The phrase “mystery of mysteries” describes a profound, historical challenge in the understanding of life. It was first famously used in biology by Charles Darwin, who borrowed the descriptor from the scientist Sir John Herschel. The term refers to the deepest, most fundamental unsolved problems in the life sciences, representing a frontier of knowledge that defies current explanation. While Darwin applied the phrase to a specific biological process, its meaning has expanded over time to encompass other monumental, unresolved questions about life’s existence and diversification.
Darwin’s Original Question About Species
For Charles Darwin, the original “mystery of mysteries” was the origin of species itself, a concept known as speciation. Speciation is the process by which one species splits into two or more distinct species, generating the vast biodiversity observed on Earth. Darwin’s theory of natural selection explained how populations adapt to their environment, but the mechanism for the permanent splitting of lineages remained less clear in his time.
His great work, On the Origin of Species, sought to address this problem, yet the precise moment of species divergence presented a conceptual hurdle. He grappled with the problem of discontinuities—the appearance of separate, well-defined species in nature with seemingly few transitional forms. The lack of a clear, continuous spectrum of life forms made the formation of new, reproductively isolated groups appear sudden and mysterious.
The modern understanding of speciation often involves reproductive isolation, where barriers prevent members of two groups from producing viable, fertile offspring. These barriers can be prezygotic, like behavioral differences or habitat separation, or postzygotic, such as the infertility of hybrid offspring. The most common model, allopatric speciation, occurs when a geographic barrier physically separates a population, allowing the two isolated groups to evolve independently until they can no longer interbreed.
The Grand Modern Challenge of Abiogenesis
In modern biology, the concept of the “mystery of mysteries” has largely shifted to a more fundamental problem: the origin of life itself, or abiogenesis. This challenge asks how non-living chemical compounds transitioned into the first self-replicating, metabolizing cellular entities approximately 3.8 billion years ago. Abiogenesis is conceptually distinct from evolution, which requires a pre-existing self-replicating entity to begin.
One of the foundational experiments exploring this, the 1953 Miller-Urey experiment, demonstrated that amino acids—the building blocks of proteins—could form spontaneously under conditions thought to resemble the early Earth’s atmosphere. By passing an electrical spark through a mixture of water vapor, methane, ammonia, and hydrogen, the researchers successfully synthesized several organic molecules. While the exact composition of the early atmosphere is now debated, the experiment confirmed that the chemical precursors to life can arise naturally.
A leading hypothesis for the next step is the “RNA world,” which suggests that ribonucleic acid (RNA) was the first genetic material. RNA has a unique ability to both store genetic information, like DNA, and catalyze chemical reactions, like proteins. This dual function would have allowed the first protocells to carry out both replication and metabolism using a single type of molecule.
The current challenge lies in explaining the assembly of these components into a stable protocell—a self-contained system surrounded by a membrane that can maintain an internal environment separate from its surroundings. This first cell must have possessed a primitive metabolism to harness energy and the ability to accurately copy its genetic material, a difficult chemical hurdle to overcome without the sophisticated machinery found in modern cells.
Mechanisms Driving Evolutionary Innovation
A related, ongoing challenge that extends Darwin’s original concern involves understanding the mechanisms that drive evolutionary innovation and complexity after life has begun. This is the field of evolutionary developmental biology, or Evo-Devo, which seeks to explain how slight changes in developmental processes lead to major changes in body plans and the emergence of novel structures. It focuses on the genetic toolkit—a relatively small set of genes that control the development of all animals.
A prime example involves the Hox genes, a family of regulatory genes highly conserved across nearly all animal phyla, from fruit flies to humans. These genes dictate the identity of body segments along the head-to-tail axis during embryonic development. Changes in the timing, location, or level of expression of these master-control genes can result in dramatic morphological shifts, such as the evolution of different numbers of limbs or segments.
Evolutionary novelty often arises not from the invention of entirely new genes, but through the duplication of existing genes or mutations in non-coding regulatory regions of the DNA. Gene duplication provides redundant copies that can evolve new functions without harming the organism, while changes in regulatory elements alter when and where a gene is turned on or off. This framework explains how a common set of genetic components can produce the immense diversity of biological forms, essentially by tinkering with the developmental instructions.
Other Fundamental Questions in Biology
The grand challenges in biology are not limited to the past, and several other fundamental questions still share the status of a modern “mystery.” One of the most profound involves the biological basis of consciousness, a problem housed within neuroscience. Scientists have yet to explain how the interaction of billions of non-conscious neurons in the brain gives rise to subjective experience, self-awareness, and sensation.
The problem of biological complexity also remains a significant frontier, particularly in systems biology. Understanding the function of an entire cell or organism requires knowing not just the individual components like genes and proteins, but how their thousands of interactions are organized and regulated as a cohesive, functioning system. Predicting the behavior of these complex biological networks remains an enormous task.
Another major puzzle is the problem of longevity and aging, or senescence. While several theories exist, including damage accumulation and programmed mechanisms, the precise biological reason for why organisms age and the extent to which this process can be manipulated remains unclear. Investigating these enduring questions continues to define the deepest frontiers of biological research.