One on One with ... Clodagh O'Shea

Clodagh O'Shea

For years scientists have been working to re-engineer the human adenovirus, which in its normal state causes acute respiratory distress syndrome, as a potential tool to wipe out cancerous tumors. Clodagh O'Shea, assistant professor in the Molecular and Cell Biology Laboratory, is at the forefront of this bold technology. Her lab has developed a new generation of the engineered adenovirus to more effectively seek out and burst cancer cells, while leaving healthy cells intact. But her lab's story doesn't end there. She and her team are also working in parallel on novel, multi-pronged strategies ranging from arming her tumor-seeking viruses with toxic proteins, to re-engineering their outer "coat" so they can home in on tissue-specific targets.

Explain how your lab is developing viruses that target specific tissues in the body.
The virus is an incredible nano machine that can be re-engineered on several levels for cancer. One way is to manipulate how the virus binds to a cell. If you can imagine the virus as a rocket ship with spikes, it uses these points to make contact with the cell's surface and thereby enters specific cells. The virus that's been used in research naturally enters the cells in our airways. But there are 52 human adenoviruses and each targets different tissues. If you're going to treat cancer in the colon, we believe you should use a virus that has evolved to target that tissue. And now that's what we're doing for the first time, and which no one has been able to do.

How are you doing this?
We're asking whether we can direct the virus that normally infects the cells in the lung to other cells by changing the "coat" or the surface of the virus so that it binds to tumor blood vessels or the colon, for example. The idea is not to change the regulatory component, but to use what we already know. The "coat" is a defined point in the virus' genome, so we're just swapping that out.

To do this, we looked at the evolution of the genome - from fish adenovirus, to chicken adenovirus and snake adenovirus, the whole way up - and we identified which parts of the genome have stayed very constant. We found that the evolution has taken place on the ends, which means the entire middle core is where the coat proteins are. So what we've been able to do is come up with a way to manipulate the genome and swap the part of the genome that encodes the coat from these different viruses into my lab's virus. So I think within the next year we'll know whether these synthetically engineered viruses can be used to target tissue-specific tumors.

How did you become interested in this area of research?
I did my Ph.D. in Immunology in London's Imperial Cancer Research Institute and was pursuing a career in tumor immunology. But as a student I heard (UCSF cancer researcher) Frank McCormick, who I did my postdoc with, come through and give a talk on this idea of making a mutant virus that can activate p53 and then kill tumor cells. (Called the "Guardian of the Genome," the p53 gene is almost always found to be inactive in all human cancers.) The idea that you depend on the loss of the p53 gene just fascinated me. How do you activate something that is just gone? I just thought, "I've got to work on this."

Clodagh O'Shea braves the peaks of Cerro Torre during an ice climbing trip to the Patagonia region of South America prior to starting her cancer research at the Salk Institute

What has been the scientific discovery that's fascinated you the most during your career?
The cell is a scale-free network, which is like the World Wide Web. By that I mean that not all nodes or points of contact in a network have the same number of connections. Some nodes, for example, are hubs, they have thousands of connections, but many others have only a few. This explains many things. Think about a tumor. There have now been 100,000 mutations identified in cancer. Many of them are probably irrelevant. You can lose about five percent of the genes in your cell and your cell will be fine. And that's because they're not connected to major processes. But some of these genes are hubs, which is why they have profound effects in so many pathways.

That for me explained why the genetic targets the virus is hitting and why the ones the tumor is hitting are the same. Even though there are 26,000 genes in a cell, the virus has just 20, so that's probably the number you need to hit to control the cell. If you can control the hub you can control many different processes. The same holds true for cancer. You can take all these mutations and still survive. But if you hit just the critical target, that's it. And that's what we need to understand in cancer. We need to understand those (genetic) hubs and how those connections have been perturbed.

What keeps you passionate about science?
Science is knowledge and knowledge improves the human condition in its purest sense. It's not so much about being published in scientific journals. For me, it's about that one moment when you know you're the only person who has ever discovered this one thing - it's extraordinary. It's a celebration of life at its deepest level. To understand even a fraction of how it can be and then to share it with others is really just amazing.

It can never be negative because you can only add to knowledge, and for me that's a very powerful thing. Also knowing that I can actually help someone beyond me by wielding that knowledge to alleviate suffering through therapies keeps me passionate about science. And finally, just seeing that joy of knowledge in my postdocs is also extraordinary.

At what point in your life did you know you wanted to become a scientist?
I was quite young. I grew up in Ireland and went to a convent school where the environment was very rigid and conservative, and you would be severely punished if you asked the teacher the reasoning behind an idea. So for me, I think science gave me a license to ask questions. It's a requirement. In many ways it was the idea that there's so much more to learn, and not just accept, that led me to this field.

Did you have family members or others in particular who encouraged you to pursue a career in science? If so, who?
Not really. I was the first in my family to go to college. I had a great biology teacher in secondary school, but my family believes that the ultimate success for anyone is achieving happiness. And for me, science makes me deeply happy. So they encouraged me to find something that made me feel fulfilled.

They actually discouraged me to become a doctor because they thought I'd have a dreadful bedside manner. (laughs) They know I have a tendency to want to understand how things work and I wouldn't have been satisfied applying cures that don't make sense to me. So I think they thought science would be where not only I'd be happier, but the people I work with. (laughs)

What's the one scientific question you'd like to answer in your lifetime?
I'd like to know if we could ever understand molecular details enough and actually translate that into more selective and potent therapies that can alleviate the suffering of patients. That's what gets me out of bed in the morning. You only really understand that which you can build from scratch. So with viruses, I can only really understand them if I can build them from their components and predict the outcome.

For me, that's the kind of knowledge that we need for cancer. I mean it's a crazy question, but you have to aim high, right? It's a huge problem to tackle and I don't even care if we're going to be foot soldiers or captains. That's not what's important to me. It's the battle itself, and probably more so that we win it. And if we contribute in any way I'll feel that it's been worth it.