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3 Questions: Daniel Lew on what we can learn about cells from yeast

New professor of biology uses budding yeast to address fundamental questions in cell biology.
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New Department of Biology faculty member Daniel "Danny" Lew uses the model yeast S. cerevisiae, and a non-model yeast with an unusual pattern of cell division, to explore fundamental questions in cell biology.
Photo: Lillian Eden

Sipping a beer on an early autumn evening, one might not consider that humans and yeast have been inextricably linked for thousands of years; winemaking, baking, and brewing all depend on budding yeast. Outside of baking and fermentation, researchers also use Saccharomyces cerevisiae, classified as a fungus, to study fundamental questions of cell biology.

Budding yeast gets its name from the way it multiplies. A daughter cell forms first as a swelling, protruding growth on the mother cell. The daughter cell projects further and further from the mother cell until it detaches as an independent yeast cell.

How do cells decide on a front and back? How do cells decode concentration gradients of chemical signals to orient in useful directions, or sense and navigate around physical obstacles? New Department of Biology faculty member Daniel "Danny" Lew uses the model yeast S. cerevisiae, and a non-model yeast with an unusual pattern of cell division, to explore these questions. 

Q: Why is it useful to study yeast, and how do you approach the questions you hope to answer?

A: Humans and yeast are descended from a common ancestor, and some molecular mechanisms developed by that ancestor have been around for so long that yeast and mammals often use the same mechanisms. Many cells develop a front and migrate or grow in a particular direction, like the axons in our nervous system, using similar molecular mechanisms to those of yeast cells orienting growth towards the bud.

When I started my lab, I was working on cell cycle control, but I've always been interested in morphogenesis and the cell biology of how cells change shape and decide to do different things with different parts of themselves. Those mechanisms turn out to be conserved between yeast and humans.

But some things are very different about fungal and animal cells. One of the differences is the cell wall and what fungal cells have to do to deal with the fact that they have a cell wall.

Fungi are inflated by turgor pressure, which pushes their membranes against the rigid cell wall. This means they'll die if there is any hole in the cell wall, which would be expected to happen often as cells remodel the wall in order to grow. We’re interested in understanding how fungi sense when any weak spots appear in the wall and repair them before those weak spots become dangerous.

Yeast cells, like most fungi, also mate by fusing with a partner. To succeed, they must do the most dangerous thing in the fungal life cycle: get rid of the cell wall at the point of contact to allow fusion. That means they must be precise about where and when they remove the wall. We’re fascinated to understand how they know it is safe to remove the wall there, and nowhere else.

We take an interdisciplinary approach. We've used genetics, biochemistry, cell biology, and computational biology to try and solve problems in the past. There's a natural progression: observation and genetic approaches tend to be the first line of attack when you know nothing about how something works. As you learn more, you need biochemical approaches and, eventually, computational approaches to understand exactly what mechanism you're looking at.

I'm also passionate about mentoring, and I love working with trainees and getting them fascinated by the same problems that fascinate me. I'm looking to work with curious trainees who love addressing fundamental problems.

Q: How does yeast decide to orient a certain way — toward a mating partner, for example?

A: We are still working on questions of how cells analyze the surrounding environment to pick a direction. Yeast cells have receptors that sense pheromones that a mating partner releases. What is amazing about that is that these cells are incredibly small, and pheromones are released by several potential partners in the neighborhood. That means yeast cells must interpret a very confusing landscape of pheromone concentrations. It's not apparent how they manage to orient accurately toward a single partner.

That got me interested in related questions. Suppose the cell is oriented toward something that isn't a mating partner. The cell seems to recognize that there's an obstacle in the way, and it can change direction to go around that obstacle. This is how fungi get so good at growing into things that look very solid, like wood, and some fungi can even penetrate Kevlar vests.

If they recognize an obstacle, they have to change directions and go around it. If they recognize a mating partner, they have to stick with that direction and allow the cell wall to get degraded. How do they know they've hit an obstacle? How do they know a mating partner is different from an obstacle? These are the questions we'd like to understand.

Q: For the last couple of years, you've also been studying a budding yeast that forms multiple buds when it reproduces instead of just one. How did you come across it, and what questions are you hoping to explore?

A: I spent several years trying to figure out why most yeasts make one bud and only one bud, which I think is related to the question of why migrating cells make one and only one front. We had what we thought was a persuasive answer to that, so seeing a yeast completely disobey that and make as many buds as it felt like was a shock, which got me intrigued.

We started working on it because my colleague, Amy Gladfelter, had sampled the waters around Woods Hole, Massachusetts. When she saw this specimen under a microscope, she immediately called me and said, "You have to look at this."

A question we're very intrigued by is if the cell makes five, seven, or 12 buds simultaneously, how do they divide the mother cell’s material and growth capacity five, seven, or 12 ways? It looks like all of the buds grow at the same rate and reach about the same size. One of our short-term goals is to check whether all the buds really get to exactly the same size or whether they are born unequal.

And we're interested in more than just growth rate. What about organelles? Do you give each bud the same number of mitochondria, nuclei, peroxisomes, and vacuoles? That question will inevitably lead to follow-up questions. If each bud has the same number of mitochondria, how does the cell measure mitochondrial inheritance to do that? If they don't have the same amount, then buds are each born with a different complement and ratio of organelles. What happens to buds if they have very different numbers of organelles?

As far as we can tell, every bud gets at least one nucleus. How the cell ensures that each bud gets a nucleus is a question we'd also very much like to understand.

We have molecular candidates because we know a lot about how model yeasts deliver nuclei, organelles, and growth materials from the mother to the single bud. We can mutate candidate genes and see if similar molecular pathways are involved in the multi-budding yeast and, if so, how they are working.

It turns out that this unconventional yeast has yet to be studied from the point of view of basic cell biology. The other thing that intrigues me is that it's a poly-extremophile. This yeast can survive under many rather harsh conditions: it's been isolated in Antarctica, from jet engines, from all kinds of plants, and of course from the ocean as well. An advantage of working with something so ubiquitous is we already know it's not toxic to us under almost any circumstances. We come into contact with it all the time. If we learn enough about its cell biology to begin to manipulate it, then there are many potential applications, from human health to agriculture.

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