My entrée into science was not some dramatic, eureka moment. For me, the interest had always been there, from an early age. While many of my friends struggled with decisions about what to do with their lives, I was lucky to know from early on that I wanted to be a scientist.
Growing up in both Ireland and England, I was fortunate to have very good teachers, who supported my scientific interests. And as far back as my teenage years, the field of genetics was what interested me the most. I found it fascinating that you could mutate or knockout genes and produce different phenotypes in model organisms. Even then, the correlation between human diseases, specific mutations, and a clinical outcome was already known. It was that relationship that drew me into genetics.
In 1990, I went to Trinity College in Dublin. It's a four-year degree program, which begins with a basic grounding in all of the sciences -- biology, chemistry, and physics. After two years, you select a major to study. I chose genetics, which, for me, was an easy choice. The genetics program at Trinity provided a broad spectrum education in the subject, starting in phage, moving to yeast, and ending with human genetics.
Genomic Imprinting
After completing my bachelor's degree, in 1994, I went to the University of Cambridge for my doctorate. The doctoral system in England is different than it is here in the U.S. Right from the start, we had to know what subject we wanted to study and whose lab we wanted to study in. Again, however, I was lucky. As part of my undergraduate thesis, we were required to do a literature review, which I wrote on the subject of genomic imprinting. I found the subject so fascinating that I knew it was what I wanted to focus on in my graduate studies. Cambridge just so happened to be a hotspot of genomic imprinting in Europe, and I had the opportunity to work with Paul Schofield, in Cambridge's Department of Anatomy.
When you first arrive at Cambridge, it's everything you imagine it to be -- people punting down the rivers under a sunny sky -- which, initially, made it a wonderful place to be. Added to the picturesque setting were the four or five other labs working on genomic imprinting. Our lab was focused on human diseases that resulted from defects in genomic imprinting, and the other labs were working on mouse models, which created a wonderful synergy between the two.
Going to California
After four years of working in Cambridge's cloistered environment, I was ready to move on. A postdoctoral fellowship in Douglas Hanahan's lab at the University of California, San Fransciso, seemed like the perfect next step.
While I received a wonderful grounding in genetics from both Trinity and Cambridge, I wanted to do my postdoctoral fellowship in the States because it offered a real opportunity to do some cutting-edge science. My graduate work had allowed me to combine my joint interests in cancer genetics and genomic imprinting by working on imprinting in patients who had a predisposition to childhood cancers. The one downside to my PhD work had been that we were characterizing human samples from human patients, which meant we couldn't experiment with possible interventions. In this scenario, you have to hope that your hypotheses will have some connection to how the disease develops. Whereas with mouse models, you can genetically manipulate your model system, allowing you to test any hypothesis.
Doug's lab, in the Biochemistry Department at UCSF, was working with mouse models of human cancers, with a focus on angiogenesis (the formation of blood vessels from surrounding tissue to support tumor growth). Also, at this same time, there was a rediscovery of the importance of the tumor microenvironment, in which Doug and his lab were doing cutting-edge work. Using transgenic and knock-out mice, we were able to look more accurately at the tumor microenvironment than by simply growing cells in culture on plastic and hoping to recapitulate how the tumors develop.
We showed that certain matrix-degrading enzymes, cathepsins and heparanase, were critically important in tumor progression, in part by facilitating angiogenesis and invasion. However, the surprising finding we made was that these enzymes were predominantly supplied by innate immune cells that infiltrate the tumor, rather than the cancer cells themselves. At Memorial Sloan-Kettering, we are now determining whether these immune cells undergo changes when they encounter cancer cells, which contributes to the upregulation of these matrix-degrading enzymes, and we are trying to understand the nature of this communication.
SKI and Translational Research
When considering faculty positions, I decided I wanted to go to an institution that offered the potential to collaborate with clinical investigators to really test whether the findings we make in our model systems have clinical relevance. Though I considered a number of institutions that promised this relationship between basic and clinical science, Sloan-Kettering Institute (SKI) is truly realizing that promise. And the fact that Sloan-Kettering is a research institute means that there isn't necessarily the same level of bureaucracy that you'd have at a major university.
The Cancer Biology and Genetics Program, which my lab is a part of, is made up of some of the biggest names in cancer biology. For a young researcher like myself, it's a lot to live up to, but it's also a very inspiring and professionally encouraging environment.
I've worked in a number of medical schools and universities and I've found that it is very easy to establish fruitful collaborations here. Many of the clinicians at Memorial Sloan-Kettering are open to and excited about working with basic science researchers like me.
Cutting Edge Collaborative Efforts - Prostate Cancer
Right now, for instance, we're starting a collaboration with Dr. Howard Scher, Chief of the Genitourinary Oncology Service, to examine the prostate tumor microenvironment.
Until recently, it was believed that host cells inhibited tumor development, but it is now understood that, in some cases, normal cells can be co-opted by the tumor to promote its growth. Our initial goal is to create three-dimensional culture systems of the prostate tumor microenvironment, which more faithfully reproduce the complexity of the cancer-host interactions than 2D cell-culture. To do this, we will grow the prostate cancer cells that Howard provides us with in an effort to recapitulate the original tumor microenvironment. Prostate cancer cells are notoriously difficult to grow in culture, and, up until fairly recently, this type of work had only been successfully done for breast cancer. We want to put the prostate cancer cells into a three-dimensional matrix, complete with all the proteins and macro-molecules that you would have in the normal prostate environment, co-culturing them with endothelial cells, fibroblasts, inflammatory cells, and the extracellular matrix.
We do this in order to look at the mechanistic way in which prostate cancer grows in the local tissue microenvironment, using genetic and molecular techniques to dissect the processes that are taking place. Once we've set up the system, we're hoping to go back and re-engineer some of our mouse models, to allow us to image these cell-cell interactions in a living animal. The ultimate goal is to apply the knowledge we gain to develop targeted cancer therapies that disrupt the mechanisms prostate tumor cells use to hijack the functions of normal host cells.
An Exciting Time and Place
It's been wonderful coming here to SKI -- everything from the guidance I've received from my fellow lab heads to the top-notch technical and administrative support. There's a well-oiled machine in place that is dedicated to setting up and helping to maintain labs. Everyone involved does an incredible job, which really allows us to focus on our research.
I'm thrilled about being in an exciting program, associated with the new Gerstner Sloan-Kettering Graduate School of Biomedical Sciences, where I'll be a faculty member, and part of the general academic environment in New York City, which is so open and collaborative. All of these factors have combined to give me a tremendous experience -- and I'm only just beginning.
|
