Oncogenetic Pioneer

Congratulations on receiving the American Association for Cancer Research (AACR) Lifetime Achievement Award.

Thank you - it is very flattering, although it does make it sound like I am being put out to pasture! I certainly have no plans to retire in the foreseeable future.

What has been the overarching theme of your work?

We are trying to determine the molecular and genetic determinants of various steps in the process of going from a fully normal to a highly oncogenic cell, including the acquired ability of a cell to disseminate and create metastases. From a young age, I’ve liked to take things apart and find out how the mechanism inside works. My research is just another manifestation of that – trying to peer inside cancer’s complex machinery.

Did you know early on where that curiosity would lead you?

I had no idea what I wanted to be. I started out as a pre-medical student but then I learned that doctors have to stay up all night to deal with patients, and decided medicine wasn’t for me – I need my sleep!

I now teach an Introduction to Biology course for undergraduates but, as I tell the class in my first lecture, when I took the same course in 1961, I got a D. As an undergraduate I didn’t enjoy biology at first, but I came to love it. In 1963 I took a genetics course here at MIT, which laid out the principles of molecular biology. Suddenly, it dawned on me that we might be able to understand the full complexity of the biosphere by studying DNA, RNA, and proteins. That was a revelation to me.

Once you had discovered your passion for biology, what drew you towards cancer research?

I am not one of those people who plans out their lives; I just put one foot in front of the next. Working in cancer research was really just a series of fortuitous accidents. I was interested in studying mRNA, and tumor viruses were a tool to do that. I ended up sharing a lab with David Baltimore, who had just discovered reverse transcriptase, and began to work on RNA tumor viruses that could infect and transform cells. Over time, my interests evolved and I ended up studying the cellular genes that control cancer. My main ambition is simply to do interesting things.

What led to your discovery of the first human oncogene?

We were working with retroviruses and found that if we transferred the DNA produced by reverse transcription in an infected cell into a naïve cell, the naïve cell would start producing retrovirus particles. We then transferred the reverse-transcribed genome of a Harvey sarcoma virus into a naïve cell and found that it transformed the cells in the same way that an infection would. Next, we transferred the genomic DNA of a Harvey sarcoma virus-infected cell and found that this too would transform a naïve cell. This indicated that one could detect a single copy transforming element through transfection followed by assay of foci of transformed cells. At that point, it occurred to me that we might be able to find cellular oncogenes that arise not through infection, but through mutagenesis. I was influenced by the work of Bruce Ames, who showed that many chemical carcinogens are also mutagens. I reasoned that the genomes of chemically transformed cells might carry mutant genes, responsible for the aberrant behavior of the cells. In 1979, we showed that the genome of a cell transformed by a chemical carcinogen contained oncogenic information – the first discovery of an oncogene in a non-virus-transformed cell, ostensibly a cellular transforming gene.

What projects are going on in your lab today?

In 2003 we started to work with genes involved in the cell biological program termed the epithelial–mesenchymal transition (EMT) and found that in primary carcinoma cells, such genes could impart the ability of these cells to physically disseminate and seed metastasis. That discovery governs our research agenda to this day. We’re interested in how activating the EMT program in a poorly invasive and poorly metastatic epithelial cancer cell can transform it into a powerful cancer-initiating cell.

What are the main roadblocks in the field right now?

There are both scientific and policy roadblocks. The epigenetics of cancer cell biology is a major scientific challenge right now. There has been a focus on the genomes of cancer cells, but it is becoming clear that their behavior is governed in large part by non-genetic elements. These epigenetic transcriptional circuits are still poorly understood.

There is also the funding issue, which means that many young people no longer view a career in preclinical cancer research as a viable option. In 10–15 years we are going to need the best and brightest young researchers to continue to move basic cancer research forward, but those people are being driven from the field. If we are to reverse that trend, the funding climate has to change dramatically.

What about President Obama’s “Cancer MoonShot?”

The question is whether the extra funding will be invested in innovative research that offers significant steps forward over the long term, or whether it will be directed to strategies that are already well-tested and well-funded. My preference would be for the money to be used for funding young researchers, but I fear that is not going to happen.

Where are the most exciting advances?

Tumor immunology. It’s an entirely new paradigm that allows us to eliminate cancer cells by unchaining the immune system. I can only look at this field from a distance – but still can say it’s very exciting!