Story, graphics, animations, and web design by Mark Belan
Carl-Philipp Heisenberg’s lab at the Institute of Science and Technology Austria (ISTA) is unraveling the physics that shape the development of life.
How do you make a baby?
Throughout history, the phenomenon of creating life has always tickled our curiosity. No matter the generation, it seems like a philosophical rite of passage for a child to eventually question where they come from.
Most of us have an idea of what it takes to bring life into this world. Many of you have likely already done it. For some, answering the question of how to make a baby begins and ends at conception. What happens after is rarely a consideration. While such an answer may be enough to deter innocent minds and their blushing parents, pondering the finer details of how life is formed and how it develops feels necessary—almost instinctual—in present company.
Carl-Philipp Heisenberg is a modest but commanding presence. He sits across from me holding a dainty demitasse and an enthusiastic gaze. His office, situated at the Institute of Science and Technology Austria, just north of Vienna, is surprisingly organized for what I've come to expect from speaking with decorated and accomplished scientists. I'm meeting with him to discuss embryos, the focus of his research at ISTA for the last 14 years.
Heisenberg - or CP, as he's more commonly known - is a developmental biologist. He studies the events driving a fertilized egg cell as it transforms into a three -dimensional structure, a process otherwise known as development. Where some choose to study how genes switch on and off during this process and others examine the chemical signals peppered throughout, CP focuses on the role mechanical forces—physics—play in the early phases of development.
Development is the process by which a three dimensional multicellular organism develops from a single fertilized cell. How form and structure change throughout development is known as morphogenesis.
When I ask "How do you make a baby?", CP is characteristically clinical in his response:
“Well...you put together two gametes, in combination, to form a single cell—but to get to an embryo you’d need a number of other things, like genetic regulation, morphogen patterning, and cellular forces.”
For more than 20 years, CP has explored aspects of the journey everyone of us has taken, but cannot recall. Where we lack a souvenir, CP has a tome of publications explaining how my cells and the tissues in your organs came to be. It's a unique situation for me: I've never spoken with a developmental biologist before. Before I sat down in this chair I barely recognized the role physics had to play in creating life. But of course it does! Physics governs virtually everything in the universe, and now I am sitting face-to-face with a stranger who knows, with the depth and breadth only experience can provide, the most intimate aspects of my creation.
CP’s work focuses tissue morphogenesis: the process through which cells that make up the gut, liver, brain, and heart take on their distinctive qualities and forms during development. It’s especially crucial for life because it’s responsible for the variety of cell types and tissue functions found in all multicellular organisms on Earth. Without it, the extent of diversity we can see in species today wouldn’t exist.
I try to frame the process of tissue morphogenesis through the lens I'm most comfortable with: art. It’s easy to look at tissue morphogenesis like an artisan’s craft. You may have heard the richness of life described as a tapestry or a painting. While it’s true the diversity of organisms is painted with many colors, all the structures and forms we see—from whale fins to fly wings—are also intricately sculpted. It’s more fitting to describe the diversity of life as a mural or relief, as if arising from a sculptor shaping clay.
The diversity of life forms is often referred to as a tapestry, but it's much more like a sculptural relief. Painting: Johann Wenzel Peter (ca. 1800-1829).
When considering tissue morphogenesis, however, there is no sculptor, and there are no hands (well, not yet, technically speaking). Instead forces—tension, compression, shear, and more—emerge as the chisels and tools for building life, sculpting living matter into intricate structures and shapes. Within the journey from a single cell to a 3D structure, developing cells ‘self-sculpt’ their destinies, and they accomplish this via a tight integration between physics and tissue-cell dynamics. It’s a process that has been a part of our origin story. Since the very first multicellular organisms arose, their development has been molded by unseen hands.
CP is interested in uncovering the principles of tissue morphogenesis because it has powerful and important implications from medicines to tissue engineering. For starters, it determines how well a body will function once it is born. Adequate and uninterrupted alignment, positioning, and growth of cells and their tissues are crucial for proper organ function. In medicine, knowing how tissue functions arise—and how to manipulate them—is necessary for regenerative therapies and the treatment of congenital defects. Emerging industries like tissue engineering and artificial cells are within grasp thanks to this line of work. There's a lot of promise in uncovering what guides the Earth's most successful , resilient organisms during development - and what typically is ruinous.
