Beat of life: Understanding the cell’s rhythms

Michael Elowitz (synthetic biologist, Caltech): “The cell, the living cell, is really the building block of all life. And I like to think of it as kind of the most amazing device we know about.

“The cell is a little tiny object, you know, maybe a few microns, 10 microns, 15 microns, in size; very small — squishy, we usually think it’s squishy — but this little device can do amazing things. It can allow itself to divide and make copies of itself so it can proliferate. Those individual cells can talk to each other in incredibly precise ways. They can remember things; there’s memory in cells, and then they can develop into multicellular organisms like ourselves.

“So what we’re going to talk about today is one of my favorite phenomena in all of biology, which is oscillations.

“What is an oscillation? You have some pattern of behavior that’s repeating over and over again. When you go to the level of the single cell, look at that individual cell and you look at the, let’s say, the concentration of a particular protein that does something in the cell. You find a lot of times that it goes up and it goes down, so the proteins are made, stay there for a while and go away, made and then go away, over and over again. That’s an oscillation — a rhythmic change in the level of the protein.

“Some of these oscillations do really fundamental things. The cell cycle is an oscillator. That’s a sequence of events that every cell goes through as it replicates its DNA and then divides that DNA into two daughter cells and then does it again.

“This video is trying to explain what’s going on when a bacterial cell divides. This is the most important thing. If the bacterial cell can’t divide, they wouldn’t be so successful. So they’ve got to kind of do this all the time over and over again. Their challenge as a cell is to divide in the middle. If they miss the middle, they run the risk of not having one copy of each chromosome of their DNA go to each daughter cell. So they have this challenge, which is finding their own middle point and then squeezing off right in the middle. And what we’ve learned is that there’s a molecular system of a few proteins that interact with each other, swish back and forth from one end of the cell to the other, and use that to actually help the cell find that midpoint.

“I think it’s a beautiful case in which you have an unexpected discovery that somebody made really just by looking at these proteins in the microscope directly for the first time. So I think this system really kind of epitomizes a lot of the trends and themes and forces that are happening right now in biology.

“There’s also a circadian clock. That means that every cell in your body actually has a clock circuit that oscillates with a 24-hour rhythm, and that those 24-hour clocks are actually guiding your body through its normal circadian cycle during the day. So that means that even if we were to put you in a cave with no signals, no temperature changes, no changes in light, you would still have this 24-hour behavioral rhythm.

“One of the things that was really astonishing, when biologists discovered it, was that actually even a single-cell organism can also have a circadian clock. So that’s true for cyanobacteria. These are photosynthetic bacteria, and they need this clock because they alternate between phases when they photosynthesize and phases in which they fix nitrogen, and those two activities are incompatible — they can’t do them at the same time in the same cell, and so that’s really why they have a circadian clock, or one of the main reasons.

“The key point about the cyanobacteria clock in particular: It’s so amazingly simple. I don’t think anybody would have anticipated that you could build such a precise clock out of just three proteins, and that that clock could operate outside of the cell altogether, can be reconstituted in a test tube. That was just amazing.

“So this example here in the cyanobacterial case really is one in which you can actually understand how a sequence of molecular events, just little interactions between molecules, actually gives rise to a change in behavior at the level of a whole cell over time, in a circadian way. So it’s a great example of, really, what you can do in biology, which is connect molecules interacting with each other to the behavior of a cell as a whole.

“When I was in grad school, I just wanted to actually build our own clock out of genes and proteins, put it into a cell, and really show that it was sufficient to give you oscillations, and then to really understand what kinds of designs are sufficient for oscillations, to really understand that directly.

“So what you’re seeing in this animation: The circle is literally a circular piece of DNA. So that circular piece of DNA contains the three genes of the repressilator. The design itself really is a kind of rock-scissors-paper circuit. That really is exactly what it is. The first gene, which we can call “rock,” turns off the second gene, which we’ll call “scissors,” that really turns off the third one that really turns off the first one. So the difference is, unlike when you might play rock-scissors-paper with your friend in order to settle some kind of decision about who’s going to do what, here the rock, scissors and paper are kind of separate entities that are each influencing each other. And so that’s the beauty of this circuit: It can’t do anything else except oscillate.

“What was most surprising is that it worked, because while I was going through that process, I told a lot people what I was trying to do and there was a really polarized response. So I think a lot of people, even very experienced biologists, felt that it just wouldn’t work. Not for any specific reason, but just because the cell is complicated. And some simple design that you dream up and should write down on a piece of paper may not work in the complicated environment of the cell, where there’s tons of different molecular interactions at play.

“The key idea is the idea that you’re building new behaviors in cells — from scratch. Why try to program new cellular behaviors? If you just want to understand how cells not only do work, but how they could work. What’s possible with these amazing genes, proteins and other biomolecules. It really changes our notion of what biology is. It’s not just a collection of organisms, it’s really a system for creating new functions in cells. So I think there’s a whole exciting world coming, I think, in the future, in which we’ll be able to think of a circuit as a therapeutic and start thinking of it as something that programs therapeutic activities in cells and kind of unlocks all those capabilities.

“It’s really like thinking about biology as a set of Legos that we have and thinking about not just, you know, if you think about with Lego kits you can sometimes build a specific thing, but you could use those Legos to build many things. And that’s what biology is about. I think there’s just a fundamental curiosity to understand what’s possible.”