AudioHelicase podcast: Iain Cheeseman discusses cell division and what can happen when it goes wrong

In this episode of AudioHelicase, Whitehead Institute Member Iain Cheeseman discusses how his work on the kinetochore provides a window into cell division and what happens when this vital cellular function goes awry.

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EDITED TRANSCRIPT

Lisa Girard: Welcome to AudioHelicase, the podcast of Whitehead Institute, unwinding the science and the people behind some of the Institute’s most exciting research. I’m Lisa Girard, director of communications at Whitehead Institute. In this episode, I’m talking with Iain Cheeseman, Member of Whitehead Institute and an associate professor of biology at MIT. Iain’s work is focused on understanding the kinetochore, a group of proteins that assembles at a particular position on the chromosome, and is critical for proper chromosome segregation during cell division. A lack of fidelity in chromosome segregation is associated with a number of diseases, including cancer. And an understanding of kinetochore mechanics has the potential to shed new light on its drivers and treatment.

 Iain, in terms of the big picture, why is cell division so important?

Iain Cheeseman: All of us started as one cell. The number of cells in the human body is about 30 trillion. If you think about the number of divisions that you had to go through all along the way: one cell becomes two, two cells become four, four cells become eight. It’s astronomical the number of times they have to do this. Even in an adult human, there’s about 50 billion cells dividing every day just to replenish the tissues we have.

Every single one of those, you have to take all 46 different chromosomes—23 from your mom, 23 from your dad—and make sure that every new cell that is made gets the entire set. So actually even small deviations from that normal number of 46 can be a huge challenge. One chromosome too many or one chromosome too few can kill that cell. It can make it work not as well.

Girard: What actually needs to happen during mitosis?

Cheeseman: As mitosis begins you take these long linear stretches of DNA, and you compact it up into pieces that are actually something you can move and distribute.

And then you have to have a physical apparatus, which is able to capture them and move them around, and that is a structure called the mitotic spindle. That’s made of microtubule polymers that are long rods capable of growing and shrinking. Essentially like you’re casting a fishing line out, and it’s this process of essentially having a long rod that can extend and shrink back again, until it finds the chromosomes, and then once it’s captured them, that growth and shrinkage can help facilitate its ability to move within a cell.

The goal of our lab is to take all of this beautiful imaging and microscopy that has been done using light microscopy from the earliest days through to electron microscopy that really probed more deeply into the cell and say, ok, how do you assemble a protein machinery that’s capable of doing these things? That division after division is capable of physically capturing the DNA, distributing it, and then doing it with such a low rate of error as to not be a problem and allow our bodies to develop and continue to function.

Girard: What was your starting point when you began looking at kinetochore biology?

Cheeseman: When I started grad school, so I started in 1997, and at that point it was assumed that the kinetochore was going to be not that much more complex than a simplified system like the one that exists in bacteria. It was assumed that there would be maybe about a dozen proteins. How many do you actually need, because you really only need these three activities: bind to DNA, bind to microtubules, hold everything together.

This idea that it was a simple structure persisted for a while, but a lot of the work I did as grad student and as a postdoc in the first few years of our lab here at Whitehead was to try to find the players that are involved in this.

It didn’t stop at 10 or 20 or 50, now there’s probably 110, 120 different human kinetochore proteins. We still know that you have to have these three activities—DNA binding, microtubule binding, holding it together—but the large number of players involved made it clear that there’s a lot the things that the cell is doing to get this right, to be able to physically achieve it and to do it with really high fidelity. I think a lot of the goal that our lab has had is to understand what are the factors that are responsible for those different processes.

Girard: So it sounds like the kinetochore is turning out to be a pretty intricate complex.

Cheeseman: What I like about this structure is that actually at both ends of that interface it’s a lot more complicated than we may’ve anticipated when you first looked at it.

It has to bind tightly and stably to DNA, but in most organisms, including our cells, that site is not defined by specific DNA sequences, and so there really has to be a protein mark that persists at that site forever. The protein mark in my cells is the same as my mom’s cells and her parents before her.

And on the microtubule side, you have to bind to this polymer. You need to be able to bind to this rod, but that rod is constantly growing and shrinking, and so it’s kind of like you are trying to drive down a highway where someone is ripping that out from under you as you’re going along. So the kinetochore needs to build a machinery, which is able to hold onto this constantly changing polymer and in particular actually get force from that.

It’s not these molecular motors that are responsible for this beautiful movement that we see as chromosomes align and segregate. Instead it actually ends up being that the major motor, the major thing that’s giving force to move a chromosome is that growth and shrinkage of a microtubule polymer.

