Darwin's Pangenesis

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Darwin’s Pangenesis: A Theory of Everything? Yongsheng Liu*, x *Henan Collaborative Innovation Center of Modern Biological Breeding, Henan Institute of Science and Technology, Xinxiang, China x Department of Biochemistry, University of Alberta, Edmonton, AB, Canada E-mail: [email protected].

Contents 1. The Origin of Species: An Incomplete Explanation of Evolution 2. The Variation of Animals and Plants Under Domestication: Darwin’s Legacy to Genetics 2.1 The Variation: Darwin’s “Big Book” 2.2 The Variation: A Valuable Storehouse of Facts and Observations 2.3 Darwin: A Pioneer of Genetics? 3. Pangenesis as an Expanded Cell Theory 3.1 Cell Theory Before Darwin 3.2 Pangenesis as the Third Version of the Cell Theory 3.3 Rethinking the Cell Theory 4. Pangenesis as a Unified Theory of Heredity, Variation, Development and Reproduction 4.1 Genetical Theory Before Darwin 4.2 The Facts That Pangenesis Was Designed to Explain 4.3 Darwin’s Confidence in Pangenesis 5. Darwin’s Pangenesis: A Sleeping Beauty? References

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Abstract This chapter briefly discusses Darwin’s The Origin of Species and its companion volume The Variation of Animals and Plants under Domestication. It is in the second great book that Darwin took a broad survey of the whole range of variation and heredity, and developed his Pangenesis, an expanded cell theory and a unified genetical theory that would strengthen his theory of evolution and explains the numerous phenomena of life. The essential assumption of Pangenesis is the existence of inherited particles or molecules called gemmules, and their production by cells at each stage of development. He assumed that besides the ordinary cellular division, cells could also “throw off”

Advances in Genetics, Volume 101 ISSN 0065-2660 https://doi.org/10.1016/bs.adgen.2018.05.001

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numerous and minute gemmules, which were capable of self-replication and dormancy, diffusion from cell to cell or circulation through the body, modification by the effects of use and disuse or environmental changes, union with nascent cells, aggregation into buds and germ cells, and transmission from parent to offspring. By his Pangenesis, Darwin not only explained the general phenomena pertaining to inheritance, variation, development and reproduction, but also the inheritance of acquired characters, prepotency, graft hybridization, reversion, regeneration, xenia, telegony, transposition, sex-linked inheritance, the inheritance and non-inheritance of mutilation, and many other facts. Darwin called Pangenesis his “beloved child”, and firmly believed that it “will turn out true some day!”

I would like to open this book serial with a quotation from Fisher and Stock (1915) on a great book: So melancholy a neglect of Darwin’s work suggests reflections upon the use of those rare and precious possessions of man d great books. It was, we believe, the custom of the late Professor Freeman to warn his students that mastery of one great book was worth any amount of knowledge of many lesser ones. The tendency of modern scientific teaching is to neglect the great books, to lay far too much stress upon relatively unimportant modern work, and to present masses of detail of doubtful truth and questionable weight in such a way as to obscure principles. . How many biological students of today have read The Origin? The majority know it only from extracts, a singularly ineffective means, for a work of a genius does not easily lend itself to the scissors; its unity is too marked. Nothing can really take the place of a firsthand study of the work itself.

2018 marks the 150th anniversary of Darwin’s publication of one of his “five great books”, The Variation of Animals and Plants under Domestication (Darwin, 1868). Now similar questions may also be asked: How many biological students of today have read Darwin’s The Variation? How many biological students of today are familiar with Darwin’s Pangenesis? As Cavalier-Smith (1997) pointed out, evolutionists are very prone to cite, and maybe even read, The Origin, but none who have not also read The Variation can truly appreciate the great scope and depth of Darwin’s contributions to genetics and evolution. His Pangenesis was neither understood nor accepted, and has been generally forgotten, ignored, or assumed to be only of historical interest. If asked, most people would say that Darwin’s Pangenesis is wrong, or they have never heard of it. I must confess here that of my shame I did not know Darwin’s Pangenesis until 1998 when I had a chance to read his The Variation. Thus before I discuss Pangenesis, it is necessary to briefly mention Darwin’s The Origin, particularly his The Variation.

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1. THE ORIGIN OF SPECIES: AN INCOMPLETE EXPLANATION OF EVOLUTION The Origin of Species, one of the most influential books of modern biology, has been so often discussed that even to mention it, seems almost superfluous. But here I would like to emphasize that Darwin always regarded The Origin as a prematurely published abstract of his evolutionary ideas, because he wrote it in a hurry. He did not feel ready to expose his theory of evolution to the harsh light of public scrutiny. In the introduction of the book, he admitted that although his work on natural selection was “nearly finished,” he would need “two or three more years to complete it” (Darwin, 1872). His original plan was to publish a large work in several volumes. In 1858, he learned that Alfred Russel Wallace had independently developed the very theory of natural selection that he himself had been working on for many years. Probably for fearing loss of priority, he rushed a brief formulation of his own version of theory into print. In this short book he could give no more than the general conclusions at which he had arrived during the 20 years of painstakingly accumulating and reflecting on all sorts of facts which could possibly have a bearing on this subject. But he was well aware of the necessity of later publishing in detail all the facts on which his theory of evolution by natural selection had been grounded (Stern, 1959). Darwin (1872) summarized his theory of evolution by natural selection in The Origin as follows: As many more individuals are produced than can possibly survive, there must in every case be a struggle for existence, either one individual with another of the same species, or with the individuals of distinct species, or with the physical conditions of life.Can it, then, be thought improbable, seeing that variations useful to man have undoubtedly occurred, that other variations, useful in some way to each being in the great and complex battle of life, should sometimes occur in the course of thousands of generations? If such do occur, can we doubt (remembering that many more individuals are born than can possibly survive) that individuals having any advantage, however slight, over others, would have the best chance of surviving and of procreating their kind? On the other hand, we may feel sure that any variation in the least degree injurious would be rigidly destroyed. This preservation of favorable variations and the rejection of injurious variations, I call Natural Selection.

Darwin’s statement is that natural selection occurs as a necessary conclusion from two premises: (1) the assumption that inherited variations useful to organisms occur; (2) the observation that more individuals are produced

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than can possibly survive. As Ayala and Fitch (1997) pointed out, the most serious difficulty facing Darwin’s theory of evolution by natural selection was the lack of an adequate theory of heredity that would explain the preservation through the generations of the variations on which natural selection could act. Evolution is the process of heredity and variation, and variation is the fountainhead of evolution. If heredity were always exact, evolution would not occur. Darwin was certainly aware of the importance of understanding heredity and variation for understanding evolution. In The Origin, only three chapters were devoted to the topic of variation, and one chapter to hybridism. He admitted that “the laws governing inheritance are quite unknown; no one can say why the same peculiarity in different individuals of the same species, and in individuals of different species, is sometimes inherited and sometimes not so; why the child often reverts in certain characters to its grandfather or grandmother or other much more remote ancestor; why a peculiarity is often transmitted from one sex to both sexes, or to one sex alone, more commonly but not exclusively to the like sex” (Darwin, 1872). Although he did not deal with essential genetic problem, it seems that he had predicted the emergence of the science of genetics. In the last chapter of The Origin, we read: “A grand and almost untrodden field of inquiry will be opened, on the causes and laws of variation, on correlation, on the effects of use and disuse, on the direct action of external conditions, and so forth” (Darwin, 1872).

