Accepted Manuscript Title: The origin and evolution of the term “clone” Author: David P. Steensma PII: DOI: Reference:
S0145-2126(17)30073-5 http://dx.doi.org/doi:10.1016/j.leukres.2017.03.004 LR 5745
To appear in:
Leukemia Research
Received date: Accepted date:
15-2-2017 2-3-2017
Please cite this article as: Steensma David P.The origin and evolution of the term “clone”.Leukemia Research http://dx.doi.org/10.1016/j.leukres.2017.03.004 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
The origin and evolution of the term “clone” David P. Steensma, MD FACP Dana-Farber Cancer Institute and Harvard Medical School
Correspondence: David Steensma, MD FACP Division of Hematological Malignancies, Department of Medical Oncology, Dana-Farber Cancer Institute Associate Professor of Medicine, Harvard Medical School 450 Brookline Ave, D2037 Boston MA 02215 USA Telephone: +1 617 632 3712 Fax: +1 617 582 7840
Support: DPS is supported by the Edward P. Evans Foundation.
Steensma – Clone origin - Page 2
ABSTRACT In biology, the term “clone” is most widely used to designate genetically identical cells or organisms that are asexually descended from a common progenitor. The concept of clonality in hematology-oncology has received much attention in recent years, as the advent of next-generation sequencing platforms has provided new tools for detection of clonal populations in patients, and experiments on primary cells have provided fascinating new insights into the clonal architecture of human malignancies. The term “clone” is used more loosely by the general public to mean any close or identical copy, and cloning of humans has been a staple of science fiction films and dystopian novels since Aldous Huxley’s Brave New World was published in 1932. Here I trace the origin and evolution of the word clone, from its first use as an agricultural and botanical term in 1903, to its widespread adoption in biology, adaptation by artists, and contemporary use in hematology-oncology.
Keywords: Clone; clonality; clonal expansion; hematological malignancy; agriculture; botany; etymology; medical history
Steensma – Clone origin - Page 3 INTRODUCTION 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.[1] However, clonal expansion is not by itself synonymous with malignancy.
Clonal expansion of B
lymphocytes in response to antigen exposure is an important process in normal immunity, for example, and numerous pre-malignant clonal states such as adenomatous colon polyps or lobular carcinoma in situ of the breast usually have an indolent natural history and can precede frank tissue-invasive disease by many years.
Recently, a substantial fraction of older adults (~10% by age 70 years) were found to 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 hematological cancers such as the myelodysplastic syndromes (MDS).[2-6] More generally, tumor composition is now known to be complex, with numerous derivative subclones with distinct genomic profiles evolving and branching off from an ancestral transformed cell, making for a convoluted architecture, and one with subclones serving as sources of anti-cancer therapy resistance.[7-9]
A deep understanding of the concept of cell clones and clonal behavior is now central to the practice of hematology and oncology, just as cloning of DNA (a different use of the term) has been an essential tool in molecular genetics labs for decades. In addition to the various scientific uses of the term “clone” in biology and medicine, this word has also been adopted widely by the general public to mean any identical or near-identical copy, in the same confusing way that “gene” has come to have a variety of meanings and nuances distinct from the formal definition of a gene as a unit of heredity.[10, 11] Clones and cloning have also become staples of science fiction and dystopian fantasy literature. In computer science, a hard disk drive or a program subroutine can be cloned, and functionally similar but non-identical hardware systems are often called clones (e.g. the many “IBM PC clones” of the 1980s). Where did this useful and versatile term originate?
CLONE: ORIGIN IN AGRICULTURE
Steensma – Clone origin - Page 4
In 1903, a widely respected US Department of Agriculture plant breeder named Herbert J. Webber (1865-1946) (Figure 1) was looking for a word to describe asexual propagation of plants by grafting or transplant of cuttings.[12] The botanical concept of asexual propagation was not a new one – a 6th century C.E. Alexandrian philosopher, John Philoponus (Ἰωάννης ὁ Φιλόπονος), had described the process using the term clados (κλάδων, meaning “twig” or “branch”), which is the origin of the contemporary taxonomy term “clade”.[13] Hybridization and grafting with resistant American rootstock saved the French wine industry after European grape cultivars was decimated by grape phylloxera insect infestation in the Great French Wine Blight of the late 19th century.[14] But there was no term in common use before the 20th century to collectively describe practices such as grafting, budding, and root and tuber transplant. A portmanteau that Webber had previously proposed, “strace” (an amalgam of “strain” and “race”), failed to catch on, so he wrote a seminal letter to Science, suggesting a new term: “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. After careful consideration, the writer believes this word much better suited to the purpose than the word strace which he previously suggested.… Clon, plural clons (pronounced with long o), is a short word, easily pronounced, spelled phonetically, and with a derivation which at least suggests its meaning. The writer would urge it as a suitable term to adopt into general usage.”[12] While Webber is usually credited with coining the term clone in most secondary sources on biological etymology, it is notable that in his initial proposal he claimed he had obtained the term from a fellow botanist, Orator Fuller Cook, Jr. (1867-1949). Cook 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, which may have been part of why clone later came to be employed in so many different ways.[11] Both botanists also published hundreds of articles on plant biology and cultivation in the early 20th century; while Cook’s primary focus was cotton, Webber’s studies of grafting citrus plants to promote disease resistance were extremely helpful in growing the American citrus industry in Florida and California.
Steensma – Clone origin - Page 5 In 1905, botanist Charles Pollard (1872-1945) proposed in a follow-up letter to Science that the spelling of the word should be clone, rather than clon as Webber had proposed, in order to emphasize that the verb sound for the o was long.[15]
Pollard was influential in botanical
language as the editor of the journal Plant World and also as consultant to the publisher of the Merriam-Webster dictionary, G. & C. Merriam Co.
