From molecule to organism: science at every size

Zoom in on a human body and you’ll find that it is made up of tissues and organs—heart, lungs, brain, skin. Zoom in again and you’ll see that each tissue is made up of collections of cells. The cells work together to build and maintain the parts of the body and keep them functioning. Zoom in further, and you’ll find that each cell contains a world of its own. Just as a body contains organs, a cell contains organelles—discrete parts that serve specialized functions but work in concert. Zoom in one more time and you’ll find that each of the organelles—and the rest of the body of the cell—contains molecules, the basic building blocks of life. One molecule might perform a very simple function: for example, facilitating one specific chemical interaction. But zoom out again and you’ll see how myriad molecules each performing small actions add up to create a working cell, a working organ, and a working body.  

In order for researchers to understand the biology of living organisms, they must consider both what is happening at every level of the size scale, as well as the interactions between them. Interactions between molecules drive interactions between cells that affect traits and behaviors, or that drive symptoms of disease. Experiences and decisions made by the organism can lead to changes at the cellular and molecular level. In order to understand the full picture, Whitehead Institute researchers study everything from molecules to cells to whole organisms. An individual researcher may not study a problem at every point along the scale, but much like the actions of many different molecules together build a functioning cell, so do our researchers’ many different discoveries build on each other to elucidate biological processes of interest.

Read on to learn about how different Whitehead Institute researchers, focusing on different points along the scale of size, are fleshing out our understanding of the ways that organisms first develop into a certain body shape and then maintain—and in some cases, regenerate—the same body shape; as well as how brains function or, in cases of disorders and disease, go awry. 

Building and rebuilding a body shape

One question that fascinates many researchers at Whitehead Institute is how bodies know to form in a certain shape and size. Embryonic development starts with one fertilized egg cell that doubles and doubles to form more cells, and these cells must coordinate to form distinct tissues and organs. How does each species end up with its own distinct body shape? How does each cell know where to go and what to become in order for the collective to build that body shape? Then, in species that can regenerate or regrow lost parts, how are the blueprints for the body maintained so that the missing part can be reassembled in the right size and shape at the right location? 

Let’s start with what Whitehead Institute researchers are learning at the level of the whole organism, and then zoom in:

The whole organism: Researchers in Whitehead Institute Member Peter Reddien’s lab study regeneration using a variety of species with a range of regenerative capacities. This allows them to compare and contrast. For example, graduate student Conor McMann is comparing the regenerative abilities of the axolotl, a salamander that can regrow its limbs, with the mouse, a mammal that cannot. Other researchers in the lab have compared two highly regenerative worms, the planarian (Schmidtea mediterranea) and three banded panther worm (Hofstenia miamia), which have similar regenerative capacities and traits in spite of being distant evolutionary relatives. Projects like these allow researchers to identify what regenerative animals have in common that other animals lack, and then to investigate if these features contribute to regeneration. In this way, they can narrow in on the biological mechanisms underlying regeneration—and perhaps learn how to enable some regenerative capabilities in non-regenerative species like humans.

Tissues and organs: Reddien lab researchers can also focus on how a specific tissue or organ within an animal regenerates to learn underlying principles of regeneration. For example, a project on how planarians regenerate their eyes led the researchers to discover some of the principles that cells involved in regeneration follow to make sure they are building the right type of tissue in the right location. The researchers were able to manipulate these principles to make planarians grow extra eyes.

Reddien lab researchers have also uncovered specialized roles that certain tissue types play in regeneration. For example, in planarians, muscle tissue contains a “GPS-like” positional information system that instructs cells on where and how to build body parts to remain true to the original body plan of the animal. Meanwhile, skin expresses a key genetic signal that informs the body to begin regeneration at a wound site. Breaking down what different tissues contribute to regeneration is necessary in order to learn how an animal is able to regenerate lost or injured body parts. It can also guide researchers in what tissues to focus on within humans when trying to trigger regenerative healing.

