Cellular Insides

A freshman professor when Michael Jordan was a first-year student-athlete, Keith Burridge, PhD, has dedicated his career to elucidating the intricate structures of cells that allow cancers to metastasize.

Cellular Insides click to enlarge Keith Burridge, PhD/Photo by Max Englund, UNC School of Medicine

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Keith Burridge was a 21-year-old aspiring scientist when he walked into a break room to listen as Francis Crick told stories from his glory days as the co-discoverer of DNA’s double-helix structure. Crick had already won his Nobel Prize. There were other winners in the building and several who would become Nobel laureates, including one of Burridge’s student colleagues.

This was heady company at Cambridge, and Burridge never thought his intellect matched his mentors, but he also knew no one would out-work him. And so when everyone had left the bench for the day, Burridge would remain behind. One night, when sleepiness tried to ruin a good experiment, Burridge went off to brew some coffee. Hearing the percolator, another scientist by the name of Sydney Brenner briskly walked into the room to see who else was working late. Brenner was already a big name in the world of molecular biology. He, too, would go on to win the Nobel Prize. 

“He was just excited that someone else was working at night,” Burridge remembered. “He was bursting with excitement about his latest great idea.” And so they drank coffee, chatted about Burridge’s work with cells, and talked about the creation of C. elegans as a model organism for which Brenner would win his prize.

After Burridge earned his PhD, he left England for the United States, thinking he had also left his work on cells behind. He wanted to study tumor viruses. But within a few days stateside, Burridge ran into Crick’s old partner – James Watson, the other co-discoverer of the DNA double helix structure. Watson had other ideas for Burridge. He wanted the young Brit to keep studying the intricate insides of cells that give them shape and make them move.

That nudge from Watson eventually led to Burridge’s first scientific grant on something called focal adhesions. This year, Burridge had that same NIH grant renewed for the eighth time. It is now more than 30 years old. But Burridge still has a youthful enthusiasm for cells and the tiny proteins that make them move, divide, and cause disease. His work has led to a deeper knowledge of how cells operate, especially cancer cells, and his research has led to the discovery of new drug targets.

We sat down with Dr. Burridge, Kenan Distinguished Professor of Cell Biology and Physiology and member of the UNC Lineberger Comprehensive Cancer Center, for a Five Questions feature to discuss his pursuit of science, how he wound up in Chapel Hill, his work as a playwright, and the science behind one of the longest-running grants at the UNC School of Medicine. 

 Why did you pursue science, an undergraduate degree from Cambridge, and then a doctorate in molecular biology also at Cambridge?

It was quite simple in some ways: I had a fantastic high school biology teacher named Peter Dawkins, who was very inspiring. He got several of us interested in potentially doing research. I owe him a huge debt of gratitude and I still visit him when I go back to the UK.

Back then we used to specialize very early. By age 14 or 15, I was already on the science track. I wanted to go somewhere with great opportunities to do research. That’s why I picked Cambridge.

I did medical school for two years and a final year of biochemistry, which is what my degree was in. There was no such thing as a MD/PhD back then in Britain, so either I had to do clinical work in London or do a PhD. I chose the latter, which was only three years in Britain. I joke with students today, saying I got a cheap PhD. When I look back on the application process, things were so different. Now it’s all so deliberative with forms and interviews and so on. Back then, in 1971, it was casual. I wrote a letter and interviewed and that was it. I was extremely lucky.

Once I was there, I thought I was out of my depth. I had the imposter syndrome. There were four Nobel Prize winners in this building that was no bigger than Lineberger. The head of my floor was Francis Crick. He would wander along and hold court in the coffee room. On the floor with him was Sydney Brenner who by that time was already quite prominent.

One of my classmates was Elizabeth Blackburn, who’s now at UC-San Francisco. She won a Nobel Prize a few years ago. The place was full of brilliant people. It was really wonderful being there.

5q-dna green What was it like to be a postdoc in James Watson’s lab at Cold Spring Harbor? While there, you focused on focal adhesions. What are those?