Therefore, the term clone was formally
adopted as proposed by Webber (but with Pollard’s suggested spelling) in 1905 by the Association of Agricultural Colleges and Experiment Stations.[16]
CLONE MOVES TO THE ANIMAL KINGDOM
While the term clone was initially suggested for agricultural purposes, it quickly took on a life of its own as its uses expanded. In 1912, George Harrison Shull (1874-1954), an eminent plant geneticist working at the new Station for Experimental Evolution in Cold Spring Harbor, New York, cited Webber’s proposal and suggested expanding the term to animals: “I believe that no violence will be done by extending this term [clone] to include animals which are similarly propagated by any asexual method, and I suggest the general adoption of the word ‘clone’ for all groups of individuals having identical genotypic character, and arising by asexual reproduction of any sort, including apogamy (i.e., so-called ‘parthenogenesis’, unaccompanied by a reduction division.)”[17] Another half century would pass before clone was used for the first time in the sense of creating a carbon copy of a human. In a November 1962 lecture at a CIBA Foundation-supported London symposium on the topic of “Man and His Future”, the great scientist and mathematician J.B.S. Haldane (1892-1964), used the term clone as he described the likelihood of creating duplicates of successful people, especially those over age 50 who had a distinguished career of accomplishment.[18] In this lecture – which was attended by Nobel laureates including Francis Crick, Joshua Lederberg, Peter Medawar, Hermann Muller, and Albert Szent-Györgi – Haldane quoted his friend, the novelist Aldous Huxley (1894-1963), whose 1932 Brave New World (Figure 2) described creation of up to 96 genetically identical servant-class humans by in vitro embryonic splitting in what was termed the Bokanovsky process. Huxley in turn had been influenced by the implications of
Steensma – Clone origin - Page 6 Haldane’s term “ectogenesis”, which Haldane had used in 1924 to describe human development outside of the uterus, and which he suggested might be necessary to restore European populations depleted by World War I, the Spanish influenza epidemic, and the predations of economic catastrophes such as the hyperinflation crisis of the 1923 Weimar Republic.[19] As Haldane stated in his 1962 CIBA Foundation lecture, “It is extremely hopeful that some human cell lines can be grown on a medium of precisely known chemical composition. Perhaps the first step will be the production of a clone from a single fertilized egg, as in Brave New World. But this would be of little social value. The production of a clone from cells of persons of attested ability would be a very different matter, and might raise the possibilities of human achievement dramatically. For exceptional people commonly have unhappy childhoods, as their parents, teachers, and contemporaries try to force them to conform to ordinary standards. Many are permanently deformed by the traumatic experiences of their childhoods. Probably a great mathematician, poet, or painter could most usefully spend his life from 55 years on in educating his or her own clonal offspring so that they avoided at least some of the frustrations of their original. On the general principle that men will make all possible mistakes before choosing the right path, we shall no doubt clone the wrong people.”[18] SCIENCE FACT AND SCIENCE FICTION
Although 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, most of the non-agricultural cloning referred to in the decades after Haldane’s speech took place solely in the realm of science fiction.[20] For instance, 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. In the Woody Allen film Sleeper, a 1973 science fiction parody, the 22nd-century main character is cloned from a few pieces of his nose remaining after an explosion. The 1993 blockbuster film Jurassic Park and its sequels were founded on the idea of cloning dinosaurs from DNA preserved in amber, and cloning of galactic bounty hunter Jango Fett to create an army of elite warriors was a key plot element in 2002’s Star Wars Episode II: Attack of the Clones.
The closest humans to clones are identical twins, but clones do not require the simultaneous conception or a shared pre-natal environment that twins enjoy. Cloning of mammalian organisms remained fiction until 1996, when British scientists first cloned a mammal by nuclear transfer from
Steensma – Clone origin - Page 7 a cell line: the famous sheep Dolly.[21] Rhesus monkeys generated by nuclear transfer followed in 1997: a primate aptly named “Ditto”.[22] Most recently, in 2013, human embryos were created by somatic cell nuclear transfer, a development that many bioethicists had anticipated and some had expressed grave concerns about.[23, 24] Cloning provides an opportunity for rapid reproduction of cells or organisms with desired or favorably competitive characteristics, but genetic identity also carries with it an inherent vulnerability. While the grape cultivars that fell prey to phylloxera were not genetically identical, they were similar and had a common vulnerability, and provide a cautionary tale of widespread population destruction due to shared susceptibility.
A more recent and germane example of the risk of clonality is the collapse of the banana crop in the mid-20th century.[25] Before 1950, almost all bananas available in North America and Europe were of 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 certain to be a Gros Michel. But “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. The first shortages may have inspired the 1920s showtune, “Yes! We Have No Bananas.” Eventually the Gros Michel variant was entirely replaced by the blander Cavendish banana, a related cultivar that is less susceptible to the Fusarium strain that destroyed Gros Michel strain.
In cancer medicine, clonality also can provide a therapeutic opportunity. Genetic identity may leave clonally derived cells vulnerable to a metabolic Achilles heel that does not afflict closely related healthy cells, just as the Gros Michel banana was killed by a pathogen that had little effect on the Cavendish banana. This differential susceptibility is the basis for “precision medicine” targeted therapies.
Neomorphic activity of a mutant enzyme such as isocitrate dehydrogenase 1/2 (IDH1/2) or activated constitutively activated tyrosine kinases such as Janus kinase 2 (JAK2) are widely recognized classes of clonally-associated targets, but there are other classes that may be less
Steensma – Clone origin - Page 8 obvious. For example, the susceptibility of MDS cells bearing clonally-restricted loss of the long arm of chromosome 5 (5q) to the drug lenalidomide depends on haploinsufficiency for the casein kinase 1 enzyme.[26] Lenalidomide accelerates degradation of casein kinase 1, which is well tolerated by healthy cells that have 100% casein kinase activity, but is lethal to clonal cells that lack 5q and have 50% casein kinase. Ongoing clinical trials of splicing inhibitors in myeloid neoplasms with somatic mutations in spliceosome components exploit a similar vulnerability.[27] This mechanism has been termed “CYCLOPS”, a somewhat tortured acronym for “Copy number alterations Yielding Cancer Liabilities Owing to Partial loSs”, alluding to the fact that a two-eyed creature that loses an eye can still see, but if a one-eyed monster such as the Cyclops of Greek myth loses an eye, the creature is blind. However, like the Cavendish banana with its resistance to fungal pressure, MDS subclonal cells that have a TP53 mutation are resistant to lenalidomide and can eventually outgrow.[28]
CONCLUSION “Clone” is a versatile term that has evolved in unexpected ways since its initial coinage for agricultural purposes a century ago. This term’s expanded usage in contemporary everyday language may be imprecise, but the description’s applications in hematology-oncology retain a specific meaning, and have both diagnostic and therapeutic implications. In the future, mammalian organismal clones that have been only imaginary until recently will continue to prompt ethical and societal debates, as they have since Haldane’s landmark lecture in the early 1960s.
