Cell division, cell structure and what they mean for understanding disease

Christine Jacobs-Wagner, the Dennis Cunningham Professor and a professor of biology, just arrived on campus and will soon move in to Stanford ChEM-H’s new building across from the School of Engineering, the School of Medicine and the Clark Center. Here, she talks about her research on cell growth and replication, why she works with chemists, physicists and more and why she’s so excited about the pub coming to the new Stanford ChEM-H and Neurosciences buildings.

You obviously have a number of individual projects. In the big picture, what is it you’re interested in studying?

The big question that we are interested in is to understand how cells self replicate. One of the defining features of life is the ability of cells to multiply, which sustains life.  We want to understand how they’re able to self replicate and also how they can do it so robustly. What is remarkable is that so many biological processes must take place for cells to replicate, and there’s a ton of noise in all of these processes, and yet every time it happens. It’s incredibly faithful.

How do you go about studying that process, and what are some of the things you have learned?

We study bacteria, and there are really two major reasons for this. One is that bacteria have a tremendous impact on pretty much everything we care about, including our health and our environment. The second reason is because they’re simpler. They’re by no means simplistic, but they are simpler than our own cells or other eukaryotic cells. Bacteria don’t have some of the regulatory mechanisms that eukaryotic cells have and depend on to replicate. Yet they multiply incredibly well. What it means to us is they’re a great playground to understand the most basic mechanisms by which cells can multiply.

A big lesson we’ve learned from studying self replication is that to get robustness, you need a great deal of spatial organization inside the cell. If you as a person want to be efficient and productive, you need to be organized. It’s the same thing for any cells, even tiny cells like bacteria. For example, we’ve shown that bacteria can use protein filaments at certain cellular locations to change their shape. They can also generate protein gradients or localize proteins or other molecules to direct or coordinate cellular processes. They can even actively transport large molecular cargos to ensure their faithful segregation to daughter cells at division. What we’ve learned is that these complex molecular behaviors and spatial patterns can emerge from simple mechanisms that involve only a few players. That has been very gratifying.

You’ve worked with researchers from a lot of different fields, including chemistry and physics. Why is that?

When we learned that you need spatial order even in bacteria, that really opened up the field of bacterial cell biology, but it was the tip of the iceberg. We also realized that we have to take into account the physical properties of the cytoplasm, which is where most things happen inside cells. A big surprise was to find out that the cytoplasm has remarkable material properties. For example, it changes from a liquid to a more glass-like state when cells become metabolically dormant, which is, for example, when they are starved.  Generally, the cytoplasm is assumed to behave like a simple fluid. But this is far from being the case.

More recently, we realized that we need to understand the chemical properties of cytoplasm since things inside the cell are not chemically inert. Take, for example, the chromosomal DNA, which is in the cytoplasm in bacteria. For simplicity, current models of chromosome structure assume that the cytoplasm is an “ideal” solvent. But is it? We don’t think so. This is important because the solvent quality will affect the compaction of chromosomes, which can have important implications for gene expression.

So it was need, really. If we want to get a complete understanding of how cells are able to multiply, I think that we will have to take into account the physics and chemistry of the cell. We will need an integrated picture.

Does your work on cell growth and replication carry over into health applications?

For the longest time we were interested in identifying mechanisms that are broadly generalizable, and then a few years ago, we decided it would be interesting to also look at the flip side. The idea was, what if there are bacteria that do things that all bacteria have to do to multiply, but they do it in a different way? And if these bacteria are pathogens, then it could be particularly interesting, because it might suggest new strategies to eradicate these pathogens without affecting the good bacteria that live within us.

We decided to test this idea with the Lyme disease-causing agent Borrelia burgdorferi. When we started to look at the cell biology of Borrelia, we found that this bacterium grows differently than other bacteria, by incorporating new cell wall material, called peptidoglycan, at specific zones along the cell body. In addition, Borrelia does not recycle its peptidoglycan during normal turnover. When bacterial cells grow, they incorporate new peptidoglycan material, but they also have to destroy existing peptidoglycan wall, just like if you want to expand your house you will have to break walls to build more walls. But in many bacteria, like E. coli, the peptidoglycan material generated during turnover is recycled. In Borrelia, this material is not recycled – instead it leaks out.

We think this is significant because this shed material can induce inflammation and all clinical manifestations of Lyme disease are inflammatory. Now, we’ve shown that peptidoglycan can stay in the inflamed joints of Lyme disease patients for extended periods of time, months after appropriate antibiotic treatment. This may contribute to the persistence of arthritis in these patients.

You came to Stanford to become part of ChEM-H. What do you like about the institute?

So many things! But for the sake of brevity, I will highlight three of them. One, I really believe that some of the most exciting discoveries are going to happen at the interface of disciplines. And ChEM-H really embodies this idea of interdisciplinary research.

The second reason is because our research really benefits from collaborations with mathematicians, physicists, chemists, biologists and clinicians, and Stanford is quite unique among top schools in having all of those people working within walking distance. In that context, the new ChEM-H building is ideally situated, so that collaborators with very different expertise and perspective are just a walk away. That’s super appealing.

And then the third is the pub! In all seriousness, I think that the pub at the new complex is going to bring other people to this building. We need to interact, and what better way to interact than at the pub?