COMMENT 150 years of Darwin’s theory of intercellular flow of hereditary information Yongsheng Liu1,2 and Qi Chen 3* In 1868, Charles Darwin published his Pangenesis theory , which proposed a mechanism for the flow of hereditary information between cells and generations. Pangenesis has since been disputed, but emerging evidence of cell-to-cell communication urges the reconsideration of this 150-year-old theory. The theory of Pangenesis each bud, ovule, spermatozoon, and pollengrain”. These In 1868, 9 years after the advent of On the Origin of Species, speculations could not be validated at the time and were Charles Darwin published his two-volume book, The considered as “the fictions of the fancy” by the physician Variation of Animals and Plants under Domestication1, and microscopist Lionel Beale, and as “a pure invention” in which he introduced the theory of Pangenesis. This by the evolutionary biologist August Weismann. In a was an attempt to strengthen the theory of evolution by series of blood transfusion experiments, Francis Galton providing a cellular or molecular mechanism of inheri- failed to detect fur colour changes in the offspring of tance, and to understand the cause of variation upon silver-grey rabbits that were transfused with the blood which natural selection acts. of lop-eared rabbits; he concluded that the blood did not In the Pangenesis theory, Darwin proposed that in carry Darwin’s hypothetical gemmules. addition to cell division as a mean of transferring infor- Second, Pangenesis attempted to explain a range mation, every cell also emits numerous particles or mol- of doubtful phenomena including the inheritance of ecules called ‘gemmules’, which diffuse to and are ‘united’ acquired characteristics; but as the evolutionary bio- with both somatic cells and germ cells. Moreover, logist and geneticist Thomas Morgan commented, Darwin proposed that gemmules could be transmitted if this premise is not tenable, such a theory is unnec- from parents to offspring and could either function in essary. Indeed, the historical dismissal of the inheri- the immediate progeny or remain dormant for gener- tance of acquired traits greatly dampened the impact ations and then be activated; the activation of gemmules of Pangenesis, and conventional wisdom considers would depend on the specific cells or other gemmules Darwin’s belief in the inheritance of acquired character- with which they were united. Importantly, Darwin pro- istics a great mistake. The Pangenesis theory was quickly posed that the environment could modify gemmules, replaced by Weismann’s Germ-Plasm theory, which pos- and thus that the composition of gemmules mirrors the tulated that information only flows from germ cells to organism’s environmental exposure. somatic cells, and not vice versa (this is also known as the Pangenesis provided a potential explanation for ‘Weismann barrier’). a range of phenomena pertaining to inheritance and 1 Henan Collaborative phenotypic variation, including ‘prepotency’ (analo- Resurrection Innovation Center of Modern Biological Breeding, Henan gous to Gregor Mendel’s ‘dominance’, introduced in If the history of science has taught us anything, it might Institute of Science and 1866), graft hybridization, reversion and the inheri- be that absence of evidence is not evidence of absence. Technology, Xinxiang, China. tance of acquired characteristics — a notion favoured One hundred and fifty years after its original publica- 2Department of Biochemistry, by Jean-Baptiste Lamarck. tion, the Pangenesis theory is reappearing in scientific University of Alberta, literature following the emergence of new evidence. The Edmonton, Alberta, Canada. The fall hypothetical gemmules that carry hereditary informa- 3 Department of Physiology Following its publication, Pangenesis was severely tion outside of cells are now being identified in modern and Cell Biology, University of Nevada, Reno School of criticized, mainly for two reasons. First, the proposed forms. Cell biologists are intensely studying extracellular Medicine, Reno, NV, USA. gemmules lacked evidence. Darwin envisioned that vesicles (such as exosomes) that are secreted from cells, *e-mail: [email protected] gemmules were “inconceivably minute and numerous which share the core features of gemmules. Exosomes https://doi.org/10.1038/ as the stars in heaven”, “barely visible under the high- can carry cell content such as RNA and proteins and s41580-018-0072-4 est powers of the microscope” and “contained within thus transfer information between somatic cells, as in the NATURE REVIEWS | MOLECULAR CELL BIOLOGY VOLUME 19 | DECEMBER 2018 | 749 COMMENT case of cancer metastasis2, or between somatic cells and RNAs transferred from somatic cells to germ cells may germ cells3. Moreover, recent