2. THE VARIATION OF ANIMALS AND PLANTS UNDER DOMESTICATION: DARWIN’S LEGACY TO GENETICS 2.1 The Variation: Darwin’s “Big Book” When Darwin published The Origin, he still had materials and notes to form the basis of four other books. The first of these is The Variation of Animals and Plants under Domestication. He began to write on The Variation on 24 March 1860, but it was not published until January 30, 1868. According to Darwin’s own reckoning, this two-volume work cost him four years and two months of hard labor (Darwin, 1888). Darwin collected a vast amount of information from the works on the practical breeding of cultivated plants and domestic animals, and from fanciers, gardeners and sportsmen. He himself conducted numerous experiments with pigeons and with various plants. As Sturtevant (1965) noted,

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one of the striking things was that Darwin had a detailed firsthand knowledge of both animals and plants, and patiently collated every bit of information about heredity and variation that he found in the literature. Thus The Variation was full of examples of how artificial selection by humans had acted on the evolution of domestic animals and plants and how natural selection was analogous to it. It is in this great book that Darwin came nearest to the subject of genetics. The first volume was devoted to a review of the history of the most important domestic animals and plants. In the second volume, he discussed various general problems pertaining to the subject of variation and inheritance. His 28 chapters range from detailed descriptions of domestic animals and plants to theoretical discussions on how variations were produced and how characters were inherited (Porter & Graham, 2015). Darwin was the first to take a broad survey of the whole range of variations in animals and plants, and clearly described almost all genetical phenomena of fundamental importance (Muntzing, 1959; de Vries, 1910). In his autobiography, Darwin said the following words regarding The Variation: My Variation of Animals and Plants under Domestication was begun, as already stated, in the beginning of 1860, but was not published until the beginning of 1868. It was a big book, and cost me four years and two months’ hard labour. It gives all my observations and an immense number of facts collected from various sources, about our domestic productions. In the second volume the causes and laws of variation, inheritance, etc., are discussed as far as our present state of knowledge permits. Towards the end of the work I give my well-abused hypothesis of Pangenesis. An unverified hypothesis is of little or no value; but if anyone should hereafter be led to make observations by which some such hypothesis could be established, I shall have done good service, as an astonishing number of isolated facts can be thus connected together and rendered intelligible. In 1875 a second and largely corrected edition, which cost me a good deal of labour, was brought out. Darwin (1888)

2.2 The Variation: A Valuable Storehouse of Facts and Observations Darwin firmly connected The Variation to The Origin by devoting its Introduction to an overview of his theory of evolution by natural selection. At the beginning of his Introduction, Darwin clearly stated that his object was not to describe all the races of domesticated animals and plants, but “to give under the head of each species only such facts as I have been able to collect or observe, showing the amount and nature of the changes which animals

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and plants have undergone whilst under man’s dominion, or which bear on the general principles of variation.” He further specified that “in one case alone, namely in that of the domestic pigeon, I will describe fully all the chief races, their history, the amount and nature of their differences, and the probable steps by which they have been formed. I have selected this case, because, as we shall hereafter see, the materials are better than in any other; and one case fully described will in fact illustrate all others” (Darwin, 1875). Of the work’s twenty-eight chapters, the first ten consists of a veritable catalog of variations found in barnyard and field. It was actually a species-byspecies survey of domesticated animals and cultivated plants. Among them eight chapters were given to the illustration of the varieties of dogs and cats; horses and asses; pigs, cattle, sheep, and goats; domestic rabbits; domestic pigeons, fowls, ducks, geese, peacock, turkey, and so on. Two chapters were occupied with the cereal and some of the commonest culinary plants, fruits, and trees. Darwin described the differences between the various breeds of each species, and making out the history of their development from each other and from the wild stock. It should be noted that Darwin devoted two chapters to pigeons, in which each variety was examined in detail. As Porter and Graham (2015) pointed out, 9 pages on pigeons in his The Origin were expanded to 94 pages in The Variation. The reason has been that his first personal experience with breeding was with pigeons. Darwin studied every variety he collected, alive or dead, inside and out, new and ancient, and even joined two London pigeon clubs. He was interested not only in their morphology, but also in their behavior and development (Bartley, 1992; Porter & Graham, 2015). In the eleventh chapter, Darwin examined several anomalous phenomena: bud variations, graft hybridization, and the direct action of the male element on the female. His notion of bud variation (spontaneous or accidental variation) was later developed into the mutation theory by de Vries (1909a,b). Darwin was the first to put forward the concept of graft hybridization. Based on Darwin’s work, Michurin (1949) elaborated a simple and efficient method for producing graft hybridsd“mentor-grafting.” Later graft hybridization as a chapter was included in the textbook of Michurinian genetics (Wang, 1998). The direct action of the male element on the female was later named xenia (pollen effects on seeds and fruits in plants) by Focke (1881, pp. 510e518) and telegony (the influence of the previous sire on offspring in animal) by Weismann (1893, pp. 383e386). Xenia and telegony were considered as doubtful phenomena by

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Weismann, Morgan and many other geneticists (Morgan, 1907). The issues discussed in this chapter are among the most controversial in genetics, although it had been largely altered and remodeled in the second edition (Darwin, 1875). In next three long chapters (from twelve to fourteen) entitled “Inheritance,” Darwin dealt with essential genetic problems. “The whole subject of inheritance is wonderful,” he exclaimed at the beginning of his account. “When a new character arises, whatever its nature may be, it generally tends to be inherited, at least in a temporary and sometimes in a most persistent manner.” He devoted the thirteenth chapter to what he termed “atavism” or “reversion,” that is, the tendency for offspring to manifest traits apparently derived from their grandparents or even remote ancestors, rather than from their parents. In the fourteenth chapter, Darwin elaborated five laws of inheritance: Finally, though many remains obscure with respect to inheritance, we may look at the following laws as fairly well established. Firstly, a tendency in every character, new and old, to be transmitted by seminal and bud generation, though often counteracted by various known and unknown causes. Secondly, reversion or atavism, which depends on transmission and development being distinct powers. It acts in various degrees and manners through both seminal and bud generation. Thirdly, prepotency of transmission, which may be confined to one sex, or be common to both sexes of the prepotent form. Fourthly, transmission, limited by sex, generally to the same sex in which the inherited character first appeared. Fifthly, inheritance at corresponding periods of life, with some tendency to the earlier development of the inherited character. Darwin (1875)

