The Women in the Mouse Business

The Women in the Mouse Business
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Many branches of science have “Noble” origins. All the philosophers in ancient Greek were a sort of noble class. In England of the 18th to early 20th century, many scientists came from aristocratic families, such as Charles Darwin (founders of Evolutionary Biology) and Henry Cavendish (discoverer of hydrogen). In France, there was Antoine-Laurent de Lavoisier, who founded modern chemistry but was guillotined during the French Revolution. These are just a few examples among many others. 

In contrast, modern genetics has a very humble origin. Every biologist learns the story of Gregory Mendel. Both his parents were farmers. Even after his sister gave him her dowry, he still could not afford the tuition of the university. At the age of 21, he became a monk in Augustinian St Thomas's Abbey for continuing the education without having to pay for it himself. There Mendel also worked as a substitute high school teacher. In 1850 (age 28), he failed the oral part of his exams to become a certified high school teacher. Between 1856 and 1863, he studied how offspring inherited their parents' features by planting peas. In 1866, he published his findings in Proceedings of the Natural History Society of Brünn. I bet you have never heard of this journal. Me neither. In fact, no one read his paper and cared about his findings for the next three decades. After Mendel was elevated as abbot in 1868, his scientific work largely ended, as Mendel became overburdened with administrative responsibilities,      

Mendel, no matter what, held a position in an institute, though not a renowned one. He was a teacher, later a supervisor, and had a title. He wrote research papers that were published in scientific journals. Compared to his work, the mouse cancer genetics was begun at an even more insignificant place. It all started from a woman who sold mice as a small business. In that sense, it’s a very American tale.

Abbie Lathrop was born in 1868 in Illinois to her parents, who were school teachers. She was homeschooled until the age of 16, attended academy for two years, and earned a teaching certificate. She taught elementary school for several years but was troubled by pernicious anemia. At the age of 32, she was forced to retire by the illness and moved to Granby, Massachusetts. She had the spirit of entrepreneurship and wanted to run a farm as her own business, and that should also benefit her health. Initially, she built a poultry farm, but the business did not work out unfortunately. Abbie noticed that “fancy mice”- domesticated mice for exhibition, often exhibiting distinct coat color and pattern- were quite popular as pets among a group of people, who were often called mouse/rat fanciers. In fact, the origin of Mickey Mouse was a fancy mouse that Walt Disney caught and kept in the rented attic when he was a poor artist. She built the second farm to breed fancy and exotic animals, including rodents, guinea pigs, rabbits, and ferrets (see her farm house in the poster image). Her business was booming, so she recruited two of her close friends to help manage the farm. They employed many neighborhood children to clean cages and feed the animals. At one point, Abbie’s farm housed more than 11,000 mice. Her customers even included the U.S. government: it purchased some of her guinea pigs and sent them to the trenches in battlefields of Europe to detect chemical weapons during World War I. 

Abbie’s success was partially attributed to her superb skill in animal breeding. She was able to select traits to breed creamy buffs, white English sables, and other desirable coat variations for mouse fanciers, her major customers. She observed the coat pattern of mice carefully, and kept the record of breeding arrangement and results persistently. Like Mendel, these professional qualities made her a natural geneticist. Not too long after her name became well-known among mouse fanciers, she received a big order from a new client who she would never expect: a professor of Harvard University. His name was William E. Castle. 

That was 1902. Two years ago in 1900, four scientists, Hugo de Vries, Carl Correns, Erich von Tschermak, and William Jasper Spillman, from different countries (Dutch, Germany, Austria, and U.S.), rediscovered Mendel’s study results and acknowledged Mendel’s Law in their own works. The urban legend went that one of these scientists traveled to Brünn, which belonged to the Austro-Hungarian Empire at that time. He was troubled by insomnia and rolled over on the bed in a small hotel room for hours. He decided to get up to do some reading, hoping to get sleepy from the boring texts, and found an old issue of Proceedings of the Natural History Society of Brünn. His eyes picked up something relevant to his own research, which was Mendel’s paper. The article did not help to cure his insomnia; instead, he could not sleep anymore after reading it. The next morning he rushed back to his own university to tell the world that Mendel had cracked the secret of inheritance thirty years ago. This story, like Newton’s apple tree, was probably made up. The truth was that the four scientists had studied genetic inheritance for their lifetime, and were running experiments similar to Mendel’s. They have prepared themselves to re-discovered Mendel’s law from the literature. However, the four accounts were all independent, completely proving the greatness of Mendel’s finding.  

Nevertheless, in 1902, Castle thought to study mammalian genetics by following Mendel’s experiments. Their short lifespans and small size, thus lower maintenance cost, made mice the ideal specimen for research. In particular, fancy mice have been inbred for generations to get  distinct phenotypes (e.g. coat color and pattern), and it was relatively easy to control and observe the genetic variables. Abbie had built her reputation in the fancy mouse business; soon she found herself fulfilling orders for mice by the pound for laboratories. 