With that said, it’s important I address the elephant in the room. Developmental biology is a sacrificial science: to enquire so much about life means regularly engaging with death. CP does not work with human embryos—that’s not allowed. Instead, his work is based on model organisms biologists have long used in humans’ place. For CP, that means working with zebrafish and sea squirts.
How can the findings from such distinct and specific species apply to the rest of the animal kingdom, including us? The answer has to do with evolution. The way many creatures form early in development is quite similar amongst species. Up to a certain point, different life forms are connected by the first stages of development before branching into unique organisms. That's powerful for CP: knowledge of the very basics of one species' development can be applied to many others. The fact that zebrafish and sea squirts have short development times, transparent tissues, and easy-to-manage genes adds a layer of practicality where other species, like monkeys or humans, are unnecessarily laborious and expensive, not to mention unethical.
Ernst Haeckel's illustration marks the similarities of an early phase of development across organisms. CP's lab studies zebrafish and sea squirts, two creatures that develop similarly to many vertebrate organisms. Illustration: Ernst Haeckel (1866).
It should come as a relief to readers to know this monologue about death and forging body parts does not mean I am sitting in Frankenstein’s lair. Though the details are technical and the lack of theatrics might be disappointing to some, learning how biology works at such tiny scales is a saga all its own. The most critical answers to how life is able to manifest lie in the tiniest recesses of our own cells, and describing development at the microscopic scale is still very much a mystery. Despite being complex, the story of life’s actions at the tiniest levels scaling into our observable world is a remarkable—and as of yet, rare—feat of the universe. In my view, the phenomenon of biology is more exciting than a work of fiction because it is real, and it’s what makes deep diving into mechanical forces and development so interesting.
Finally, while it’s true that CP is no Frankenstein, it’s a bit of a starstruck moment that I am able to explore this topic with him. It’s hard to ignore the Heisenberg name. It may conjure images of Walter White’s meth-cooking, Mr. Hyde-style alter ego from Breaking Bad, but this name’s cultural importance traces back much further. Werner Heisenberg is considered the grandfather of the uncertainty principle and quantum mechanics—and he's the grandfather of CP, too. It’s remarkable that Martin and Jochen Heisenberg, each a renowned geneticist and physicist, respectively, are also uncles to CP. I’m delighted, if not slightly overwhelmed, that my work has brought me to the threshold of a bloodline so heavily steeped in academic and scientific excellence, and I couldn’t ask for a more fitting person to introduce me to the curiosities of development, the marvels of mechanical biology, and the forces that build us.
I wriggle in my seat, a little anxious for what’s to come. With pen in hand, the lesson begins.
Forces are one part of the toolbox of tissue morphogenesis. Understanding how they are generated and applied at different scales is an important part of CP’s work.
We’ll start at Level 1:
how forces are generated at the cell scale.
Cells react to forces because they are moldable. This property is controlled by an intricate network of proteins that forms the cell’s structure, called a cytoskeleton.
The cytoskeleton consists of three main parts: microtubules, intermediate filaments, and actin filaments. Part of CP’s work looks at how these fibres make forces and how they interact with them.
We’ll focus on actin filaments since they inhabit the boundaries of the cell and are able to create quick changes to cell structure.
Actin is a filamentous protein that polymerizes (builds) in one direction. When it polymerizes in the direction of a cell’s membrane, it pushes the cell’s edge outwards.
This is an example of extension, one of two principal forces generated by actin.
The other force - contraction - is more complicated as it involves an additional protein called myosin.
Myosin has two ‘hands’ that grab onto strands of actin. When myosin takes up chemical energy, it physically pulls on the strands of actin, drawing them together.
Actin and myosin make up a complex network of proteins called actomyosin. Their partnership forms an elaborate web that connects to the cell’s edges via specialized molecules.
When many actin filaments experience coordinated pulling by myosin, they can generate sizable amounts of contractile force that pull on the cell’s membrane, making it smaller.
Actomyosin and other cell components move at various rates and locations in a cell, creating flows that can control where forces are applied within the cell.
The dynamics of cellular flows can also determine how forces are applied, such as in pulses/waves (i) or just evenly (ii).
These dynamics create more options for actin and other filaments to alter cell shape.
Some common examples are shown here, as well as formation that may result from individual cell movements.
