How Elizabeth Hay Unlocked the Secrets of the Extracellular Matrix
For decades, scientists saw it as mere scaffolding. One woman's pioneering vision revealed it as the master director of life itself.
Imagine a building under construction. You might focus on the workers, the cranes, and the machinery. But what about the intricate scaffold that guides the structure's shape, supports the workers, and even tells them where to go? In the grand construction project of life, that essential scaffold is the extracellular matrix (ECM).
For much of scientific history, the ECM was considered a passive, structural support system—little more than cellular "glue." That perception was forever changed by the pioneering work of Dr. Elizabeth Dexter Hay, whose insightful experiments revealed a dynamic, communicative network that actively directs embryonic development, enables regeneration, and influences disease. This is the story of how her "matrix biology" transformed our understanding of life's fundamental processes.
The ECM is not passive scaffolding but an active signaling network that directs cellular behavior.
At Harvard Medical School, she became the first woman to receive tenure and founded the field of matrix biology 2 .
Studied limb regeneration in salamanders at Smith College, sparking her interest in developmental biology.
Earned MD from Johns Hopkins and began using electron microscopy to study cellular structures.
Conducted groundbreaking experiments proving epithelial cells produce collagen, challenging established dogma.
Discovered and named Epithelial-Mesenchymal Transition (EMT) while working at Harvard Medical School.
Her work became foundational for understanding cancer metastasis, tissue engineering, and regenerative medicine.
Before Hay's work, the ECM was poorly appreciated. Today, we understand it as the non-cellular component present within all tissues and organs, a complex network of proteins and carbohydrates that provides not just physical scaffolding but also crucial biochemical and biomechanical cues 4 7 .
A thin, sheet-like scaffold that underlies epithelial cells and surrounds organs 1 .
A more fibrous, flexible network that fills the spaces between cells 1 .
| ECM Component | Primary Function | Key Characteristics |
|---|---|---|
| Collagen | Provides tensile strength; the most abundant protein 7 | Forms strong, fibrous triple-helices; multiple types (e.g., Type I in skin, Type IV in basement membranes) 4 |
| Elastin | Confers elasticity and recoil to tissues like lungs and blood vessels 7 | Forms cross-linked, stretchy fibers that can return to their original shape 4 |
| Fibronectin | Acts as "biological glue" for cell adhesion and migration 7 | A dimer with binding sites for cells and other ECM components like collagen 4 |
| Proteoglycans | Resist compression, retain water, and act as growth factor reservoirs 4 | Core protein with attached glycosaminoglycan (GAG) chains; highly hydrophilic 7 |
| Laminin | A key structural protein in basement membranes 7 | Forms cross-linked networks that interact with cell surface receptors 7 |
In the early 1960s, the scientific consensus was clear: only fibroblasts produced collagen. The idea that epithelial cells could do the same was considered impossible 2 .
Hay and Revel's experiments proved that epithelial cells also produce collagen, challenging the established dogma and revealing the ECM as an active signaling entity 2 .
They treated the regenerating salamander limb with radioactive proline, an amino acid abundant in collagen 2 .
As the limb developed, they used electron microscopy to track where the radioactive proline moved 2 .
The proline was incorporated into the collagen layer, but it was present in both fibroblasts and the epithelial cells before arriving there 2 .
By growing epithelial cells in isolation, they eliminated fibroblast involvement and confirmed that epithelial cells produced collagen on their own 2 .