Steensma – Clone origin - Page 9
Disclosures: None relevant. Acknowledgements: Dr. Steensma’s work in myelodysplastic syndromes is supported by the Edward P Evans Foundation and the James and Lois Champy Foundation. REFERENCES [1] P.C. Nowell, The clonal evolution of tumor cell populations, Science 194(4260) (1976) 23-8. [2] L. Malcovati, M. Cazzola, The shadowlands of MDS: idiopathic cytopenias of undetermined significance (ICUS) and clonal hematopoiesis of indeterminate potential (CHIP), Hematology Am. Soc. Hematol. Educ. Program 2015 (2015) 299-307. [3] G. Genovese, A.K. Kähler, S.A. Rose, R.E. Handsaker, K. Chambert, E. Mick, S.F. Bakhoum, B. Neale, M. Fromer, S.M. Purcell, M. Landén, J. Moran, P.F. Sullivan, P. Sklar, C.M. Hultman, S.A. McCarroll, Clonal hematopoiesis and cancer risk in blood derived DNA sequence, N. Engl. J. Med. 371(December 25) (2014) 2477-2487. [4] S. Jaiswal, P. Fontanillas, J. Flannick, A. Manning, P.V. Grauman, B.G. Mar, R.C. Lindsley, C.H. Mermel, N. Burtt, A. Chavez, J.M. Higgins, V. Moltchanov, F.C. Kuo, M.J. Kluk, B. Henderson, L. Kinnunen, H.A. Koistinen, N. Ladenvall, G. Getz, A. Correa, B.F. Banahan, S. Gabriel, S. Kathiresan, H.M. Stringham, M.I. McCarthy, M. Boehnke, D. Altshuler, J. Tuomilehto, C. Haiman, L. Groop, G. Atzmon, J.G. Wilson, D. Neuberg, D. Altshuler, B.L. Ebert, Age-related clonal hematopoiesis associated with adverse outcomes, N. Engl. J. Med. 371(December 25) (2014) 2488-2498. [5] M. Xie, C. Lu, J. Wang, M.D. McLellan, K.J. Johnson, M.C. Wendl, J.F. McMichael, H.K. Schmidt, V. Yellapantula, C.A. Miller, B.A. Ozenberger, J.S. Welch, D.C. Link, M.J. Walter, E.R. Mardis, J.F. Dipersio, F. Chen, R.K. Wilson, T.J. Ley, L. Ding, Age-related mutations associated with clonal hematopoietic expansion and malignancies, Nat. Med. 20(12) (2014) 1472-8. [6] D.P. Steensma, R. Bejar, S. Jaiswal, R.C. Lindsley, M.A. Sekeres, R.P. Hasserjian, B.L. Ebert, Clonal hematopoiesis of indeterminate potential and its distinction from myelodysplastic syndromes, Blood 126(1) (2015) 9-16. [7] M. Gerlinger, A.J. Rowan, S. Horswell, J. Larkin, D. Endesfelder, E. Gronroos, P. Martinez, N. Matthews, A. Stewart, P. Tarpey, I. Varela, B. Phillimore, S. Begum, N.Q. McDonald, A. Butler, D. Jones, K. Raine, C. Latimer, C.R. Santos, M. Nohadani, A.C. Eklund, B. Spencer-Dene, G. Clark, L. Pickering, G. Stamp, M. Gore, Z. Szallasi, J. Downward, P.A. Futreal, C. Swanton, Intratumor heterogeneity and branched evolution revealed by multiregion sequencing, N. Engl. J. Med. 366(10) (2012) 883-92. [8] M.J. Walter, D. Shen, L. Ding, J. Shao, D.C. Koboldt, K. Chen, D.E. Larson, M.D. McLellan, D. Dooling, R. Abbott, R. Fulton, V. Magrini, H. Schmidt, J. Kalicki-Veizer, M. O'Laughlin, X. Fan, M. Grillot, S. Witowski, S. Heath, J.L. Frater, W. Eades, M. Tomasson, P. Westervelt, J.F. DiPersio, D.C. Link, E.R. Mardis, T.J. Ley, R.K. Wilson, T.A. Graubert, Clonal architecture of secondary acute myeloid leukemia, N. Engl. J. Med. 366(12) (2012) 1090-8. [9] S. Venkatesan, C. Swanton, Tumor Evolutionary Principles: How Intratumor Heterogeneity Influences Cancer Treatment and Outcome, Am Soc Clin Oncol Educ Book 35 (2016) e141-9. [10] L.M. Silver, What are clones?, Nature 412(6842) (2001) 21. [11] U. Mittwoch, "Clone": the history of a euphonious scientific term, Med. Hist. 46(3) (2002) 381-402.