I’m unsure what to do within the lengths of silence that’s filled the room. I’ve been scribbling furiously into my notebook up until now, nose to the table, so I decide to steal a glance in front of me. CP is sipping on his espresso.
Most people are able to avoid acknowledging banal observations—I cannot. I’m in that rare headspace where trivial matters are suddenly interesting, my attention is redirected, and time moves slower. In the brief moments when CP turns the teacup from his lips and lowers it back to the saucer in his lap, I’m marveling at how his fingers are curled around the teacup. A bit oversized, they clutch the handle in a delicate pinch.
Not many species have hands as developed as ours. Years of evolutionary refinement have bestowed our fingers with extreme capabilities. Compared to apes, we are much more dexterous, flexible, and versatile in what we can do with them. Fine motor skills and tool-use have helped humans to write symphonies, scale mountains, build skyscrapers, or scroll through web articles.
It’s a common adage in biology classes that gets repeated around the world: form begets function. Our capabilities are ultimately determined by the journey our cells go on when becoming our organs and limbs. Without fingers and their complex musculature and tendons, we wouldn’t be able to use our hands in the many ways that distinguish us from our primate cousins, or the rest of the animal kingdom.
And so how CP’s fingers have come to manipulate into the delicate arrangement before me is the good fortune of how they formed in development as much as it is a remarkable achievement in evolution. This is why focusing on tissue development is so important to CP: the large structural formations that come from forces pushing and pulling cells into place need to be optimized in order to provide the best function possible. At the cellular scale, the few shape changes or movements I’ve described above are insufficient for the complexity needed at the functional scale. At the tissue scale, ensuring the best possible outcome for function depends not only on the forces being made by its cells, but the various properties affecting how these forces are applied together.
I can see now why focusing on these small matters is so crucial to CP and researchers like him.
All that from a swig of a cup.
Beyond a single cell, the coordination and combination of forces across tissues begins to shape 3D forms. Tissue morphogenesis relies on several properties that help transmit and apply forces across greater scales.
This is Level 2
how forces are applied at the tissue scale.
Cell-to-cell adhesion is a property where cells attach and interact with one another through specialized molecules at their cell surfaces.
Through this connection, forces generated in one cell can travel along filament networks and affect other cells at the adhesion molecules.
Just like our planet has North and South poles, cells have polarity. It’s another property that indicates where a cell’s proteins may flow (i), and where certain forces will arise.
A simple example of polarity affecting forces is actomyosin gathering in the top face (ii), where contraction affects only one side of the cell.
Combining these properties of polarity and cell adhesion, apical actomyosin contraction can pull neighboring cells into more sophisticated forms, such as a cupped structure.
When cells share similar characteristics (like actomyosin networks) they tend to apply forces in a similar way. An example of this is uniform contraction (i), which creates rounded structures.
But these characteristics are not always consistent. Gradients of actomyosin concentration across cells, for example, pull on tissue in a graded fashion. This creates an uneven contraction (ii) that can enhance rounding.
These differences are an example of spatial patterning: how proportions of actomyosin vary between cells and how these differences are patterned in a plane of tissue.
Other filaments and many cellular properties contribute to spatial patterning. Myosin gradients are only one example of this, though they contribute to the folding of tissue across several species.
The spatial patterns of force-generating components combine and coordinate forces to fold tissue into a variety of different structures.
Here are some of the major movements that tissues can undergo during embryonic development.
I let out a sigh. The defeated kind—I’m tired.
It's like I've run a marathon and CP hasn't broken a sweat. He's still completely engaged. He's sitting with his hands folded over his knee. The teacup is on the floor, empty.
We return to the beginning: how do you make a baby?
Fr. Humans have been doing it for almost 200,000 years, other species have been doing it for billions of years, and despite these lengths of time we still don’t really understand much of what’s going on. Morphogenesis on its own is deeply complicated, and poorly understood.
After all, mechanical forces are only one piece of the puzzle. There are elements to CP’s work that I haven’t discussed. I’ve touched on how biology creates forces, but I haven’t explored the ways biology talks back. There is a branch of investigation called mechanotransduction that looks at how molecules react to forces. For every fold and squish that cells make against one another, a Rube-Goldberg machine of molecules signals the start and stop of millions of other chemical reactions and their subsequent forces. This intricate ping-ponging of physics and chemistry, one igniting the other, is a sort of ‘chicken-or-the-egg’ conundrum that CP reminds me is deeply intertwined within every millisecond of development.
