Research
Hay is best known for her research in limb regeneration, the process of epithelial-mesenchymal transitions (EMT) during development, and the role of the extracellular matrix (ECM) in cell differentiation. When beginning her research career with Rose, their focus was on the induction of limb regeneration in animals that were not able to regenerate their limbs. They worked on tracing the origin of the cells in regenerating blastema. By transmission electron microscopy (TEM) they showed that the blastema that formed on the amputated surface of the amphibian limb contained uniform undifferentiated cells. These cells lost all remnants of their myofibrils or any other sign of previous differentiation. Hay was able to show the stages of myofibril loss by differentiated muscle cells using TEM. She confirmed that the limb tissues gave rise to undifferentiated blastema cells. Through this research, Hay came to the final conclusion that the differentiated somatic cells of the amphibian limb preserved enough developmental strength to fully regenerate a perfect limb. In other words, the regeneration of the limb is achieved when differentiated cells begin to dedifferentiate and become stem cells.
In 1957, Don Fischman started as a medical student at Cornell and immediately joined Betty's laboratory due to his undergraduate experience of working with amphibian limb regeneration. They traced the blastema cells with titrated thymidine and discovered that the epidermis did not enter the blastema. The blastema was the formed internal tissues, not the reserve cells or the epidermis, that gave rise to the regenerating limb. Their autoradiography observations on regenerating limbs also proved that mononuclear blood cells are the source of osteoclasts. When looking at the limbs, they could only obtain labeled nuclei from the monocytes. Therefore, Hay specifically labeled the blood and exhibited that the osteoclasts came from the blood cells.
In 1965, Hay met Jim Dobson, who was a scientist that was very good at culturing and growing up epithelium. Hay needed his help in order to prove that the epidermis produced collagen, which was an idea that she and Jean-Paul Revel originally postulated. They used avian corneal epithelium rather than salamander epidermis in order to provide more examples of epithelium secreting collagen. They produced a monograph of their findings, which was published in 1969. Steve Meier joined soon after, and in about 1974, their lab was becoming known for promoting the new idea that the ECM interacted with cells. They cultured corneal epithelium in all types of ECM and were able to show that the ECM can induce cell differentiation and that it directly interacts with cells in the embryo and adult. In 1972, Jonathan Bard came to spend a postdoctoral year in the Hay lab, working on two projects. The first was on corneal endothelium morphogenesis and they, with Sam Meller, showed that the key constraint on migration was space. The second was using Nomarski optics to study how corneal fibroblasts migrated through the stroma in vivo and in collagen gels (a technique developed by JB and Tom Elsdale in Scotland). This work showed that contact inhibition of movement occurred in vivo and in 3D gels.
Gary Greenburg then entered Betty' lab as a graduate student, and they started working with 48-hour chick embryos. They were able to see epithelia transform into mesenchyme when they were suspended in collagen gels. Jim Fitchett also entered the lab at about the same time. He worked with Hay using TEM to prove that EMT removed the palatal seam that forms when the opposite shelves fuse. Furthermore, their studies of the signaling pathways involved in EMT during development led to the discovery that Smads can activate these pathways in the embryo, instead of β-catenin.
Many colleagues and fellow scientists claim that Betty's greatest scientific contribution was revealing the role of extracellular matrix in regulating cell behavior, which led to the birth of a new field of cell and developmental biology. Hay believed that knowledge of the ECM was essential in order to understand other subjects including the cytoskeleton, cell migration, cell shape, and the control of cell growth and differentiation. She asserted that the basis of many scientific ideas originate from the full understanding the ECM's composition, relationship to the cell surface, and role in development. In all, Betty's passion for science, dedication to her work, and love for teaching others have all contributed to the legacy she has left.