Steensma – Clone origin - Page 10 [12] H.J. Webber, New Horticultural and Agricultural Terms, Science 18(459) (1903) 501-3. [13] A.A. Diamandopoulos, P.C. Goudas, Cloning's not a new idea: the Greeks had a word for it centuries ago, Nature 408(6815) (2000) 905. [14] G.D. Gale, Dying on the Vine: How Phylloxera Transformed Wine, University of California Press, Los Angeles, 2011. [15] C.L. Pollard, 'Clon' versus 'Clone', Science 22 (1905) 469. [16] March 11, 2011. National Public Radio. Science Diction: The Origin Of The Word 'Clone' Host: Joe Palca. , Transcript: http://www.npr.org/2011/03/11/134459358/Science-Diction-TheOrigin-Of-The-Word-Clone 2011, p. 3:58. [17] G.H. Shull, "Genotypes," "Biotypes," "Pure Lines" and "Clones", Science 35(888) (1912) 279. [18] J.B.S. Haldane, Biological Possibilities for the Human Species in the Next Ten Thousand Years, in: G. Wolstenholme (Ed.), Man and his future, J&A Churchill, London, 1963. [19] J.B.S. Haldane, Daedalus or Science and the Future, Kegan Paul, Trench, Trübner & Company, London, 1924. [20] R. Briggs, T.J. King, Transplantation of Living Nuclei From Blastula Cells into Enucleated Frogs' Eggs, Proc. Natl. Acad. Sci. U. S. A. 38(5) (1952) 455-63. [21] K.H. Campbell, J. McWhir, W.A. Ritchie, I. Wilmut, Sheep cloned by nuclear transfer from a cultured cell line, Nature 380(6569) (1996) 64-6. [22] L. Meng, J.J. Ely, R.L. Stouffer, D.P. Wolf, Rhesus monkeys produced by nuclear transfer, Biol. Reprod. 57(2) (1997) 454-9. [23] M. Tachibana, P. Amato, M. Sparman, N.M. Gutierrez, R. Tippner-Hedges, H. Ma, E. Kang, A. Fulati, H.S. Lee, H. Sritanaudomchai, K. Masterson, J. Larson, D. Eaton, K. Sadler-Fredd, D. Battaglia, D. Lee, D. Wu, J. Jensen, P. Patton, S. Gokhale, R.L. Stouffer, D. Wolf, S. Mitalipov, Human embryonic stem cells derived by somatic cell nuclear transfer, Cell 153(6) (2013) 122838. [24] L.R. Kass, J.Q. Wilson, The Ethics of Human Cloning, AEI Press, Washington, D.C., 1998. [25] D. Koeppel, Banana: The Fate of the Fruit That Changed the World, Penguin (USA), New York, 2007. [26] J. Kronke, E.C. Fink, P.W. Hollenbach, K.J. MacBeth, S.N. Hurst, N.D. Udeshi, P.P. Chamberlain, D.R. Mani, H.W. Man, A.K. Gandhi, T. Svinkina, R.K. Schneider, M. McConkey, M. Jaras, E. Griffiths, M. Wetzler, L. Bullinger, B.E. Cathers, S.A. Carr, R. Chopra, B.L. Ebert, Lenalidomide induces ubiquitination and degradation of CK1alpha in del(5q) MDS, Nature 523(7559) (2015) 183-8. [27] S.C. Lee, H. Dvinge, E. Kim, H. Cho, J.B. Micol, Y.R. Chung, B.H. Durham, A. Yoshimi, Y.J. Kim, M. Thomas, C. Lobry, C.W. Chen, A. Pastore, J. Taylor, X. Wang, A. Krivtsov, S.A. Armstrong, J. Palacino, S. Buonamici, P.G. Smith, R.K. Bradley, O. Abdel-Wahab, Modulation of splicing catalysis for therapeutic targeting of leukemia with mutations in genes encoding spliceosomal proteins, Nat. Med. 22(6) (2016) 672-8. [28] M. Jadersten, L. Saft, A. Pellagatti, G. Gohring, J.S. Wainscoat, J. Boultwood, A. Porwit, B. Schlegelberger, E. Hellstrom-Lindberg, Clonal heterogeneity in the 5q- syndrome: p53 expressing progenitors prevail during lenalidomide treatment and expand at disease progression, Haematologica 94(12) (2009) 1762-6. FIGURE CAPTIONS
Steensma – Clone origin - Page 11 1) A. Herbert John Webber (1865-1946) was a noted plant breeder and botanist who worked for the US Department of Agriculture from 1892-1907 after graduating from the University of Nebraska, then directed Cornell University‘s New York State College of Agriculture Department of Plant Breeding for 5 years. From 1912 until his retirement in 1929, Webber served as director of the University of California’s Citrus Experiment Station. His 1903 letter to Science proposed the term “clone” to describe asexual propagation and reproduction. Image source: Herbert John Webber - Eustis, Florida. 19-. Black & white photonegative. State Archives of Florida, Florida Memory. Accessed 15 Feb. 2017.. B. Herbert Weber standing under a carob tree. This picture was taken near Coconut Grove, Florida, about this time the Sub-Tropical Laboratory was started by Swingle and Webber..” Source: Special Collections, USDA National Agricultural Library. Accessed February 13, 2017, https://www.nal.usda.gov/exhibits/speccoll/items/show/303. C. Orator Fuller Cook, Jr. (1867-1949). This line drawing of a young Cook accompanied an article about the importance of scientific advance and agricultural education in securing the future of the young West African colony of Liberia, where Cook worked for a time in the 1890s. Image source: The Philipsburg Mail. (Philipsburg, Mont.), 23 May 1895. Chronicling America: Historic American Newspapers. Library of Congress. http://chroniclingamerica.loc.gov/lccn/sn83025320/1895-05-23/ed-1/seq-3/ 2) First Edition cover of Aldous Huxley’s 1932 dystopian novel Brave New World. This best-selling book introduced the concept of human cloning performed in automotive assembly-line fashion in a 25th century future (though a different term – Bokanovsky’s process - was used). The idea of embryonic division and non-womb-requiring ectogenesis was influenced by a 1924 book about the future of science by J.B.S. Haldane, who was the first to use the term “clone” to describe copying of humans in 1962. 3) A, Gros Michel bananas and B, Cavendish bananas. Gros Michel bananas are genetically homogeneous and were susceptible to fungal infection, and were decimated in the 1950s by Panama disease, due to a Fusarium fungus. Only a few plantations of Gros Michel banana trees remain in Asia (e.g., Malaysia and Thailand). They have largely been replaced commercially by Cavendish bananas, which are genetically similar to Gros Michel but have reduced sensitivity to Panama disease. Both Gros Michel and Cavendish bananas are members of the genetically triploid AAA group of Musa acuminate, which suggests that the Cavendish banana may also face catastrophe in the near future. However, other strains such as the genetically tetraploid AAAA (e.g., Golden Beauty banana), the distinct ABB (e.g. Blue Java banana), or “somaclones” created by micropropagation with induced genetic variation could provide replacements if the unthinkable happened. Image A, courtesy of Washington Banana Museum. Image B, photo taken by the author 15 February 2017.
