Beyond Selection's Shadow: Early Theoretical Biology, Epigenetics, and the New Unfolding Synthesis

"It is doubtful, however, whether even the most statistically minded geneticists are entirely satisfied that nothing more is involved than the sorting out of random mutations by the natural selective filter." - Conrad Waddington, father of Epigenetics, Letter to Nature journal the year the Modern Synthesis (the theory of evolution) was released in '42

The narrative of 20th-century biology has been dominated by Neo-Darwinism, also known as the Modern Synthesis. This framework fused Darwin's theory of natural selection with Mendelian genetics, population genetics, and paleontology, establishing random genetic mutation and natural selection as the primary engines of evolutionary change. However, lurking in the historical background, particularly in the early decades before the Synthesis fully cemented its dominance, were alternative attempts to unify biology. The journal article title "A synthesis without Darwin: unification attempts in early theoretical biology" points towards these fascinating, often overlooked, efforts that sought grand biological principles not solely reliant on selection acting upon random variation. These early explorations, focused on form, development, and intrinsic organizational principles, resonate surprisingly well with modern discoveries in epigenetics, and together, they pose significant challenges to the completeness of the traditional Neo-Darwinian view.

Early theoretical biologists, often inspired by the unifying power of physics, sought to uncover fundamental laws governing life, particularly concerning morphology, development, and biological organization. Figures like D'Arcy Wentworth Thompson, in his seminal work On Growth and Form, argued that physical forces and mathematical principles played a crucial role in shaping organisms, suggesting that many biological forms were necessary consequences of physics and geometry, rather than solely products of adaptive selection. Others explored concepts like orthogenesis (directed evolution along predetermined pathways) or structuralism, emphasizing inherent constraints and properties within developing organisms that channel evolutionary trajectories. While often lacking robust mechanistic explanations and sometimes veering into vitalism or Lamarckian ideas, the core motivation was frequently a dissatisfaction with natural selection as the sole creative force, especially concerning the origin of major body plans and evolutionary novelties. They perceived a need for principles governing the generation of form (development, 'evolvability') alongside the selection of adapted forms. This implicit focus was on how organisms are built and how developmental processes themselves might guide or constrain evolution – a synthesis centered on the organism's internal dynamics and its interaction with physical laws, rather than primarily on population-level sorting of random genetic variants.

This historical focus on development, environmental influence, and the organism's intrinsic properties finds a powerful modern echo in the field of epigenetics. 

Epigenetics involves modifications to DNA or its associated proteins (like histones) that alter gene expression without changing the underlying DNA sequence. These modifications (e.g., DNA methylation, histone acetylation) act as a layer of control, switching genes on or off in response to various cues, including environmental signals, developmental programs, and physiological states. 

Crucially, these epigenetic marks can be stable through cell divisions and, can even be transmitted across generations.

The involvement of epigenetics connects conceptually to the aspirations of early theoretical biologists in several ways. Firstly, it provides concrete molecular mechanisms for how the environment can directly influence the phenotype. Early theorists often stressed the organism-environment interaction but lacked the tools to see how this translated into heritable or stable changes. Epigenetics demonstrates how environmental factors (diet, stress, toxins) can leave molecular marks that stably alter gene activity, leading to different developmental outcomes or physiological states (phenotypic plasticity). This resonates with the early focus on development as a responsive, dynamic process rather than merely the unfolding of a fixed genetic blueprint. Secondly, transgenerational epigenetic inheritance, offers a mechanism, distinct from DNA sequence change, by which parental experiences could potentially influence offspring phenotypes. This touches upon the Lamarckian flavour present in some early non-Darwinian thinking – the idea that acquired characteristics might be inherited – but provides a specific molecular pathway, avoiding the vagueness of older proposals.

The insights from both early theoretical biology's focus on inherent form-generating principles and modern epigenetics collectively challenge the standard Neo-Darwinian framework, suggesting it may be incomplete rather than incorrect. The challenge unfolds on multiple fronts:

1. Source of Variation: Neo-Darwinism posits random genetic mutation as the ultimate source of variation upon which selection acts. Epigenetics introduces variation at the level of gene expression, which can be environmentally induced and potentially non-random or directed towards specific pathways in response to environmental cues. 

This suggests that phenotypic variation available for selection might not be entirely random in its origin or its nature.

2. Inheritance: The Modern Synthesis is fundamentally gene-centric, assuming inheritance occurs primarily through DNA. Epigenetic inheritance, even if limited, introduces additional channels (epialleles, RNA molecules) through which information shaping the phenotype can pass between generations.

3. Agency of the Organism and Development: Early theorists emphasized the organism's intrinsic properties and developmental dynamics. Epigenetics highlights how developmental pathways are flexible and responsive, shaped by environmental inputs via epigenetic modifications. This frames the organism not just as a passive object of selection but as an active participant whose developmental system interacts with the environment to produce phenotypes, potentially biasing evolutionary direction.

4. Tempo and Mode of Evolution: The emphasis on developmental plasticity mediated by epigenetics suggests mechanisms for potentially rapid adaptation or response to environmental change, complementing the typically slower process of fixing advantageous genetic mutations. It might also contribute to explaining macroevolutionary patterns and the origin of novelty, areas where early theoretical biologists felt Neo-Darwinism was less explanatory.

In conclusion, the quest for a "synthesis without Darwin" in early theoretical biology represented a legitimate scientific endeavour to understand the principles of biological organization, development, and form, seeking laws beyond selection alone. While lacking the mechanistic detail we have today, their focus on internal factors, physical constraints, and developmental dynamics presaged themes now vividly illuminated by epigenetics. Epigenetics provides tangible molecular mechanisms for environmental influence on phenotypes, developmental plasticity, and potentially limited non-genetic inheritance. Together, these historical perspectives and modern findings challenge the exclusivity of the Neo-Darwinian paradigm, pushing towards a more integrated or extended evolutionary synthesis that incorporates development, physiology, and epigenetic processes alongside genetics and selection as key components of the evolutionary drama.