The Pink Virus 101: Peas, Genes, and Cancer

By Dr. Kathleen T. Ruddy

The next installment in my lecture series on the history of the Pink Virus (i.e., the breast cancer virus) continues …

It was not noisy prejudice that caused the work of Mendel to lie dead for thirty years, but the sheer inability of contemporary opinion to distinguish between a new idea and nonsense.
Wilfred Trotter

Gregor Johann Mendel was a friar, a celibate who never had any children of his own. Yet despite the prohibition against marriage imposed by his religious order, the Augustinians, Mendel created a vast progeny with an impressive legacy, for he is known as the Father of Genetics.

Mendel was born in 1822, the second child of a German family that had lived and farmed the same land located in what is now the Czech Republic for more than four generations. As a child, Mendel kept a garden and raised bees, natural occupations for a farmer’s son. But as Mendel got older he felt a calling to the church and made the decision in late adolescence to become a monk. In 1843 Mendel chose the Order of St. Augustine for his vocation. Augustinian friars pray throughout the day but, unlike cloistered monks who live in a self-sufficient enclave, they are active in the community, typically functioning as teachers and scholars. Mendel enrolled at St. Thomas, a small and beautiful stone abbey . He received his orders eight years later, taking the vows of poverty, chastity, and obedience – otherwise known as the evangelical counsels.

Mendel then moved to Vienna to study physics at the University of Austria. He returned to St. Thomas two years later, where he once again kept a garden, raised bees, and taught physics. His garden and beehives were more than a source of sustenance for Mendel and his fellow friars at the Abbey. They functioned as natural laboratories where Mendel could conduct experiments with God as his mystical assistant. What better way to understand the practical hand of God than to study God revealed in nature? Fueled by a love of mathematics fostered in the study of physics, Mendel began a series of experiments whose goal was to formulate the mathematical principles of what he and others assumed were ‘inherited’ traits. You didn’t need to be a scientific scholar to know that if everyone in a particular family had blond hair and blue eyes, it was unlikely that a child with black eyes and black hair would suddenly appear. And if one did, it would be fair to assume that some dark invader had mustered in. Farmers and breeders of farm animals knew well that traits were inherited and passed along to offspring. Mendel and his relatives must have used this information in the decades they spent on their farm. Everyone involved in farming and animal husbandry must have been well versed in the practical application of inheritance of traits, but Mendel wanted to work out the exact mathematics involved in these observed patterns. Mendel chose to begin his series of experiment using the pea plants in his monastery garden.

Using different colored peas, Mendel bred and crossbred different plants, first to record the results, and then to see if he could create mathematical models to predict the results of the next round of experiments. The experiments and models went very well as long as he confined himself to his garden, but when he turned his sights on bees his experiments took a dangerous turn. Unwittingly, his crossbreeding experiments produced a vicious strain of bees whose queens were notoriously insatiable in their mating behavior. Mendel abandoned the bees and returned to his pea plants to begin a new series of crossbreeding experiments.
Mathematics is often considered to be the language of science, especially of physics. And as a physicist, Mendel was adept at using mathematics to express scientific observations, and even to predict them. Mendel used the data he collected as a result of his crossbreeding experiments in pea plants to generate mathematical models that could explain and predict his observations. After generating his mathematical models based on his experimental observations, he was able to predict the outcome of an experiment in which he would crossbreed, say, a pea plant with a green pod pea with a plant that had a yellow pea pod. It wasn’t long before he was pretty good at predicting results, good enough to formulate some rules of inheritance. This was actually quite clever, for apparently no one had thought to do this before. Without benefit of formal training in biology or botany, per se, Mendel recorded his observations, generated his mathematical models, and discovered that traits were passed from one generation to the next in a mathematically predictable fashion. The field of genetics was thus born in Mendel’s garden. Mendel’s mathematical models of inheritance indicated something else beside a canny ability to predict outcomes of crossbreeding experiments: it was clearly evidence from the experiments that each plant provided exactly one-half of the biologic information needed to form the results observed in its offspring. In fact, Mendel’s models spoke of more than merely numerical outcomes, they spoke of the hidden genes involved in making the oh-so-predictable predictable outcomes so.
Mendel’s experiments and their results, and the mathematical models derived from them allowed him to put forth the first law of inheritance, known as the Law of Segregation: Each trait requires a combination of information, half of which is inherited from one parent, and half from the other. Each parent contributes equally to the traits observed in their offspring. You can depend, and even bet on that.

