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Polyelectrolyte theory of the gene

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The Polyelectrolyte Theory of the Gene proposes that for a linear genetic biopolymer dissolved in water, such as DNA, to undergo Darwinian evolution anywhere in the universe, it must be a polyelectrolyte, a polymer containing repeating ionic charges [1]. These charges are needed to maintain the uniform physical properties needed for Darwinian evolution, regardless of the information encoded in the genetic biopolymer (Benner 2017). DNA has this property as it has the same physical properties regardless of its nucleic acid sequence.

The Polyelectrolyte Theory of the Gene was first proposed by Steven A. Benner and Daniel Hutter in 2002[2] and has largely remained a theoretical framework astrobiologists have used to think about how life may be detected throughout the universe. This theory was later linked by Benner [3] [1] to Erwin Schrödinger's view of the gene as an aperiodic crystal[4] to make a robust generalized theory of a genetic biopolymer.

Benner, and others who build on his work, have proposed methods for how to concentrate and identify genetic biopolymers on other planets using electrophoresis[1][2][3].

Although few have tested the Polyelectrolyte Theory of the Gene, in recent years lab experiments have challenged the universality of this theory[5][6].  

The physical structure of polyelectrolytes

A polyelectrolyte is a polymer with repeating electrically charged units {create image}. In the context of the Polyelectrolyte Theory of the Gene, this polyelectrolyte is a biopolymer with a repeating charged unit, similar to the genetic biopolymer in modern biology, DNA. RNA may also be considered a genetic biopolymer. Although RNA does not act as a genetic biopolymer in modern biology, except in the case of some viruses such as coronavirus[7] and HIV[8], the RNA World hypothesis suggests that RNA may have preceded DNA as life’s first genetic biopolymer[9]. DNA and RNA nucleotide building blocks are connected by negatively charged phosphate groups; these phosphodiester linkages create the repeated negative charges on the molecule’s backbone that give DNA and RNA their polyelectrolyte nature[10]

Polyelectrolytes in the context of genetic biopolymers

Fundamentally, Darwinian evolution can be summarized as "descent with modification." In other words, Darwinian evolution requires a unit of inheritance capable of imperfect replication, occasionally resulting in a new unit of replication slightly different that from the unit it was copied from, yet still possessing the ability to be replicated. This creates the variation on which evolution can act; and to act, evolution needs a selecting environment to winnow that pool of variants to their most evolutionarily fit forms[11]. The Polyelectrolyte Theory of the Gene attempts to understand modern biology’s inheritable unit, the genetic biopolymer DNA, at a basic generalizable level that may be applied to a theoretical framework of life that can be used to search for it throughout the universe. In 2002, Steven A. Benner and Daniel Hutter identified the repeated negative charges in DNA's phosphodiester linkages as crucial to its function as a genetic biopolymer and a generalizable requirement for all water-dissolved genetic biopolymers to undergo Darwinian evolution anywhere in the Cosmos [2].

This theory works in tandem with the view of the gene as an “Aperiodic Crystal” as proposed by Erwin Schrödinger’s book “What is Life?” published in 1944 [4]. An aperiodic crystal, as Schrödinger describes it, has a discrete set of molecules in a non-repeating arrangement, like how DNA is composed of the discrete nucleobases (A, T, C, and G) which are arranged based on the information they encode, not in any repeated format. While this idea of an “Aperiodic Crystal” was not initially linked to the polyelectrolyte theory of a gene, Benner, in later work connects the two to develop a more robust generalized view of the unit of genetic inheritance [3][1].

