Time for #HematologyTweetstory 7: the origin and expanding use of the word “clone”, which describes an essential concept in cancer biology and hematology. This tale involves a global banana catastrophe, a nearly-blind dystopian novelist, and an excursion to the planet Kamino./1 
In 1903, the year of the Wright Brothers’ first flight, a widely respected US Department of Agriculture plant breeder named Herbert J. Webber (1865-1946) was looking for a word to describe asexual propagation of plants by grafting or by transplant of cuttings./2
As a botanical concept, asexual propagation was certainly not a new one – a 6th century C.E. Alexandrian philosopher, John Philoponus, had described the process using the term clados (κλάδων, meaning “twig” or “branch”), the origin of the contemporary taxonomy term “clade”./3
Hybridization and grafting with resistant American rootstock, for example, saved the French wine industry after European grape cultivars were decimated by grape #phylloxera insect infestation in the ‘Great French Wine Blight’ of the late 19th century./4
But there was no term in common use before the 20th century to collectively describe all these practices such as grafting, budding, and root and tuber transplant. Enter Webber. Here he is under a grafted carob tree at a USDA facility in Florida./5
A portmanteau that Webber initially proposed, “strace” (an amalgam of “strain” and “race”), failed to catch on. So after talking with colleagues, he wrote a seminal letter to Science, suggesting a brand new term./6
As Webber wrote, “Mr. O. F. Cook, of the Department of Agriculture, has called the writer's attention to the Greek word clon (κλών) meaning a twig, spray, or slip, such as is broken off for propagation, which could be used in the connection desired.”/7
Webber evidently had a strain of humility: “After careful consideration, the writer [Webber] believes this word [that Cook suggested] is much better suited to the purpose than the word strace which he previously suggested.” We don’t have enough of this in science…/8
Orator Fuller Cook, Jr. (1867-1949) was a taxonomist who also coined the term “speciation”. Both Cook and Webber valued terms like clone that were easy to pronounce and simple to use./9
In 1905, Charles Pollard (1872-1945), an editor of the journal Plant World & consultant to @MerriamWebster Merriam-Webster, proposed in a follow-up letter that the spelling of the word should be “clone”, rather than clon, in order to emphasize that the o verb sound was long./10
"Clone" stuck. While the term clone was initially suggested for agricultural purposes, it quickly took on a life of its own and its uses expanded. In 1912, George Harrison Shull (1874-1954), an eminent plant geneticist, suggested expanding the term to animals:/11
“I believe that no violence will be done by extending this term to include animals which are similarly propagated by any asexual method, and I suggest...adoption of the word ‘clone’ for all groups of individuals having identical genotypic character.” He was ahead of his time./12
In a November 1962 London symposium on the topic of “Man and His Future”, the impressively-mustached scientist J.B.S. Haldane (1892-1964), used the term clone to describe creating duplicates of successful people, especially those over age 50 with distinguished careers./13
(IMHO this is actually a bad idea, because so many senior luminaries become entrenched in positions of power and suppress young upstarts with good ideas even as their own ideas tend to stagnate; recall the old joke, “Science advances one senior scientist obituary at a time.”) /14
In Haldane's lecture – sponsored by CIBA, and attended by Nobel laureates including Francis Crick, Joshua Lederberg, Peter Medawar, Hermann Muller, and Albert Szent-Györgi – Haldane extensively quoted his friend, the novelist Aldous Huxley (1894-1963)./15
Huxley went to Oxford and seemed destined for a career in biology like his brothers or medicine, but developed keratitis punctata, which in that pre-antimicrobial, pre-steroid world left him nearly blind for 3 years and with poor vision for the rest of his life. /16
His brother, noted biologist Julian Huxley, wrote, “I believe his [Aldous'] blindness was a blessing in disguise. For one thing, it put paid to his idea of taking up medicine as a career ... His uniqueness lay in his universalism.”/17
In 1932, he wrote Brave New World, set in a futuristic World State populated by genetically modified citizens in a strict social hierarchy based on intelligence./18
Brave New World described creation of up to 96 genetically identical servant-class humans by in vitro embryonic splitting: the "Bokanovsky process." Huxley was influenced by Haldane’s “ectogenesis”, which he'd used in 1924 to describe human development outside of the uterus./19
In the 1920s Haldane suggested cloning might be necessary to restore European populations depleted by World War I, the Spanish influenza epidemic, and economic catastrophes such as the hyperinflation crisis of the 1923 Weimar Republic. Here is a Weimar currency note./20
