The next lecture in this series about the breast cancer virus takes us back 100 years, to a spinster’s farm in rural Massachusetts.
Dr. John Bittner of the University of the University of Michigan discovered the breast cancer virus in 1936 while working at the Jackson Memorial Laboratory in Bar Harbor Maine under the direction of Dr. Clarence Little of Harvard University. These eminent scientists with impeccable academic credentials were pointed in the direction of their momentous, albeit surprising discovery by Miss Abbie Lathrop, a spinster who bred small animals to be sold as pets on old chicken farm in Granby, Massachusetts. If contrast is the key to clarity, there could have been no sharper distinction between the pedigrees of these men and this woman. Yet they shared one thing in common, a keen intellect driven by laser vision.
Lathrop was born in Illinois in 1868. Her parents, both teachers, chose to home-school Abbie, their only child, until she was sixteen years old when Abbie decided to become a teacher too. She attended a year of formal schooling and received a teaching certificate. Lathrop then took a teaching position at an elementary school but was forced to retire after just a few years because of illness: she suffered from pernicious anemia, a disease of the lining of the stomach that prevents proper absorption of vitamin B12. Patients with pernicious anemia suffer from a slowly worsening spectrum of metabolic and neurologic problems that ultimately leads to an early demise. (Lathrop died at the age of 50.)
Although Lathrop was not strong enough to continue teaching, she felt she had the stamina to run a small chicken farm and so in 1900, she retired to the Massachusetts countryside outside of Boston to begin a new, less demanding life. But chicken farming did not go well for her either. Lathrop gave it up after a few years and switched to raising small animals to sell as pets. She bred guinea pigs, rabbits, ferrets, canaries, and mice. Yes, mice. Having mice as pets was all the rage, a cultish pastime that had started in Japan in the 1700’s, made its way west to China, from there to Great Britain via the export trade, and then on to New England. Mice were raised, bred, and sold just as we breed cats, dogs, and horses today. Mice were bred for appearance (coat and eye color) and behavior: “waltzing” mice, born with an inherited dysfunction of the inner ear that made their gait unstable, were the most prized of all. A waltzing mouse with a sable coat and ruby eyes might fetch a great sum in a demanding market, well worth the time effort a breeder spent producing and raising them. Mouse conventions, mouse clubs, and mouse newsletters reflected the robust market for pet mice and the expanding opportunity for breeders, especially in New England. At the height of the mouse craze, Lathrop got rid of her chickens and purchased a single pair of waltzing mice. And with these two little mice Lathrop built an empire. Years later she confessed she had no idea what she was getting into, for within a few years she had an inventory of more than 11,000 animals and was barely able to keep pace with the growing demand of a growing market.
From the beginning Lathrop intended to expand her product line beyond the original waltzers, and so advertised in local newspapers to purchase other kinds of mice. In addition to finding new breeding sources she could use to expand her own inventory, she began to receive inquiries from clients, called “mouse fanciers”, who wanted to buy mice from her. Then, quite unexpectedly, Lathrop began to receive inquiries from scientists who wanted to purchase mice for experiments. This was a relatively new endeavor – animal experiments using mice – but it was the fastest growing portion of the market. The demand for experimental mice was growing exponentially, with scientists everywhere scouring the land for mouse breeders. The scientists at nearby Harvard University were no exception. Researchers in Harvard’s Department of Biology had just begun to use mice for laboratory experiments, were playing catch-up with other academic institutions around the world, and were keen to have a ready source of experimental animals for their studies. Lathrop’s farm, with it thousands of mice, was the answer to many prayers. Her farm became the source of mice for researchers at New York University, the University of Pennsylvania, and nearby Harvard University. Orders mounted so rapidly that Lathrop began to enlist the help of local schoolchildren, whom she paid seven cents an hour to feed the animals and clean their cages. Her success produced a steady, handsome income and, more importantly, financial security. But her interest in mice did not end at the bottom of her ledger book, for she developed her own curiosity about the experiments that were being done on her mice. Despite her lack of formal education – we can assume Lathrop had only a scant knowledge of biology and certainly no knowledge of genetics – she had an alert, curious, and incisive mind worthy of the most prestigious academic institutions in the world. By discovering what other scientists were doing, and by consulting and collaborating with them in experiments she carried out on her farm, Lathrop pointed men far more educated, but none wiser than she in the direction of one of the most significant discoveries ever made in the field of breast cancer research.
Lathrop noticed that certain strains of mice had a tendency to develop breast lumps that she believed were malignant. By listening attentively and by asking probing (but, one can imagine, non-threatening) questions, Lathrop was became aware that scientists at Harvard and other universities wanted to understand the genetic causes of cancer by studying the inheritance patterns of cancer in mice. As soon as she got wind of that, she suggested that if they wanted to learn more about cancer in mice they ought to take a good look at the strains of mice on her farm that had a tendency to develop breast cancer. Then she sent out letters of inquiry to researchers at other academic institutions offering to send along some of her tumor-prone mice so they might “determine the cause of the malady.” One of the researchers Lathrop contacted was Dr. Leo Loeb, a pathologist at the University of Pennsylvania, who was more than happy to take a look at Lathrop’s mice. Loeb confirmed that Lathrop’s mice had breast cancer. For Loeb, this cold call from a retired, spinster teacher-turned-mouse-breeder was a terrific opportunity to learn more about how and why mice developed breast cancer. It proved to be an auspicious beginning of a short but productive collaboration between two unlikely strangers who shared passion for understanding the cause of cancer. Loeb and Lathrop began experimenting with two strains of mice, those that appeared to be predisposed to breast cancer and those that did not. Loeb designed the experiments, sent the instructions to Lathrop, who then carried them out on her farm and recorded the results, sending the data back to Loeb for his analysis. In an arrangement that was highly unusual, they appeared as co-authors in a series of papers published in medical journals between 1907 and 1918 that summarized the results of their experiments on mice with breast cancer.
