“How would you like to live in Looking-glass House, Kitty? I wonder if they’d give you milk in there? Perhaps Looking-glass milk isn’t good to drink…” wrote Louis Carroll in ‘Through the Looking-Glass and What Alice Found There’ - the 1871 sequel to his celebrated masterpiece ‘Alice’s Adventures in Wonderland’.
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The left and right hands are an example of chirality in the human body, as they are non-superimposable mirror images
(Photo: shutterstock)
At the time the concept of chirality was already known, a fact that apparently did not go unnoticed by Carroll. While scientists of that era hadn’t yet isolated the mirror-image molecule of lactose—the main sugar in milk—we now know that Carroll was right: milk through the looking-glass would indeed be unfit to drink.
Distorted mirror
Chirality is a fundamental property in chemistry. Two molecules can have an identical chemical structure: they contain the same atoms and the same chemical bonds —a carbon atom bonded to a hydrogen atom, a nitrogen atom bonded to an oxygen atom, etc.—but their spatial arrangement in relation to the center of the molecule differs. This difference affects their chemical activity and properties, as they are mirror images of each other. These mirror images are non-superimposable, much like our hands. The term "chirality" is derived from the Greek word χείρ (kheir), meaning ‘hand’, conveying the essence of handedness and highlighting the intrinsic asymmetry that defines chiral structures.
Understanding chirality is closely intertwined with the mystery of the origin of life. It appears that there are equal amounts of molecules with left and right chirality in the universe. However, in the living world, certain types of molecules predominantly exhibit one chirality over the other. Almost exclusively, amino acids—the building blocks of proteins and by extension, the building blocks of life - exhibit left-handed chirality, while sugars, which are central components of DNA and RNA, display right-handed chirality. Efforts to understand the reasons behind this have been ongoing for many years, and recently a new and promising direction in research has emerged.
When Pasteur's heart was merry with wine
The study of chirality began in France in the mid-19th century. Louis Pasteur, often regarded as the father of modern microbiology, was first and foremost a crystallographer—an expert in the study of crystals. In 1848, at the start of his scientific career, Pasteur examined crystals of tartaric acid - commonly known as wine acid - provided to him by French winemakers seeking to enhance the quality of their wine. He discovered that different crystals of this acid reacted differently to polarized light, which is light, consisting of light waves that oscillate in a single, well-defined direction, rather than in multiple planes as ordinary light does. One of the crystals deflected the light, while another did not; an essential characteristic of chiral substances. The two types of crystals are mirror images of each other, known in chemical terms as enantiomers. However, how can a molecule’s chirality (right- or left-handed) be determined? This fundamental question remained a mystery.
Nearly a century later, Dutch chemist Johannes Bijvoet developed a method to identify chiral molecules based on their macroscopic properties—using X-ray diffraction. At the time, this method was considered esoteric, requiring expertise in advanced X-ray technology.
In the 1980s, Professors Meir Lahav and Leslie Leiserowitz from the Department of Surface Chemistry at the Weizmann Institute of Science, along with their colleagues, demonstrated a connection between a crystal’s internal and external structure and its spatial symmetry - specifically its chirality. In other words, they established a link between the structure of a single molecule and the macroscopic structure of the crystal. Thus, after 140 years of mystery, researchers were finally able to determine which molecules exhibited left-handed chirality and which exhibited right-handed chirality. This marked the emergence of a new field of research: the stereochemistry of organic crystals. Stereo in Greek means ‘solid’, and by extension, it also refers to spatial properties. Stereochemistry, therefore, is the science of the spatial arrangement and the structure of organic crystals. Stereochemistry is crucial for drug development, which relies on our understanding of the mechanisms of crystal formation and growth in biological systems - for example, in malaria research. For their contributions Lahav and Leiserowitz were awarded the 2016 Israel Prize for Physics and Chemistry Research and the 2021 Wolf Prize in Chemistry.
Chirality can also have serious consequences, some of which are harmful. One prominent example is the drug thalidomide, taken by pregnant women in the early 1960s to relieve nausea, which tragically led to the birth of babies with severe limb deformities. While the right-handed enantiomer of the drug alleviated nausea, the left-handed enantiomer was found to cause irreversible damage to the developing fetus. In Europe, thalidomide was sold without a prescription, but in the United States the vigilant physician Frances Oldham Kelsey raised concerns about its safety and blocked its approval. For this, she was awarded the President's Award for Distinguished Federal Civilian Service (PADFCS) in 1962 by President John F Kennedy.
That's life
Why is a particular molecule chiral? And why does one chiral form of a molecule dominate in the living world? Even if, in Earth's early days, there was an abundance of left-handed molecules, there was no guarantee that this preference would persist over time. An external force might have been necessary to maintain the bias toward the left. A recent study published in Nature sought to address this riddle.
Researchers from the Scripps Research Institute in San Diego attempted to trace the early growth stages of chiral crystals. They accelerated the formation of dipeptides - molecules formed by two amino acids - using a sulfur-based catalyst sensitive to the chirality of the amino acids. They chose certain amino acids and a sulfur catalyst and conducted experiments in an aqueous environment to mimic chemical processes likely to have occurred during the early development of life.The results were surprising: 80% of the dipeptides formed were heterochiral - composed of one left-handed and one right-handed amino acid - while the other 20% were homochiral - with both amino acids sharing the same chirality. Auguste Rodin’s sculpture The Cathedral offers a poignant metaphor for this: it portrays two intertwined right hands in an irreplicable pose by one person alone.
“We thought it was bad news,” said Donna Blackmond, the lead researcher and co-author of the study. The initial assumption was that the chirality bias would dissipate over time as new proteins formed. If we assume that the molecules indicative of life have a left-handed chirality, the findings do not explain how this bias has been preserved over billions of years. Most of the dipeptides formed were heterochiral, while essential macromolecules, such as DNA, are homochiral.
The domino effect
The researchers began their dipeptide growth experiments with a mixture containing a slight excess of left-handed amino acids—60%. Although heterochiral dipeptides (comprising one left-handed and one right-handed amino acid) were formed, equal amounts of left- and right-handed molecules were involved in their formation, and thus the initial bias was preserved throughout the process. As a result, the likelihood of formation of left-handed homochiral dipeptides composed solely of left-handed amino acids, increased.
“It’s like a domino effect,” said Mathew Powner, an origin-of-life chemist whose earlier research laid the groundwork for this study. Powner noted that the first heterochiral reaction promotes the formation of more homochiral molecules. “And it’s a general process that works with all amino acids,”
However, the new discovery is not yet sufficient to solve the puzzle. Follow-up experiments revealed that heterochiral dipeptides precipitate in solution more quickly during the reaction than homochiral dipeptides. The researchers remain uncertain about the cause of this difference, but they suspect it reflects another bias effect that reinforces the preference for one type of molecule. Future experiments will likely explore whether these findings extend to longer peptide chains containing more than two amino acids.
The path to understanding the secrets of life is long and winding. We may never stop walking it, but along the journey, let us not forget to look in the mirror.
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