The Resurrection of Darwin's Pangenesis theory?

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Is Darwin's long forgotten and discredited theory of Pangenesis resurrected from the dead? A publication in Nature Reviews Molecular Cell Biology [1] suggests his theory is at least partly true and was the inspiration for a number of scientists after Darwin.

What is Pangenesis? Darwin published his Pangenesis theory in volume 2 of The Variation of Animals and Plants under Domestication (1868). According to the authors the Pangenesis theory proposed a mechanism for the flow of hereditary information between cells and between generations.
Strinkingly, this definition merges two completely different phenomena in one concept: cell-to-cell communication and the transmission of genetic information from parent to child. Next, the authors claim that "emerging evidence of cell-to-cell communication urges the reconsideration of this 150-year-old theory."

More precisely, the Pangenesis theory says (according to the authors) that in addition to cell division as a means of transferring information, every cell emits numerous gemmules. They travel through the body and unite with other somatic cells and germ cells. So, it appears that both parts of the theory cannot be separated. It is a complex theory. Darwin knew this.

Additionally, and importantly, gemmules can be modified by the environment. If those modified gemmules end up in germ cells, and are transmitted to the next generation, it is called 'Lamarckian inheritance'. The consensus in the biological community is that Lamarckian inheritance is not possible and should be rejected.

What is the new evidence according to the authors? They point to extracellular vesicles such as exosomes [2] which transport information in the form of RNA and proteins between cells, including germ cells. In particular small RNAs have been found in sperm. They are the carriers of acquired phenotypes such as diet-induced metabolic disorders and mental stress phenotypes. This is an extra-chromosomal type of inheritance. There is no integration in DNA. The authors propose that also circulating cell-free DNA and mobile RNAs could be viewed as instances of Darwin's pangenes. If these factors are indeed inherited, they seem to me a form of transient inheritance.

The transmission of exosomes is not the same as Transgenerational epigenetic inheritance because transgenerational epigenetic inheritance is the transmission of epigenetic markers of DNA or histones. Those markers are inherited together with chromosomal DNA and follow therefore a Mendelian pattern.
However, the authors also include epigenetic inheritance as evidence for Darwin's Pangenesis theory. This is confusing because these markers are not transmitted in exosomes. Exosomes carry small pieces of RNA and proteins and not whole genomes with epigenetic markings attached. Epigenetic markers cannot be transmitted as free floating individual molecules. They could not be viewed as modern incarnations of Darwin's gemmules. And gemmules are at the heart of Pangenesis. Therefore, I do not consider epigenetic markers an evidence in favour of Darwin's Pangenesis. In a more general sense, epigenetic markers could be  evidence for the rather vague idea of inheritance of acquired characteristics. But one should be careful to distinguish those different meanings.

I think it is a little far-fetched to interpret Darwin's gemmules in cellular or molecular terms as the authors do [5]. Darwin did sometimes use the word 'cells', but he certainly could not think in molecular terms. Furthermore, in my view his Pangenesis theory tries to unite too many different phenomena in one theory: ordinary heredity, the inheritance of acquired characteristics, recessiveness, causes of variation, and more.
I think it is confusing that the authors of the Nature article lump together chromosomal inheritance -which equals the complete genome of an organism- with modifications of that DNA, or a few small RNA molecules. The difference in the amount of information can easily be a million fold. Human sex cells contain three billion DNA base pairs. That is huge compared with what could be present for example in exosomes. Furthermore, chromosomal DNA is necessary to create a new organism (plant, animal) and inherited epigenetic modifications are mostly facultative additions.

The well-known role of histone methylation in animal development [3] has nothing to do with inherited epigenetic modifications, since those tissue-specific embellishments are necessarily newly created in the embryo. One cannot inherit tissue-specific instructions through one sperm and egg cell.

The authors downplay the fundamental difference of Darwin's theory of heredity with the current theory. Heredity means for Darwin the aggregation of the gemmules produced by all somatic cells. For Darwin gemmules are not an addition to the main mechanism, they are the main mechanism of heredity. We now know that this is completely wrong [4]. Furthermore, I think the authors do not present an overwhelming amount of new evidence to justify the resurrection of Darwin's Pangenesis theory.

Having said all that, I still think that the chapter about Pangenesis in The Variation of Animals and Plants under Domestication deserves a fresh study. It should be interesting to investigate how Darwin thought about the material basis of heredity without knowledge of Mendelian inheritance, chromosomes and DNA. I think it is interesting despite the fact that Darwin had a profound Lamarckian view of heredity. Darwin collected an enormous amount of data and his theory of Pangenesis was designed to explain them all. And as usual he discussed objections to his theory. I expect that reading Darwin will learn us a lot about his struggle with those objections, and how he tried to create a synthesis of the knowledge of his time, just as he did with his theory of evolution. Undeniably, it is one and the same person who created the theory of evolution and the Pangenesis theory.

Notes

1. Yongsheng Liu, Qi Chen (2018) 150 years of Darwin’s theory of intercellular flow of hereditary information, Nature Reviews Molecular Cell Biology volume 19, pages 749–750 2018.
2. Do not confuse 'exosomes' with 'exomes' because 'exome' refers to the part of the genome that codes for proteins in contrast to 'introns' which are eliminated from a gene before being translated in to a protein.
3. Ashwini Jambhekar, Abhinav Dhall, Yang Shi (2019) Roles and regulation of histone methylation in animal development, Nature Reviews Molecular Cell Biology volume 20, pages 625–641 (2019)
4. One of the main problems with gemmules (pangenes) as the mechanism of heredity is: if gemmules are continuously produced by all body cells and spread through the body, what mechanism guarantees that exactly the right amount and types of the gemmules, not too many, not too few of the same kind are collected in the germ cells (egg, sperm)? Imagine many copies of 20.000 free floating genes through the whole body! Total chaos! We now know that the function of chromosomes and cell division is to ensure that the daughter cells get the right amount of genes. I do not know whether Darwin was aware of that problem. [ 9 Oct 2019 ]
5. Darwin knows about cells: "Virchow, the great supporter of the cellular theory" but the theory was not well established at the time. [ 9 Oct 2019 ]

Further Reading

• Charles Darwin (1868) THE VARIATION OF ANIMALS AND PLANTS UNDER DOMESTICATION, CHAPTER XXVII. PROVISIONAL HYPOTHESIS OF PANGENESIS.
• Yongsheng Liu, Xiuju Li (2014) Has Darwin's Pangenesis Been Rediscovered? BioScience, Volume 64, Issue 11, November 2014, Pages 1037–1041 (free access) (this paper presents a lot of evidence supporting Darwin's Pangenesis theory - according to the authors)
• Yongsheng Liu (2019) Darwin and Nature’s 150th anniversary, Correspondence 1 October 2019, Nature 574, 36 (2019) (free access)