According to Noguera-Solano and Ruiz-Gutiérrez (2009), Darwin’s five laws of inheritance can be simply summarized as follows: (1) First Law: transmission of all characters; (2) Second Law: atavism or reversion; (3) Third Law: prepotency; (4) Fourth Law: sex-limited inheritance; (5) Fifth Law: inheritance at corresponding age. In genetics, Mendel’s laws are well known. Little is known about Darwin’s laws of inheritance. Actually, Darwin’s laws are far more comprehensive than Mendel’s. Darwin’s third law of prepotency was similar to Mendel’s dominance. The following five chapters (from fifteen to nineteen) were devoted to hybridism. Darwin made strong statements affirming the efficacy of hybridization in producing new breeds. As he stated, “crossing, like any other change in the conditions of life, seems to be an element, probably a potent one, in causing variability, the offspring of the first generation being

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generally uniform, but those subsequently produced displaying an almost infinite diversity of character” (Darwin, 1875). He repeatedly discussed the evil effects of inbreeding and the beneficial effects of crosses, believing that it is a great law of nature that crossing is beneficial, whereas longcontinued close inbreeding is injurious. Chapters twenty and twenty-one consisted of detours into the mechanism of artificial and natural selection; whereas chapters twenty-two to twenty-six focused on the “laws of variation.” This subject was the objective of the entire book. His primary concern was with the causes of variation. Again and again he pointed to changed conditions of life as being responsible for variability. He maintained that environmental changes, acting either on the sexual organs or the body, were necessary to generate variation. As he wrote, “If it were possible to expose all the individuals of a species during many generations to absolutely uniform conditions of life, there would be no variability.” He supported the view that “variations of all kinds and degrees are directly or indirectly caused by the conditions of life to which each being, and more especially its ancestors, have been exposed” (Darwin, 1875). Finally, all the major lines were brought to a wonderful concluding chapter on his “provisional hypothesis of Pangenesis.” Part one of this chapter summarized the phenomena that the hypothesis was designed to explain, and part two explained the hypothesis. This is of great interest and importance, and so characteristic of Darwin’s power of viewing the most divergent facts from a common standpoint, that it is necessary to give a tolerably full account of it in the next three sections.

2.3 Darwin: A Pioneer of Genetics? As Bunting (1974, p. 114) correctly pointed out, “Darwin was a great man in every respect and it will be many, many years e if ever e before we see his like again. He opened up an entirely new field for scientific investigation e a field later to be exploited by such leading biologists as Mendel, Morgan, ., and it is doubtful whether we could have acquired our present knowledge of heredity had not it been for Darwin’s painstaking work of a lifetime.” Muntzing, the former president of Sweden Society of Mendelian Genetics, suggested that geneticists read Darwin in the original: “It still pays to go back to Darwin’s works not only for historical reasons but also because in many respects they are surprisingly modern. They contain such a richness of empirical data that most geneticists will find several points with important bearings on their own fields of work” (Muntzing, 1959). Moreover,

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someone who even disliked Darwin’s The Origin, still admired Darwin’s The Variation. As he said: “On the origin of species, Mr. Darwin has nothing, and is never likely to have anything, to say; but on the vastly important subject of inheritance, the transmission of peculiarities once acquired through successive generations, this work is a valuable storehouse of facts for curious students and practical breeders” (cited in Robinson, 1979, p. 23). In 1906, the late William Bateson coined the word “genetics” in his inaugural address to the Third Conference on Hybridization and Plantbreeding: “I suggest for the consideration of this Congress the term Genetics, which sufficiently indicates that our labors are devoted to the elucidation of the phenomena of heredity and variation: in other words, to the physiology of Descent, with implied bearing on the theoretical problems of the evolutionist and the systematist, and application to the practical problems of breeders, whether of animals or plants.” He regarded Darwin as a pioneer of genetics: “Darwin made a more significant contribution. Not for a few generations, but through all ages he should be remembered as the first who showed clearly that the problems of heredity and variation are soluble by observation, and laid down the course by which we must proceed to their solution. Evolution is a process of variation and heredity. The older writers, though they had some vague idea that it must be so, did not study variation and heredity. Darwin did, and so begat not a theory, but a science” (Bateson, 1910).

3. PANGENESIS AS AN EXPANDED CELL THEORY 3.1 Cell Theory Before Darwin Darwin’s study of inheritance and variation did beget a scienced genetics, as Bateson (1910) noted. But it also begat a theory, that is, what he named Pangenesisdan expanded cell theory. Darwin habitually thought big. But the cell theory allowed him to think small. The cell theory ranks with Darwin’s evolutionary theory as one of the foundation stones of modern biology, representing a decisive advance in the development of biological thought. Although Darwin’s theory of evolution is well known, little is known about his contribution to the development of the cell theory. According to Gerould (1922), the cell theory was proposed originally by Mirbel and Lamarck. In 1808, Mirbel demonstrated that all plants are composed of cells, and laid especial emphasis upon cell walls, which he

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thought to be porous, allowing free circulation of the contained fluids. In 1809, the year of Darwin’s birth, the French naturalist, Lamarck published his Philosophie Zoologique. In this great book, Lamarck claimed that “No body can possess life if its containing parts are not a cellular tissue, or formed by cellular tissue” (Lamarck, 1809). To him, cellular tissue was the matrix in which the organs were shaped by the movements of the contained fluids. Both Mirbel and Lamarck considered the organism as a cellular whole. In the late 1830s, Schleiden and Schwann formulated the cell theory, proposing that cells might arise in two different ways, either by division of a preexisting mother cell or by spontaneous generationdthe cells could form themselves (Swanson, 1960). Cell theory in its modern form was formulated by Rudolf Virchow. In his Cellular Pathology, he rejected spontaneous generation, and maintained that cells come only from existing cells (Swanson, 1960). The English translation of Virchow’s book was published in 1863. Darwin read it and was strongly influenced by it (Ghiselin, 1975). He wrote The Origin without any reference to cellular structure in animals and plants, and the word “cell” is not to be found in the index of the book. In The Variation, Darwin (1868) incorporated the cell theory into his ideas on variation, heredity, reproduction and development. At that time in England, Virchow’s doctrine was by no means exclusively held. There were some who still maintained that cells and tissues of all kinds may be formed by spontaneous generation, as Schleiden and Schwann originally suggested. Darwin (1868) felt it would be “presumptuous” to express an opinion on the two opposed doctrines.