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S0145-2126(17)30073-5 http://dx.doi.org/doi:10.1016/j.leukres.2017.03.004 LR 5745
To appear in:
Leukemia Research
Received date: Accepted date:
15-2-2017 2-3-2017
Please cite this article as: Steensma David P.The origin and evolution of the term “clone”.Leukemia Research http://dx.doi.org/10.1016/j.leukres.2017.03.004 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
The origin and evolution of the term “clone” David P. Steensma, MD FACP Dana-Farber Cancer Institute and Harvard Medical School
Correspondence: David Steensma, MD FACP Division of Hematological Malignancies, Department of Medical Oncology, Dana-Farber Cancer Institute Associate Professor of Medicine, Harvard Medical School 450 Brookline Ave, D2037 Boston MA 02215 USA Telephone: +1 617 632 3712 Fax: +1 617 582 7840
Support: DPS is supported by the Edward P. Evans Foundation.
Steensma – Clone origin - Page 2
ABSTRACT In biology, the term “clone” is most widely used to designate genetically identical cells or organisms that are asexually descended from a common progenitor. The concept of clonality in hematology-oncology has received much attention in recent years, as the advent of next-generation sequencing platforms has provided new tools for detection of clonal populations in patients, and experiments on primary cells have provided fascinating new insights into the clonal architecture of human malignancies. The term “clone” is used more loosely by the general public to mean any close or identical copy, and cloning of humans has been a staple of science fiction films and dystopian novels since Aldous Huxley’s Brave New World was published in 1932. Here I trace the origin and evolution of the word clone, from its first use as an agricultural and botanical term in 1903, to its widespread adoption in biology, adaptation by artists, and contemporary use in hematology-oncology.
Keywords: Clone; clonality; clonal expansion; hematological malignancy; agriculture; botany; etymology; medical history
Steensma – Clone origin - Page 3 INTRODUCTION 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.[1] However, clonal expansion is not by itself synonymous with malignancy.
Clonal expansion of B
lymphocytes in response to antigen exposure is an important process in normal immunity, for example, and numerous pre-malignant clonal states such as adenomatous colon polyps or lobular carcinoma in situ of the breast usually have an indolent natural history and can precede frank tissue-invasive disease by many years.
Recently, a substantial fraction of older adults (~10% by age 70 years) were found to 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 hematological cancers such as the myelodysplastic syndromes (MDS).[2-6] More generally, tumor composition is now known to be complex, with numerous derivative subclones with distinct genomic profiles evolving and branching off from an ancestral transformed cell, making for a convoluted architecture, and one with subclones serving as sources of anti-cancer therapy resistance.[7-9]
A deep understanding of the concept of cell clones and clonal behavior is now central to the practice of hematology and oncology, just as cloning of DNA (a different use of the term) has been an essential tool in molecular genetics labs for decades. In addition to the various scientific uses of the term “clone” in biology and medicine, this word has also been adopted widely by the general public to mean any identical or near-identical copy, in the same confusing way that “gene” has come to have a variety of meanings and nuances distinct from the formal definition of a gene as a unit of heredity.[10, 11] Clones and cloning have also become staples of science fiction and dystopian fantasy literature. In computer science, a hard disk drive or a program subroutine can be cloned, and functionally similar but non-identical hardware systems are often called clones (e.g. the many “IBM PC clones” of the 1980s). Where did this useful and versatile term originate?
CLONE: ORIGIN IN AGRICULTURE
Steensma – Clone origin - Page 4
In 1903, a widely respected US Department of Agriculture plant breeder named Herbert J. Webber (1865-1946) (Figure 1) was looking for a word to describe asexual propagation of plants by grafting or transplant of cuttings.[12] The botanical concept of asexual propagation was not a new one – a 6th century C.E. Alexandrian philosopher, John Philoponus (Ἰωάννης ὁ Φιλόπονος), had described the process using the term clados (κλάδων, meaning “twig” or “branch”), which is the origin of the contemporary taxonomy term “clade”.[13] Hybridization and grafting with resistant American rootstock saved the French wine industry after European grape cultivars was decimated by grape phylloxera insect infestation in the Great French Wine Blight of the late 19th century.[14] But there was no term in common use before the 20th century to collectively describe practices such as grafting, budding, and root and tuber transplant. A portmanteau that Webber had previously proposed, “strace” (an amalgam of “strain” and “race”), failed to catch on, so he wrote a seminal letter to Science, suggesting a new term: “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. After careful consideration, the writer believes this word much better suited to the purpose than the word strace which he previously suggested.… Clon, plural clons (pronounced with long o), is a short word, easily pronounced, spelled phonetically, and with a derivation which at least suggests its meaning. The writer would urge it as a suitable term to adopt into general usage.”[12] While Webber is usually credited with coining the term clone in most secondary sources on biological etymology, it is notable that in his initial proposal he claimed he had obtained the term from a fellow botanist, Orator Fuller Cook, Jr. (1867-1949). Cook 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, which may have been part of why clone later came to be employed in so many different ways.[11] Both botanists also published hundreds of articles on plant biology and cultivation in the early 20th century; while Cook’s primary focus was cotton, Webber’s studies of grafting citrus plants to promote disease resistance were extremely helpful in growing the American citrus industry in Florida and California.
Steensma – Clone origin - Page 5 In 1905, botanist Charles Pollard (1872-1945) proposed in a follow-up letter to Science that the spelling of the word should be clone, rather than clon as Webber had proposed, in order to emphasize that the verb sound for the o was long.[15]
Pollard was influential in botanical
language as the editor of the journal Plant World and also as consultant to the publisher of the Merriam-Webster dictionary, G. & C. Merriam Co.
