Central Dogma or Central Debate?
2018; American Physiological Society; Volume: 33; Issue: 4 Linguagem: Romeno
10.1152/physiol.00017.2018
ISSN1548-9213
Autores Tópico(s)Mitochondrial Function and Pathology
ResumoPHYSIOLOGY'S IMPACTCentral Dogma or Central Debate?Denis NobleDenis NobleUniversity of Oxford, Oxford, United KingdomPublished Online:06 Jun 2018https://doi.org/10.1152/physiol.00017.2018MoreSectionsPDF (75 KB)Download PDF ToolsExport citationAdd to favoritesGet permissionsTrack citations ShareShare onFacebookTwitterLinkedInWeChat IntroductionThe Central Dogma of molecular biology has been widely misinterpreted to be a modern version of the Weismann Barrier. This confuses cellular-level inheritance with DNA inheritance and is therefore incorrect. The consequences for biology generally and for physiology in particular are profound. Removing the confusion completely alters our understanding of the relationship between physiology and evolutionary biology. The Weismann Barrier is permeable, and organisms are capable of transmitting non-DNA inheritance.Lay Summary of Physiological ImportanceA central feature of evolutionary biology as it developed during the last century was that acquired characteristics could not be inherited. Physiologists now know that there are many paternal and maternal effects transmitted to subsequent generations. The implications for health are important. The way in which parents live inevitably influences their children even from birth. It is not "all in the genes.""Weismann's barrier, as now embodied by the Central Dogma of molecular biology (DNA makes RNA and RNA makes protein, and not the reverse) has not yet been falsified. No one has yet shown that protein sequences can be translated into nucleic acid sequences."Anonymous referee, 20171What is the Debate About?About 125 years ago, the hugely influential German biologist August Weismann gave an inaugural lecture, "On Inheritance,"2 in which he set out his agenda to remove the possibility of the inheritance of acquired characteristics from Darwin's theory of evolution.3 He wrote:"In my opinion this [the hereditary substance] can only be the substance of the germ cells; and this substance transfers its hereditary tendencies from generation to generation, at first unchanged, and always uninfluenced in any corresponding manner, by that which happens during the life of the individual which bears it. If these views . . . be correct, all our ideas upon the transformation of species by means of exercise (use and disuse), as proposed by Lamarck, and accepted in some cases by Darwin, entirely collapses."Thus Weismann knew that Darwin had accepted Lamarck's idea. In fact, that kind of inheritance was widely assumed well before Lamarck, who did not invent the theory that usually carries his name. Darwin did not just passively accept the idea. He also developed a theory on how it could occur. He supposed that tiny particles, which he called gemmules, could pass from the soma to the germline and so modify what was passed on to subsequent generations (5). Physiologists today know that Darwin was right. We characterize this kind of transmission as maternal and paternal effects (8). We have even identified some of Darwin's imagined particles; they are the innumerable RNAs in sperm in the male line (23), and the many cytoplasmic materials in the inherited egg cell in the maternal line, including the eukaryotic cell structure and metabolism (25).Weismann did not know any of this, of course. But he did have a brilliant simplifying thought. This was that he could explain all the examples of the phenomenon given by Darwin in The Origin of Species even if one supposed that there were no such particles and/or that there was a completely tight barrier between the soma and the germline. His idea was that random variations in the inherited material would be sufficient, together with Darwin's theory of Natural Selection, to explain evolution entirely. As the evolutionary biologist and historian Ernst Mayr showed very clearly in his magisterial book, The Growth of Biological Thought (12), this idea, together with Mendelian genetics, formed the cornerstone of what became called The Modern Synthesis, often also called neo-Darwinism.The origin of what I refer to here as the "Central Debate" of modern biology therefore came about through a disagreement between Darwin and Weismann. This is the reason why I often say that Darwin was not a neo-Darwinist (Ref. 15, p. 126). But the debate never became a reality between the two men since Darwin passed away in 1882, a year before Weismann gave his 1883 lecture. It is hard though to imagine that Darwin would have agreed with Weismann, since he included not only the inheritance of acquired characteristics but several other processes as also necessary, including sexual selection in which individual organisms give evolution a direction (4). The more general version of this idea, now called the adaptability driver (1), is also central to physiology since it restores functionality and purpose to our discipline (19).Why is the Debate Important to Physiology?The reason that the debate is important is that three major errors were made during the process by which the Weismann Barrier became considered to be "embodied by the Central Dogma of molecular biology." These errors were in turn responsible for completely and unnecessarily sidelining physiology during the second half of the 20th century.The first error was to think that the barrier had indeed become so embodied. As Steele writes in Ref. 24:"Indeed the rigid dictum DNA→RNA→Protein is the earlier 1960s rendition which is often mistakenly confused with Weismann's Doctrine. It must be made clear that Weismann's Barrier enshrines a cellular theory of information flow whereas the Central Dogma is a theory of information flow at the molecular level."The difference is fundamental. The cell contains much more than its genome. In most of life on earth, it is the complete organism. Moreover, it can be shown that the information content of the rest of the cell matches that of the genome (16). So how did the idea that the barrier could be embodied in the dogma come about?This development is explained by a