Polyelectrolytes remain physically uniform regardless of the information encoded

In biochemistry, the structure of a biomolecule dictates its function, and therefore changes in structure cause changes in function[12]. To work as a unit of inheritance, the genetic biopolymer must maintain shape and therefore physical and chemical consistency regardless of the information the structure encodes. DNA is such a molecule. No matter what the nucleic acid sequence is, DNA maintains a consistent double helix structure and therefore the consistent physical properties that allow it to remain dissolved in water and be replicated by cellular machinery. For example, thymidine nucleotides (T) are very soluble in water while guanosine nucleotides (G) are insoluble; however, an oligonucleotide composed of only thymine and one composed of only guanine has the same structure and physical properties[13]. If changes in nucleic acid sequence, which encodes the genetic information, change the physical properties of DNA, these changes could break down the mechanism by which DNA replicates. This physical uniformity is very rare in nature. Take another biopolymer, for example, proteins. The nucleic acid sequence in DNA codes for the sequence of amino acids that make up proteins. A change to even a single amino acid in the primary sequence of a protein can completely change the physical properties of that protein. For example, the sick-cell trait is caused by a single mutation of an adenine to a thymine at the 17th nucleic acid of the hemoglobin gene causing a switch from a glutamic acid to a valine [14]. This completely changes the three-dimensional structure of hemoglobin and thus changes the physical properties of hemoglobin that lead to the sickle-cell trait . The Polyelectrolyte Theory of the Gene reasons that DNA can maintain its shape regardless of mutations because the negative charges on the phosphate backbone dominate the physical interactions of the molecule to such a degree that changes in the nucleic acid sequence, the encoded information, do not affect the overall physical behavior of the molecule[2].

Proteins are sensitive to changes in amino acid sequence because the 20 different amino acid side chains form bonds and partial bonds with each other [15]. In addition, the protein backbone has a dipole (having partial positive and partial negative ends) which can further create interactions within the molecule. These side-chain and backbone interactions are sensitive to changes in environmental and amino acid sequence. Because of the sensitivity of the physical nature of proteins to changes in amino acid sequence, it is unlikely they could act as a genetic biopolymer[2].  

Benner and Hutter initially described this property of DNA as being capable of surviving modifications in constitution without loss of properties essential for replication (COSMIC-LOPER)[2]. It should be noted that although RNA is often described as a genetic biopolymer because of its theorized role as life’s first unit of inheritance, it is not entirely COSMIC-LOPER. RNA, especially sequences high in guanine (G), is capable of folding and performing enzyme-type chemistry[2][16]. Folding in G-rich RNA sequences prevents the templating ability of RNA and thus its ability to be replicated in an RNA-world scenario[2].  

Repeated ionic charges increase solubility in water

The repeated negative charges increase the solubility of DNA and RNA in water. Because ionic charges are highly soluble in water, having ionic charges on the molecule's backbone increases the molecule's solubility[17]. If the backbone of a hypothetical genetic biopolymer were linked together in a non-ionic fashion, the solubility of the whole molecule would decrease[18].

Repeated ionic charges promote Watson-Crick base pairing specificity

The repeated negative charges of the DNA backbone repel each other, preventing interactions both within and between DNA strands. This repulsion promotes specific interactions along the Watson-Crick 'edge' of the nucleobases, promoting Watson-Crick base pairing—A pairs with T and C pairs with G—with specificity [2].

Repeated ionic charges prevent folding

Polyelectrolyte biopolymers tend towards linearity due to like-charge repulsive interactions on the backbone. DNA, for example, tends towards linearity due to repulsive interactions between the negative charges of its phosphodiester-linked backbone. Neutral biopolymers tend to fold and aggregate due to the lack of like-charge repulsive interactions. Folding is generally a favorable process in neutral biopolymers because it creates favorable intramolecular interactions. For example, proteins tend to fold because this produces favorable interactions between the dipole moments of the backbone, between complementary amino acid side chains, and the exchange of unfavorable hydrophilic-hydrophobic interactions for favorable hydrophobic-hydrophobic interactions of the protein core.

The repeated negative charges on the backbone keep DNA and RNA molecules from folding and allow them to act as templates. In water, molecules take on a conformation that is the most energetically favorable, meaning it has the lowest Gibbs free energy[10]. This configuration maximizes favorable interactions (hydrogen bonding, positive-negative charge interactions, van der Waals interactions) and minimizes unfavorable interactions (ie hydrophilic-hydrophobic interactions and like charge interactions). In the case of double-stranded DNA and RNA, the most energetically favorable form is the linear double helix configuration because it maximizes interactions between the base pairs and between the negatively charged backbone and the surrounding water molecules while minimizing interactions between the negatively charged phosphodiester linkages of the backbone[10]. If the double-stranded DNA or RNA molecule folded it would have into exchange favorable water-backbone interaction for unfavorable backbone-backbone interactions. A biopolymer without an ionically charged backbone, like proteins, would not produce unfavorable backbone-backbone interaction during folding and thus would readily fold and aggregate. This inherent tendency towards linearity improves DNA’s ability to act as a template for replication[2]. It should be noted that single-stranded RNA can and does fold in modern biology, especially when it has a G-rich sequence [2].  

