The seamstress and the scientist: Pauline Gross and Family G
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The year is 1895, in the bustling midwestern university town of Ann Arbor in Michigan, and a ambitious and brash young doctor named Aldred Warthin is about to have a life-changing encounter with a young seamstress named Pauline Gross.
Warthin is in a buoyant mood. He’s just been made an instructor in pathology at the University of Michigan, and he’s taking the long way home through the city’s industrious German Quarter when he meets Pauline. They get chatting, and in the course of their conversation she says, ‘I’m healthy now, but I fully expect to die an early death.’
It’s a sentence that will set the two of them off on a 25-year-long scientific crusade.
Pauline’s grim prediction wasn’t mere pessimism. Her grandmother and grandfather had come to the US from Germany in the 1830s and produced a family with a dismal history of stomach, bowel and womb cancers stretching down the generations. In Pauline’s mind, her fate was sealed.
Her story piqued Warthin’s curiosity. I like to think he was moved by pure human emotion, but he may also have seen the opportunity for a research project through which to advance his career.
Either way, together they set about tracing as far as they could go up and down Pauline’s family tree, gathering as many details as possible about each member, their ages when they first developed cancer and the types of tumours afflicting them, and when they finally succumbed to the disease.
It was an impressive piece of scientific detective work, which took a huge amount of time and dedication on Pauline’s part - not to mention overcoming the skepticism of her family, who were perhaps understandably more than a little suspicious of the medical profession, given that so many seemed to end up dying after their well-meaning but ultimately futile interventions.
As might be expected, when a young single woman starts spending a lot of time with a young single man, it’s often for less lofty reasons than scientific research. Indeed, there was plenty of speculation among Pauline’s relatives that the young professor might make a good match - notions that were clearly put to rest when Warthin married a no-nonsense doctor from Chicago named Katherine Angell.
In fact, Pauline had no desire to marry at all, at least in part due to the weight of her genetic legacy. ‘Why look for love when you know your life will be cut short?’ was her thinking. Warthin backed her up, somewhat cruelly likening her family history to inferior animal breeding stock - a metaphor that Pauline, as a farmer’s daughter, was quick to grasp.
This way of thinking wasn’t unusual at the time, thanks to the flourishing eugenics movement in Europe and the US. Charles Darwin’s problematic cousin Francis Galton wrote in 1904 that:
“All creatures would agree that it was better to be healthy than sick, vigorous than weak, well-fitted than ill-fitted for their part in life; in short that it was better to be good rather than bad specimens of their kind, whatever that kind might be. So with men.”
Similarly, Warthin described Pauline’s family as an example of “progressive degenerative inheritance - the running-out of a family line through the gradual development of an inferior stock.”
He wasn’t alone in his thinking. The American Breeders Association was just one of the many eugenics-based groups that sprang up in the US in the early 20th century, emphasising the importance of ‘superior blood’ through activities such as ‘Fitter Family’ and ‘Scientific Baby’ competitions and collecting family pedigrees just like Pauline had, but to be used for much more sinister ends.
A report from the Carnegie Institute suggested euthanasia as just one of a number of methods for removing these ‘genetic defectives’ from the population.
We should not forget that many geneticists of the past embraced eugenic ideas - including Warthin himself, who is quoted as saying in a 1922 lecture:
“Today it is recognized that all men are not born equal. We are not equal so far as the value of our bodily cells is concerned.”
I believe the technical term is “Yikes!”
There is a reckoning that we need to do as a field to address how science has been used in the past to discriminate against those who are different rather than to improve life for all. And, as current events prove, that work is still necessary and it must continue today.
In 1913, Warthin published the first paper about Family G, as it became known, in the Archives of Internal Medicine, titled “Heredity with Reference to Carcinoma”, proving through his studies of Pauline’s family what Maud Slye was trying to show with all her mice. He concludes,
“A marked susceptibility to carcinoma exists in the case of certain family generations and family groups.”
Although Pauline was pleased that her family’s story was becoming more widely known, she was frustrated by some of the errors that Warthin had managed to introduce into the family tree along the way.
Over the summer of 1919 she fastidiously amended and extended the original pedigree, correcting dates and missing descendants, marking the deaths, and adding new members as they came into the family, whether through birth or through marriage. It had been 25 years since they first started working together, and she was proud to hand her perfect paperwork over to Warthin.
Just a few days later, her role in the project started to draw to its inevitable close. Pauline is rushed to hospital, only to be diagnosed with advanced womb cancer. Surgery revealed that the cancer had started to spread inside her body. But while the cancer would probably have claimed her life in short order, blood poisoning as a result of the operation hastened her death at the age of just 46.
By the time Pauline’s grim prediction came true, she had provided Warthin with detailed medical information about nearly 150 relatives, revealing a clear pattern of cancer inheritance tracking back to her German settler grandfather.
