medicine like my father, a family doctor and a cardiologist. But after a year, I realized I wasn't that good at it, and that I was never going to be as good a doctor as my father.
At the same time, I had come to realize I really liked research. During medical school, I did research at the University of California, San Diego, for several months as a visiting student. I was able to conduct some experiments regarding DNA repair in colon cancer. I really enjoyed the way of doing science in the US, the degree of freedom I had to explore any hypothesis. There's a lack of hierarchy here compared with how science is practiced in Italy. That made a big impression on me and gave me the idea of someday returning to the US.
After medical school I went to the European Institute of Oncology in Milan to get my PhD. That was where I really learned the scientific approach to testing theories — it was a great place to do research. When I finished my PhD, I kept thinking about how much I missed the US and wanted to do research there.
I accepted an offer from MIT, and it was the best decision I've made in my life. I worked in the laboratory of Tyler Jacks, a leader in studying the genetic events that lead to cancer. He has been the best mentor I've had and greatly influenced my career. His lab had a very supportive and collaborative atmosphere. It was a lot of fun doing science but also fun just being there. My goal is to have a lab that resembles Tyler's.
When I started at MIT, I was mostly interested in the study of tumor-suppressor genes, especially p53. Many cancers arise when the p53 gene is mutated, and cells lose their ability to suppress uncontrolled growth. I wanted to ask the question: Once you have a tumor that has developed because it has lost one of its tumor-suppressor genes, what happens if you reactivate the gene? It was tricky to do the experiment, but the lab at MIT had the right technology. We found that if you actually did add p53 function back to the tumor, it would regress very quickly — a dramatic response. We published the finding in Nature in 2007, and it was very well received by the scientific community.
I also began following some of the new research being conducted on RNAs. I became especially interested in microRNAs, which are a family of small non-coding RNAs known to modulate gene expression. In other words, they are not involved in making proteins but in regulating genes by repressing translation of DNA into messenger RNA.
Uncharted Territory
Although microRNAs are pervasive throughout the animal and plant kingdom, the field is still very new; the first microRNA was discovered just 15 years ago. There are more than 600 in the human genome, and we don't know the function of most of them. We don't even know exactly how they repress translation, and it's difficult finding the genes through which they act. There is evidence that one microRNA can control the expression of hundreds of genes. If you think how pervasive this mode of regulation is, it's really surprising that it's gone undiscovered for so many years. It just shows that there's still a lot we can discover. We think we know everything that's happening in the cell, but we really don't.
I thought there was lots of interesting biology there, so I decided to study microRNAs that were suspected to be involved in tumor formation. There's now a growing body of evidence that suggests that altered microRNA expression is involved in the development and progression of human cancers. In most cancers, the microRNA expression is found to be lower -- and that low expression somehow promotes tumor growth. But there are a few notable exceptions. In particular, one microRNA cluster, Oncomir-1, appears to be involved in the pathogenesis of B cell lymphoma and small-cell lung cancers. This cluster is found in abundance in these cancers -- there is too much of it. But we didn't really know how this cluster of microRNAs works or what the normal function is of the genes they control. To further complicate the scenario, in mice and humans there are two additional miRNA clusters that look very much like Oncomir-1 (technically called "paralogs"), and we know even less about their function and their role in cancer.
Early Development and Cancer
To investigate the role of these microRNA clusters, I created various mouse models in which I knocked out each one individually. The knockout technology has been used for a long time on protein-coding genes, but when I started this project there was not a single knockout of a microRNA published. My experiments went well, and in a relatively short time I got nice data suggesting that Oncomir-1 is very important for the survival of B cell lymphocytes. In the absence of Oncomir-1, the B lymphocytes fail to develop properly and die. And when you have too much Oncomir-1, the B cells proliferate too much and cause B cell lymphoma. So the gene's essential function early in development -- promoting B cell lymphocyte growth -- can lead to cancer later if it is overexpressed. The results were published in Cell in March 2008.
This opens a new way of treating cancers because there are several ways we can interfere with microRNAs in vivo. One way is to design short nucleic acids that bind to the microRNAs and prevent them from acting on the genes. You don't have to screen chemical libraries to see what works; you just know the microRNA sequence and design the molecule that complements it so it will bind. Or you can do the opposite: design a molecule that mimics the microRNA to boost its effect in the cell. The limitation so far is figuring out how to deliver this type of small molecule in a systemic way. But I'm very optimistic that within the next five years we will have powerful ways of exploiting this technology.
Supportive Environment
I wanted to continue investigating this area of research in a laboratory of my own, so I began looking at openings around the US. Obviously, I knew about Sloan-Kettering from its reputation, and I saw an opening in the Cancer Biology and Genetics program and decided to apply. I am very lucky to have the chance to continue researching microRNAs and their links to cancer here at Sloan-Kettering because there's no better place in the world to do science. I arrived in August 2008 and began setting up my lab and recruiting people to do research.
The best thing about Sloan-Kettering so far has been the interaction with people here, especially the other young investigators who have been very open to discussing ideas and possibly establishing collaborations. That's my strong preference — I think science should be as open an endeavor as possible. There is a critical mass of good scientists here that has no equal, and many more are going to be hired soon. Sloan-Kettering as an institution is very supportive of junior investigators when it comes to funding. This is especially important now that it's not so easy for young scientists to get funding from outside. Also, the facilities here are fantastic. I think microRNAs need to be investigated in an entire organism, and the mouse facility is very good. Finally, it's great to be right next door to The Rockefeller University and Weill Cornell Medical School so you can be exposed to a wide range of scientific subjects. That expands the collaborative possibilities even more.
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