A crucial, secondary observation cemented the importance of their find. Hay and Revel noticed that when epithelial cells were not placed on an extracellular matrix, they failed to produce collagen 2 . This was the revolutionary insight: the ECM was not a passive product of cells but an active participant in development, providing signals that influenced cellular behavior.
| Experimental Condition | Cell Type Used | Result: Collagen Production? | Significance |
|---|---|---|---|
| In vivo (in the organism) | Salamander limb epithelium | Yes (radioactive proline present) | Challenged the existing dogma that only fibroblasts make collagen. |
| In vitro (cell culture) | Bird eye epithelium, isolated | Yes | Confirmed epithelial cells have an intrinsic ability to produce collagen. |
| In vitro (cell culture) | Bird eye epithelium, without ECM | No | Revealed the ECM is not just a product, but a signal for cell behavior. |
The following table details essential tools and reagents that have powered discoveries in matrix biology, from Hay's era to modern labs.
| Research Tool | Function in ECM Research | Example Use Case |
|---|---|---|
| Electron Microscope | Allows visualization of ECM ultrastructure at high magnification. | Hay used it to track radioactive proline and view collagen fibrils 2 . |
| Radioactive Tracers (e.g., Proline) | Tags and tracks the synthesis and movement of specific molecules. | Crucial for Hay's experiment to trace the origin of new collagen 2 . |
| Cell Culture (In Vitro) | Isolates cells to study their behavior in a controlled environment. | Hay used bird eye epithelial cultures to prove collagen production without fibroblasts 2 . |
| Collagen Gels | A 3D matrix used to study cell migration and differentiation. | Hay used these to discover Epithelial-Mesenchymal Transition (EMT) 2 . |
| Integrin Inhibitors | Blocks cell-ECM adhesion to study the function of specific interactions. | Used in modern research to dissect how ECM adhesion affects cell signaling 1 9 . |
| Matrix Metalloproteinase (MMP) Inhibitors | Inhibits enzymes that degrade the ECM, allowing study of remodeling. | Used to understand tissue repair and the role of ECM turnover 7 . |
Electron microscopy becomes available for cellular studies
Radioactive tracing techniques developed and refined
Cell culture methods become standardized
Molecular biology techniques (PCR, cloning) revolutionize ECM research
Advanced imaging, omics technologies, and bioengineering approaches
Elizabeth Hay's work laid the foundation for modern matrix biology, with applications stretching far beyond the salamander limb.
The goal of tissue engineering is to create biomaterials that mimic the natural ECM to guide tissue repair. By understanding the ECM's composition and signaling capabilities, scientists now design ECM-inspired scaffolds that promote healing in everything from corneal injuries to heart muscle 9 .
Hay's discovery of EMT proved critical for oncology. We now know that cancer cells use the EMT program to break away from a primary tumor, migrate through the ECM, and metastasize 2 6 . The dense ECM in tumors, like pancreatic cancer, is also a major barrier to treatment, making ECM-targeting therapies a hot area of research 6 .
Recent research shows that with age, the ECM becomes degraded, releasing fragments known as matrikines 3 . One 2025 study found that elastin-derived fragments accumulate in the blood, promoting chronic inflammation and driving systemic aging in mice. This suggests that the ECM is not just a victim of aging but an active driver of the process, opening new avenues for anti-aging interventions 3 .
Hay's subsequent work with collagen gels led her to another landmark discovery. She observed that epithelial cells placed in a 3D collagen matrix could lose their polarity and transform into migratory mesenchymal cells. She named this process Epithelial-Mesenchymal Transition (EMT) 2 . This process is crucial for normal embryonic development and, when reactivated in adults, contributes to wound healing, but also to cancer metastasis and fibrosis 2 .
Creating ECM-mimicking scaffolds for organ repair
Using ECM components for targeted therapies
Studying fibrosis, cancer, and genetic disorders
ECM biomarkers for disease detection and monitoring
Elizabeth Hay's story is one of intellectual courage and visionary science. By questioning a fundamental assumption, she transformed our view of the microscopic world around our cells. She revealed the extracellular matrix as a dynamic, information-rich environment that instructs cells on when to divide, where to move, and what to become.
Her legacy is a vibrant field that continues to uncover how this hidden architect builds, maintains, and repairs our bodies—a testament to a scientist who saw the active, living scaffold where others saw only static glue.