Cellular circuits: Even animals that cannot regenerate body parts must be able to coordinate cells to build tissues and organs in the right size, shape, and location during development. Whitehead Institute Member Pulin Li studies this process. An embryo contains stem cells that are capable of differentiating into all of the types of cells that the body will require—but how does each stem cell know what to become? Morphogens are signaling molecules that some cells secrete in order to provide a blueprint for tissue patterning. The signal gets weaker the farther it spreads from its source, creating a gradient. Cells can orient themselves using this gradient and assume an identity based on their position—for example becoming an anterior wing cell instead of a posterior wing cell in a fruit fly. Li is working to discover the underlying principles of morphogen signaling networks to understand how tissues are patterned, and how a small set of signals can lead to tissues of such different sizes and shapes.

Molecules: Communication between cells is essential for building a body. However, researchers also need to know what’s happening inside of each individual cell. What actually changes within the cell so it can assume a specific identity—liver cell, neuron, skin cell, blood cell—and carry out specialized functions? Whitehead Institute Member David Bartel studies how messenger RNA, the intermediary between gene and protein product, is regulated. Cells use a variety of mechanisms to precisely control the amount of messenger RNA available to make protein, and the rate at which this RNA is degraded. These rates of degradation can vary by as much as 1000 fold, allowing for a broad range of differences in order to tailor different cells’ identities. Much of Bartel’s work focuses on microRNAs, tiny regulatory RNAs that can target messenger RNAs for destruction. Researchers in his lab have gained a detailed understanding of many aspects of how microRNAs regulate messenger RNAs and are themselves regulated.

Whitehead Institute Member Iain Cheeseman’s work also provides insights into what’s happening inside of cells during the development and maintenance of a body. Cheeseman studies the cellular machinery that enables cell division—the process by which a single fertilized egg cell becomes two cells, then four, and so on to build an entire body. Cheeseman’s research often focuses on the kinetochore, a protein complex that coordinates the division of chromosomes between the two daughters of a dividing cell. Researchers in his lab have also gained insights into other aspects of cell division, such as how a hidden variant of a known protein, generated from an atypical starting point in the corresponding messenger RNA, helps to regulate the suspension of cell division when the cell detects an error.

Putting the pieces together: By combining everything that Whitehead Institute researchers and their peers have discovered at different points along the scale of size, researchers can assemble a more complete picture of how animals grow, maintain, and in some cases regenerate their bodies. The process requires molecules inside of cells that allow the cells to divide and cue them to assume separate identities; then the dividing cells must coordinate to determine where to go and what to become; meanwhile, different tissues maintain some of these signaling networks; and the entire organism grows, changes, and replenishes itself as a result of these biological processes.

The brain and brain disorders

Our brains are the repositories of everything we know, and yet there is a lot we don’t know about the brain. For example, what exactly goes awry inside of a brain in cases of disorders or diseases such as neurodegeneration? Whitehead Institute researchers seek to understand brains at every level: peeling back the layers to understand the mechanisms of neurobiology from the molecular on up.

The whole organism: For a researcher interested in a subject that involves behavior or cognition, it often makes sense to study the whole organism in order to observe the organism thinking and behaving. Whitehead Institute Valhalla Fellow Allison Hamilos uses mice to study neurological and psychiatric diseases, as well as decision-making. Hamilos trains mice to play games that require them to perform actions and make decisions similar to those that might prove difficult for patients with neurological and psychiatric diseases. She also trains them to play games that require decision-making under uncertainty. Observing how the mice act in these situations can provide insights into cognition and brain diseases.

Meanwhile, Whitehead Institute Member Siniša Hrvatin uses several types of animals, including hamsters and microscopic animals called tardigrades—colloquially known as water bears — to study how the brain regulates states of stasis, like hibernation and torpor. Animals in these states may experience slower tissue damage, disease progression, and aging. By observing what triggers cause the animals to enter these states, Hrvatin can discover the mechanisms underlying dormancy—knowledge that might be advantageous in order to achieve slower tissue damage, disease progression, and aging in humans.

Tissues and organs: Our ability to monitor what’s happening between and especially inside of living brain cells is limited, so when the organ a researcher wants to study is the human brain, sometimes they need to get creative. Whitehead Institute Founding Member Rudolf Jaenisch sometimes uses brain organoids, which are spherical structures made of stem cell-derived brain cells. Having the cells grow in a 3D shape that more closely resembles their natural environment leads them to become more like cells in an actual brain. Jaenisch lab researchers have used this sort of model to study microcephaly, a type of abnormal brain development; how the Zika virus infects brain cells; and more.