shift in the definition of a gene. When Johannsen first introduced the word in 1909, it was defined as an inheritable phenotype characteristic (9). This was also essentially Mendel's concept. Their concept of a gene would therefore have included anything that went through the germline cells. Johannsen made this clear when he explained that the gene could be anything (ein etwas) in the organism that was responsible for inheritance of the characteristic. Had he known of them, RNAs, and epigenetic marks on DNAs and histones, would have been included, as would cellular structures that make the replication and inheritance possible. This is clearly not the modern molecular biological definition of a gene, which is restricted to a DNA sequence forming a template for a protein (10).Why Does it Matter to Evolutionary Biology?This major shift in definition was not known at the time the Modern Synthesis was formulated. DNA was not even known to be the genetic material, so it is not surprising that the shift in definition did not matter to those who formulated the Modern Synthesis. The great advances in, for example, the mathematical theories of population genetics (7) worked perfectly well with the gene being defined as a phenotype characteristic. In fact, for most applications of genetics to the social sciences, such as economics and sociology, retaining the phenotype definition is important and even necessary. As with the results of GWAS (genome-wide association studies) generally, the associations at the genome sequence level are remarkably weak and, with the exception of certain rare genetic diseases, may even be meaningless (13, 21). The reason is that if you gather a sufficiently large data set, it is a mathematical necessity that you will find correlations, even if the data set was generated randomly so that the correlations must be spurious. The bigger the data set, the more spurious correlations will be found (3). The current rush to gather sequence data from ever larger cohorts therefore runs the risk that it may simply prove a mathematical necessity rather than finding causal correlations. It cannot be emphasized enough that finding correlations does not prove causality. Investigating causation is the role of physiology.Nor does finding higher overall correlations by summing correlations with larger numbers of genes showing individually tiny correlations solve the problem, even when the correlations are not spurious, since we have no way to find the drugs that can target so many gene products with the correct profile of action.But, to return to the definition of a gene, the difference between phenotype and genotype definitions matters enormously to versions of neo-Darwinism, such as selfish gene theory, based on distinguishing the replicator (regarded as DNA) from the vehicle (the phenotype).There are two fatal difficulties in the selfish gene version of neo-Darwinism. The first is that, from a physiological viewpoint, it doesn't lead to a testable prediction. The problem is that the central definition of selfish gene theory is not independent of the only experimental test of the theory, which is whether genes, defined as DNA sequences, are in fact selfish, i.e., whether their frequency in the gene pool increases (18). The second difficulty is that DNA can't be regarded as a replicator separate from the cell (11, 17). The cell, and specifically its living physiological functionality, is what makes DNA be replicated faithfully, as I will explain later.This difficulty leads to the next error in the development toward the Central Dogma, since the fact that the cell, not its DNA, is the real replicator is fundamental. This is the core issue in the Central Debate. I will now explain how the development toward the Central Dogma got this part of the story wrong.When the Central Dogma was first formulated, Watson and Crick acknowledged their indebtedness to Schrödinger's famous book What is Life? (6, 22). In that book, Schrödinger made two predictions, one of which was spectacularly successful, the other is necessarily incorrect (Ref. 15, p. 176–181).The correct prediction was that the genetic material would be found to be what he called an aperiodic crystal. If one allows a polymer to be regarded as a kind of crystal, this is a good description of DNA.The incorrect prediction was that the molecule would behave like a determinate crystal. This idea leads directly to strong interpretations of the Central Dogma that attribute faithful replication and determinate qualities to DNA alone. These strong interpretations permeate the language of modern biology, particularly in its popularizations ("we found the gene for X"), and even more so of sociology and economics, with immense implications for a possible rehabilitation of eugenics. Many examples can be found in the brilliant analysis by the sociologist Catherine Bliss (2).Resolution of the DebateNow, if the reader has borne with me this far, she may well be extremely puzzled. Surely DNA is a fantastically accurate replicator? Isn't the debate over—game, set, and match—even before it begins?Well, yes. If you compare the DNA in a daughter cell with that of its parent cell, you will indeed find a copying error rate of less than one base pair in a complete genome. The error rate is around only 1 in 1010 base pairs, which is remarkably accurate. But now suppose that we could compare the DNA sequence immediately after being copied. We would find an error rate of around 1 in 104, which in a genome of 3 billion base pairs would mean millions of errors. No eukaryotic cell could survive such an error rate. Schrodinger was therefore wrong about the molecule itself behaving like a determinate crystal. Crystal structure growth is indeed determinate, but that is the wrong metaphor for DNA. That is not how it grows and replicates. On its own, it would be left with millions of errors.It replicates accurately only in a complete cell containing all the objective functionality that enable cells to be alive. Cells achieve this outcome through a very complex three-stage process in which the millions of errors are detected and corrected (https://en.wikipedia.org/wiki/DNA_replication). Those processes rely on an army of