All cells have a system of protein filaments (the cytoskeleton) that are like little muscles that can help move a cell or give the cell structure. My PhD project was to work on myosin, a major muscle protein, but I worked on myosin that was found in a non-muscle context. At that point, it was not clear whether it would be anywhere other than muscle. We showed that myosin was in other cells and that there were multiple types.

When I left Cambridge after my PhD, I was looking to do something completely different. I was really interested in tumor viruses and DNA transcription. In 1975, I went to Cold Spring Harbor to join a lab that focused in these areas. But within a couple days of being there, Jim Watson – who was the director of the institute – cornered me and said, “I don’t think you should work on tumor viruses; you should continue to work on the cytoskeleton.”

Most people don’t know this because Watson didn’t put his name on our papers, but he had this small group studying the cytoskeleton. So I ended up unintentionally being a postdoc for him.

At that time, the term “focal adhesion” didn’t exist. People realized that there were bundles of actin filaments – strings of proteins that helped the cells move, contract, etc. But no one knew how the filaments attached to the cell membrane surrounding the cell’s cytoskeleton. The focal adhesion is the complex of proteins that mediates attachment and it also anchors the cell to the underlying substrate to which the cell is adhering.

As a student, I had already made an antibody against a protein called alpha-actinin. When I got to Cold Spring Harbor, a student there had also made antibodies against it. We pooled our results and published a paper jointly, showing that alpha-actinin was distributed along these bundles of filaments and concentrated in patches at their ends, sites that would become known as focal adhesions.

It was the first time people had identified a protein in focal adhesions. I speculated that this might be involved in attachment, and this got me thinking about what else was at the ends of the filaments.

With the help of another postdoc, we began purifying alpha-actinin from muscle. As we were doing this, another protein popped out of the purification. Turned out that this protein was also at the ends of these bundles of filaments. This protein was ultimately called vinculin.

At around this time, the term focal adhesion was coined. Now we know there are hundreds of proteins in these sites of adhesion. We wrote a grant based on this initial work in the summer of 1979. It’s now been renewed for the eighth time. Our goal has always been to characterize what the focal adhesion proteins are and how they contribute to cell movement. In cancer, that’s metastasis.

5q-basketball In 1981, you formed your first lab as a junior faculty member at UNC. How did you wind up here and, as a British national, why did you stay?

Well, I met my wife when she was a graduate student at Penn. Mutual friends set us up, and we were married in 1978. We had planned to go to Peru for our honeymoon, but the immigration people told me that I was fine to go but my visa wouldn’t allow me back into the US, even though I had just married an American.

So our honeymoon became a trip to the Outer Banks, and while driving west across the state we stopped in the Triangle. We thought, “Hmm, there are couple of universities here; I wonder if they have any jobs?”

A couple years later, I was talking with someone from UNC who said they were looking for people, so I sent an application.  My wife and I wanted to live in a small town. So, we looked at UNC, Cornell, and Oxford. All three offered me positions. I chose UNC.

Oxford couldn’t believe I turned them down. I still remember the call. They said, “You’re turning us down to go to Chapel where?” I told them, “Hill. Chapel Hill.

When I interviewed at UNC in April 1980, it was glorious. The dogwoods were out. Walking through campus I thought, “Wow. This is a beautiful place.” I could see similarities to Cambridge. I loved it.

UNC didn’t have the prestige it has now. It was much less known for research then. But when I looked at the potential trajectory, I could see how it could become great. I saw department chairs energetically recruiting exciting faculty. Chapel Hill looked to me like a place on the rise.

I was a freshman faculty here when Michael Jordan was a freshman student. I had never watched a basketball game before I came here, but quickly became addicted. My wife was horrified to discover that I actually had a sports gene. Shelley Earp [former director of the UNC Lineberger Comprehensive Cancer Center] was an assistant professor at the time and took me to my first game in Carmichael in 1983. We played NC State and just thrashed them. I couldn’t believe State went on to win it all that year.

5q-stemcells What do you consider your key contributions to the fields of cell biology and basic science as it relates to cancer?

