MONDAY, 4 MARCH 2024
THE STORY OF DEVELOPMENT, by which the descendants of a single cell form a mature organism, has fascinated and perplexed scientists in equal measure for centuries. Its significance reaches far beyond mere scientific curiosity; it is a vital step towards understanding the mechanisms behind disorders of huge clinical significance, and so designing rational therapies. The societal benefits of revealing how our bodies are built are spurring major research efforts, but a new era is dawning.For several decades, developmental biology has overwhelmingly focused on biochemical models – intricate networks of genes and proteins, the biological agents of developmental processes. Development is now increasingly being appreciated as a highly physical and mechanical process; cells change shape, position and fate in a complex choreography known as morphogenesis. To truly understand the steps of this dance, genes and proteins alone will not be enough. Engaging the mindset and principles of physics to integrate biochemistry with mechanics is currently revolutionising our models of how tissues and organs are sculpted.
MOLECULAR FORCE FACTORIES | All movement requires force. Development is an incredibly dynamic process, with cells serving as their own engines. They are equipped with an internal ‘cytoskeleton’, including linear filaments of a protein called actin. Recruiting new subunits to the end of actin filaments can generate a ‘pushing’ force against the cell membrane as they grow. Actin polymers also form tracks for another protein, myosin, to crawl along. Myosin is able to convert cellular energy into mechanical force – a molecular motor – that can slide actin filaments past each other. By strategically arranging their actin filaments, cells can use this force to remodel their shape, such as shortening one edge. These polarised contractions, coordinated across a tissue, can convert a flat sheet of cells into a three-dimensional structure like a tube. This is how our neural tube (the precursor to the nervous system) and the gut first form.
If the cell can latch onto its environment through adhesion proteins (e.g. integrins and cadherins), internal forces can also be used to drive their motion; like a rower drawing an oar blade through water, the ‘equal and opposite’ force pushes the boat (the cell) forward. Engaging this ‘molecular clutch’ can propel a cell, or a cell population, through the developing embryo. For example, neural crest cells, which all form near the neural tube, migrate all over the body to ultimately contribute to many tissue types (e.g. bone, muscle and skin). If cells are anchored to their neighbours instead, they can tug on them, allowing cell sheets to flow and achieve vast shape changes at a tissue scale. During the process of gastrulation, the embryo undergoes radical restructuring, folding inwards to transform from a single[1]layered structure to a three-layered one. The newly established germ layers of the ectoderm, mesoderm and endoderm (from outside-in) can now kick off the process of differentiation, heading off along vastly different developmental paths.
Even local forces in sub-cellular structures can achieve great developmental feats. Neurons in the developing brain must extend a long, thin axon to connect with their downstream targets. The workhorse of axon growth is a tiny, hand-like structure at its tip called the growth cone. Wiggling and writhing forward, it tugs on the axon while surveying its environment, seeking out cues to ensure it stays on the right trajectory.
NO CELL IS AN ISLAND - MECHANICAL ENVIRONMENTS | Every cell in a developing embryo sits within a constantly evolving environment, being physically connected to a three-dimensional scaffold called the extracellular matrix along with many other cells. This matrix can be decorated with molecular signals that influence cellular behaviour. Signals can also diffuse from their source, creating gradients of positional information. Via these connections, cells are subjected to many types of external forces, with consequences for their developmental trajectory.
Cells have developed ingenious mechanisms to sense and interpret the mechanical properties of their local neighbourhood. This is achieved by proteins that switch their structure when deformed by a force. One example is a mechanosensitive ion channel such as Piezo1, which opens in response to mechanical stimulation to flood a cell with ions and initiate a signal. The adhesions that connect cells to their surroundings also contain force-sensitive components, such as talin, which is found in integrin-containing adhesion complexes. Talin molecules unfold in discrete steps when pulled, exposing previously concealed binding sites for its partner, vinculin. The signalling cascades leading from these proteins can converge with well-known biochemical pathways, enabling mechanical and biochemical signalling to regulate each other.
One parameter useful for cells to measure is the stiffness of their surroundings. Stiffness is a measure of how much a material deforms in response to force. Biological tissues span a vast spectrum of stiffness values, ranging from the toughest bone to the softest fat, and factors in cell density, matrix composition and cell mechanical properties. Substrate stiffness can change over both time and space and can be used as a cue to initiate a process; neural crest cells only swing into action when the mesoderm tissue they sit on becomes stiffer. Gradients of stiffness can also serve as guidance cues. Confronted with such a gradient in brain tissue, growth cones of frog retinal neurons on their journey from the eye turn towards the softer side, allowing them to reach the visual area of the brain.
Another key developmental process is tissue growth, which faces mechanical constraints if space to grow into is lacking. Imagine a flat sheet of epithelial cells, dividing and attempting to expand when coupled to another tissue that does not grow in proportion. This subjects the tissue sheet to a compression force. One way to overcome this is to buckle, like a ruler being pushed at both ends. A once-flat sheet can invaginate to make a curved structure such as a cup, loop or branch, as seen in the developing eye, gut and lung respectively. In three-dimensional expanding tissues, compressive squeezing may drive mechanical signalling that reins in cell division and prevents overgrowth.
FROM DEVELOPMENT TO DISEASE | To tackle the pathological, we must first study the normal, and the principles of development may have a great impact on modern medicine. The mechanical niches of our cells continue to evolve as we age; for instance, brain tissue generally becomes stiffer with age and softer with neurological conditions such as Alzheimer’s disease. Additionally, cancer cells have altered mechanical properties and are capable of remodelling their mechanical environment to their own benefit (e.g. by stiffening the matrix to promote metastasis). If we can deploy molecular manipulations to fight against this, we may have a way of restraining its otherwise relentless progression.
Developmental concepts can also be harnessed by regenerative medicine, with potentially huge payoffs for treating adult-onset diseases and injuries. Stem cells, the starting point of many therapeutic projects, are mechanically sensitive and can be persuaded to form different cell types depending on the physical environments they are cultured in. Studies have shown that reversing age-related stiffening can rejuvenate neural stem cells. With their youthful vigour, they can potentially combat functional decline. Refining culture protocols improves the prospects of these cells in achieving clinical benefits when replacing damaged or defunct tissues in animal models or eventually patients. Mechanical fine[1]tuning within our bodies may also encourage our own self-repair programmes. To design scaffolds able to coax an injured system to repair, such as a lesioned spinal cord, its biomechanical properties must be supportive of neuronal growth and guidance.
One thing is clear – the future of science is interdisciplinary. Biochemical and mechanical signalling operate hand-in-hand and need to be studied together. Blurring traditional barriers between scientific disciplines, spearheaded by initiatives such as the Cambridge Centre for Physical Biology, is vital in facing some of the biggest challenges of the modern day. Bringing together the skillsets of biologists, engineers, physicists and computational scientists to address the same questions changes the very way we do science, turning it from a compartmentalised into a collaborative enterprise. For in science, the whole truly is greater than the sum of its parts.
Rachel Mckeown is a PhD student in Developmental Neuroscience at the University of Cambridge, interested in how our brains form connections in early development. As President of BlueSci, she is passionate about all things science communication. Artwork by Josh Langfield.