specialized proteins and on the lipid membranous structures for which there are no DNA sequences. Outside a living cell, DNA is inert, dead. The living functionality is crucial.Causation and StochasticitySo far in this brief editorial I have outlined the experimental evidence for the restoration of functionality and for an integrative physiological interpretation of the central ideas of modern biology and how to characterize life itself, its reproduction, and its evolution.Now I want to finish by making a few necessary conceptual points.There are different forms of causation (Ref. 15, p. 176–181). DNA is a passive cause. As Watson said to Crick when they first made their momentous discovery of the double helix: "Francis, it's a template" (https://www.dnalc.org/view/15474-RNA-s-role-in-the-cell-James-Watson.html). Active causation lies at the level of the cell, or of multicellular structures and organisms. This distinction in forms of causation is absolutely fundamental. It is why we don't regard viruses as really alive, and why DNA probably was not the origin of life (20).Stochasticity, which is the origin of the massive copying error rate, is usually presented by evolutionary biologists as just the origin of variation, which indeed it is. The remaining errors after correction form one of the bases of evolutionary variation. But stochasticity is much more than that. It is also the origin of functionality and creativity in organisms. They achieve that by harnessing stochasticity (17). The harnessing process is a complete physiological control process that achieves creativity through finding new solutions to new environmental challenges, much as the immune system does.As Karl Popper argued in a very significant, but little known, debate with Max Perutz, there is a fundamental difference between biology and chemistry (14). Biology necessarily requires the concept of function, of goals toward which a process tends to go. To slightly misquote JBS Haldane,4 teleology might indeed be a great mistress, but she can be an even greater openly acknowledged wife.ConclusionsPhysiology was mistakenly sidelined from mainstream biology, including evolutionary biology, during the second half of the 20th century. The consequences are serious.There is no way in which the Weismann Barrier can be regarded as "embodied by the Central Dogma of molecular biology," as widely thought. That completely confuses cellular and molecular level processes.The results of GWAS do not reveal the secrets of life, nor have they delivered the many cures for complex diseases that society badly needs. The reason is that association studies do not reveal biological mechanisms. Physiology does. Worse still, "the more data, the more arbitrary, meaningless and useless (for future action) correlations will be found in them" is a necessary mathematical statement (3).Nor does applying a highly restricted DNA sequence-based interpretation of evolutionary biology, and its latest manifestation in GWAS, to the social sciences augur well for society.Stochasticity is not only the source of genetic variation, it is also the clay from which organisms actively seek solutions to environmental challenges. Causation operates from the cellular and higher levels. This is what enables cells and organisms to be alive and maintain their integrity.For all these reasons, let the Central Debate replace the debate on the Central Dogma. The uni-directionality of sequence information transfer from DNA to proteins no more determines life than the QWERTY keyboard determines what I wrote in this article.FOOTNOTES1The idea that the Weismann Barrier is now "embodied by the central dogma" is widespread. It even appears on the Simple Wikipedia entry on the central dogma: "The dogma is a modern version of the Weismann barrier" (https://simple.wikipedia.org/wiki/Central_dogma_of_molecular_biology). The statement on the main Wikipedia page is more circumspect: "This [the Weismann Barrier] does not predict the central dogma, but does anticipate its gene-centric view of life, albeit in non-molecular terms." The grossly misleading statement on Simple Wikipedia is repeated on a website designed for schoolchildren (https://wiki.kidzsearch.com/wiki/Central_dogma_of_molecular_biology). I want to acknowledge, however, that more careful and scholarly textbooks on evolutionary biology do make the distinction clear.2The lecture entitled Über die Vererbung was delivered in 1883 and published in 1889 in English translation by OUP in Essays upon Heredity (chapt. 2).3The idea is present in ~12 places in Darwin's Origin of Species (1859).4The original statement attributed to Haldane is, "Teleology is like a mistress to a biologist: he cannot live without her but he's unwilling to be seen with her in public" (Mayr E. Boston Studies in the Philosophy of Science. Dordrecht, Holland: D. Reidel Publishing, 1974, vol. XIV, p. 91–117).This article was written while working as a guest researcher at the Mayo Clinic in Rochester MN. I thank Michael Joyner and his laboratory for the great hospitality. I thank Stephen Bergman, Michael Joyner, Anthony Kenny, Hans-Joachim Niemann, and Raymond Noble for valuable comments and discussion. I also thank many colleagues in the International Union of Physiological Sciences (IUPS) for countless productive discussions during the period from 2009 to 2017 when I served as its President.No conflicts of interest, financial or otherwise, are declared by the author(s).References1. Bateson P. The adaptability driver: links between behaviour and evolution. Biol Theory 1: 342–345, 2006. doi:10.1162/biot.2006.1.4.342.Crossref | Google Scholar2. Bliss C. Social by Nature. The Promise and Peril of Sociogenomics. Palo Alto, CA: Stanford University Press, 2017.Google Scholar3. Calude CS, Longo G. The deluge of spurious correlations in big data. Found Sci 22: 595–612, 2017. doi:10.1007/s10699-016-9489-4.Crossref | ISI | Google Scholar4. Darwin C. The Descent of Man, and Selection in Relation to Sex. London: John Murray, 1871.Google Scholar5. Darwin C. The Variation of Animals and Plants under Domestication. London: John Murray, 1868.Google Scholar6. Dronamraju KR. 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