A Temporal Perspective on the Effects of Chirality in Biology

Introduction

In 1848, the young Louis Pasteur discovered that small crystals of tartaric acid had some asymmetrical properties — the crystals had tiny facets on their surfaces that sometimes faced right or faced left. This was the first documented discovery of chirality in history. Chirality is a type of stereoisomerism in which molecules of the same structure and molecular formula cannot be superimposed over each other. This is often due to a “chiral carbon” with four different substituents. Chiral molecules are ubiquitous throughout living organisms — from simple sugars to enzymes, the overwhelming majority of these molecules have enantiomers, that is to say, the mirror image of a chiral molecule. Intriguingly, life seemingly always favours one enantiomer of the other — a phenomenon known as homochirality. There are many conflicting theories with regard to the origins of homochirality billions of years ago. Some speculate over what may have happened if the opposite enantiomers were used to synthesise life, and if this would have even been possible. Because of life’s homochiral nature, the effect of using opposite enantiomers would likely be disastrous. This is not only a theory relevant to the origins of life, enantiomers have many real-world effects as well. The drastic disparity in the properties of different enantiomers are well documented; the most infamous example being the thalidomide tragedy which occurred in the late 50’s and 60’s of the 20th century. A simple morning sickness drug was unknowingly sold as a racemate, causing many teratogenic effects. While today, the difference in properties is much better understood, advances in synthetic biology and synthetic chemistry suggest ‘mirror life’ (synthetic organisms built from the opposite chirality) is a plausible breakthrough in the near future, attached to many profound opportunities and benefits, but with potential catastrophic consequences. The following essay will explore how chirality has shaped biology from its origins in primordial soup, to modern day pharmacology and potential future synthetic organisms with the opposite chirality.

Homochirality in Living Organisms

If we look at every organism today, one thing they all have in common is the chirality of the molecules. DNA is right handed. Amino acids are always L-configured, sugars are always D-configured. The first observation of the homochiral nature of living organisms was observed by Louis Pasteur (Vantomme & Crassous, 2021). He discovered that some organisms only metabolised (+) tartaric acid and left behind (−) tartaric acid. This was the first clue that organisms are homochiral. Active kinetic isomerisation is an example of a phenomenon which causes molecules to switch between opposite enantiomers, particularly in aqueous or liquid environments (Bada, 1972). This would imply that almost, if not all living organisms in history have had to prevent the racemisation of chiral molecules in order for the molecules to have consistent properties for biological processes and for the construction of biological structures such as DNA. One theory for why this has evolved to be necessary is because organisms are interdependent on each other. Therefore, if one organism were to consume another, it would not be able to digest the ‘incorrect’ enantiomer as enzymes are enantioselective and stereospecific (Mu et al., 2020). I would propose that ‘chiral compatibility’ is or has been a selection pressure for organisms. This would be because organisms that did not solely produce the ‘correct’ or ‘standard’ enantiomer might not as effectively metabolise other organisms, because the opposite enantiomers are redundant, a waste of resources and therefore may be selected against. Perhaps the fact that nucleic acids in a heterochiral nucleic acid are unable to be naturally synthesised is a feature of this (Rossi et al., 2013).

Origins of Homochirality

However, this still doesn’t explain how homochirality originated. There is much debate about how homochirality occurred in ‘primordial soup’. One thought-provoking piece of evidence is the Murchison meteorite (Macko, 2001). This was a chondritic meteorite discovered in Australia in 1969. It is of particular interest as it had mineral deposits of many amino acids, some recognisably common, such as Glycine, Valine and Leucine, and other ‘exotic’ amino acids like Aminoisobutyric acid and Isovaline. While it does not prove anything, these ‘exotic’ amino acids point towards at least some of the amino acids being synthesised in isolation from terrestrial life. The oddest thing about the meteorite, however, is that just like on earth, it did not show a racemic distribution of enantiomers, instead having a significant excess of L-configured amino acids. This suggests that either some external factor caused both terrestrial synthesis of amino acids and also in space on the Murchison meteorite (in other words, synthesis of L-amino acids within our solar system), or perhaps that L-configured amino acids will inevitably break symmetry. A possible explanation for this is circularly polarised light (Fukue et al., 2010). This describes how the net circularly polarised light within our star system would cause the photolysis of D-amino acids, leaving behind the L-amino acids more readily available. Coincidentally, this supports another theory for total homochirality on Earth — the Soai reaction (Blackmond, 2004). This experiment conducted around 50 years ago demonstrated that an initial small break in symmetry allows for the autocatalysis for a reaction, thus one enantiomer of a molecule would become dominant. This synergises with both the Murchison meteorite and ideas about circularly polarised light. It could explain how a small change in the racemic environment in the beginning, perhaps caused by the photolysis of D-amino acids might have instigated the autocatalysis of L-amino acids. (Note that the Soai reaction was used here as an analogy for autocatalysis; the study used aldehydes, not amino acids). Ultimately, as exhibited by all modern organisms, chirality underpins many biological processes and is necessary for life to have developed as we know it.