As Abbie became very busy in mouse breeding, she did not just produce the number for supply. She carefully observed every mouse born in her farm. She noticed skin lesions on some of her mice, so contacted her customers in the universities to ask if theirs had also developed lesions. Leo Loeb, well-known pathologist in the University of Pennsylvania, did reply, saying that he had found similar lesions in his mice, and they were cancerous. Instinctively, Abbie realized that the cancer in these mice should be associated with their strains, which were “pure” from inbreeding in her farm (though she may not have the idea of genetically homogeneous).

In 1910, Abbie started to collaborate with Loeb to test how the strain influenced the cancer incidence. At that time, mouse facilities were not a thing in research institutes. It must be Abbie who did all the mouse breeding and recorded her observation on each mouse, and Loeb ran pathological analyses on the lesions. They confirmed that the incidence of tumors were associated with strains of mice. When strains of high cancer incidence were bred with strains of low cancer incidence, the offspring would have high cancer incidence. In 1915, they even further showed a connection between hormones and breast cancer: mammary tumors decreased in female mice with ovariectomies while the tumors increased in pregnant mice. Eight years later, the factor was found to be estrogen. After another 35 years, estrogen receptors (ER) were discovered, and soon the ER-positive subtype of breast cancer was identified. In 1967, the anti-ER compound, tamoxifen, was identified. Six years later, tamoxifen was approved as a chemopreventive agent for breast cancer treatment. It has been almost 60 years since Abbie and Loeb’s mouse experiment. 

Meanwhile, Castle began to use the mice purchased from Abbie for genetic studies. He became the Director of the Bussey Institute for Biological Research at Harvard University. In the following 30 more years, he trained most of the leaders in the mammalian genetics field, including Nobel Laureate George D. Snell and Clarence Cook (“C.C.”) Little (1888-1971). Little, an undergraduate student in Castle's laboratory, was given the job to take care of mouse colonies. He initiated the mouse breeding program to build the inbred, “pure”, strains, and applied these mice in genetic research. It would be hard to believe that he was never aware of Abbie and Loeb’s experiments, whose results proved the value of inbred mice in research of cancer genetics. However, it is Little who is credited with developing inbred mice and using them in the studies of genetics and cancer. In 1929, Little founded Jackson Laboratory (JAX), the world’s leading supplier for laboratory mice. The all-time most frequently used laboratory mouse strain, C57BL/6J (“Black 6”), is derived from one of Lathrop's mice, No. 57, bred by Little. 

(“J” stands for JAX. When the mice of a specific strain are transferred and bred in a geographically segregated site, the neutral genetic drifting will make them genetically separate from the original strain, becoming a substrain. For example, the BL6 mice in the colony located in NCI are named C57BL/6N, whose “N” stands for NCI.)

Between 1913 and 1919, Lathrop and Loeb co-authored 10 scientific papers published in prestigious journals, including the Journal of Experimental Medicine and the Journal of Cancer Research (later became AACR’s Cancer Research). Thanks to the digital era; today you can find their papers in the website of Journal of Experimental Medicine (e.g.  https://rupress.org/jem/article/28/4/475/8924/FURTHER-INVESTIGATIONS-ON-THE-ORIGIN-OF-TUMORS-IN). At that time, it was highly unusual for a woman to receive full co-authorship. Little only acknowledged Abbie as “a mouse fancier of more than ordinary care and scientific interest.” in one of his papers. 

When I joined NCI as a postdoc in 2005, female employees were already the majority of mouse technicians. At that time, I had a very naive explanation for that: women usually had more caring and tender personalities that better suit for the animal care job. This, for sure, is very stereotyping. When Abbie and Loeb published their papers, the news report’s focus on Abbie was not her scientific contribution, but "she overcame the female's usual fear of rodents"- the opposite stereotyping. The stereotypes, either "feminine fear of rodents", or women not suitable for STEM jobs, impacted employment. For my first decade in NCI, in the mouse facility at Frederick campus, the men's changing room was much bigger than women's, though women were already the majority of the employees. It was obviously a relic that the facility used to hire more men than women to do mouse works. After two more years, one day as I entered the mouse facility at Frederick campus, I found that the two changing rooms swapped the space. Now the number of female employees is way more than that of male. The smaller changing room was just too crowded for females.

Unlike Mendel, Abbie was never recognized as one of the founders of cancer genetics. The truth is, without Abbie, I would not have my career today in modeling melanoma progression and treatment in mice. Her story always reminds me of the mouse study team of our laboratory- Cari Smith, Sung Chin, and Jessica Ebersole. I’ve worked with Cari for 17 years, with Sung for 10 years, and with Jessica for 4 years. They are the eyes, hands, and hearts of our research program. Their diligent and skillful works ensure the reproducibility of our preclinical studies. For too many times, their observation has been proved to be critical for our findings in our publications. In academic research, there are too many unsung heroes who are ignored all the time.  

Reference:

https://www.smithsonianmag.com/science-nature/history-breeding-mice-science-leads-back-woman-barn-180968441/

https://www.mayoclinicproceedings.org/article/S0025-6196(11)60108-0/fulltext

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