The single most remarkable thing about Beatrice Mintz was that she did so many remarkable things. Working mostly on her own through a seven-decade career, her work was foundational to several different areas of biology: embryonic development, stem cell dynamics, epigenetics, the clonal theory of cancer, and the importance of the tumor microenvironment. In a world of hedgehogsscientists who focus on one big idea and are often known for one big discovery—Bea was the ultimate fox, with a wide range of interests and a diverse set of key discoveries.

Bea passed away in January 2022 at age 100. She was born in the Bronx as the youngest of four children in a working-class family and attended Hunter College, at the time exclusively a woman's college, on a New York State Regents Scholarship. After completing graduate work at the University of Iowa in the lab of the embryologist Emil Witschi, in 1946, she obtained a faculty position at the Whitman Laboratory of Experimental Zoology at the University of Chicago. During that time (in 1951), she was awarded a Fulbright Scholarship to study in the Universities of Paris and Strasbourg. Bea's early research focused on development in amphibians but eventually expanded to include other vertebrates. It was at the Whitman Laboratory that she got the idea for her first big advance. She believed that it might be possible to develop embryos that had more than two parents by mixing cells from two different 32-cell blastocysts. The question was, if one transferred cells from a blastocyst derived from parents that had white fur to one derived from parents that had black fur, what might the resulting pups look like? Would the resulting progeny have black, white, gray, or a mixed coat color? Each possible result would reveal something profoundly important about development.

For a variety of reasons, Bea was not able to carry out her embryo mixing experiment while in Chicago. It was partly for this reason that in 1960 she was eager to join the supportive geneticist Jack Schultz at the Institute for Cancer Research in Philadelphia, which later became Fox Chase Cancer Center. There, freed from the obligation to teach, and with institutional funding, she set up a one-woman lab and put her ideas to the test. It was at Fox Chase that Bea devised the techniques that allowed cells from genetically distinct embryos to be assembled into a single group in culture, and then transferred to surrogate mothers. Amazingly, the progeny from her experiments came out bearing not one coat color but mixtures of black and white fur in defined striped patterns depending on how many cells were transferred between blastocysts. Of gray fur, there was none. It is difficult to recount the awe with which these first creatures, which she called “allophenic” mice, possessing four rather than two parents, were beheld. More importantly, the distinguishable genetic markers available in the cells opened the way to numerous, previously inaccessible avenues of investigation and laid the groundwork for understanding the fundamental principles of how organs are constructed in the embryo, illuminating the developmental origin and migration of particular kinds of cells and the occurrence of specific cell interactions.

In a following groundbreaking series of experiments, Bea used her newly developed expertise to investigate the relationship between oncogenesis and normal cell differentiation. For this work she focused on the presumed stem cells of mouse teratocarcinomas (EC cells), which had previously formed only tumors with a disorganized and limited variety of tissues. Testing the hypothesis that such cells might be deregulated counterparts of early embryo cells, she introduced them into normal early mouse embryos of another genetic strain, enabling the mitotic descendants of the introduced cells to be identified. What she found was again paradigm shifting: The stem cells became permanently “normalized” and differentiated in an orderly way along with cells from the host embryo. In addition to the demonstration that such manipulation could be successful, these experiments had deep scientific implications; they revealed that the accompanying embryo cells influenced the teratocarcinoma stem cells profoundly. This work demonstrated that cancer might be regarded as a defect in cell differentiation, ushering in new ideas for cancer treatment. Bea's results, important in their own right, also influenced the thinking of her Fox Chase colleague, Al Knudson, who was at that time working out the two-hit theory of tumor suppression. In light of Bea's startling results, they both recognized that, in addition to genetic causes for cancer, there must also be a second layer of epigenetic control that regulated tumorigenesis, opening the possibility of reprogramming the nuclei of differentiated, somatic cells.