Warthin acknowledged her contribution in a later paper, saying:
“The writer had also an unusual opportunity of obtaining accurate information concerning various lines of descent in this family from an intelligent and cooperative member of the family.”
Despite this compelling evidence of hereditary cancer, Warthin struggled to gain acceptance of his work, just as Maud Slye had with her mice.
This may have been because the message that cancer was hereditary and inevitable was viewed as depressing and doom-laden to the new-founded American Society for the Control of Cancer (now the American Cancer Society), who preferred to pin responsibility for cancer prevention and detection on the individual.
It might have also had something to do with his enthusiasm for eugenics, which was becoming increasingly distasteful in most parts of polite society.
Although Warthin’s assistant, Carl Weller, tried to pick up the baton and carried on researching Family G following Warthin’s death in 1931, the project fizzled out as it became clear that while there definitely was a clear pattern of inherited cancer in the family, he was no closer to finding out what was actually causing it.
Pauline’s meticulous efforts may have been lost forever, languishing in a closet in the pathology department after Weller’s unexpected death in 1956, had it not been for the work of American doctor Henry Lynch and social worker Anne Krush, then working at Creighton University School of Medicine in Omaha, Nebraska in the 1960s.
Together, they picked up where Pauline had left off, tracing more than 650 blood relatives of Family G with ninety-five cancers between them, mostly bowel, womb and stomach as before, and publishing their findings in the paper “Family G revisited” in 1971.
Lynch originally referred to the condition affecting Family G as ‘Cancer Family Syndrome’. But when a second family was found with a legacy of bowel cancers similar to those affecting Pauline’s family, but no womb or stomach cancers, people started to refer to ‘Lynch 1’ and ‘Lynch 2’ syndromes. By the 1980s, Lynch himself was talking about “hereditary non-polyposis colorectal cancer” or HNPCC to describe the bowel cancers that characterised the disease.
By the early 1990s, Lynch and his colleagues, including legendary cancer geneticist Bert Vogelstein at Johns Hopkins University, finally achieved what Warthin had only dreamed of: pinning down the genetic cause of Family G’s misery.
Vogelstein and his team had already discovered that faults in so-called ‘mismatch repair’ genes were common in families affected by HNPCC. Mismatch repair is important for fixing errors in DNA where the usual correct pairing of the two strands of the double helix has gone awry.
Failure to fix these molecular ‘typos’ causes a characteristic pattern of DNA damage that gets perpetuated when cells copy their DNA, leading to genetic mistakes causing them to multiply out of control and head down the road to cancer.
After gathering samples from family members far and wide, the researchers discovered that members of Family G affected by cancer all have an inherited fault in a gene known as MSH2, which plays a crucial role in the molecular ‘toolkit’ that fixes these DNA mismatches.
Once it was clear that there were several forms of hereditary cancer that were caused by various inherited faults in mismatch repair genes, they all started to come under the banner of Lynch Syndrome.
There are many cases in the scientific literature that start with a curious doctor or researcher hearing a patient’s story and setting off on a journey towards finding a gene or a cure - maybe even ending up with a disease named after them along the way. But it’s important we don’t overlook the often nameless people and families whose real lived experiences form the basis for this work.
Writer Ami McKay, whose great-great-aunt was Pauline Gross, has brought her long-dead relative back to life in her wonderful memoir, Daughter of Family G. She writes:
“My Pauline… is not a nameless seamstress who confessed her woes to a doctor and then vanished into thin air. She was an outspoken and courageous woman who came from a family who loved her. She was intuitive, yes, but also an astute observer of human nature and a stickler for detail. In many ways, for what was to unfold, Warthin needed Pauline far more than she needed him.”
Family G is the longest and most detailed cancer genealogy that has ever been studied, going all the way back to Pauline and her encounter with Warthin in 1865. As Henry Lynch is quoted as saying,
“There is probably no other instance in which one family has contributed so much understanding of an important genetic disease such as this.”
Today, members of the family - and others around the world affected by Lynch syndrome - are able to get genetically tested to see if they have inherited a rogue version of one of the mismatch repair genes. They can then have regular screening to spot tumours at an early stage when they’re much more likely to be treated successfully.
However, although current research suggests that around one in every 279 people has Lynch syndrome, only around 5 per cent of those know that they are positive for one of the underlying genetic variations. Clearly, much more could be done to make people aware of the condition and of testing, so they can make informed decisions about their health.
There are other options on the table for these ‘previvors’ - people who know they carry a harmful version of a ‘cancer gene’ but haven’t yet developed the disease, including prophylactic surgery to remove tissues and organs that are highly likely to develop tumours.
Some studies have pointed towards the potential for anti-inflammatory drugs like aspirin to reduce the risk of bowel cancer in people with Lynch syndrome, while other researchers are working on preventative vaccines.
A century after Pauline Gross’ death, her commitment to researching her family is helping to save their lives - and that is a remarkable legacy indeed.
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