Like the death of CS Lewis the same day, Huxley’s death on November 22, 1963 went virtually unnoticed since the world’s attention was occupied by the Kennedy assassination in Dallas. His wife gave him LSD on his death bed so he could ‘trip out of this world.’/21
Cloning of humans has been a staple of science fiction films and dystopian novels since Huxley’s Brave New World./22
In the Woody Allen film Sleeper, for example, a 1973 science fiction parody, the 22nd-century main character is cloned from a few pieces of his nose remaining after an explosion./23
The Boys from Brazil, a 1976 novel in which 94 clones of Hitler were engineered by Josef Mengele in Paraguay, was made into 1978 thriller film starring Laurence Olivier and Gregory Peck. /24
And then came Jurassic park... amber... dinosaurs... /25
#HematologyTweetstory 7 on clones continues. In 2002’s Star Wars Episode II: Attack of the Clones, a major plot point is a clone army secretly created by the Galactic Republic on the planet Kamino./26
Those clones were created from mercenary Jango Fett's tissue. (Does he seem an ideal model to you?) One of his clones was bounty hunter Boba Fett, who Jango raised as his son, and who brought frozen Han Solo to Jabba the Hutt for failure to pay a debt in Empire Strikes Back/27
In the real world, cloning of tadpoles by nuclear transfer from oocytes had been successfully performed in 1952, followed by tadpole cloning using differentiated cells in 1958, and the first gene (also from a frog) was cloned in 1973./28
For a while, one would see T-shirts like this one – “Born to Clone” – on cocky molecular biologists. One of my med school professors (pre-all the genome projects) told us, “If you never clone a gene you’ll never be anything in academic medicine.” Hah./29
Cloning of mammalian organisms remained fiction until 1996, when British scientists first cloned a mammal by nuclear transfer from a cell line: the infamous sheep Dolly. /30
Rhesus monkeys generated by nuclear transfer followed in 1997. Here is Neti and clone “Ditto”. /31
Clonality, genetic identity and uniformity, can be risky if it confers susceptibility to disease traits. In contrast, genetic diversity can contribute to species survival after a massive culling event such as a viral pandemic. /32
An informative historical example: bananas. Before 1950, almost all bananas sold in North America and Europe were the Gros Michel cultivar, nicknamed the “Big Mike” banana. If a schoolchild carried a banana to school in her lunchbox in 1950, this banana was a Gros Michel. /33
“Panama disease” due to infection by the fungus Fusarium oxysporum caused widespread disease in Central American Gros Michel banana plantations, resulting in intermittent supply disruptions from the 1920s and eventually complete collapse of the commercial banana in the 1950s./34
Gros Michel was entirely replaced by the blander Cavendish banana, a related cultivar that is less susceptible to the Fusarium strain that destroyed Gros Michel strains. (The Gros Michel picture above I took at "Robert Is Here" in S Florida; these were from a local store.)/35
Some people think that the reason banana candies like these Banana Heads don’t taste like the bananas we're used to is because artificial “banana flavor” created decades ago is based on Gros Michel rather than Cavendish bananas. I don’t know if this is true./36
Now to hematology. Clonal expansion of cells – i.e., growth of a group of genetically identical cells, often without respect to anatomical or physiological constraints – is a hallmark of malignancy. However, clonal expansion is not by itself synonymous with malignancy. /37
We now know for instance that many older adults have clonal hematopoiesis, characterized by somatic mutations in potential pre-leukemic driver genes, raising questions about where the border should be drawn between clonal hematopoiesis and a hematological cancer like #MDS./38
Clonality is not unique to blood; it's seen in every tissue where it has been looked for. For instance, Martincorena et al reported @sciencemagazine that mutant cells colonize healthy esophageal epithelium; each panel is a representative 1 cm2 area of normal donor esophagus./39
The key difference is that cells of the esophagus and brain do not circulate in large numbers – blood does, so clonally derived monocytes can contribute to inflammation and cardiovascular events./40
The term “clone” is used more loosely by the general public to mean any close or identical copy – e.g., the “IBM PC clones” of the 1980s, the first of which was Columbia Data Products’ MPC 1600 "Multi Personal Computer” in June 1982./41
And that, my friends, is all I have to say today about clones. This story was in part based on this article I published in #LeukemiaResearch in 2017. /42End sciencedirect.com/science/articl…