And that’s not all. Phenomena such as ‘cell-like compartments’ are another angle to CP’s work. Recently, it has been discovered that the cytoplasm (the jelly-like space where the cytoskeleton resides) can separate under certain conditions into tiny compartments that resemble cells. The transformation is almost like a Matryoshka doll, something like cells stacked inside cells. It’s raised questions about cell stability, reassembly, and the mechanics that sustain this reorganization. For CP and his lab, there’s plenty of work to be done in uncovering how biology is programmed to respond to such dramatic structural changes. How might these compartments replicate and what kind of forces are they supported or hindered by? That's where CP and his lab are focusing their attention now.
Replicating cell-like compartments are a new phenomenon that's been observed in the cytoplasm of cells. CP and his lab are investigating how cells implement this, and where forces arise to support it.
While CP may handle the mechanical aspects of development, others are focused in areas that investigate how genetics, morphogen patterning, protein structure, and other factors might all contribute to the developing embryo. Some of those are even based at ISTA, working alongside CP to untangle the mysteries of the earliest moments of life. I wasn’t kidding when I said morphogenesis was complicated; it’s going to take a long, long time before we can answer the question of how we develop.
There’s one more force I haven't acknowledged and it’s the power of a first impression. With all this talk about cells bending into three dimensions, it’s apparent that life is susceptible to the forces around us. I didn’t imagine that meeting with CP and his lab could enrich my appreciation of forces, or physic's place in biology.
Weeks later, on my flight back home to Canada, I'm waxing philosophical again over more banal observations. I don’t immediately dismiss the crying child on the plane, or the snoring elderly man seated next to me, without imagining how deeply complex both of their life histories are. It's so easy to overlook the marvel that any of us exist, and the extensive, unseen work our bodies have undergone to make it possible. Exploring the recesses of development is a deeply fulfilling endeavor that continues to write the greatest story of our lives: where we come from, how we are made into being, and the delicate rarity of life in our solar system. To me, there's no doubt that the invisible and seemingly immaterial things matter. Just as forces shape living matter into organisms, the experiences we have and the impressions we make continue to mold our identities long after we’re born.
On the flight home, I take a cup of tea from the stewardess, savoring the warmth while noticing the curl in my fingers, gripping the handle.
References
Heer, N.C. and Martin, A.R. (2017). Tension, contraction and tissue morphogenesis. Development, 144(23), pp.4249–4260. doi:https://doi.org/10.1242/dev.151282.
Heisenberg, C.-P. and Bellaïche, Y. (2013). Forces in Tissue Morphogenesis and Patterning. Cell, 153(5), pp.948–962. doi:https://doi.org/10.1016/j.cell.2013.05.008.
Krieg, M., Yohanna Arboleda-Estudillo, Pierre-Henri Puech, Jos Käfer, Graner, F., Muller, D.R. and Carl-Philipp Heisenberg (2008). Tensile forces govern germ-layer organization in zebrafish. Nature Cell Biology, 10(4), pp.429–436. doi:https://doi.org/10.1038/ncb1705.
Miao, H. and J. Todd Blankenship (2020). The pulse of morphogenesis: actomyosin dynamics and regulation in epithelia. Development, 147(17). doi:https://doi.org/10.1242/dev.186502.
Shamipour, S., Caballero-Mancebo, S. and Heisenberg, C.-P. (2021). Cytoplasm’s Got Moves. Developmental Cell, 56(2), pp.213–226. doi:https://doi.org/10.1016/j.devcel.2020.12.002.
Sutlive, J., Haning Xiu, Chen, Y., Gou, K., Xiong, F., Guo, M. and Chen, Z. (2021). Generation, transmission, and regulation of mechanical forces in embryonic morphogenesis. Small, 18(6). doi:https://doi.org/10.1002/smll.202103466.
Embryological models by University of Dundee, CAHID (Sophia Lappe) and zoological models by The WarVet are licensed and modified under Creative Commons Attribution (CC BY-NC-SA 4.0 DEED). All other models, graphics, and animations are made by Mark Belan | artsci studios.
