AudioHelicase special: When cells are in their element

This article is part of our series, “Biology in its natural habitat: studying cellular processes in context”. To view the entire collection, click here.

In this episode of AudioHelicase, we sit down with four Whitehead Institute researchers who are gaining unique insights into biological processes—from regeneration, organ function, and immune response to embryonic development—by studying them within the rich context of their natural environment.

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Transcript:

Shafaq Zia: Cells are a bit like people. Just as an individual’s personality is shaped by their experiences and surroundings, a cell’s identity and behavior are sculpted by its environment.

Zia: This is AudioHelicase, the podcast of Whitehead Institute. Here we unwind the science and the people behind some of the Institute’s most exciting discoveries. I’m your host Shafaq Zia, and today we’ll hear from four Whitehead Institute researchers who are studying key biological processes in their natural environment to observe and understand certain aspects of biology that are lost when studied in isolation.

Zia: Whitehead Institute Member Peter Reddien has always been drawn to big problems in biology, where the phenomenon is spectacular and sparks the imagination. This inclination has led him to study regeneration, the capacity of certain animal species to regrow missing body parts. He investigates this process primarily in freshwater flatworms called planarians.

Peter Reddien: If the process involves multiple components and contextual cues, then your capacity to observe them is greater in the context in which they’re naturally existing. Regeneration is a process, in particular, where the contextual cues are really what is being studied. So, I think that is a place where having model systems you can study in the lab becomes very powerful.

Zia: The contextual cues Reddien is talking about are the signals a cell receives from neighboring cells and its environment. In regeneration, the cues are many. Cells must detect and respond to them to coordinate the rebuilding of missing tissue at the right location and at the right pace.  

Zia: The first cue comes right after the injury when signals spread outwards from the site of the wound, alerting nearby cells it’s time to start rebuilding the body. Stem cells, called neoblasts, quickly spring into action. These immature cells are incredibly versatile and can give rise to almost any type of cell in the worm’s body.

Reddien: They could choose to make head cell fates like brain cells or eye cells or mid-body cell fates like pharynx cells. And they must make these choices based on their position.

Zia: But how do stem cells know where they are in the worm’s body and which types of cells are needed to recreate missing tissue? It turns out, planarians have a pretty sophisticated GPS system embedded in their muscles. These muscle cells express genes that communicate the “coordinates” of the head, tail, and everything in between, letting stem cells know which part of the body has been injured and where they need to migrate in order to restore it.  

Zia: But often, rebuilding missing tissue like a functional eye or brain requires multiple cell types.

Reddien: We realize there’s a challenge in regeneration, where two cell types need to appear in the right numbers relative to one another and in the same positions. So how do you coordinate the regeneration of these two cell types in space and number?

Zia: Restoring a planarian head, for example, requires regenerating both neurons and glia—a cell type that supports and protects neurons—at the same location and at specific proportions. How planarians manage to coordinate this process was a mystery until Reddien and staff scientist Lucila Scimone discovered something new: a signal directing immature cells—capable of becoming glia or various other cell types—to commit to glial fate. And this cue was coming directly from the neurons themselves.

Here’s what the researchers know now:  

Reddien: The neurons regenerate first. They express a molecule, delta-two, that interacts with progenitors that are widely dispersed and have not yet decided what to become. If they interact with the delta-two positive neurons, then they choose to become glia there, at that location.

Zia: Had the researchers looked at glia or neurons in isolation, they would have missed the coordinated dance between the two cell types.

Reddien isn’t the only one who understands the importance of this approach. Another Whitehead Institute researcher is leveraging it to learn more about immune response.  

Pulin Li: My name is Pulin Li. I’m a member of the Whitehead Institute.

Zia: Li is investigating how cells communicate with each other and the outside world in order to understand how they make decisions as a group about their condition and how they would respond to external signals.

Li: You could imagine, for a single cell, they will need genes that would be able to detect this stimulation from the outside world or from its neighbors, and the cells have to be able to process this information and make a decision. And in turn, the decision a single cell makes will have to be propagated, or, sensed by the neighboring cells.

Zia: This type of communication within a community of cells involves thousands of genes, so cells use an instruction manual to decide which genes to turn on or off and when. This manual is called a gene regulatory network. But to use it, cells first need to receive signals from their environment. Signaling pathways, which act like roads, carry these signals to the cells using small molecules as messengers.

Li: If you think about interpersonal communication, we use a lot of communication apps like iMessage or emails or Snapchat. But each app we use for a specific purpose because each app has its own design features that allow you to do something different from what you can do with the other apps.

Zia: Based on this idea, Li and her team are looking at a group of molecules called pattern recognition receptors that alert immune cells and epithelial cells, which line the surface of our lungs, of potential threats like pathogens.