Lab experiments

Lab experiments conducted with non-electrolyte analogs of DNA and RNA initially inspired Benner and Hutton to publish on the Polyelectrolyte Theory of the Gene[3]. During the late ‘80s and '90s, scientists developed synthetic DNA-like molecules to bind to and silence unwanted mRNA gene products as a way to treat disease [2][19]. As part of this exploratory research, researchers developed a variety of non-electrolyte RNA and DNA analogs that would be able to cross the cell membrane, which DNA and RNA are incapable of doing because of their charged backbone. One of these analogs substituted a sulphone (SO₂) for the natural phosphodiester (PO₂⁻) linkage. While initial experiments showed the sulphone analog to have very similar properties to DNA as a dimer, two nucleotides linked together, when longer sulphone analogs were synthesized they folded, lost Watson-Crick base pair specificity, and had dramatic changes in physical properties on small changes in nucleic acid sequence[2]. The reduction in the quality of the traits that make DNA a good genetic molecule was seen with all the nonionic linkers that were tested as of 2002[2]. The closest non-electrolyte analog to maintain the qualities of DNA was the polyamide-linked nucleic acid analog (PNA) that replaced the phosphodiester linkage of DNA with an uncharged N-(2-aminoethyl)glycine linkage. Even Benner and Hutter questioned if PNA might disprove their polyelectrolyte hypothesis; however, even though PNA maintained the qualities of DNA up to a length of 20 nucleotides, beyond that length the molecules started to lose Watson-Crick base pair specificity, aggregated, and become sensitive to changes in nucleic acid sequence[2].

Lab experiments that challenge The Polyelectrolyte Theory of the Gene

In 2019, a group led by Philipp Holliger at Cambridge developed non-electrolyte P-alkylphosphonate nucleic acids (phNA) DNA analogs that were able to undergo templated synthesis and directed evolution[20]. The phNA analogs substituted the charged oxygen on DNA’s phosphate backbone with an uncharged methyl or ethyl group. While other DNA analogs have been shown to undergo templated synthesis and directed evolution, this discovery was the first time a non-electrolyte DNA analog had been shown to have these properties and the first time the Polyelectrolyte Theory of the Gene had been challenged in the lab[21]. However, it should be noted that template-directed synthesis of phNA was only performed up to a length of 72 nucleotides[20].

The Polyelectrolyte Theory of the Gene as an Agnostic Biosignature

From its inception, the polyelectrolyte theory of a gene has been put in the context of searching for life in the universe. This theory, combined with Schrödinger's view of a gene as an aperiodic crystal, provides a potential agnostic biosignature[1], a sign of life that does not pre-suppose any biochemistry[22]. In other words, a generalized view of life that should hold anywhere in the universe because the polyelectrolyte and aperiodic crystal theory of the gene are based on the universal laws of chemistry and physics[1].

Since the theorized genetic polyelectrolyte biomolecules could be charged either positively or negatively, as in the case of DNA and RNA, they can be concentrated in water with an electric field using electrophoresis or electrodialysis. This hypothetical concentration device has been called an agnostic life-finding device[1]. Similar to how electrophoresis works to separate DNA molecules, negatively charged molecules, like DNA or RNA, would be attracted to a positively charged anode, and positively charged genetic biomolecule would be attracted to a negatively charged cathode[13].  

Once the polyelectrolyte biomolecule has been concentrated, Benner suggests the molecules be tested for size and shape uniformity. In addition they should be tested for the usage of limited number of building blocks arranged in a non-repeating fashion, an aperiodic crystal structure[1]. Benner has suggested that this could be done using matrix-assisted laser desorption ionization (MALDI) paired with an orbitrap high-resolution mass spectrometer[23]. Another suggested approach has been to use nanopore sequencing technology, although questions of whether the solar radiation experienced during transit and on-site would affect the functionality of the device remain[24]. While space agencies have yet to use any of these proposed systems for agnostic life detection, they may be used in the future for Mars[23], Enceladus[1], and Europa[24] exploration.

