#HematologyTweetstory 27: “Down syndrome in Down House.” This story, based on a @BloodJournal article I wrote in 2005, sits at the intersection of history, hematology, and evolutionary biology. (Image of girl with trisomy 21 and AML blasts is from “Cancer Therapy Advisor”.) /1 
People with trisomy 21 – reviewed this past week in @NEJM – are at risk for hematological disorders. These include a transient myeloproliferative disorder (TMD) in infancy & markedly increased risk of AML, especially the megakaryocytic subtype (AML-M7)./2 nejm.org/doi/full/10.10…
Outside urban London (but within the notorious M25 Ring) lies the village of Downe, nestled in Kent's rolling hills. The chief attraction of Downe is Down House (the spelling for the estate is different from that of the village), the family home of Charles Darwin (1809-1882)./3
Down House has been extensively restored, and the property is now maintained in the public trust by @EnglishHeritage. The site is a popular pilgrimage destination for biologists & others with interest in the history of the natural sciences./4 english-heritage.org.uk/visit/places/h…
In 2004, when I was a post-doc at the @MRC_WIMM and we were living in Oxford, my daughter Annie and I visited Down House on a rainy Saturday. Here she is on Darwin’s famous gravel “thinking path” behind Down House. (Photo posted with permission of the photographed subject.🙂)/5
We were fascinated by Darwin family photos scattered about the cluttered Victorian-era rooms on the ground floor of Down House. I was inspired to read the sensitive & engaging account of Darwin's family life, “Annie’s Box”, published by his great-great-grandson, Randal Keynes./6
By all accounts, Darwin & his wife - first cousin Emma Wedgewood - enjoyed a close, warm, & generally happy domestic life at Down House, limited by Charles' poorly-defined chronic ailments (possibly Chagas disease from his Beagle voyage) & premature deaths of 3 of 10 children./7
Keynes' book focuses on the death of 10-year-old Annie Darwin in 1851 after a long illness, probably TB. He speculates the pain of those events shaded Charles' ideas during the period of intellectual turmoil when he was formulating theories in "On the Origin of Species" (1859)./8
Darwin's daughter Mary died at 3 weeks in 1842. The Darwins also lost their youngest child, Charles Waring, born December 1856 when Emma was 48. There is only one (grainy) picture of Charles Waring; this is it. (I got a print from @EnglishHeritage years ago.) Take a close look./9
From early on, it was clear that the Darwins' last infant was not “normal”. There was no name yet in 1856 for his condition (more on that below). The grainy, underdeveloped picture is far from definitive, but reveals *possible* facial features of trisomy 21. But there's more./10
Darwin père, always a careful observer of nature (even in his own home), took meticulous notes on the development of all of his children, which have been preserved. Several of his descriptions of Charles Waring are potentially consistent with an infant with trisomy 21: /11
“Small for his age, backward in walking & talking...remarkable sweet, placid & joyful disposition, but had not high spirits...often made strange grimaces...would lie for a long time placidly on my lap looking with a steady and pleased expression at my face."/12
In addition to baby's facial features & hypotonia, Emma's advanced maternal age also supports a retrospective diagnosis of +21. (Retrospective diagnoses are admittedly always dangerous.) For a woman >45 years, the odds of giving birth to an infant with Down syndrome are >1/30./13
In the summer of 1858, when Charles Waring was 19 months old, scarlet fever swept through the region. The Darwin's oldest surviving daughter, Henrietta, had been chronically unwell since a bout with diphtheria the year before & her parents were anxious about her vulnerability./14
But it was the baby who became ill. On June 25, 1858, Darwin shared his growing concern about his youngest child's condition in a letter to his friend Charles Lyell - chiefly written to ask Lyell for advice about asserting intellectual priority over Alfred Russel Wallace./15
“I fear we have a case of scarlet fever in House with Baby. Etty [Henrietta] is weak but is recovering. My dear good friend forgive me. This is a trumpery letter influenced by trumpery feelings.” (Note def. 1 of "trumpery", which dictionary says is "Obsolete"🤔).@rosslevinemd/16
On July 1, 1858 when the Linnean Society in London heard the sensational 1st announcement of Darwin's (& Wallace's) theory of natural selection- an idea that changed biology forever- Darwin wasn't in attendance. He was at the funeral of little Charles Waring, who died June 28./17
Sir Mel Greaves and others interested in the evolving (sorry) field of evolutionary or “Darwinian” medicine argue convincingly that many diseases, especially cancer, may be best understood within an evolutionary framework. /18
As Greaves wrote, “Cancer doesn't just parody evolution, it is a form of evolution played by the same Darwinian ground rules as apply to evolution in general and particularly for asexually propagating species…. evolution in the fast track.” How does this relate to trisomy 21?/19
The usual model cited for cellular “natural selection” - clonal evolution in the setting of malignancy - is the work of Vogelstein on somatic mutations in colonic mucosa as cells progress through adenomatous stages to form carcinoma in situ & eventually frankly invasive cancer.20
Back to trisomy 21. Dr John Langdon Haydon Down (1828-1896), was an advocate for compassionate care for people w/ intellectual disability, but was misguided in other respects. In 1862, he was at Earlswood Asylum in Surrey & noted 16 patients at the asylum with large tongues./21
That year he published a monograph in London Hospital Reports on what he & others would call “mongolism” based on a racist & terribly wrong Victorian-era theory. While "mongolism" was an awful name, he had recognized a distinct syndrome, finally renamed in 1965 by @WHO ./22
A cause of Down syndrome was finally found In 1959 in Paris when Jérôme Jean Louis Marie Lejeune (1926–1994) & Marthe Gautier in Raymond Turpin's lab found an extra chromosome in cells from children with Down syndrome. (Like Rosalind Franklin & DNA, Gautier got little credit.)/23
So why are TMD and AML so common in trisomy 21? Wechsler & colleagues (John Crispino) described in 2002 @NatureGenet that hematopoietic cells that acquire a mutation in the key X-encoded transcription factor GATA1 in the setting of trisomy 21 gain a proliferative advantage./24
However, this advantage is dependent on permissive environment. In evolution environment *always* matters. Switching of hematopoiesis from liver to marrow often results in extinction of GATA1 mutant clones.
When that doesn't occur, & other mutations arise, leukemia develops./25
When that doesn't occur, & other mutations arise, leukemia develops./25
A footnote: Charles Darwin Sr knew nothing of modern genetics, but worried that his consanguineous pairing with Emma had somehow contributed to the illnesses & deaths of his 3 children. He advocated collecting “inbreeding” data as part of the British National Census for 1871./26
Darwin's suggestion about collecting inbreeding data was rejected because of concerns over privacy. There’s no evidence that consanguineous partnerships predispose to tuberculosis, or trisomy 21 - although they do predispose to other conditions./27
The tremendous advances in cellular and molecular biology in the more than 150 years since the publication of "On the Origin of Species" in 1859 have highlighted parallels between the development of cancer clones and the evolution of new species.../28
But only recently was it demonstrated that one of the clearest examples of evolutionary parallel involves GATA1 mutations arising in infants with the condition that likely afflicted the great naturalist's youngest son. What would Darwin have thought?!/End ashpublications.org/blood/article/…
