Life Can’t Exist Without Repair Mechanisms, and That’s a Problem for Origin-of-Life Theories
A cell is often described as a factory — a quite extraordinary factory that can run autonomously and reproduce itself. The first cell required a lengthy list of components, layers of organization, and a large quantity of complex specified information, as described by previous episodes of Long Story Short. The latest entry in the series emphasizes yet another requirement for life: an abundance of specific repair mechanisms.
Damage to the “factory” of the cell occurs on two levels: damage to the stored information (either during replication or by natural degradation over time) and damage to the manufacturing machinery (either from faulty production of new machinery or damage incurred during use). Each type of damage requires specific repair mechanisms that demonstrate foresight — the expectation that damage will occur and the ability to recognize, repair and/or recycle only those components that are damaged. All known life requires these mechanisms.
Damage to Stored Information
The initial process of DNA replication is facilitated by a polymerase enzyme which results in approximately one error for every 10,000 to 100,000 added nucleotides.1 However, no known life can persist with such a high rate of error, if left uncorrected.2 Fortunately, DNA replication in all life includes a subsequent proofreading step — a type of damage repair — that enhances the accuracy by a factor of 100 to 1,000. The current record holder for the sloppiest DNA replication of a living organism, under normal conditions, is Mycoplasma mycoides (and its human-modified relative, JVCI-syn 3A), where only 1 in 33,000,000 nucleotides are incorrectly copied.3
Following the replication of DNA, a daily barrage of DNA damage occurs during normal operating conditions. Life therefore requires sophisticated and highly specific DNA repair mechanisms. In humans, DNA damage response is estimated to involve a hierarchical organization of 605 proteins in 109 assemblies.4 Efforts to make the simplest possible cell by stripping out all non-essential genes has successfully reduced DNA repair to a minimal set of six genes.5 But, these six genes are encoded in thousands of base pairs of DNA, and the machinery to transcribe and translate those genes into the repair enzymes requires a minimum of 149 genes.6 Thus, the DNA code that is required to make DNA repair mechanisms easily exceeds 100,000 base pairs. Here, we encounter a great paradox, first identified in 1971 by Manfred Eigen7: DNA repair is essential to maintain DNA but the genes that code for DNA repair could not have evolved unless the repair mechanisms were already present to protect the DNA.
Faulty Production of New Machinery
We used to think that the metabolic machinery in a cell always produced perfect products. But the reality is that faulty products are unavoidable, resulting in the production of interfering or toxic garbage. All living organisms must therefore have machinery that identifies problems and either repairs or recycles the faulty products.
The cell’s central manufacturing machine is the ribosome, a marvel that produces functional proteins from strands of mRNA (with the help of many supporting molecules). Unfortunately, about 2-4 percent of mRNA strands get stuck in the ribosome during translation into a protein.8 Not only does this halt production, but it could result in production of a toxic, half-finished protein.
If the mitochondria could not get “unstuck,” life as we know it would end. In the process of self-replication, a single cell must produce an entire library of proteins, placing a heavy burden on the cell’s mitochondria. But with a 2-4 percent rate of stuck mRNA strands, the average cell would have each of its mitochondria get stuck at least five times before the cell could replicate.9 Therefore, life could never replicate and metabolism would cease unless this problem was solved.
Fortunately, all forms of life, even the simplest,9 are capable of trans–translation, typically involving a three-step process. First, a molecule combining transfer and messenger RNA and two helper molecules (SymB and EF-Tu) recognizes that mRNA is stuck in the ribosome and attaches a label to the half-formed protein. This label, called a degron, is essentially a polyalanine peptide. The condemned protein is recognized, degraded, and recycled by one of many proteases. Finally, the mRNA must also be labeled and recycled to keep it from clogging other ribosomes. In some bacteria,10 a pyrophosphohydrolase enzyme modifies the end of the mRNA, labeling it for destruction. An RNAse (another enzyme) then recognizes this label, grabs hold of the mRNA, and draws it close to its magnesium ion, which causes cleavage of the RNA. Another RNAse then finishes the job, breaking the mRNA up into single nucleotides which can be re-used.
The required presence of tools that can destroy proteins and RNA also comes with a requirement that those tools are highly selective. If these tools evolved, one would expect the initial versions to be non-selective, destroying any proteins or RNA within reach, extinguishing life and blocking the process of evolution.11
Note that the set of tools for trans-translation and protein and RNA recycling are all stored in DNA, which must be protected by repair mechanisms. And, these tools cannot be produced without mitochondria, but the mitochondria cannot be unstuck without the action of trans-translation. Thus, we encounter another case of circular causality.