Girard: So how did you become interested in the kinetochore?

Cheeseman: I really like protein machineries. Before I even realized that the kinetochore existed, what I first fell in love with in science was the physical players that have to do stuff. The things in cells where you have protein assemblies that build up to actually achieve something, move something, do something, or accomplish something for the cell. I really like protein machineries, and I really like how they’re precisely controlled. The kinetochore is I think by far the best example.

One of my favorite features of the kinetochore is just how dynamic it is. The kinetochore is a machine that has those 110-120 proteins but exists in that form for only really a narrow window. In a human cell growing in culture, it takes about 24 hours for that cell to divide. To go from one cell to two takes about 24 hours. Most of that time is about it growing, about it replicating its DNA—DNA replication might take about 8 hours for example—you’ve got to copy that genetic material first, which can take a while. The actual process of mitosis, where you’re dividing and segregating your chromosomes, takes less than an hour. So it’s a pretty small portion of the whole cell cycle from one cell to two cells.

You have about a 5 to 10-minute window to go from having none of the proteins there to having it fully assembled for mitosis. The thing that’s kind of crazy about it is even while you’re beginning this process of segregation to the two new cells in anaphase, you’re stripping away this kinetochore. So you have a window of about 10 to15 minutes where you have to disassemble the kinetochore again to get back to that original interface state. Even while you’re still holding onto the chromosomes and segregating, you’re starting to take away the bricks that build up that machine.

Girard: So it seems like a lot really depends on the kinetochore properly functioning or things can really go terribly wrong.

Cheeseman: I think it’s still fascinating that we exist. You think about all of the things that could’ve gone wrong to go from the one cell that we started with to who we are today. The more you learn about how intricate and beautiful the biology is the more you realize how often it could’ve gone wrong in different ways, and that certainly does happen. I think the nice thing about the machines that exist is that they have been well optimized to work well. You have the physical things in place to segregate the chromosomes and you have a lot of players that come in add robustness, add security to that. And you have the regulatory components so that if there is a problem, you can recognize that and correct it.

Chromosomes do missegregate, and I think often that will end up in that cell dying. We have enough cells that we can tolerate some amount of that and get away with that okay. But chromosome missegregation is certainly, can have catastrophic consequences. Chromosome segregation during meiosis, the process by which you’re making sperm and egg, can result in an individual who has a misbalance in chromosomes from the beginning. Down syndrome for example is incorrect numbers of chromosome 21, and that can have developmental consequences. That is a big effect for an organism, but on some level kind of a small change overall. A single chromosome missegregating, one extra copy of that. And it’s basically the only chromosome that can be tolerated that way on an organismal level.

Chromosome missegregation in a person is also happening periodically and is something that you frequently see in cancers. Most solid tumors, if you were to go in and count their chromosomes, you would probably see a number that ranges from between 50 and 90. There’s a lot of thought that this incorrect chromosome number, which is also called aneuploidy, is something that is driving the formation of a cancer.

Girard: The more you’re learning about mitosis, what are the big questions that are emerging for you?

Cheeseman: For the longest time I thought about cell division as being always the same, that every time a cell needs to divide, it has the same challenges, it has the same requirements, it has the same processes, but I think increasingly we’re seeing examples where that’s not the case. If you imagine and step back and think about the different challenges that cells face, meiosis as a division to make the sperm and egg has two very different division processes. One looks a little like mitosis and one is a reductional division, you’re getting reducing the DNA. That division is very different, it has different requirements. And so how do you take this machine and adapt it to those circumstances? How do you think about the divisions that are happening early in the embryo versus the ones that are happening in the tissues. How do you think about enabling the cells that have to hang out in your body years and decades to facilitate different cell division events and processes. And I really am enamored with this idea of rewiring. You’ve got a machine, how do you rewire it under these different circumstances?

Girard: That was Iain Cheeseman, a Member of Whitehead Institute and an associate professor of biology at MIT. You can learn more about Whitehead science on our website at wi.mit.edu. And you can listen to other AudioHelicase episodes on SoundCloud and iTunes. For Whitehead Institute, I’m Lisa Girard. Thanks for listening.

Produced by Nicole Giese Rura

Original music by Chocolat Billy. CC BY-NC-ND 4.0

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Iain Cheeseman’s primary affiliation is with Whitehead Institute for Biomedical Research, where his laboratory is located and all his research is conducted. He is also an associate professor of biology at Massachusetts Institute of Technology.

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