My lab has moved away from the initial identification of proteins in focal adhesions, which is what got me established and first got my grant renewed. Now we’re more into cell signaling, particularly focusing on proteins called Rho GTPases. Rho proteins belong to the Ras superfamily (Ras is an oncogene) and Rho proteins regulate many cell activities, especially the cytoskeleton and cell movement.

Rho was shown to drive formation of focal adhesions but no one knew how. I thought Rho might work by driving contraction of the cell, and a wonderful student here named Magda Chrzanowska-Wodnicka and I established this. We showed that Rho stimulates myosin-mediated contraction, and that if you block contraction, focal adhesions don’t form. The idea was that, for these bundles of actin filaments and focal adhesions to work properly, contraction and myosin were really important. 

I think the grant got funded again this year because we’ve moved onto mechanotransduction – the idea that cells will respond to mechanical forces. Cells are pushed and pulled throughout our lives. The fact that mechanical force on cells can stimulate signaling pathways is now a hot area of study.

We’ve had a wonderful collaboration with Richard Superfine’s group in physics and astronomy at UNC. He uses 3D force microscopy. It’s like a pair of magnetic tweezers. We take a magnetic bead, coat it so that it binds to a cell and then we can pull it with magnetic tweezers. You can look at the cell’s response to the pulling. A brilliant French postdoc in my lab, Christophe Guilluy, showed that in response to tension the cell stiffens and he identified the signaling pathways responsible.

We’ve known for a time that cells respond to mechanical force all the way down to the nucleus. We can affect specific genes – turn them on or off – by exposing cells to force. Christophe Guilluy figured out how to pull on an isolated nucleus to show that the nucleus would respond to pulling.  As with whole cells, he showed the nucleus would stiffen, and figured out the signaling pathway involved.

What I’m excited about is that this relates to cell behavior and gene expression. The work has gone through an evolution from focal adhesions to mechanical force. The adhesions respond to force, too.

5q-target Everyone wants better treatments and cures for cancer. After more than 30 years running a lab at the UNC Lineberger Comprehensive Cancer Center, how would you describe the role of basic scientific research in our quest to help patients?

I believe basic science is driving a lot of the innovative treatments that we’ve seen and that are coming down the pike. I think, in general, the public does hear that there are new treatments usually tailored toward one or two types of cancer. The way I view it is that there’s a research continuum from cell biology to biochemistry to molecular biology to pharmacology. When it comes to creating a new treatment, in the end, maybe the pharmacologists claim the treatments as their invention, but really all of these disciplines have contributed. For example, some of these signaling proteins we’ve been talking about have become targets for drugs.

Rho GTPases are often hyper-activated in various tumors. Many people in our field are interested in targeting them or targeting steps in their signaling pathways. It could be that we could block invasion or metastasis or tumor growth. We’ve been thinking of the Rho family in terms of the cytoskeleton, but they’re also involved in cell multiplication.  A lot of what we do underlies the basic characteristics of cancer cells.

We have to learn about these things if we’re going to stop cancer without harming other cells in the body. This, ultimately, is what the research is about.

Bonus question.

You’re a playwright, too. What are you working on now?

It’s a play that has to do with World War I. It’s about President Woodrow Wilson, who was a pacifist. There was an interesting push-pull going on. Germany was trying to keep the United States out of the war, while Britain was trying to get Wilson to enter it. I think it has a great deal of relevance for today’s conflicts.

The play is called, “Manipulated, a President’s Path to War.”

I like true stories. For this one, I found all this information at Davis Library and I just got caught up in the stories.

For example, Wilson’s first wife died just after the war started in 1914. Then, Wilson got totally enamored with another woman. In Davis, there’s a collection of love letters to his second wife. It’s so interesting. The war is raging and he’s writing these passionate letters to her. He proposed to her after just two months. 

These letters inspired me to create a play. Typically, I write at night and weekends. We’ll see how it goes. I hope I can turn it into a performance.

Check out this video on Burridge the playwright.

 

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