3.2 Pangenesis as the Third Version of the Cell Theory If we regard the cell theory proposed by Schleiden and Schwann as the first version, and Virchow’s cell theory as the second, Darwin’s Pangenesis may be considered as the third version (Fig. 1 shows a portion of the first page of his manuscript). In chapter 27 of The Variation, Darwin (1868) asserted: It is almost universally admitted that cells, or the units of the body, propagate themselves by self-division or proliferation, retaining the same nature, and ultimately becoming converted into the various tissues and substances of the body. But besides this means of increase I assume that cells, before their conversion into completely passive or ‘form-material,’ throw off minute granules or atoms, which circulate freely throughout the system, and when supplied with proper nutriment multiply by self-division, subsequently becoming developed into cells like those from which they were derived. These granules for the sake

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Figure 1 A portion of the first page of Darwin’s manuscript of Pangenesis. Reproduced with permission from Olby, R. C. (1963). Charles Darwin’s manuscript of pangenesis. British Journal for the History of Science, 1, 251e263. 11

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of distinctness may be called cell-gemmules, or, as the cellular theory is not fully established, simply gemmules. They are supposed to be transmitted from the parents to the offspring, and are generally developed in the generation which immediately succeeds, but are often transmitted in a dormant state during many generations and are then developed. Their development is supposed to depend on their union with other partially developed cells or gemmules which precede them in the regular course of growth. Why I use the term union, will be seen when we discuss the direct action of pollen on the tissues of the mother-plant. Gemmules are supposed to be thrown off by every cell or unit, not only during the adult state, but during all the stages of development. Lastly, I assume that the gemmules in their dormant state have a mutual affinity for each other, leading to their aggregation either into buds or into the sexual elements. Hence, speaking strictly, it is not the reproductive elements, nor the buds, which generate new organisms, but the cells themselves throughout the body. These assumptions constitute the provisional hypothesis which I have called Pangenesis.

Darwin admitted that the cells multiply by division, and that in so doing they preserve essentially the same nature, as Virchow suggested. He recognized that this rule formed the basis of heredity, explaining the general genetic phenomenon. However, he was still not satisfied with Virchow’s version of the cell theory, because it failed to explain all the phenomena of life. Particularly, it could not explain the Lamarckian inheritance of acquired characters, graft hybridization, the direct action of male element on the female and many other facts. Thus he supposed that, in addition to cellular division, there existed another means of transfer of hereditary characters. He assumed that cell could “throw off” minute granules (molecules or atoms) called gemmules. These gemmules were the bearers of the characters of the cells from which they were derived, and thus transmitted those characters to the germs cells and to the buds. He reasoned this way: If cells could divide and produce other cells, probably they could also produce other bodies with the characters of his so-called gemmules by a similar process (Moore, 1963). In his own words, “The existence of free gemmules is a gratuitous assumption, yet can hardly be considered as very improbable, seeing that cells have the power of multiplication through the self-division of their contents” (Darwin, 1868). As Holterhoff (2014) pointed out, in the second edition of The Variation Darwin (1875) changed and expanded several phrases. Starting in a deceptively similar fashion Darwin wrote, “all the units of the body, besides having the universally admitted power of growing by self-division, throw off minute gemmules which are dispersed through the system” (Vol. 2, p. 397). He substitute “of the body” for “organic” to describe units

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which may undergo pangenesis. Similarly, he substitute “universally” for “generally” to indicate the degree to which the “power of growing by self-division” was admitted. In addition, he removed words in the 1875 version which he considered unnecessary like “free” and “atoms of their contents” as additional adjectives with the apparently essential “minute” describing gemmules. The primary assumption of Darwin’s Pangenesis was the existence of the gemmules, their production by cells, and cellecell communications. The term “gemmule” is a diminutive of “gemma” or bud, implying a little bud. “Gemmule” had been used by other biologists before Darwin, but with different meanings (Ghiselin, 1975). According to Darwin’s description expressed in his book and letters, the characters of gemmules can be summed up as follows: 1. Gemmules are pangenetic, and are thrown off by cells of the entire body at every developmental stage. In other words, the entire body (“pan”) participates in the formation (“genesis”) of a new individual (Ghiselin, 1975). 2. Gemmules exist as minute granules or particles and even might live outside the body. Darwin supposed that they are extremely small and compared them with molecules, atoms or viruses. 3. Gemmules are numerous. Darwin imagined that gemmules were “inconceivably minute and numerous as the stars in heaven”, and that “many thousand gemmules must be thrown off from the various parts of the body at each stage of development” (Darwin, 1875). 4. Gemmules multiply by self-division or self-propagation (selfreplication). 5. Gemmules, like seeds in the ground and buds in the bark of a tree, are capable of dormancy. 6. Gemmules are capable of diffusion form cell to cell or circulation through the body. 7. Gemmules are capable of variation, and can be modified by the effects of use and disuse, or environmental changes. 8. Gemmules have elective affinity, and are capable of union with other gemmules and nascent or young cells. The gemmules had different patterns of elective affinity, undergoing different chemical unions. 9. Gemmules are capable of aggregation into buds and germ cells. 10. Gemmules are capable of transmission from parent to offspring. It is worth noting that in his The Variation, Darwin supposed that gemmules could develop into cells. But later he changed his mind. In a letter to

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Hooker, he wrote: “I believe I quite agree with you in the manner in which the cast-off atoms or so-called gemmules probably act. I have never supposed that gemmules were developed into free cells, but that they penetrated other nascent cells and modified their subsequent development” (Darwin & Seward, 1903). It is also interesting to note that, in another letter to Hooker, Darwin suggested that gemmules might live outside the body and “multiply under proper conditions” (Darwin & Seward, 1903). This may strike us as the now widely used polymerase chain reaction (PCR) and reverse-transcriptase polymerase chain reaction (RT-PCR) techniques, used to make a huge number of copies of a gene in vitro (Liu, 2008). In “In Search of Darwin’s Imaginary Gemmules,” I will compare Darwin’s gemmules with circulating cell-free DNA, mobile RNAs, prions and other extracellular vesicles, and will see that many of its features are surprisingly modern.