In a 1915 article, “Further Investigations on the Origin of Tumors in Mice,” Loeb and Lathrop noted that in strains of mice in which the incidence of breast cancer was highest, the tumors also formed at an earlier age. They concluded that tumor rate and age of tumor onset represented “distinct factors which frequently, but not in all cases, are in some way linked to each other.” What they were observing was that in the strains of that had a tendency to develop breast cancer, the mice also tended to get breast cancer at an earlier age than that seen in strains of mice in which breast cancer was relatively rare. They were just beginning to understand, therefore, that a genetic predisposition to breast cancer also tended to drive down the age at which the breast cancer would occur. Of course, today we know that this is absolutely true: women who carry a BRCA mutation tend to get breast cancer at a much earlier age than women who do not carry these mutations. But it was Loeb and Lathrop who, nearly a century before, first observed the notable link between a genetic predisposition for breast cancer and the age of onset of the disease.
In another experiment, Loeb and Lathrop discovered that the age at which mice got breast cancer was linked to the age at which their ovaries began to function. They noticed that even in strains of mice with a high incidence of breast cancer, the tumors did not appear before adolescence. Furthermore, Loeb and Lathrop discovered that breast cancer in all strains of mice, but especially in those with a high incidence of breast cancer, could drastically reduced if their ovaries were removed before they reached puberty. Of course, they really had no idea then what, precisely, the ovaries did in relation to the breasts or breast cancer; but they could readily observe that without their ovaries the mice did not develop breast cancers at all, or at a reduced rate and at a later age. Without knowing exactly why, Loeb and Lathrop provided that shutting down the ovaries, for the most part, shut down the risk for breast cancer. It was these two unlikely collaborators, an academician and an amateur, who first opened the door to our present day understanding of the relationship between the ovaries, the breasts, and cancer.
Once they had nailed the ovaries as co-conspirators in the development of breast cancer, Loeb and Lathrop moved on to undertake a series of experiments involving pregnancy and breast cancer. Using strains of mice with a high and a low risk for breast cancer, they performed studies to better understand how pregnancy affected the incidence of breast cancer in each group. Loeb and Lathrop observed that strains of mice with a high incidence of breast cancer always developed breast cancer after puberty, usually after several pregnancies. Pregnancy seemed to have little affect on the incidence of breast cancer in strains with a lower incidence of breast cancer. Thus, a genetic predisposition, the presence of functioning ovaries following puberty, and whatever other changes occurred as the result of pregnancy seemed to work in concert to increase the onset of breast cancer in susceptible mice.
Loeb and Lathrop published their last paper together in 1918, the year Lathrop died. In it they revealed their most interesting discovery. They had performed the first experiments cross-breeding strains of mice in which there was a high incidence of breast cancer with mice from strains that didn’t seem to get breast cancer at all. These crossbreeding studies, later adopted by Harvard researchers, became the nexus for understanding the inheritance patterns – that is, the genetics – of breast cancer. Loeb and Lathrop took mice from high and low-risk strains, allowed them to crossbreed, and recorded the results to see if they could identify reproducible patterns of inheritance, clues to the genes that might be responsible for the disease. What they found was both startling and confusing: The risk of breast cancer tended to follow the mother; the father’s contribution was imperceptibly small. This didn’t make sense if breast cancer was inherited like any other trait like, say, eye color, in which both parents shared equally in the results observed in the offspring. Loeb and Lathrop found that cancer was inherited down the maternal line, almost exclusively. That didn’t fit the patterns of genetic inheritance worked out elsewhere. Loeb and Lathrop also discovered that once the risk for breast cancer had been inherited (via the mother), the increased risk endured forever: all subsequent females carried the increased risk in perpetuity; the increased risk for breast cancer could not be diluted over time as can happen with other inherited traits like eye color.
In summary, Loeb and Lathrop showed that breast cancer was, in part, genetic: certain strains of mice tended toward breast cancer and others seemed immune to it. They found that breast cancer inheritable, but not in the exact same way as other traits like eye color. They showed that the ovaries were involved and that pregnancy played a role in breast cancer formation, though they had no idea was, precisely, the ovaries contributed. (Only later would we discover that what the ovaries contribute is the hormone, estrogen, a strong promoter of breast cancer growth.) Loeb and Lathrop had discovered hints of breast cancer genes, hints of ovarian involvement, hints of pregnancy-driven breast cancer, but no solid answers about what caused breast cancer in some animals while sparing others.
The experiments that Loeb and Lathrop carried out may seem primitive, even trite, by today’s standards, but they were profoundly important and revealing. There is no doubt that this unlikely pair, working together as trusted strangers without ever meeting, opened the frontier for research on the genetics and hormonal factors that contribute to breast cancer. The results of their very clever, prescient experiments – his design and her execution – remain apt and accurate to this very day.
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