The Thalidomide Tragedy

What we’ve explored so far is very much speculative and may seem removed from the modern day. However, theories surrounding the properties of different enantiomers and chirality are still extremely relevant today. An infamous case of this is the Thalidomide tragedy of the 50s and 60s. A drug intended to treat morning sickness in pregnant women led to tens of thousands of children being born with debilitating malformations (Vargesson, 2015). While the effects of R-Thalidomide were positive and apparently ‘safe’ to use, the S-configured Thalidomide was not, and was a teratogenic substance. The medicine was unknowingly sold as a racemic mixture, so the S-Thalidomide was also ingested. What makes Thalidomide more dangerous, is that even if the dangerous enantiomer were to have been identified, this disastrous event still may not have been avoided. Thalidomide can be hydrolysed in body fluid, and it can racemise between enantiomeric states, so even if sold as an enantiomerically pure drug it would inexorably have converted to the S-configuration. This incident depicts the importance of chirality in pharmacology.

Chirality in Modern Pharmacology

Moving to the modern day, Thalidomide has been discovered to have a plethora of uses in medicine. Firstly, it’s been found effective against myeloma (cancer of the bone marrow) (Singhal et al., 1999). They found that by gradually increasing the thalidomide dosage given, they were able to reduce the paraprotein levels in over 50% of the patients, with 2 people with a complete remission. In most of the cases that had a decrease in paraprotein levels, improvements were seen in around 2 or 3 months. The study notes that many patients had mild to moderate adverse effects, conceivably due to racemisation, but the study also demonstrates that our modern understanding of chirality and the different properties of enantiomers has positive benefits to healthcare. The incident has undoubtedly shifted more attention to ensuring that the risks of enantiomers is more well understood, adding a layer of regulation to drug testing. A key example of where this has been implemented is in the 1992 revision to the United States Food and Drug Administration (Brooks et al., 2011). Concerns around ideal enantiomeric interactions being a “coin toss” led to this guideline led to ‘absolute stereochemistry’ being necessary before a drug is tested and distributed. The effect of this has been made clear; in the 2000s, worldwide sales grew 13% annually. From this, we can glean that an increase in our understanding of stereospecificity and chirality has had a measurable, meaningful impact upon the pharmaceutical industry, and more holistically, on global health.

Mirror Life

Our increased understanding of enantiomers and the paradigm of homochirality has led us to question whether it is possible to synthesise life with the opposite chirality, otherwise known as mirror life. Amino acids, sugars, nucleotides, hormones and receptors and so on are all chiral. As shown with nucleic acids such as DNA and RNA, many of these molecules fail to propagate if even a single molecule of the opposite chirality is introduced (Rossi et al., 2013). However, it has been shown that these molecules and structures can be synthesised in their opposite chiral form. This is one piece of evidence that hints that it is possible for a full organism to be synthesised with the opposite chirality. Recently, it’s been shown that it is possible to synthesise the mirror images of small proteins (Callahan et al., 2024) suggesting that in the near future the necessary proteins for a full organism will be able to be synthesised.

New frontiers in synthetic biology may permit the assembly of mirror cells. We have been able to construct phospholipid membranes for over 50 years now (Chang, 2007). In addition to this, recent breakthroughs in synthetic biology with key features of cells being replicated, such as the minimal genome of JCVI-syn1.0 (Sleator, 2010). Developments here indicate that a ‘bottom up’ construction of a minimal mirror cell may be possible. The effects of such cells in our ecosystem are highly theoretical, as while mirror life is highly plausible it still is not something that has been created. As an example, some theorise that human PRRs (pattern recognition receptors) may not recognise mirror MAMPs (microbe-associated molecular patterns, which are almost always chiral) (K. Adamala et al., 2024). Typically, PRR’s would recognise MAMPs which would trigger further immune responses. However, because the interactions between MAMPs and PRRs are stereospecific and enantioselective, this suggests the PRRs ability to bind to and recognise MAMPs would be significantly impaired. This means that the ability of dendritic cells to trigger T-cell responses would be significantly impaired. An argument could be made that new T-cells could be clonally selected to have shapes more stereospecific to the chiral antigens, however, a logical assumption would be that this stage would not be reached as dendritic cells would not recognise the MAMPs in the first place.

While this does seem bleak, mirror molecules do have their place, again in modern medicine. Many have speculated that mirror sugars such as L-Glucose may prove a very useful sweetener, as it may still taste sweet, yet unprocessable by the body, potentially making it effective for weight loss.

Mirror molecules, and mirror life are both very recent developments in biology, made accessible through a better understanding of chirality. While it may be too early to see whether it would be a good development or bad development, it remains that it will likely be a pivotal point in biology if it is ever accomplished.

Conclusion

This leads to the conclusion that chirality and stereospecificity has an incredibly broad reach over many fields in biology. From the initial conditions required for homochirality to emerge from primordial soup, to the public health implications of mirror biology. It is therefore paramount that we attempt to understand more about the nature of chiral molecules, in order to prevent catastrophes like the thalidomide tragedy and possible future disasters like an uncontrolled mirror life. As with many things in biology, chirality has a strange harmony to it — how such a tiny change in a molecule can lead to profound effects.