3.3 Rethinking the Cell Theory The modern version of the cell theory, although varies in different writings, is often described as follows (Sekeres and Zarsky, 2018): 1. All living things are composed of one or more cells; 2. Cells are organisms’ basic units of structure and function; 3. Cells come only from existing cells. Obviously, this is mainly based on Virchow’s version of the cell theory. As mentioned at the beginning of this section, the founders of the cell theory believed that cells could be formed not only within previously existing cells, but also from a structureless fluid, or cytoblastema, by a process analogous to crystal growth. Unfortunately, their viewpoint has been largely thought to be wrong, and was replaced by Virchow’s view that cells come only from existing cells. Virchow’s view of course could well explain cell reproduction and proliferation. But it certainly was not obvious that it also could explain the origin of cell. During the evolution of the earth, there ought to have been stages in which rather primitive living forms developed into cellular ones. Actually, several independent groups of researchers repeatedly proved the concept of spontaneous generation held by Schleiden and Schwann. A remarkable example is Lepeshinskaya’s concept of “the origin of cells from living substance.” According to Lepeshinskaya (1954), living substance includes proteins, nucleic acids and everything necessary for cell formation. She demonstrated that these tiny particles could assemble into new cells. Interestingly, Lepeshinskaya’s experimental results were confirmed by Chishima (1972)

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from Japan and Bei et al. (1983) from China. Recently, Lee, Lee, and Kang (2013) provided evidence for the self-assembly of DNA molecules toward cell-like structure, suggesting that an alternative pathway to making new cells independently from cell mitosis may exist. Thus, while we recognize that cells come mainly from existing cells, we also should realize that cells could arise from organic matter under certain circumstances (Liu, 2006b). During the one hundred and fifty years, which have since elapsed, a number of new observations have also been made which are in good agreement with Darwin’s version of the cell theory. Today, it has been universally accepted that almost all types of cells not only shed molecules such as cellfree DNA (including genomic DNA, tumor DNA and fetal DNA), RNAs (including mRNA and small RNAs) and prions, but also release into the extracellular environment diverse types of membrane vesicles (known as extracellular vesicles) containing DNA, RNA and proteins. In recent years, a new concept of “cell body” has been proposed by Baluska, Volkmann, and Barlow (2004), who suggested that a new cell theory is needed to explain complex intercellular connections. Hopefully, Darwin’s Pangenesis, the third version of the cell theory, can be incorporated into the new cell theory in the future.

4. PANGENESIS AS A UNIFIED THEORY OF HEREDITY, VARIATION, DEVELOPMENT AND REPRODUCTION 4.1 Genetical Theory Before Darwin It is a historical fact that the term “Pangenesis” was coined by Darwin, though the pangenetic idea can date back to ancient times. According to Zirkle (1946), the first actual description of this idea has been found in the works of Hippocrates, the father of medicine: “the seed comes from all parts of the body, healthy seed from healthy parts, diseased seed from diseased parts.” Hippocrates called the particles “seeds,” and Darwin was to call them “gemmules.” It is interesting to note that, when Williams Ogle pointed out to Darwin that he had been preceded in Pangenesis even by Hippocrates, Darwin replied: “I wish I had known of these views of Hippocrates, before I had published, for they seem almost identical with mine, merely a change of terms, and an application of them to classes of facts necessarily unknown to the old philosopher” (Darwin, 1888). Later in the chapter on Pangenesis of the second edition of The Variation,

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Darwin (1875) quoted Ogle in this citation: “More than 2,000 years ago Aristotle combated a view of this kind, which, as I hear from Dr. W. Ogle, was held by Hippocrates and others.” In the chapter on Pangenesis of the first edition of The Variation, Darwin (1868) admitted that his Pangenesis was not totally original: “Nearly similar views have been propounded, as I find, by other authors, more especially by Mr. Herbert Spencer; but they are here modified and amplified.” In 1864, one year before Darwin sent his Pangenesis manuscript to Huxley, Spencer proposed the existence of “physiological units” that derived from the body-cells of the parent, forming the germ-cells and then developing into the body-cells of the offspring. Both Darwin and Spencer recognized that their views were different. After reading the chapter on Pangenesis, Wallace wrote Darwin and told him how much he admired it: “You have now fairly beaten Spencer on his own ground, for he really offered no solution of the difficulties of the problem” (Darwin & Seward, 1903). In another letter to Darwin, Wallace wrote that though he was a great admirer of Spencer, he felt “how completely his view failed to go to the root of the matter, as yours does. His [view] explained nothing. . Yours, as far as I can see, explains everything in growth and reproduction.” (Darwin & Seward, 1903) Darwin’s Pangenesis was also entirely different from Owen’s hypothesis. The gemmules proposed by Owen were “progeny of the primary impregnated germ-cell,” which was not “required for the formation of the body,” “remain unchanged, and become included in that body.” But Darwin’s gemmules were supposed to be thrown off from every cell of the body, and to become aggregated into the reproductive cells (Geison, 1969). Darwin could have borrowed the pangenetic idea from others, but his Pangenesis is much more complex. It represents the crystallization of Darwin’s thoughts for about 27 years (Olby, 1966). Darwin explicitly stated that he had invented Pangenesis around 1840 or 1841, but not published until 1868. It was perhaps just a coincidence that in 1865, the year Mendel presented his paper “Experiments in plant hybridization” before the Natural History Society of Brno, Darwin finished his Pangenesis, a comprehensive theory he constructed to explain a far wider range of phenomena than Mendel had considered. He dispatched his manuscript of Pangenesis to Thomas Henry Huxley for comments on May 27, 1865 (Darwin, 1888).

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4.2 The Facts That Pangenesis Was Designed to Explain It is in this unified theory that Darwin tried to account for all the observable facts and laws of heredity and variationda considerable variety of phenomena to unite under a common theory. According to my understanding, Darwin’s Pangenesis at least explains the following twelve categories of phenomena: 1. Inheritance and prepotency: Darwin repeatedly emphasized that “Inheritance is a rule and non-inheritance the anomaly.” He was also aware of what he called prepotency and what we now call dominance. According to Pangenesis, the appearance of the same characters in parent and offspring was made possible by the production of gemmules from all parts of the parents’ body. These gemmules entered the sexual cells and were transmitted to the offspring where they expressed their specific characters. The tendency of hybrids to resemble one parent might be due to superabundance of gemmules in the fertilized germ, those from one parent having “some advantage in number, affinity, or vigour over those derived from the other parent.” The more gemmules there were from one parent, the more that parent’s specific characters would be prepotent. This explains the dominance associated with Mendelian inheritance. Darwin imagined that the sexual elements of a hybrid included two kinds of gemmules or character-carriers: pure gemmules and hybridized gemmules, which are essentially the same as our modern term “homozygote” and “heterozygote,” as Roberts (1919) pointed out. This will be discussed in detail in the chapter “Darwin and Mendel: the historical connection.” 2. Variability and the inheritance of acquired characters: Darwin considered variability as the result of the action of changed conditions of life. He held that the causes of hereditary variation mainly lie in the environment changes and the effects of use and disuse. According to him, variation depended either “on the reproductive organs being injuriously affected by changed conditions” or on “the direct action of changed conditions, when certain parts of the body were directly affected by the new conditions.” In the former case, gemmules derived from the various parts of the body were “probably aggregated in an irregular manner, some superfluous and others deficient.” In the latter case, the affected part threw off modified gemmules, which were “transmitted with their newly acquired peculiarities to the offspring.”

