After completing a Ph.D. at the University of Iowa, followed by a teaching-and-research position at the University of Chicago, Beatrice Mintz accepted a full-time independent research appointment in Philadelphia at the Fox Chase Cancer Center.
Mintz would now be able to embark on the novel program she had only imagined when she was still a graduate student. Her plan was to bring together two genetically distinguishable cells in the same embryo, to reveal specific cell lineages and interactions, not only in the embryo but throughout life. The mouse would be the ideal subject, as many inbred strains with known genes already existed.
She soon confronted the many technical problems. Culture media for early mouse embryos were available. She found that the membrane around the egg and early embryo could be easily removed with a proteolytic enzyme. She then made a critical new observation: The cell surface becomes spontaneously sticky in the third cleavage cycle. Thus, the embryos need only be placed in contact to adhere, with no physical restraint. She designed and published simple equipment to facilitate handling and culturing the doublet-embryos. After they were surgically transferred to the uterus of pseudopregnant females, high viability resulted.
The first mice to be born had orderly transverse patterns of two separate coat colors, attributable to their genetically dissimilar origin. Beatrice Mintz has referred to the first sight of these beautiful animals as the most exciting moment of her scientific life. She termed the mice “allophenic,” but that nomenclature was generally resisted in favor of the misleading mythological reference to “chimeras.”
Mice demonstrably comprising cells of different histocompatibility genotypes remained “intrinsically” tolerant of both types, thus further enlarging their experimental usefulness for many investigators. Among the developing systems effectively investigated in Mintz’s laboratory, in addition to the pigmentary system, were muscle development from fusion of uninucleated myoblasts and hematopoiesis of all blood cell lineages from a small pool of multipotent precursors. Such analyses also enabled a better understanding and, in some cases, treatment of diseases such as anemias and anomalies of sex development.
As the investigations continued, Mintz proposed a new unifying principle, which she described in 1970 and entitled “The clonal basis of mammalian differentiation.” According to this view, differentiation originates from small groups of stem-like cells each capable, at mitosis, of yielding a more differentiated cell as well as a cell similar to the precursor. Clones and subclones of increasing specialization could evolve in this way. Moreover, a control mechanism to regulate gene expression would be required.
Mintz then realized that neoplasia might be fundamentally an aberration of development, in which a stem cell can shift its mitotic balance toward cell division rather than cell differentiation.
Her laboratory then undertook a series of experiments with cells from a mouse teratocarcinoma, which was thought to originate in early development. When the cells were placed in normal host embryos of another mouse strain, most of the resulting mice were tumor-free and had normally functioning cells of both the tumor-strain and host-strain in all tissues studied. This was the first instance of normalization of genetically tumor-prone stem cells. It led Mintz to conclude that the tissue microenvironment plays a major role in the development of stem cells.
Mintz used other approaches aimed at producing whole-animal models of human cancers or other diseases in mice. She showed that specific DNA could be injected into a fertilized mouse egg, incorporated into the genome, expressed, and transmitted to progeny.
Based on her previous work on development of melanocytes in chimeric mice, Mintz now chose to produce mouse models of malignant skin melanoma. Her lab injected into the egg a transgene of her design. With additional manipulations, mice were eventually produced in which metastatic melanoma resembling the chief subtypes of human melanoma were obtained.
Beatrice Mintz’s ongoing work, with mouse models, is now chiefly directed at obtaining a better understanding of this disease and discovering effective treatment.