The mix-and-match approach to produce allophenic mice suggested another, equally audacious line of experiments for Bea to consider. Rather than simply mixing cells in the blastocyst, would it be possible to introduce foreign DNA into a fertilized egg, thereby producing a “transgenic” mouse? With the help of visiting postdoctoral fellow Rudolf Jaenisch, this was accomplished in her laboratory by injection of purified SV40 DNA, even before cloned genes were available. Much to the scientific community's surprise, they found that the viral DNA was incorporated successfully and was retained in the animal's genome! Her laboratory thus became one of four, working independently, in which the DNA of a specific gene was introduced into fertilized eggs and became functional. The production of these transgenic mice provided Mintz (and others) valuable experimental systems to study oncogenesis and therapies in tractable animal models.

The animal model of oncogenesis that Bea chose to focus on was malignant melanoma, one of the most rapidly increasing cancers in the United States and one of the most serious. In 1991, Bea derived a transgenic mouse model in which the expression of the SV40 oncogene is directed to the melanocyte lineage. Such animals are genetically susceptible to cutaneous melanomas, which are inducible experimentally by tissue growth factors or by ultraviolet irradiation. Surgical removal of the cutaneous tumor often results in increased growth of preexisting metastases, a useful parallel with results in human surgical oncology. Her laboratory also explored novel strategies for treatment of melanoma in this mouse model. With this system she pioneered the notion of targeting antigens that are expressed preferentially on tumor cells (now called tumor-specific antigens) as an avenue for cancer detection and treatment.

Bea's style of doing science was unique. She believed in making her own reagents and tools when none were available. However, her real strength was in identifying what she considered the most fundamental questions and determining the most direct and convincing way to address them. Whether her ideas fit current dogma was totally irrelevant; she was absolutely fearless in pursuing whatever she felt to be interesting and important. As she claimed many times during her long career, she was only interested in big problems and could be dismissive of those whom she felt were wasting time on more minor affairs.

Over the years, Bea had a small handful of collaborators, postdoctoral fellows, and technicians, and only one graduate student. She set special rules for her laboratory staff. One was that they needed to live close by. To ensure that they did, she would take out a map and compass and draw a one-mile circle centered on Fox Chase Cancer Center. Living inside the circle was acceptable; living outside of it was not. On the other hand, she did take the month of August off every year and expected her staff to do the same. Despite these unusual practices, several of those few who managed to get accepted into her lab went on to do great things themselves, including Rudolf Jaenisch, Michael Karin, Lionel LaRue, and Bea's sole graduate student, Blanche Capel.

Even among the highly idiosyncratic world of top scientists, Bea was unique, with a personality that could be both inviting and formidably imposing. At her best, Bea was warm and generous with her time. She would give long and detailed descriptions of her ideas to those she deemed truly interested. On the other hand, she did not, as they say, suffer fools gladly, and she could be painfully blunt in her assessments. But for those who could keep pace with her thinking, her piercing questions could be most helpful for rethinking one's assumptions.

In terms of longevity, creativity, and impact, Bea can be compared with Barbara McClintock and Rita Levi-Montalcini, two scientists whom she admired unreservedly. We found among her papers several reprints of articles by and about McClintock. These were heavily underlined in places, including a double bracket around a quote about her colleagues' occasional lack of acceptance of her prescient ideas, “It didn't bother me, I just knew I was right”; words that could equally have applied to Bea herself. One of us (A.M. Skalka) who knew both Barbara and Bea can attest to the fact that their feelings of admiration were mutual. Bea also knew Levi-Montalcini personally and was in frequent correspondence with her. Like these two pioneering woman scientists, Bea had to deal with the many barriers for women in science, and she was not shy about describing her struggles as a young researcher.

Knowing Bea as we did, we are fairly certain that were she still alive to read this article, she would be pleased to be remembered, but also quick to criticize us for getting certain details wrong. That was Bea in a nutshell. She was brilliant, exacting, and a bit vain at times, but ultimately right about almost everything she turned her mind to. Her peers were few, her accomplishments many, and we miss her greatly.