Cellular circuits: After Hamilos trains her mouse subjects to play games, she not only observes them passively, but also uses a variety of methods to affect specific neural circuits. Seeing whether and how the mice’s actions change when a specific neural circuit is perturbed indicates whether that neural circuit is involved in the behavior or cognitive task of interest. By zooming in to the level of neural circuits, Hamilos can gain insights into the neurology underlying different behaviors, and can potentially identify targets for therapies.

Organelles: Some Whitehead Institute Members study what occurs inside of brain cells that might contribute to the symptoms of brain disorders and diseases. For example, membrane-less organelles called condensates play important roles in organizing the contents of our cells. Condensates form when proteins or RNAs glom together and separate from the fluid of the cell into a discrete droplet, like a bead of oil in water. They bring together certain molecules in the right combination and the right location to perform functions such as regulating gene expression. Researchers from Whitehead Institute Member Richard Young and Jaenisch’s labs found that condensate dysregulation may play a role in the neurodevelopmental disorder Rett syndrome. The primary gene implicated in Rett syndrome is MeCP2, and possible therapies have typically targeted either the gene or the individual proteins. However, Young and Jaenisch’s research shows that MeCP2 proteins form condensates, and that Rett mutations disrupt their ability to do so. This suggests that another approach might be to treat the disease by rescuing condensate formation—a strategy that only became apparent when the researchers considered the structures that MeCP2 proteins form at the organellar scale.

While condensates can be useful for cells, sometimes proteins and RNAs glom together to form structures that are harmful. Whitehead Institute Member Ankur Jain studies the role of such harmful aggregates in a class of neurological disorders called repeat expansion disorders. These include ALS, Huntington’s, and Fragile X syndrome. In these diseases, atypical repetitive sequences in the disease causing-gene create RNAs and proteins that are prone to clump together when they shouldn’t. The clumping molecules form gels that trap other proteins, preventing them from doing their jobs in the cell, and as the gels grow they distort the cell and can eventually cause cell death. Researchers in Jain’s lab have gained insights into how the gels form and how they affect cells, which could suggest therapeutic strategies for treating repeat expansion disorders.

Molecules: Jain’s research to understand the mechanisms underlying repeat expansion disorders also considers the aberrant RNAs and proteins that are involved on an individual level. Work on the organellar level lets Jain observe how aberrant RNA gels behave in and affect cells, and work on the molecular level provides insight into why these molecules form harmful structures in the first place. Recently, researchers in Jain’s lab discovered that the repetitive sequences in repeat expansion disease genes lead to issues in how RNA sequences from those genes are cut and pasted together to form the final RNA product, in turn leading the RNA to code for a different, aberrant protein.

Meanwhile , some Whitehead Institute researchers work at the molecular level to develop therapies that could treat diseases, including those of the brain. Whitehead Institute Fellow Aditya Raguram is working on how to deliver large molecules into cells, including molecules that could switch off or correct disease-causing genes. His strategy is to use engineered virus-like particles as vehicles for delivering these large therapeutic molecules into diseased cells, since viruses have evolved a form that is adept at getting inside of cells. Whitehead Institute Member Jonathan Weissman is also working on approaches to switch off disease genes, and recently developed a tool that can switch off any gene. In a collaborative effort, Weissman and colleagues then applied this tool to the prion protein gene which is implicated in neurodegenerative prion diseases.

Putting the pieces together: Understanding the brain requires connecting the dots between what’s happening at the level of traits and behaviors to what’s happening in neural circuits to what’s happening inside of brain cells. For example: changes in the sequence of individual RNAs can cause them to form atypical structures, which in turn affect the health and normal function of the cells they are in, contributing to the symptoms of neurodegenerative diseases like ALS. The best way to understand the disease—and so to figure out how to prevent or treat it—is to consider what’s happening at every level and synthesize that knowledge.

To explore other stories in this collection, highlighting Whitehead Institute researchers’ work across scales of process and time, click here.