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With respect to mental habits, Darwin believed that it was highly probable that a fixed habit induced some changes in the nervous system, and the gemmules derived from modified nerve-cells were transmitted to the offspring. If Darwin’s term “modified gemmules” is replaced by “methylated DNA” or “small RNAs”, it seems to be consistent with our current epigenetic explanation (Liu, 2008). This will be discussed in detail the chapter “Darwin’s Pangenesis and the Lamarckian inheritance of acquired characters.” 3. Graft hybridization: Darwin coined the term graft hybridization, which means the formation of hybrids between distinct species or varieties, through plant grafting, without the intervention of the sexual organs. He believed that gemmules thrown off from the cells of the rootstock (or scion) could be transferred across the graft junction and combined with the gemmules thrown off from the cells of the scion (or rootstock), resulting in the formation of graft hybrids. Obviously, his pangenetic explanation of graft hybridization is analogous to our modern concept of horizontal (or lateral) gene transfer (Liu, 2006a). This will be discussed in detail in the chapter “Darwin’s Pangenesis and graft hybridization.” 4. Reproduction: There are two main types of reproduction: sexual and asexual. An animal like Hydra is capable of both. In Darwin’s opinion, inheritance is the same whether by sexual or asexual method, because the basis is the samedthe transmission of gemmules. In the case of Hydra, every cell of the body would produce gemmules, which could transfer to all parts, including the sexual organs and the buds. Therefore, the individual would receive the same gemmules irrespective of whether they are derived from a fertilized ovum or from a bud. 5. Development: For Darwin, heredity was a developmental process, and variation was a change in the developmental process of change. He insisted that an acceptable theory of heredity had to include development: “Two distinct elements are included under the term ‘inheritance’ e the transmission, and the development of characters; but as these generally go together, the distinction is often overlooked.” (Darwin, 1874) The study of heredity required the study of development, because the latter would demonstrate how gemmules interacted with other gemmules, other pre-existing cells, and external conditions of life to produce more cells, tissues and organs. According to Pangenesis, characters that appeared at a certain

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stage of development were explained as a series of particulate interactions: “the organic units, during each stage of development throw off gemmules, which, multiplying, are transmitted to the offspring. In the offspring, as soon as any particular cell or unit in the proper order of development becomes partially developed, it unites with (or, to speak metaphorically, is fertilized by) the gemmule of the next succeeding cell, and so onwards” (Darwin, 1875). Thus Darwin’s Pangenesis is also regarded as a developmental theory of heredity (Ghiselin, 1975; Winther, 2000). Atavism (Reversion): This is the presence in an individual of some characters not expressed in its immediate parents, but resembling their grandparents or more distant ancestors. According to Pangenesis, this is due to the long-dormant ancestral gemmules becoming active after the dormant transmission of many generations. Regeneration: Darwin thought that the ability of animals to regenerate missing parts was a wonderful fact. According to Pangenesis, the regeneration of lost parts is possible because the gemmules for the lost parts were produced prior to the loss and are present in the rest of the body. For example, if the leg of a salamander has been cut, the leg gemmules, which are present in the body, can move to the cut surface, union with the cells of the cut surface and develop into a new limb, identical to the old one (Moore, 1963). Direct action of the male element on the female (Xenia and Telegony): According to Pangenesis, xenia, or the effects of pollen on seeds and fruits, is because “the gemmules derived from the foreign pollen do not become developed merely in contact with pre-existing cells, but actually penetrate the nascent cells of the mother plant” (Darwin, 1875). Telegony, or the power of the male to influence offspring of a given female, was “intelligible through the diffusion, retention, and action of the gemmules included within the spermatozoa of the previous male” (Darwin, 1875). Sex-linked inheritance: Some traits are transmitted from father to son but never to daughters, or from mother to daughter but never to sons. According to Darwin (1875), “most, or perhaps all, of the secondary characters, which appertain to one sex, lie dormant in the other sex; that is, gemmules capable of’ development into the secondary male sexual characters are included within the female; and conversely female characters in the male.”

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10. Inheritance and non-inheritance of mutilations: Mutilations seems to be inherited in some instances, particularly which was followed by disease. According to Darwin’s record, one case was “a cow that had lost a horn from an accident with consequent suppuration, produced three calves which were hornless on the same side of the head.” There were other cases where mutilations appeared not to inherited, such as in docking the tails of certain domesticated breeds. According to Pangenesis, the inheritance of a part that had been removed during many generations would not result in an anomaly if gemmules formerly derived from the part were still multiplied and transmitted between generations. However, mutilation-induced change would be inherited by the offspring if the gemmules of the removed part were gradually attracted to the diseased surface and were therefore destroyed. 11. Transposition: The cases of abnormal transposition or multiplication of organ, such as the development of teeth in the palate or of pollen in the edge of a petal, was explained by supposing that the gemmules unite with wrong cells instead of the right ones. 12. Other facts: According to Pangenesis, the sterility of hybrids is due to the reproductive organs being affected; in the instance of plants they continue to propagate by grafting and cutting. The hybrid cells throw off hybrid gemmules that collect in the buds fail to do so in the reproductive organs. With regard to the inheritance at corresponding age, it was due to gemmules’ constant production by cells at each stage of development. Although Darwin’s Pangenesis could explain the diverse phenomena of inheritance, variation, development and reproduction, it is not a theory of everything. Darwin (1868) recognized that Pangenesis could not explain why gemmules do not spread from bud to bud in plants, and that it has no explanation for some differences in tendencies to reversion between plants propagated from buds rather than seeds. It also failed to explain the worker phenotype in social insects (West-Eberhard, 2003). In addition, as Stanford (2006) noted, Darwin’s private correspondence also admitted empirical anomalies for Pangenesis, as when he wrote to Hooker that “even Pan.[genesis] won’t explain” the selective importance of pollen when contacting ovules of same plant (Darwin & Seward, 1903).

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4.3 Darwin’s Confidence in Pangenesis When first published in 1868, Darwin’s Pangenesis was widely rejected by his contemporaries, but Darwin himself explicitly linked his confidence that Pangenesis will turn out true someday. He called Pangenesis his “beloved child,” “pet child,” and his “baby.” This may be reflected in his letters. To C. Lyell (August 22, 1867) I have been particularly pleased that you have noticed Pangenesis. I do not know whether you ever had the feeling of having thought so much over a subject that you had lost all power of judging it. This is my case with Pangenesis (which is 26 or 27 years old), but I am inclined to think that if it be admitted as a probable hypothesis it will be a somewhat important step in biology. Darwin (1888, p. 72)

To A. Gray (October 16, 1867) The chapter on what I call Pangenesis will be called a mad dream, and I shall be pretty well satisfied if you think it a dream worth publishing; but at the bottom of my mind I think it contains a great truth. Darwin (1888, p. 73)

To J. D. Hooker (November 17, 1867) I shall be intensely anxious to hear what you think about Pangenesis; though I can see how fearfully imperfect, even in mere conjectural conclusions, it is; yet it has been an infinite satisfaction to me somehow to connect the various large groups of facts, which I have long considered, by an intelligible thread. I shall not be at all surprised if you attack it and me with unparalleled ferocity. Darwin (1888, p. 74)

To F. Hildebrand ( January 5, 1868) I sincerely congratulate you on your success in making a graft-hybrid, for I believe it to be a most important observation. I trust that you will publish full details on this subject and on the direct action of pollen. . You will see why I think these two subjects so important. They have led me to form a hypothesis on the various forms of reproduction, development, inheritance, etc., which hypothesis, I believe, will ultimately be accepted, though how It will be now received I am very doubtful. Darwin and Seward (1903, p. 285)

To J. D. Hooker ( January 6, 1868) I heard yesterday to my joy that Dr. Hildebrand has been experimenting on the direct action of pollen on the mother-plant with success. He has also succeeded in making a true graft-hybrid between two varieties of potatoes, in which I failed.

