Cracking Cancer’s Code

How did you get into studying the role of RNA in cancer?

It was entirely down to chance. I was born in Romania, which at that time was a Communist country. The study of genetics was frowned upon, but I was lucky to have the geneticist Dragos Stefanescu as a mentor; he taught me cytogenetics, but also how to do good science. I wanted to study abroad, so I wrote 120 letters to 120 scientists all over the world – and ended up moving to Italy, where I studied molecular genetics in Massimo Negrini’s laboratory before moving to the United States. I was at Kimmel Cancer Center in Philadelphia in Carlo Croce’s laboratory when we discovered a link between microRNAs and human cancer. It was the first time a link had been made between any type of non-coding RNA (ncRNA) and a human disease.

But the initial paper was rejected, right?

Yes, by a famous journal in just 12 hours. Attached was a simple note saying that our discovery was random, and because it wasn’t proven that microRNAs were important in cancer, our work would be better suited to a smaller journal. Today, that paper has probably been cited more than 4,000 times, and there are over 30,000 papers in PubMed on microRNAs or long ncRNAs and cancer. That discovery opened the door, both for me and for many thousands of other scientists to enter an exciting and entirely new field of molecular oncology. But much of it was actually luck and perseverance!

In 1992, when I was a young student in Romania, the first scientist who helped me write a research essay was Thomas Cech, who received a Nobel Prize for his work with RNA and his discovery of ribozymes. It’s funny to think that now, 25 years later, I am working in the field that Thomas popularized: the role of RNAs in biology, and in pathology in general.

You aim to produce the first complete catalog of human ncRNAs. How close are you?

Day by day, I think I am getting further away! The genome is complex, and there have been many surprises. A colleague at Thomas Jefferson, Isidore Rigoutsos, and I recently had a paper accepted on the topic of human- and primate-specific ncRNAs that have no homology with other species. Essentially, these transcripts represent a fingerprint of humanity, which could have big implications for research – many scientists, including me, spend a lot of time and money using mouse models of human cancers. But as geneticists and clinician-scientists, we know that mouse models don’t reproduce human cancers very well. Without a deep and meticulous understanding of the genome and how it functions, I don’t believe we will make big advances in developing new biomarkers and therapeutics for cancer. I hope our new ncRNA research will help to bridge that gap. We are heading in the right direction, but it’s going to take a long time. Luckily, the journey is fascinating and full of unexpected turns, which is great – it keeps life interesting!

Why focus on cancer in particular?

If you or I were to go to a doctor, receive a cancer diagnosis, and be told we might only have weeks or months left to live, it would be absolutely devastating news. Patients with advanced cancer are in serious need of a better understanding of their disease, which can lead to better management and potentially to new treatments. And that’s why I choose to focus on identifying the mechanisms of metastasis and the ways we can block the spread of cancer cells.

Another reason to focus on cancer is the potential to use ncRNAs to predict cancer occurrence. It’s my hope that, one day, we’ll be able to take a body fluid, such as plasma, and develop a relatively noninvasive test that looks at ncRNAs and tries to identify which people will get lung cancer, prostate cancer, and so on. Of course, these are goals that many researchers have been pursuing – some looking at DNA, others at proteins or RNA. I believe that combining these biomarkers will yield the biggest advantage. We can’t fully treat any type of disease if we don’t understand it, and nucleic acids – both coding and non-coding – are like the different words of a sentence. We have to understand it all and look at it in the right way to truly understand a disease.

When you look back at your career, would you do anything differently?

I don’t think there’s anything I would change. My path has led me to one of the biggest cancer centers in the world, where I’m lucky to have great collaborators and colleagues. But so much of my success is down to other people that I cannot thank them enough. It’s important to thank my mentors, because without them, I wouldn’t be where I am. We should all thank our fellows more as well – no matter how clever you are, how good your ideas are, or how much funding you bring, you are in debt to the people in your lab who work to make your ideas a reality. So, I’d like to thank both those who came before  me and those who came after for making my work possible.