Therefore, the term clone was formally
adopted as proposed by Webber (but with Pollard’s suggested spelling) in 1905 by the Association of Agricultural Colleges and Experiment Stations.[16]
CLONE MOVES TO THE ANIMAL KINGDOM
While the term clone was initially suggested for agricultural purposes, it quickly took on a life of its own as its uses expanded. In 1912, George Harrison Shull (1874-1954), an eminent plant geneticist working at the new Station for Experimental Evolution in Cold Spring Harbor, New York, cited Webber’s proposal and suggested expanding the term to animals: “I believe that no violence will be done by extending this term [clone] to include animals which are similarly propagated by any asexual method, and I suggest the general adoption of the word ‘clone’ for all groups of individuals having identical genotypic character, and arising by asexual reproduction of any sort, including apogamy (i.e., so-called ‘parthenogenesis’, unaccompanied by a reduction division.)”[17] Another half century would pass before clone was used for the first time in the sense of creating a carbon copy of a human. In a November 1962 lecture at a CIBA Foundation-supported London symposium on the topic of “Man and His Future”, the great scientist and mathematician J.B.S. Haldane (1892-1964), used the term clone as he described the likelihood of creating duplicates of successful people, especially those over age 50 who had a distinguished career of accomplishment.[18] In this lecture – which was attended by Nobel laureates including Francis Crick, Joshua Lederberg, Peter Medawar, Hermann Muller, and Albert Szent-Györgi – Haldane quoted his friend, the novelist Aldous Huxley (1894-1963), whose 1932 Brave New World (Figure 2) described creation of up to 96 genetically identical servant-class humans by in vitro embryonic splitting in what was termed the Bokanovsky process. Huxley in turn had been influenced by the implications of
Steensma – Clone origin - Page 6 Haldane’s term “ectogenesis”, which Haldane had used in 1924 to describe human development outside of the uterus, and which he suggested might be necessary to restore European populations depleted by World War I, the Spanish influenza epidemic, and the predations of economic catastrophes such as the hyperinflation crisis of the 1923 Weimar Republic.[19] As Haldane stated in his 1962 CIBA Foundation lecture, “It is extremely hopeful that some human cell lines can be grown on a medium of precisely known chemical composition. Perhaps the first step will be the production of a clone from a single fertilized egg, as in Brave New World. But this would be of little social value. The production of a clone from cells of persons of attested ability would be a very different matter, and might raise the possibilities of human achievement dramatically. For exceptional people commonly have unhappy childhoods, as their parents, teachers, and contemporaries try to force them to conform to ordinary standards. Many are permanently deformed by the traumatic experiences of their childhoods. Probably a great mathematician, poet, or painter could most usefully spend his life from 55 years on in educating his or her own clonal offspring so that they avoided at least some of the frustrations of their original. On the general principle that men will make all possible mistakes before choosing the right path, we shall no doubt clone the wrong people.”[18] SCIENCE FACT AND SCIENCE FICTION
Although 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, most of the non-agricultural cloning referred to in the decades after Haldane’s speech took place solely in the realm of science fiction.[20] For instance, 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. In the Woody Allen film Sleeper, a 1973 science fiction parody, the 22nd-century main character is cloned from a few pieces of his nose remaining after an explosion. The 1993 blockbuster film Jurassic Park and its sequels were founded on the idea of cloning dinosaurs from DNA preserved in amber, and cloning of galactic bounty hunter Jango Fett to create an army of elite warriors was a key plot element in 2002’s Star Wars Episode II: Attack of the Clones.
The closest humans to clones are identical twins, but clones do not require the simultaneous conception or a shared pre-natal environment that twins enjoy. Cloning of mammalian organisms remained fiction until 1996, when British scientists first cloned a mammal by nuclear transfer from
Steensma – Clone origin - Page 7 a cell line: the famous sheep Dolly.[21] Rhesus monkeys generated by nuclear transfer followed in 1997: a primate aptly named “Ditto”.[22] Most recently, in 2013, human embryos were created by somatic cell nuclear transfer, a development that many bioethicists had anticipated and some had expressed grave concerns about.[23, 24] Cloning provides an opportunity for rapid reproduction of cells or organisms with desired or favorably competitive characteristics, but genetic identity also carries with it an inherent vulnerability. While the grape cultivars that fell prey to phylloxera were not genetically identical, they were similar and had a common vulnerability, and provide a cautionary tale of widespread population destruction due to shared susceptibility.
A more recent and germane example of the risk of clonality is the collapse of the banana crop in the mid-20th century.[25] Before 1950, almost all bananas available in North America and Europe were of 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 certain to be a Gros Michel. But “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. The first shortages may have inspired the 1920s showtune, “Yes! We Have No Bananas.” Eventually the Gros Michel variant was entirely replaced by the blander Cavendish banana, a related cultivar that is less susceptible to the Fusarium strain that destroyed Gros Michel strain.
In cancer medicine, clonality also can provide a therapeutic opportunity. Genetic identity may leave clonally derived cells vulnerable to a metabolic Achilles heel that does not afflict closely related healthy cells, just as the Gros Michel banana was killed by a pathogen that had little effect on the Cavendish banana. This differential susceptibility is the basis for “precision medicine” targeted therapies.
Neomorphic activity of a mutant enzyme such as isocitrate dehydrogenase 1/2 (IDH1/2) or activated constitutively activated tyrosine kinases such as Janus kinase 2 (JAK2) are widely recognized classes of clonally-associated targets, but there are other classes that may be less
Steensma – Clone origin - Page 8 obvious. For example, the susceptibility of MDS cells bearing clonally-restricted loss of the long arm of chromosome 5 (5q) to the drug lenalidomide depends on haploinsufficiency for the casein kinase 1 enzyme.[26] Lenalidomide accelerates degradation of casein kinase 1, which is well tolerated by healthy cells that have 100% casein kinase activity, but is lethal to clonal cells that lack 5q and have 50% casein kinase. Ongoing clinical trials of splicing inhibitors in myeloid neoplasms with somatic mutations in spliceosome components exploit a similar vulnerability.[27] This mechanism has been termed “CYCLOPS”, a somewhat tortured acronym for “Copy number alterations Yielding Cancer Liabilities Owing to Partial loSs”, alluding to the fact that a two-eyed creature that loses an eye can still see, but if a one-eyed monster such as the Cyclops of Greek myth loses an eye, the creature is blind. However, like the Cavendish banana with its resistance to fungal pressure, MDS subclonal cells that have a TP53 mutation are resistant to lenalidomide and can eventually outgrow.[28]
CONCLUSION “Clone” is a versatile term that has evolved in unexpected ways since its initial coinage for agricultural purposes a century ago. This term’s expanded usage in contemporary everyday language may be imprecise, but the description’s applications in hematology-oncology retain a specific meaning, and have both diagnostic and therapeutic implications. In the future, mammalian organismal clones that have been only imaginary until recently will continue to prompt ethical and societal debates, as they have since Haldane’s landmark lecture in the early 1960s.