serum transfusion exper- carry information representing environmental exposure iments in mammals have been shown to induce epige- and introduce changes to the germ line that mirror the netic signatures in sperm that enable transgenerational environmental input. Such modified RNAs may also inheritance of paternal, liver-specific wound-healing provide means to bypass epigenetic reprogramming pro- responses. This suggests that soluble factors in the serum cesses, as they are mobile and can act in trans to establish (of unknown identity, but possibly modern forms of an epigenetic modification that could stably transmit an gemmules) can indeed transfer acquired information acquired phenotype. These speculations and preliminary from somatic cells to germ cells and thus induce the data represent tantalizing directions for understanding expression of parentally acquired traits in the offspring3. the extent of epigenetic inheritance of acquired traits An increasing number of studies in plants, worms in mammals. and flies now clearly support the notion that certain parental traits acquired through environmental experi- The ongoing scientific legacy ences can be inherited4. There is also evidence in mam- Darwin’s Pangenesis should be credited also for the mals to suggest that adaptations to diet, temperature, concept of cell–cell communication through extra- mental stress and chemical exposure can be transmitted cellular molecular carriers, which resonates well with to offspring, although the underlying molecular mech- current exciting research into intercellular communica- anisms are far less understood than in non-mammalian tion2 and even extends to the population level, as exem- organisms4. In these cases, parentally acquired charac- plified by oral transfer of information in social insects, teristics are possibly transmitted not through the DNA and to inter-species and cross-kingdom interactions, as sequence but through epigenetic information carriers exemplified by bidirectional exosomal transfer of small such as DNA methylation, histone modifications and RNAs between plants and fungi in immune responses. RNAs in the germ line, or even outside the germ line, These contemporary breakthroughs are expected to for example, through seminal fluid3. These emerging promote future studies on horizontal gene transfer, data weaken the Weismann barrier and lend support to microbiome–host interactions, graft hybridization and Darwin’s Pangenesis theory. plant–animal interactions. Historically, the theory of Pangenesis has been The principles and the unknown neglected by the scientific community compared with At the heart of Pangenesis is the flow of (hereditary) Darwin’s widely accepted theory of natural selection, information through gemmules, which enables environ- which was presented in On the Origin of Species (1859). ment–somatic, somatic–somatic and somatic–germ line However, Pangenesis is of great value to Darwin’s scien- interactions. This idea was visionary in Darwin’s time tific system. In a letter to Joseph Hooker in 1868, Darwin and raised many outstanding questions that remain wrote: “You will think me very self-sufficient, when I unresolved. For example, despite the identification of declare that I feel sure if Pangenesis is now stillborn it some physical forms of gemmules as exosomes or mobile will, thank God, at some future time reappear, begot- RNAs, it remains unclear whether and how a specific ten by some other father, and christened by some other life experience can be encoded by the labile epigenetic name.” One hundred and fifty years later, Pangenesis information carriers. In addition, if such ‘coded’ infor- is apparently reborn as a conceptual framework for mation is transferred from somatic cells to germ cells, by the intercellular flow of hereditary information that what mechanism are the data ‘decoded’ during develop- continues to push the boundaries of science. ment to precisely mirror in the offspring the parentally 1. Darwin, C. The Variation of Animals and Plants under Domestication acquired traits? Especially in mammals, these changes (John Murray, 1868). 2. van Niel, G., D’Angelo, G. & Raposo, G. Shedding light on the cell must escape the extensive reprogramming processes biology of extracellular vesicles. Nat. Rev. Mol. Cell. Biol. 19, that erase most epigenetic modifications first in the 213–228 (2018). 3. Chen, Q., Yan, W. & Duan, E. Epigenetic inheritance of acquired preimplantation embryo (to allow intergenerational traits through sperm RNAs and sperm RNA modifications. Nat. Rev. inheritance) and then during germline development (to Genet. 17, 733–743 (2016). 4 4. Skvortsova, K., Iovino, N. & Bogdanovic, O. Functions and allow transgenerational inheritance) . These quintessen- mechanisms