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Same-Handed Molecules Are an “Overarching Design Principle” in Life, Say Researchers

Photo credit: Shoeib Abolhassani via Unsplash.

Homochirality, the same-handedness of building blocks of DNA and proteins, poses a severe challenge for those who deny the intelligent design of life. Design advocates have explained the problem: James TourCasey LuskinRob Stadler, and many others (see a description of the problem here). The odds of random, blind forces selecting every amino acid in a protein to be left-handed, and every sugar in a DNA chain to be right-handed, are vanishingly small. 

Materialists also recognize this hurdle in their origin-of-life theories, because homochirality would have had to become established before natural selection could be called upon for assistance. But what happens when heterochiral molecules do make it into our cells? Bad things happen.

Heterochirality Syndrome

Normally, cells do a good job of keeping our molecules 100 percent homochiral. Stray wrong-handed molecules are either destroyed or turned into the correct hand before a protein or nucleic acid goes into service. A research team in France wondered what would happen if they forced certain genes to go rogue, or heterochiral. (Good thing they tried this on fruit flies and not humans.) They published the dire results in Nature Communications (open access). The Abstract of the paper by Banreti et al., “Biological effects of the loss of homochirality in a multicellular organism,” hints at troubles to come:

Homochirality is a fundamental feature of all known forms of life, maintaining biomolecules (amino-acids, proteins, sugars, nucleic acids) in one specific chiral form. While this condition is central to biology, the mechanisms by which the adverse accumulation of non-l-α-amino-acids in proteins lead to pathophysiological consequences remain poorly understood. To address how heterochirality build-up impacts organism’s health, we use chiral-selective in vivo assays to detect protein-bound non-l-α-amino acids (focusing on aspartate) and assess their functional significance in DrosophilaWe find that altering the in vivo chiral balance creates a ‘heterochirality syndrome’ with impaired caspase activity, increased tumour formation, and premature death. Our work shows that preservation of homochirality is a key component of protein function that is essential to maintain homeostasis across the cell, tissue and organ level. [Emphasis added.]

The authors call homochirality “an overarching design principle in all living organisms.” They do not delve into the origin of homochirality, and say essentially nothing about evolution (except for noting that a certain amino acid in a specific position of a gene is “evolutionarily conserved,” meaning it has not evolved). 

Surprisingly, the health effects of heterochirality have not been studied in detail before, they say.

Furthermore, a direct link between the partial loss of homochirality and protein dysfunction has not been shown, and hence the underlying molecular and cellular mechanisms connecting heterochirality to pathophysiological sequelae remains unknown.

The bulk of the paper documents what happened to hapless flies forced to endure “heterochirality syndrome.” For example, one intervention involved knocking out the Pimt gene. This gene is an enzyme essential for repair of heterochiral proteins. It recognizes wrong-handed aspartame residues after translation and converts them into the correct left-handed form. Here’s what happened to the poor fly:

Importantly, Pimt knock-out flies showed premature death, dying 14 days earlier than control flies (Fig. 5a). Premature death was due solely to the lack of Pimt activity, as the phenotype could be fully rescued by a Pimt wild type (Pimtwt), but not a Pimt catalytic dead (PimtS60Qknock-in construct (Fig. 5a), in which the evolutionarily conserved serine60 residue (Supplementary Fig. 5) was replaced by glutamine. Furthermore, we found that loss of Pimt activity led to the formation of protein aggregates and large melanotic tumours inside the body (Fig. 5b, c).

The loss of the heterochirality repair enzyme also gives mice a miserable, short life. And when the enzyme fails in humans, brain damage and lung cancer can result.

Importantly, Pimt knock-out mice showed significant growth retardation succumbing to fatal seizures at an average of 42 days after birth, and increased proliferation and granule cell number in the dentate gyrus. Pimtexpression and enzyme activity were significantly decreased in human astrocytic tumours and promoted epithelial mesenchymal transition in lung adenocarcinoma cell lines, indicating that impaired Pimt activity has several pathophysiological consequences.

The team excised the working part of Pimt using CRISPR-Cas9. Their observations of the aftereffects demonstrated that Pimt is “ubiquitously expressed in tissues throughout the fly life cycle” and in probably most other life forms. This fact adds to the materialist’s challenge, because even if simple cells found a way to start homochiral, they would quickly succumb to what we could dub the “right hook punch” from a wrong-handed amino acid.

What Causes the Trouble?

The team found that wrong-handed amino acids change the 3-D conformation of proteins. One right-handed aspartate (D-aspartic acid, as opposed to the correct L- form), induces structural changes to the caspase cleavage site where the correction must occur. So altered, the enzyme cannot “fit” the repair site. Caspases are involved in cutting out defective parts of proteins. They also participate in programmed cell death, or apoptosis.

Our results show that caspases malfunction when the consensus cleavage site of target proteins suffer a stereoinversion, which could potentially affect many important cellular processes.

In summary, heterochirality syndrome reduces lifespan, increases susceptibility to tumors, inhibits apoptosis, and more. People suffering from even one enzyme with a wrong-handed amino acid “are expected to have massive physiological consequences on cell and tissue homoeostasis,” and the defect “might be implicated in many human diseases.” Due to cascading effects from a heterochiral building block, it’s all downhill when random chance lands a right hook.

Overall, our results show that accumulation of non-l-α-AAs in proteins, promotes a progressive heterochirality syndrome, through a cascading effect across biological scales spanning from loss of molecular homochirality to increased resistance to caspase activity in cells, increased tumour susceptibility in organs and, consequently, premature death of the chiral-deficient animal (Fig. 6h). We further suggest that heterochirality spreading in living organisms represents a novel causal factor that may be associated with a broad range of defective cellular processes, diseases and ageing.

What Are the Implications?

Without foresight to solve heterochiral incidents, a primordial cell would quickly perish even if, against all odds, it began homochiral. These authors have shown one of the enzymes that prevents heterochirality syndrome by recognizing and fixing a single D-amino acid to its L- form. This is fascinating to ponder, since even intelligent chemists have difficulty separating the isoforms of chiral molecules (example 1example 2). 

Biochemists realize that homochirality is functionally beneficial and would tend to be preserved by natural selection. A paper in the journal Chem explained why but failed to address the origin of homochirality. Occasionally a materialist will attempt to speculate about how a protocell “emerged” from a pool of heterochiral building blocks and evolved toward homochirality via “chance aided by luck,” but those attempts usually end like this example from 2010:

Whether or not we will ever know how this property developed in the living systems represented on Earth today, studies of how single chirality might have emerged will aid us in understanding the much larger question of how life might have, and might again, emerge as a complex system.

Statements like this beg the question of emergence. Must it be materialistic? If understanding is the goal, Ockham’s razor would favor the simplest cause that is capable of separating thermodynamically equivalent objects that differ only in geometry. That cause is intelligence. Even a child could easily separate left- and right-handed toy soldiers of equal mass. 

It’s been over 170 years since Louis Pasteur recognized chirality as a fundamental feature of biology (see here). Were it not for the philosophical preferences of some, the strength of intelligence over randomness in achieving perfect homochirality and maintaining it with molecular machines would universally be recognized as the most obvious choice to account for this “overarching design principle in all living organisms.”