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Disclosures: None relevant. Acknowledgements: Dr. Steensma’s work in myelodysplastic syndromes is supported by the Edward P Evans Foundation and the James and Lois Champy Foundation. REFERENCES [1] P.C. Nowell, The clonal evolution of tumor cell populations, Science 194(4260) (1976) 23-8. [2] L. Malcovati, M. Cazzola, The shadowlands of MDS: idiopathic cytopenias of undetermined significance (ICUS) and clonal hematopoiesis of indeterminate potential (CHIP), Hematology Am. Soc. Hematol. Educ. Program 2015 (2015) 299-307. [3] G. Genovese, A.K. Kähler, S.A. Rose, R.E. Handsaker, K. Chambert, E. Mick, S.F. Bakhoum, B. Neale, M. Fromer, S.M. Purcell, M. Landén, J. Moran, P.F. Sullivan, P. Sklar, C.M. Hultman, S.A. McCarroll, Clonal hematopoiesis and cancer risk in blood derived DNA sequence, N. Engl. J. Med. 371(December 25) (2014) 2477-2487. [4] S. Jaiswal, P. Fontanillas, J. Flannick, A. Manning, P.V. Grauman, B.G. Mar, R.C. Lindsley, C.H. Mermel, N. Burtt, A. Chavez, J.M. Higgins, V. Moltchanov, F.C. Kuo, M.J. Kluk, B. Henderson, L. Kinnunen, H.A. Koistinen, N. Ladenvall, G. Getz, A. Correa, B.F. Banahan, S. Gabriel, S. Kathiresan, H.M. Stringham, M.I. McCarthy, M. Boehnke, D. Altshuler, J. Tuomilehto, C. Haiman, L. Groop, G. Atzmon, J.G. Wilson, D. Neuberg, D. Altshuler, B.L. Ebert, Age-related clonal hematopoiesis associated with adverse outcomes, N. Engl. J. Med. 371(December 25) (2014) 2488-2498. [5] M. Xie, C. Lu, J. Wang, M.D. McLellan, K.J. Johnson, M.C. Wendl, J.F. McMichael, H.K. Schmidt, V. Yellapantula, C.A. Miller, B.A. Ozenberger, J.S. Welch, D.C. Link, M.J. Walter, E.R. Mardis, J.F. Dipersio, F. Chen, R.K. Wilson, T.J. Ley, L. Ding, Age-related mutations associated with clonal hematopoietic expansion and malignancies, Nat. Med. 20(12) (2014) 1472-8. [6] D.P. Steensma, R. Bejar, S. Jaiswal, R.C. Lindsley, M.A. Sekeres, R.P. Hasserjian, B.L. Ebert, Clonal hematopoiesis of indeterminate potential and its distinction from myelodysplastic syndromes, Blood 126(1) (2015) 9-16. [7] M. Gerlinger, A.J. Rowan, S. Horswell, J. Larkin, D. Endesfelder, E. Gronroos, P. Martinez, N. Matthews, A. Stewart, P. Tarpey, I. Varela, B. Phillimore, S. Begum, N.Q. McDonald, A. Butler, D. Jones, K. Raine, C. Latimer, C.R. Santos, M. Nohadani, A.C. Eklund, B. Spencer-Dene, G. Clark, L. Pickering, G. Stamp, M. Gore, Z. Szallasi, J. Downward, P.A. Futreal, C. Swanton, Intratumor heterogeneity and branched evolution revealed by multiregion sequencing, N. Engl. J. Med. 366(10) (2012) 883-92. [8] M.J. Walter, D. Shen, L. Ding, J. Shao, D.C. Koboldt, K. Chen, D.E. Larson, M.D. McLellan, D. Dooling, R. Abbott, R. Fulton, V. Magrini, H. Schmidt, J. Kalicki-Veizer, M. O'Laughlin, X. Fan, M. Grillot, S. Witowski, S. Heath, J.L. Frater, W. Eades, M. Tomasson, P. Westervelt, J.F. DiPersio, D.C. Link, E.R. Mardis, T.J. Ley, R.K. Wilson, T.A. Graubert, Clonal architecture of secondary acute myeloid leukemia, N. Engl. J. Med. 366(12) (2012) 1090-8. [9] S. Venkatesan, C. Swanton, Tumor Evolutionary Principles: How Intratumor Heterogeneity Influences Cancer Treatment and Outcome, Am Soc Clin Oncol Educ Book 35 (2016) e141-9. [10] L.M. Silver, What are clones?, Nature 412(6842) (2001) 21. [11] U. Mittwoch, "Clone": the history of a euphonious scientific term, Med. Hist. 46(3) (2002) 381-402.