Despite the Polyelectrolyte Theory of the Gene and the aperiodic crystal view of the gene being described as agnostic biosignatures, these theories are terra-, or earth-life, centric. It is unknown what life on another world might be, while it is often stated that life of any kind needs biomolecules and water, this may not be true[17].    

Incompatibility with the RNA World hypothesis

Main article: RNA World

The RNA World hypothesis is a popular hypothesis among origin-of-life scientists. It proposes life emerged as a single biopolymer that acted both as the genetic unit of inheritance as well as the catalyst that could perform replication[9]. This dual role a genetic biopolymer would have to play in an RNA World-like scenario is largely incompatible with the Polyelectrolyte Theory of the Gene. One of the pillars supporting the Polyelectrolyte Theory of the Gene claims that the repeated negative charges on the backbone prevent the biopolymer from folding, but for a single biopolymer system to work, that biopolymer would have to be capable of folding to perform catalysis and remain linearized to act as a template for replication. In addition, this biopolymer would need to be sensitive to changes in encoded information so it could explore evolutionary space and evolve fitter catalysts, but be insensitive to changes in encoded information to maintain the physical properties required for replicated[2].  

References

  1. ^ a b c d e f g h i Benner, Steven A. (2017-09). "Detecting Darwinism from Molecules in the Enceladus Plumes, Jupiter's Moons, and Other Planetary Water Lagoons". Astrobiology. 17 (9): 840–851. doi:10.1089/ast.2016.1611. ISSN 1531-1074. PMC 5610385. PMID 28665680. {{cite journal}}: Check date values in: |date= (help)CS1 maint: PMC format (link)
  2. ^ a b c d e f g h i j k l m n o p Benner, Steven A.; Hutter, Daniel (2002-02-01). "Phosphates, DNA, and the Search for Nonterrean Life: A Second Generation Model for Genetic Molecules". Bioorganic Chemistry. 30 (1): 62–80. doi:10.1006/bioo.2001.1232. ISSN 0045-2068.
  3. ^ a b c d Benner, Steven A. (2023-02-27). "Rethinking nucleic acids from their origins to their applications". Philosophical Transactions of the Royal Society B: Biological Sciences. 378 (1871). doi:10.1098/rstb.2022.0027. ISSN 0962-8436. PMC 9835595. PMID 36633284.{{cite journal}}: CS1 maint: PMC format (link)
  4. ^ a b Schrödinger, Erwin (1944). What is Life? The Physical Aspect of the Living Cell. United Kingdom: Cambridge University. ISBN 0-521-42708-8.
  5. ^ Brown, Asha; Brown, Tom (2019-06). "Curtailing their negativity". Nature Chemistry. 11 (6): 501–503. doi:10.1038/s41557-019-0274-1. ISSN 1755-4349. {{cite journal}}: Check date values in: |date= (help)
  6. ^ Arangundy-Franklin, Sebastian; Taylor, Alexander I.; Porebski, Benjamin T.; Genna, Vito; Peak-Chew, Sew; Vaisman, Alexandra; Woodgate, Roger; Orozco, Modesto; Holliger, Philipp (2019-06). "A synthetic genetic polymer with an uncharged backbone chemistry based on alkyl phosphonate nucleic acids". Nature Chemistry. 11 (6): 533–542. doi:10.1038/s41557-019-0255-4. ISSN 1755-4349. {{cite journal}}: Check date values in: |date= (help)
  7. ^ "Shibboleth Authentication Request". login.offcampus.lib.washington.edu. doi:10.1186/s13578-021-00643-z. PMC 8287290. PMID 34281608. Retrieved 2023-12-05.{{cite web}}: CS1 maint: PMC format (link) CS1 maint: unflagged free DOI (link)
  8. ^ Harwig, Alex; Das, Atze T.; Berkhout, Ben (2015-03). "HIV-1 RNAs: sense and antisense, large mRNAs and small siRNAs and miRNAs". Current Opinion in HIV and AIDS. 10 (2): 103. doi:10.1097/COH.0000000000000135. ISSN 1746-630X. {{cite journal}}: Check date values in: |date= (help)