Li: One unique feature we’re studying is actually about how sloppy these signaling pathways are, meaning even though they’re like the first line of defense in in our body and for all the cell types, in many cases, when the cells are infected, only very a small fraction of the cells actually would activate this pathway.

Zia: But when the researchers looked at stromal cells, which sit deeper within the lung tissue, they found these cells were much better at initiating an immune response. This led them to suspect that the “sloppiness” of this signaling pathway isn’t a flaw—it is a key design principle.

Li: If you think about it, epithelial cells are lining the outermost layer in the lung. They’re being constantly exposed to different types of threats. So, if they are hypersensitive, then they might get activated all the time, and as a result, you will be activating the immune system constantly, and that’s a double-edged sword.

Zia: That’s right—the immune system protects cells from infection, but when it’s chronically activated, it can start misfiring and even damage healthy tissue.

What’s fascinating is that this signaling pathway, while not precise, allows cells to coordinate their immune response. It’s a kind of tiered immunity—epithelial cells don’t act alone; they work in relation to stromal cells. But to really understand how tiered immunity works in the lung, researchers can’t just study epithelial cells in isolation. They have to look at how these cells are interacting with their surroundings.

Zia: And looking at cells as a community isn’t just essential for learning about the immune system—it can also give scientists important clues about what happens to cells during disease like organ failure.

Jonathan Weissman: The real push to go in vivo is that there are just physiologies and communications that are very difficult to recapitulate in a petri dish.

Zia: That’s Whitehead Institute Member Jonathan Weissman, who, much like Reddien and Li, is focused on a scientific question that requires studying cells in their native environment.

Zia: The question Weissman and his team have been working to answer is how the spatial arrangement of cells within the liver, along with each cell’s genetics, influence the liver’s overall function.

Weissman: We think of the liver as a central dispatcher of energy. So, it can make sugar or can consume sugar, it can make lipids, or can consume lipids. And it does this in response to what the body needs. We’re very interested in this process by which the liver is communicating, understanding the metabolic state and the nutrient state of the rest of the body, responding to this and dispatching or using energy accordingly.

Zia: Typically, scientists study cell function in an organ by taking cells out of the organ and looking at them in the petri dish. But in the case of the liver, cells in different regions experience different concentrations of oxygen and nutrients, which influences what genes that are active in the cell and to what degree. Once removed from the organ, these cells lose their specialized roles and start behaving less like liver cells.

Zia: Now, Weissman and his team have found that turning off certain genes—one at a time—in a single liver cell can cause fat to build up within the cell, a key feature of liver disease. So far, the researchers have identified four genes that trigger this process in the mouse liver.

But what’s especially fascinating is that turning off each gene triggers a different cascade of events, all leading to the same outcome but through different pathways. Each pathway is shaped by the cell’s unique microenvironment within the liver and its interactions with its surroundings.

Weissman: The beauty of this is you can look at cells as non-autonomous. You can say, I change this gene, what’s happening to the neighbor, and how does the neighbors affect how the cell responds to the perturbation, and how does perturbation impact the neighbors? And we think that being able to manipulate the zonation and the activities in different zones would help us think about how you could intervene therapeutically.

Zia: Even if we were to look at the earliest stages of life, we would observe cells responding to their environment. Take germ cells, for example—the cells that eventually become egg and sperm. In most species, they are born far from the somatic cells that make up the rest of the body, and have to embark on a complex journey through the embryo to reach the developing ovaries or testes.

Ruth Lehmann: The germ cells, on their own cannot give rise to egg and sperm, although they are what makes egg and sperm. They need this whole machinery around. But the journey is interesting because that is a very conserved principle of germ cells. They migrate in pretty much every organism, whether it’s a mouse, a human or a fruit fly.

Zia: This is Whitehead Institute director Ruth Lehmann, and she’s explaining why this journey is so remarkable. If the germ cells don’t migrate to the right location in the embryo, she says, they risk becoming part of the somatic tissue. This means critical genetic information that needs to be passed onto the next generation is lost, resulting in infertility.  

Lehmann: There are so many different steps when you look at migration. You need lots of guidance components. This is like an airplane and you have different towers, which at different times, are telling them what the directions are. In a dish, you can capture one gradient but they’re seeing more. So, it’s incorporating all that information that leads to this path, and that path doesn’t have to be one line.

Zia: In fact, every germ cell takes a unique path to reach the ovaries or testes. And the process of shepherding these cells through multiple cues across different signaling pathways ensures that they reach their destination, allowing life to go on. It’s a truly impressive feat, but one that can only be achieved when germ cells can sense and respond to the complexity of their environment.  

Zia: To learn more about ongoing research at Whitehead Institute, go to our website at wi.mit.edu. This is also where you can find past episodes of AudioHelicase and tune in for new ones. Thank you for listening!

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Interviews, production, and hosting by Shafaq Zia.

Music:
little ukulele melody.mp3 by InVolumes (CC0)

Illustration: 
Madeleine Turner