Mendel increased the complexity of his experiments by crossbreeding peas that differed in two ways. For instance, he took plants with green pods and yellow peas and bred them with plants that had yellow pods and green peas. By making his experiments more complicated via increasing the number of traits being tracked in the crossbreeding studies, Mendel wanted to know whether these individual traits (pod color, pea color) were passed independently or if they were linked together as they made their way up and across the family tree. It didn’t take long for Mendel to discover that individual traits are inherited independent of one another. This became Mendel’s second law of inheritance, known as Independent Assortment. It’s exactly why when you look in the mirror you may see your mother’s nose, your father’s eyes, your grandmother’s hair, and your grandfather’s jaw. It explains the incomparably handsome confluence of features seen in the personage of John F. Kennedy, Jr. – his father’s strong facial bone structure, jaw and brow (Irish traits) and his mother’s dark hair and eyes, which she inherited from her father. His height seems to have been passed down from his mother’s side of the family. We can all agree, it was a sensational combination of inherited traits, indeed; each one passed independently of one another, all converging in one glorious man.

Back at the monastery, Mendel continued to work in his garden laboratory recording observations, collecting data, and generating ever more clever predictions of pea pod inheritance patterns. Mendel created great harvests of food and scientific information, while managing to attend to his other duties as a friar in his monastery. And as long as he was puttering around with peas in the garden, his superiors left him alone. But when Mendel attempted to expand the range of his experiments to include animal studies in mice, his provincial superior, Bishop Anton Schaffgoth, had a fit. Why were peas acceptable as study subjects but not mice, you ask? Though hard to believe by today’s standards, the Bishop balked at experimental studies of inheritance patterns in mice because that would involve, nay encourage, unrestrained copulation. Such wanton behavior, even in mice and even if done to better understand God’s plan for the universe, was unacceptable, intolerable, and out of the question. Amen.

A chastened Mendel retreated to his garden, to the 29,000 peas in his abbey laboratory, and contented himself with the use of non-threatening, non-copulating plants to refine the mathematical formulae that predicted nature’s inheritance patterns.

Mendel published the results of his experiments in 1868, but because of his increasing responsibilities at St. Thomas’s abbey—by then he was its Abbott – he lacked sufficient time, or energy, to submit further papers to the scientific journals. Right from the start, Mendel’s work was well received among the academic community. His work and his data were rarely criticized; but, nevertheless, the results of Mendel’s experiments were cited only three times in the scientific literature over the course of the next thirty-five years. The whole idea of genetics, per se, and the utility of mathematical modeling in predicting inheritance patterns, did not immediately capture the imagination of the broader scientific community. evolutionary ideas almost never explode on the scene all at once, but rather smolder unattended until, after a good long while, a few passers by blow on the embers and, so, set the world on fire. And, thus, Mendel’s research, his data, his mathematical models, and his papers lingered like smoking, glowing ashes well past his death.

Unfortunately, Mendel died of kidney disease in 1884 never knowing what a profound contribution he had made to science. Indeed, today the field of genetics is in the throes of explosive growth, thanks to the work that he did in his garden with his peas.

Mendel’s work was unearthed and recognized as buried treasure around the year 1900, the same year Abbie Lathrop moved to her farm in Granby, Massachusetts. The second coming of his resurrected research created a new religion of its own – genetics – and with it, a stampede to test Mendel’s Laws of Inheritance in animals; and, perhaps one day, in humans too. One of the first men to grasp the importance of Mendel’s mathematical models and laws was a senior at Harvard University, a transfer student in biology who moved to Boston just eight years after Mendel died. His name was William Castle. He was from Ohio and he, too, grew up on a farm. Castle, ever prescient, was intent on making a name for himself in the newly emerging field of genetics, an area that he believed held a vast, uncharted horizon with plenty of room for fame and fortune. Castle studied Mendel’s papers intently and decided to see if Mendel’s Laws of Inheritance applied to animals as well as plants. Fortunately, though Harvard University had been founded by an Anglican minister (John Harvard, of puritan inclination) no one there during Castle’s tenure had any qualms about the role copulation might play in the study of animal genetics.
Castle began breeding small animals: guinea pigs, rats, and mice. Mice were an especially good choice for animal experiments because they bred quickly, reached maturity within three months, and produced several large litters every year thereafter. Just as Mendel’s bishop feared, their natural fecundity yielded abundant data for genetic studies in Castle’s laboratory, a mountain of data he could analyze and compare to Mendel’s results with plants.