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I look at this as splendid for pangenesis, as being strong evidence that bud-reproduction and seminal reproduction do not essentially differ. Darwin and Seward (1903, p. 286)

To F. Muller ( January 30, 1868) I send by this post, by French packet, my new book, the publication of which has been much delayed. The greater part, as you will see, is not meant to be read; but I should very much like to hear what you think of ‘Pangenesis,’ though I fear it will appear to every one far too speculative. Darwin (1888, p. 75)

To J. D. Hooker (February 3, 1867) I did read Pangenesis the other evening, but even this, my beloved child, as I had fancied, quite disgusted me. The devil take the whole book; and yet now I am at work again as hard as I am able. It is really a great evil that from habit I have pleasure in hardly anything except Natural History, for nothing else makes me forget my ever-recurrent uncomfortable sensations. But I must not howl any more, and the critics may say what they like; I did my best, and man can do no more. What a splendid pursuit Natural History would be if it was all observing and no writing! Darwin (1888, p. 75)

To J. D. Hooker (February 23, 1868) I fear Pangenesis is stillborn; Bates says he has read it twice, and is not sure that he understands it. H. Spencer says the view is quite different from his (and this is a great relief to me, as I feared to be accused of plagiarism, but utterly failed to be sure what he meant, so thought it safest to give my view as almost the same as his), and he says he is not sure he understands it.Am I not a poor devil? yet I took such pains, I must think that I expressed myself clearly. Sir H. Holland says he has read it twice, and thinks it very tough; but believes that sooner or later ‘some view akin to it’ will be accepted. You will think me very self-sufficient, when I declare that I feel sure if Pangenesis is now still-born it will, thank God, at some future time reappear, begotten by some other father, and christened by some other name. Have you ever met with any tangible and clear view of what takes place in generation, whether by seeds or buds, or how a long-lost character can possibly reappear; or how the male element can possibly affect the mother plant, or the mother animal, so that her future progeny are affected? Now all these points and many others are connected together, whether truly or falsely is another question, by Pangenesis. You see I die hard, and stick up for my poor child. Darwin (1888, p. 77e78)

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To A. R. Wallace (February 27, 1868) You cannot well imagine how much I have been pleased by what you say about Pangenesis. None of my friends will speak out.Hooker, as far as I understand him, which I hardly do at present, seems to think that the hypothesis is little more than saying that organisms have such and such potentialities. What you say exactly and fully expresses my feeling, viz. that it is a relief to have some feasible explanation of the various facts, which can be given up as soon as any better hypothesis is found. It has certainly been an immense relief to my mind; for I have been stumbling over the subject for years, dimly seeing that some relation existed between the various classes of facts. I now hear from H. Spencer that his views quoted in my foot-note refer to something quite distinct, as you seem to have perceived. . Hearty thanks for your letter. You have indeed pleased me, for I had given up the great god Pan as a stillborn deity. Darwin (1888, p. 80e81)

To J. D. Hooker (February 28, 1868) I heard yesterday from Wallace, who says (excuse horrid vanity), ‘I can hardly tell you how much I admire the chapter on Pangenesis. It is a positive comfort to me to have any feasible explanation of a difficulty that has always been haunting me, and I shall never be able to give it up till a better one supplies its place, and that I think hardly possible, &c.’ Now his foregoing [italicised] words express my sentiments exactly and fully: though perhaps I feel the relief extra strongly from having during many years vainly attempted to form some hypothesis. When you or Huxley say that a single cell of a plant, or the stump of an amputated limb, has the ‘potentiality’ of reproducing the wholedor ‘diffuses an influence,’ these words give me no positive idea but, when it is said that the cells of a plant, or stump, include atoms derived from every other cell of the whole organism and capable of development, I gain a distinct idea. But this idea would not be worth a rush, if it applied to one case alone; but it seems to me to apply to all the forms of reproduction d inheritance d metamorphosis d to the abnormal transposition of organs d to the direct action of the male element on the mother plant, &c. Therefore I fully believe that each cell does actually throw off an atom or gemmule of its contents; but whether or not, this hypothesis serves as a useful connecting link for various grand classes of physiological facts, which at present stand absolutely isolated. I have touched on the doubtful point (alluded to by Huxley) how far atoms derived from the same cell may become developed into different structure accordingly as they are differently nourished. Darwin (1888, p. 81e82)

To W. Ogle (March 6, 1868) I wish I had known of these views of Hippocrates before I had published, for they seem almost identical with mine d merely a change of terms d and an

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application of them to classes of facts necessarily unknown to the old philosopher. The whole case is a good illustration of how rarely anything is new.Hippocrates has taken the wind out of my sails, but I care very little about being forestalled. I advance the views merely as a provisional hypothesis, but with the secret expectation that sooner or later some such view will have to be admitted.I do not expect the reviewers will be so learned as you: otherwise, no doubt, I shall be accused of wilfully stealing Pangenesis from Hippocrates, d for this is the spirit some reviewers delight to show. Darwin (1888, p. 82e83)

To V. Cams (March 21, 1868) I am very much obliged to you for sending me so frankly your opinion on Pangenesis, and I am sorry it is unfavourable, but I cannot quite understand your remark on pangenesis, selection, and the struggle for life not being more methodical. I am not at all surprised at your unfavourable verdict; I know many, probably most, will come to the same conclusion.Sir C. Lyell says to everyone, ‘You may not believe in Pangenesis, but if you once understand it, you will never get it out of your mind.’ And with this criticism I am perfectly content. All cases of inheritance and reversion and development now appear to me under a new light. Darwin (1888, p. 83)

To G. Bentham (April 22, 1868) I am not at all surprised that you cannot digest pangenesis: it is enough to give any one an indigestion; but to my mind the idea has been an immense relief, as I could not endure to keep so many large classes of facts all floating loose in my mind without some thread of connection to tie them together in a tangible method. Darwin and Seward (1903, p. 371)