  9. ^ a b "RNA World", SpringerReference, Berlin/Heidelberg: Springer-Verlag, retrieved 2023-12-05
  10. ^ a b c Nelson, David L.; Cox, Michael M.; Nelson, David L. (2013). Lehninger, Albert L. (ed.). Lehninger principles of biochemistry (Sixth edition ed.). Basingstoke: Macmillan Higher Education. ISBN 978-1-4292-3414-6. {{cite book}}: |edition= has extra text (help)
  11. ^ Gregory, T. Ryan (2009-06). "Understanding Natural Selection: Essential Concepts and Common Misconceptions". Evolution: Education and Outreach. 2 (2): 156–175. doi:10.1007/s12052-009-0128-1. ISSN 1936-6434. {{cite journal}}: Check date values in: |date= (help)
  12. ^ "2.3: Structure & Function- Proteins I". Biology LibreTexts. 2017-01-21. Retrieved 2023-12-05.
  13. ^ a b Benner, Steven A. "Making Operational the Polyelectrolyte Theory of the Gene in the Agnostic Search for Martian Life – The Primordial Scoop". Retrieved 2023-12-05.
  14. ^ "Genetic Mutation | Learn Science at Scitable". www.nature.com. Retrieved 2023-12-07.
  15. ^ "Protein Folding". Chemistry LibreTexts. 2013-10-02. Retrieved 2023-12-07.
  16. ^ Talini, Giulia; Branciamore, Sergio; Gallori, Enzo (2011-11). "Ribozymes: Flexible molecular devices at work". Biochimie. 93 (11): 1998–2005. doi:10.1016/j.biochi.2011.06.026. {{cite journal}}: Check date values in: |date= (help)
  17. ^ a b Benner, Steven A. (2010-12). "Defining Life". Astrobiology. 10 (10): 1021–1030. doi:10.1089/ast.2010.0524. ISSN 1531-1074. PMC 3005285. PMID 21162682. {{cite journal}}: Check date values in: |date= (help)CS1 maint: PMC format (link)
  18. ^ "4.5: Solubility of Ionic Compounds". Chemistry LibreTexts. 2022-01-20. Retrieved 2023-12-07.
  19. ^ Crooke, Stanley T. (2000), "Progress in antisense technology: The end of the beginning", Methods in Enzymology, vol. 313, Elsevier, pp. 3–45, doi:10.1016/s0076-6879(00)13003-4, ISBN 978-0-12-182214-9, retrieved 2023-12-07
  20. ^ a b Arangundy-Franklin, Sebastian; Taylor, Alexander I.; Porebski, Benjamin T.; Genna, Vito; Peak-Chew, Sew; Vaisman, Alexandra; Woodgate, Roger; Orozco, Modesto; Holliger, Philipp (2019-06). "A synthetic genetic polymer with an uncharged backbone chemistry based on alkyl phosphonate nucleic acids". Nature Chemistry. 11 (6): 533–542. doi:10.1038/s41557-019-0255-4. ISSN 1755-4330. PMC 6542681. PMID 31011171. {{cite journal}}: Check date values in: |date= (help)CS1 maint: PMC format (link)
  21. ^ Brown, Asha; Brown, Tom (2019-06). "Curtailing their negativity". Nature Chemistry. 11 (6): 501–503. doi:10.1038/s41557-019-0274-1. ISSN 1755-4330. {{cite journal}}: Check date values in: |date= (help)
  22. ^ "NASA Astrobiology". astrobiology.nasa.gov. Retrieved 2023-12-07.
  23. ^ a b Špaček, Jan; Benner, Steven A. (2022-10-01). "Agnostic Life Finder (ALF) for Large-Scale Screening of Martian Life During In Situ Refueling". Astrobiology. 22 (10): 1255–1263. doi:10.1089/ast.2021.0070. ISSN 1531-1074.
  24. ^ a b Sutton, Mark A.; Burton, Aaron S.; Zaikova, Elena; Sutton, Ryan E.; Brinckerhoff, William B.; Bevilacqua, Julie G.; Weng, Margaret M.; Mumma, Michael J.; Johnson, Sarah Stewart (2019-03-29). "Radiation Tolerance of Nanopore Sequencing Technology for Life Detection on Mars and Europa". Scientific Reports. 9 (1). doi:10.1038/s41598-019-41488-4. ISSN 2045-2322. PMC 6441015. PMID 30926841.{{cite journal}}: CS1 maint: PMC format (link)
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