After graduation, Castle remained at Harvard to begin a doctoral program in the Department of Biology. He focused his research and doctoral thesis on mammalian patterns of inheritance, what we would call Modern Genetics today. Keep in mind that at the time no one knew that genes even existed or how they worked. They just knew that there were separately inherited traits passed along to offspring from both parents in equal portion, and that these patterns of inheritance fit mathematical models derived from observational data that accurately predict them. It would be years before anyone knew that it was the genes themselves, biologic structures composed of DNA, that carried the information that were made manifest as observable, inherited traits.
Castle was appointed to the faculty at Harvard in 1897, and was then given free rein to launch his career and the field of mammalian genetics. In 1902, as one of a many scientists queuing up outside the gate of Lathrop’s farm in nearby Granby, Castle placed his first order for mice. Over the years, Castle obtained the majority of mice for his experiments from Lathrop, the schoolteacher-turned-entrepreneur who’d engaged a scientist from Philadelphia (Loeb) to study the genetics of breast cancer for herself.
Castle’s mouse experiments soon cluttered the cramped offices he was given in a building on Harvard’s campus in Cambridge. As soon as the opportunity presented itself, he gladly moved his operation to the much larger, open space at Harvard’s Bussey Institute for Applied Biology, located in Forest Hills, a farming community an hour outside of Boston. Bussey had been Harvard’s center for husbandry and agriculture for years. It was the perfect place for Castle and his teeming mice. His move to Bussey also put a safe distance between Castle and a fierce band of competitive colleagues back in Cambridge, many who were enthralled to the real power players in academia, the men who ran Harvard Medical School. The medical men were skeptical about the value of studying mammalian genetics, for they could not see its practical application to the see its to clinical medicine. Altogether, Castle was relieved to be essentially out of the reach of glancing blows from uniformed and not always benignly ignorant academics. He was more than content to be a full day’s drive away in the Massachusetts countryside, free to convert a large, abandoned greenhouse at Harvard’s Bussey Institute into a mouse dormitory, factory, and breeding ground. About as soon as he arrived, he got busy filling his distant empire with mice from Abbie Lathrop’s farm. With no one to stand in his way or slow him down he designed animal experiments in the manner of Mendel’s studies in plants, and than he enthusiastically allowed nature to take its course.
Meanwhile, others were hot on the trail of animal genetics, particularly as it related to cancer. While Castle was busy at Bussey, Loeb continued trying to understand why breast cancer was found in such high rates in certain breeds of mice on Lathrop’s farm. In 1928, ten years after Lathrop died, Loeb published another paper, this one with Ida T. Genther, a pathologist from Washington University School of Medicine in St. Louis. In it Loeb and Genther suggested that there were at least two factors working together to produce breast cancer in Lathrop’s mice. The title of the paper, published in the journal Experimental Biology and Medicine, said it all: “Heredity and Internal Secretion on Origin of Mammary Cancer in Mice.” Loeb and Genther began their paper by stating that “heredity was a factor of very great significance in the origin of cancer in mice. While certain strains had a cancer rate approaching zero, other strains had a rate approaching 80% or more. In successive generations these differences in the rates of breast cancer between different strains of remained approximately constant.” What Loeb and Genther were saying was that breast cancer was, at least in part, an inherited trait; and it was an inherited trait that was variable depending on the strain of mice being studied. But there was something else at work besides pure inheritance. Pink eyes might be inherited by mice in a purely mathematical and predictable fashion, but breast cancer (though inherited in part) had other factors working on it, apart from the genes themselves. Specifically, Loeb and Genther showed (as Loeb and Lathrop had done before) that the ovaries were very much involved in bringing breast cancer to light.
Loeb and Genther stated, “However, in the further analysis of the causes of mammary cancer in mice we found that in addition to heredity, the functional activity of the sex organs played a significant part in the origin of cancer.” Loeb and Genther discovered that if they castrated the mice (surgically removed their ovaries) the risk for breast cancer fell sharply. Furthermore, the earlier in life that castration was performed the more profound the protective effect was observed in preventing breast cancer. “A quantitative relation was thus established between the internal secretion of the ovary and the frequency with which cancer appeared in the breast of mice.” It was pretty clear – the ovaries were linked to breast cancer: no ovaries, no breast cancer.

Lathrop died in 1918, ten years before Loeb published this paper confirming work they’d done together. Loeb’s 1928 paper demonstrated once again that genetics was an important risk factor for the development of breast cancer, but even then they knew that other factors played a role too. Ovarian function appeared to increase the risk for breast cancer in high-risk mice, sometimes to a great extent. Surgical castration to ablate ovarian function caused the risk for breast cancer to plunge. Indeed, when it came to cancer, the clearly ovaries fed the breast tumors. While scientists like Loeb and Genther noted the importance of other confounding variable involved in modulating breast cancer risk in mice, the majority of scientists pursuing the genetic cause of cancer focused almost entirely on identifying the genes involved. Pure genetics, the mathematically pure and simple models and formulations first recorded by Mendel in his monastery garden, became the Holy Grail for cancer research. Many would argue and argue well that it still is. But like the Holy Grail, it was and is more talked about than touched upon.