Steensma – Clone origin - Page 10 [12] H.J. Webber, New Horticultural and Agricultural Terms, Science 18(459) (1903) 501-3. [13] A.A. Diamandopoulos, P.C. Goudas, Cloning's not a new idea: the Greeks had a word for it centuries ago, Nature 408(6815) (2000) 905. [14] G.D. Gale, Dying on the Vine: How Phylloxera Transformed Wine, University of California Press, Los Angeles, 2011. [15] C.L. Pollard, 'Clon' versus 'Clone', Science 22 (1905) 469. [16] March 11, 2011. National Public Radio. Science Diction: The Origin Of The Word 'Clone' Host: Joe Palca. , Transcript: http://www.npr.org/2011/03/11/134459358/Science-Diction-TheOrigin-Of-The-Word-Clone 2011, p. 3:58. [17] G.H. Shull, "Genotypes," "Biotypes," "Pure Lines" and "Clones", Science 35(888) (1912) 279. [18] J.B.S. Haldane, Biological Possibilities for the Human Species in the Next Ten Thousand Years, in: G. Wolstenholme (Ed.), Man and his future, J&A Churchill, London, 1963. [19] J.B.S. Haldane, Daedalus or Science and the Future, Kegan Paul, Trench, Trübner & Company, London, 1924. [20] R. Briggs, T.J. King, Transplantation of Living Nuclei From Blastula Cells into Enucleated Frogs' Eggs, Proc. Natl. Acad. Sci. U. S. A. 38(5) (1952) 455-63. [21] K.H. Campbell, J. McWhir, W.A. Ritchie, I. Wilmut, Sheep cloned by nuclear transfer from a cultured cell line, Nature 380(6569) (1996) 64-6. [22] L. Meng, J.J. Ely, R.L. Stouffer, D.P. Wolf, Rhesus monkeys produced by nuclear transfer, Biol. Reprod. 57(2) (1997) 454-9. [23] M. Tachibana, P. Amato, M. Sparman, N.M. Gutierrez, R. Tippner-Hedges, H. Ma, E. Kang, A. Fulati, H.S. Lee, H. Sritanaudomchai, K. Masterson, J. Larson, D. Eaton, K. Sadler-Fredd, D. Battaglia, D. Lee, D. Wu, J. Jensen, P. Patton, S. Gokhale, R.L. Stouffer, D. Wolf, S. Mitalipov, Human embryonic stem cells derived by somatic cell nuclear transfer, Cell 153(6) (2013) 122838. [24] L.R. Kass, J.Q. Wilson, The Ethics of Human Cloning, AEI Press, Washington, D.C., 1998. [25] D. Koeppel, Banana: The Fate of the Fruit That Changed the World, Penguin (USA), New York, 2007. [26] J. Kronke, E.C. Fink, P.W. Hollenbach, K.J. MacBeth, S.N. Hurst, N.D. Udeshi, P.P. Chamberlain, D.R. Mani, H.W. Man, A.K. Gandhi, T. Svinkina, R.K. Schneider, M. McConkey, M. Jaras, E. Griffiths, M. Wetzler, L. Bullinger, B.E. Cathers, S.A. Carr, R. Chopra, B.L. Ebert, Lenalidomide induces ubiquitination and degradation of CK1alpha in del(5q) MDS, Nature 523(7559) (2015) 183-8. [27] S.C. Lee, H. Dvinge, E. Kim, H. Cho, J.B. Micol, Y.R. Chung, B.H. Durham, A. Yoshimi, Y.J. Kim, M. Thomas, C. Lobry, C.W. Chen, A. Pastore, J. Taylor, X. Wang, A. Krivtsov, S.A. Armstrong, J. Palacino, S. Buonamici, P.G. Smith, R.K. Bradley, O. Abdel-Wahab, Modulation of splicing catalysis for therapeutic targeting of leukemia with mutations in genes encoding spliceosomal proteins, Nat. Med. 22(6) (2016) 672-8. [28] M. Jadersten, L. Saft, A. Pellagatti, G. Gohring, J.S. Wainscoat, J. Boultwood, A. Porwit, B. Schlegelberger, E. Hellstrom-Lindberg, Clonal heterogeneity in the 5q- syndrome: p53 expressing progenitors prevail during lenalidomide treatment and expand at disease progression, Haematologica 94(12) (2009) 1762-6. FIGURE CAPTIONS
Steensma – Clone origin - Page 11 1) A. Herbert John Webber (1865-1946) was a noted plant breeder and botanist who worked for the US Department of Agriculture from 1892-1907 after graduating from the University of Nebraska, then directed Cornell University‘s New York State College of Agriculture Department of Plant Breeding for 5 years. From 1912 until his retirement in 1929, Webber served as director of the University of California’s Citrus Experiment Station. His 1903 letter to Science proposed the term “clone” to describe asexual propagation and reproduction. Image source: Herbert John Webber - Eustis, Florida. 19-. Black & white photonegative. State Archives of Florida, Florida Memory. Accessed 15 Feb. 2017.. B. Herbert Weber standing under a carob tree. This picture was taken near Coconut Grove, Florida, about this time the Sub-Tropical Laboratory was started by Swingle and Webber..” Source: Special Collections, USDA National Agricultural Library. Accessed February 13, 2017, https://www.nal.usda.gov/exhibits/speccoll/items/show/303. C. Orator Fuller Cook, Jr. (1867-1949). This line drawing of a young Cook accompanied an article about the importance of scientific advance and agricultural education in securing the future of the young West African colony of Liberia, where Cook worked for a time in the 1890s. Image source: The Philipsburg Mail. (Philipsburg, Mont.), 23 May 1895. Chronicling America: Historic American Newspapers. Library of Congress. http://chroniclingamerica.loc.gov/lccn/sn83025320/1895-05-23/ed-1/seq-3/ 2) First Edition cover of Aldous Huxley’s 1932 dystopian novel Brave New World. This best-selling book introduced the concept of human cloning performed in automotive assembly-line fashion in a 25th century future (though a different term – Bokanovsky’s process - was used). The idea of embryonic division and non-womb-requiring ectogenesis was influenced by a 1924 book about the future of science by J.B.S. Haldane, who was the first to use the term “clone” to describe copying of humans in 1962. 3) A, Gros Michel bananas and B, Cavendish bananas. Gros Michel bananas are genetically homogeneous and were susceptible to fungal infection, and were decimated in the 1950s by Panama disease, due to a Fusarium fungus. Only a few plantations of Gros Michel banana trees remain in Asia (e.g., Malaysia and Thailand). They have largely been replaced commercially by Cavendish bananas, which are genetically similar to Gros Michel but have reduced sensitivity to Panama disease. Both Gros Michel and Cavendish bananas are members of the genetically triploid AAA group of Musa acuminate, which suggests that the Cavendish banana may also face catastrophe in the near future. However, other strains such as the genetically tetraploid AAAA (e.g., Golden Beauty banana), the distinct ABB (e.g. Blue Java banana), or “somaclones” created by micropropagation with induced genetic variation could provide replacements if the unthinkable happened. Image A, courtesy of Washington Banana Museum. Image B, photo taken by the author 15 February 2017.
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