To A. Gray (May 8, 1868) Your article in the Nation [Mar. 19] seems to me very good, and you give an excellent idea of Pangenesis d an infant cherished by few as yet, except his tender parent, but which will live a long life. There is parental presumption for you! Darwin (1888, p. 84)

To J. D. Hooker (May 21, 1868) Your notice of pangenesis has been particularly pleased me, for it has generally neglected or disliked by my friends; yet I fully expect that it will someday be more successful. I believe I quite agree with you in the manner in which the cast-off atoms or so-called gemmules probably act: I have never supposed that gemmules were developed into free cells, but that they penetrated other nascent cells and modified their subsequent development. This process I have actually compared with ordinary fertilization. The cells thus modified, I suppose cast off

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in their turn modified gemmules, which again combine with other nascent cells, and so on. Darwin and Seward (1903, p. 310)

To F. Muller ( June 3, 1868) I have yet hopes that you will think well of Pangenesis. I feel sure that our minds are somewhat alike, and I find it a great relief to have some definite, though hypothetical view, when I reflect on the wonderful transformations of animals,dthe re-growth of parts,dand especially the direct action of pollen on the motherform, &c. It often appears to me almost certain that the characters of the parents are ‘photographed’ on the child, only by means of material atoms derived from each cell in both parents, and developed in the child. Darwin (1888, p. 83e84)

To A. Weismann (October 22, 1868) Whether it would be prudent to allude to despised pangenesis I cannot say, but I fully believe pangenesis will have its successful day. Darwin and Seward (1903, p. 320)

To E. R. Lankester (March 15, 1870) I was pleased to see you refer to my much despised child, ‘Pangenesis’, who I think will someday, under some better nurse, turn out a fine stripling. Darwin (1888, p. 120)

To F. Muller (May 12, 1870) You will remember having given me in a former letter an account of a very curious popular belief in regard to the subsequent progeny of asses, which have borne mules; and now I have another case almost exactly like that of Lord Morton’s mare, in which it is said the shape of the hoofs in the subsequent progeny are affected. (Pangenesis will turn out true some day!) Darwin and Seward (1903, p. 359)

To G. J. Romanes (May 29, 1876) As you are interested in pangenesis, and will someday, I hope, convert an ‘airy nothing’ into a substantial theory. Darwin and Seward (1903, p. 364)

5. DARWIN’S PANGENESIS: A SLEEPING BEAUTY? Darwin (1868) repeatedly emphasized that he regarded his Pangenesis merely as a “provisional hypothesis.” As he himself remarked, “I am aware that my view is merely a provisional hypothesis or speculation; but until a

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better one be advanced, it may be serviceable by bringing together a multitude of facts which are at present left disconnected by any efficient cause. As Whewell, the historian of the inductive sciences remarks: ‘Hypotheses may often be of service to science, when they involve a certain portion of incompleteness, and even error.’” It should be noted that Darwin’s use of the adjective “provisional” does not mean that he doubted its correctness. It was Darwin’s custom to proceed in a more cautious way; that is, to begin with the accumulation of a tremendous amount of genetic data, and then to deduce by a careful analysis a causal explanation. He used not to publish anything before he thought he had succeeded in refuting all eventual objections (Heimans, 1962). Darwin’s Pangenesis has been analyzed by many historians (Bulmer, 1999; Churchill, 1987; Endersby, 2003; Galton, 2018; Gayon, 1998; Geison, 1969; Ghiselin, 1975; Hodge, 1985, 2010; Holterhoff, 2014; Johnson, 2015; Kampourakis, 2013; Noguera-Solano & Ruiz-Gutiérrez, 2009; Stanford, 2006; Towers, 1968; Wainwright, 2008; Winther, 2000). For example, Olby (1966) and Mayr (1982) regarded Darwin’s Pangenesis as a scheme of transmission idea (Noguera-Solano & Ruiz-Gutiérrez, 2009). Ghiselin (1975) stated that Pangenesis “had to do with what we now call genetics, but, like our contemporary molecular genetics, its primary concern was with developmental, rather than with transmissional, genetics,” thus considering Darwin’s Pangenesis as a developmental theory of heredity (Winther, 2000). Ghiselin (1975) further commented, “One might take a ‘relativistic’ position, and say that even in its details Pangenesis was a good scientific theory. It was a plausible idea in its day, and had an important role in stimulating the development of genetical theory. Yet the provisional hypothesis does seem to me to have one major fault: it was anachronistic. It gave a nineteenth century answer to an eighteen century question that needed to be dealt with in twentieth century terms.” Mantegazza praised Pangenesis as Darwin’s most brilliant achievement, and the one, which showed his genius most clearly (cited in Heimans, 1962). Wilson (1900) believed that Darwin’s Pangenesis was one of his most interesting and important contributions to science. Pollock (1976) believed that Darwin’s Pangenesis was one of the first attempts to explain the mechanism of heredity at a molecular or a subcellular level, and argued that Darwin should have been considered as the forefather of molecular biology. Generally speaking, if a theory could account for numerous and diverse kinds of facts, it was much more likely to be true than if supported

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by facts of just one kind. The more a theory could successfully explain, the more likely it was to be true (Endersby, 2003; Oldroyd, 1986). Darwin’s Pangenesis explains the numerous phenomena of life, but why has it been thought to be wrong for so long a time? According to Luyet (1940) and Lindegren (1966), a theory is often considered acceptable if it is useful and if it allows one to predict unknown facts. Darwin’s Pangenesis has foreseen the discovery of circulating cell-free DNA, mobile RNAs (including small RNAs), prions, extracellular vesicles, and even PCR technique, but why has it not been accepted by most geneticists? According to Lindegren (1966), “a theory must be beautiful. It must be aesthetically satisfying by making an orderly arrangement of knowledge possible.” From Darwin’s writing on Pangenesis, I believe that it also fit this point. Is Darwin’s Pangenesis too good to be true, or a Sleeping Beauty? A Sleeping Beauty in science is referred to a paper whose importance is not appreciated for several years after publication. Its citation history shows a long hibernation period followed by a sudden spike of popularity (Ke, Ferrara, Radicchi and Flammini, 2015). Lonnig (2017) considered Mendel’s paper published in 1866 as the most famous Sleeping Beauty in science. However, Darwin’s Pangenesis seems to me to be a Sleeping Beauty more than anything else. With the discovery of circulating nucleic acids, prions and extracellular vesicles, Darwin’s assumption that invisible gemmules are the carriers of hereditary characters, they are thrown off from cells, and they diffuse from cell to cell and circulate through the body, now has been removed from the position of a provisional hypothesis to that of a well-found theory. It will be a fascinating episode in the history of science if Darwin’s Pangenesis, like Mendelian laws, should eventually be rediscovered.

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