Damage Incurred During Use
The normal operation of enzymes or metabolites like co-enzymes or cofactors involves chemical reactions that follow specific paths. Deviations from the desired paths can occur from interferences like radiation, oxidative stress, or encountering the wrong “promiscuous” enzyme. These deviations result in rogue molecules that interfere with metabolism or are toxic to the cell. As a result, even the simplest forms of life require several metabolic repair mechanisms:
“[T]here can be little room left to doubt that metabolite damage and the systems that counter it are mainstream metabolic processes that cannot be separated from life itself.”12
“It is increasingly evident that metabolites suffer various kinds of damage, that such damage happens in all organisms and that cells have dedicated systems for damage repair and containment.”13
As a relatively simple example of a required repair mechanism, even the simplest known cell (JVCI Syn 3A) has to deal with a sticky situation involving sulfur. Several metabolic reactions require molecules with a thiol group — sulfur bonded to hydrogen and to an organic molecule. The organism needs to maintain its thiol groups, but they have an annoying tendency to cross link (i.e., two thiol groups create a disulfide bond, fusing the two molecules together). Constant maintenance is required to break up this undesired linking. Even the simplest known cell requires two proteins (TrxB/JCVISYN3A_0819 and TrxA/JCVISYN3A_0065) to restore thiol groups and maintain metabolism.12 Because the repair proteins are themselves a product of the cell’s metabolism, this creates another path of circular causality: You can’t have prolonged metabolism without the repair mechanisms but you can’t make the repair mechanisms without metabolism.
An Ounce of Prevention is Worth a Pound of Cure
In addition to life’s required repair mechanisms, all forms of life include damage prevention mechanisms. These mechanisms can destroy rogue molecules, stabilize molecules that are prone to going rogue, or guide chemical reactions toward less harmful outcomes. As an example, when DNA is replicated, available monomers of the four canonical nucleotides (G, C, T, and A) are incorporated into the new strand. Some of the cell’s normal metabolites, like dUTP (deoxyuridine triphosphate), are similar to a canonical nucleotide and can be erroneously incorporated into DNA. Even the simplest cell (once again, JVCI-syn3A) includes an enzyme (deoxyuridine triphosphate pyrophosphatase) to hydrolyze dUTP and prevent formation of corrupted DNA.6
Summing Up the Evidence
Those who promote unguided abiogenesis simply brush off all of these required mechanisms, claiming that life started as simplified “proto-cells” that didn’t need repair. But there is no evidence that any form of life could persist or replicate without these repair mechanisms. And the presence of the repair mechanisms invokes several examples of circular causality — quite a conundrum for unintelligent, natural processes alone. Belief that simpler “proto-cells” didn’t require repair mechanisms requires blind faith, set against the prevailing scientific evidence.
Notes
Babenek A, and Zuizia-Graczyk I. Fidelity of DNA replication — a matter of proofreading. Curr Genet. 2018; 54: 985-996.
Some viruses have high error rates when replicating, but viruses cannot replicate without the help of cellular life, which requires very low error rates. Some specialized DNA polymerases intentionally operate with lower fidelity on a temporary basis for purposes such as antibody diversity.
Moger-Reischer RZ, et al. Evolution of a Minimal Cell. Nature. 2023; 620: 122-127.
Kratz A, et al. A multi-scale map of protein assemblies in the DNA damage response. Cell Systems 2023; 14: 447-463.
Hutchison CA, et al. Design and synthesis of a minimal bacterial genome. Science 2016; 351: aad6253.
Breuer M, et al. Essential Metabolism for a Minimal Cell. eLife 2019;8:e36842 DOI: 10.7554/eLife.36842.
Eigen, M. Self-organization of matter and evolution of biological macromolecules. Naturwissenschaften, 1971; 58: 465–523.
Ito K, et al. Nascentome analysis uncovers futile protein synthesis in Escherichia coli. PLoS One 2011; 6: e28413
Keiler KC, Feaga HA. Resolving nonstop translation complexes is a matter of life or death. Journal of Bacteriology 2014; 196: 2123-2130.
Mackie GA. RNase E: at the interface of bacterial RNA processing and decay. Nature Reviews Microbiology 2013; 11: 45-57.
“Because RNA degradation is ubiquitous in all cells, it is clear that it must be carefully controlled to accurately recognize target RNAs.” Houseley J and Tollervey D. The many pathways of RNA degradation. Cell 2009; 136: 763-776.
Hass D, et al. Metabolite damage and damage control in a minimal genome. American Society for Microbiology 2022; 13: 1-16.
Linster CL, et al. Metabolite damage and its repair or pre-emption. Nature Chemical Biology 2013; 9: 72-80.
No comments:
Post a Comment