A Concept of Complementarity Between Complexity and Redundancy can Account for Kant's Biological Teleology and Unify Mechanistic and Finalistic Biology.

Over 160 years after Darwin and 70 years after the discovery of DNA, two fundamental questions of biology remain unanswered: What differentiates the living from the nonliving? How can mechanistic and finalistic or holistic biology be unified? Niels Bohr introduced a concept of complementarity in quantum physics and based on the paradox of light as a simultaneous wave and particle, conjectured that a similar concept might exist in biology that would solve the paradox of life originating from the nonliving. Bohr proposed that two mutually exclusive-independent observations may be necessary to explain a phenomenon and provided support to Immanuel Kant's idea that the "purposive" behaviour of organisms could only be explained in teleological terms and that mechanical and teleological approaches were necessary and complementary to explain biology. We present a concept of complementarity whereby biochemical pathways or cellular channels for the flow of information are simultaneously complex and redundant and complexity and redundancy complement each other. The postulates of biological complementarity are that (1) it was an essential condition in the origin of life; (2) it provided physiological flexibility that allowed organisms to mount self-protection response and complexity to evolve in the face of deleterious mutations before the evolution of bi-parental sex; (3) it laid the foundation for the evolution of a choice of response when confronted with threat; and (4) it applies to all levels of biological organizations and, thus, can serve as a basis for the unification of mechanistic and holistic biology. It is proposed that teleology is simultaneously constitutive and heuristic: constitutive because organisms' "purposive" behaviours are adaptive and are grounded in mechanism (complexity and redundancy), and heuristic because with our finite cognition and our goal-oriented (humans alone are aware of "tomorrow") and anthropomorphic pre-disposition, teleology will remain useful as a guide to our making sense of the world, even how to ask a meaningful question.

A Law of Redundancy Compounds the Problem of Cancer and Precision Medicine.

Genetics and molecular biology research have progressed for over a century; however, no laws of biology resembling those of physics have been identified, despite the expectations of some physicists. It may be that it is not the properties of matter alone but evolved properties of matter in combination with atomic physics and chemistry that gave rise to the origin and complexity of life. It is proposed that any law of biology must also be a product of evolution that co-evolved with the origin and progression of life. It was suggested that molecular complexity and redundancy exponentially increase over time and have the following relationship: DNA sequence complexity (Cd) < molecular complexity (Cm) < phenotypic complexity (Cp). This study presents a law of redundancy, which together with the law of complexity, is proposed as an evolutionary law of biology. Molecular complexity and redundancy are inseparable aspects of biochemical pathways, and molecular redundancy provides the first line of defense against environmental challenges, including those of deleterious mutations. Redundancy can create problems for precision medicine because in addition to the issues arising from the involvement of multiple genes, redundancy arising from alternate pathways between genotypes and phenotypes can complicate gene detection for complex diseases and mental disorders. This study uses cancer as an example to show how cellular complexity, molecular redundancy, and hidden variation affect the ability of cancer cells to evolve and evade detection and elimination. Characterization of alternate biochemical pathways or "escape routes" can provide a step in the fight against cancer.

Origin of Sex-Biased Mental Disorders: Do Males and Females Experience Different Selective Regimes?

The origins of sex-biased differences in disease and health are of growing interest to both medical researchers and health professionals. Several major factors have been identified that affect sex differences in incidence of diseases and mental disorders. These are: sex chromosomes, sex hormones and female immunity, sexual selection and antagonistic evolution, and differential susceptibility of sexes to environmental factors. These factors work on different time scales and are not exclusive of each other. Recently, a combined Sexual Selection-Sex Hormones (SS-SH) Theory was presented as an evolutionary mechanism to explain sex-biased differences in diseases and mental disorders (Singh in J Mol Evol 89:195-213, 2021). In that paper disease prevalence trends were investigated, and non-sex-specific diseases were hypothesized to be more common in males than in females in general. They showed signs of exceptions to this trend with inflammatory diseases and stress-related mental disorders that were more common in females. We believe that the SS-SH theory requires the consideration of psycho-social stress (PSS) to explain the predominance of female-biased mental disorders and some other exceptions in their findings. Here we present a theory of sex-differential experience of PSS and provide quantitative support for the combined SS-SH-PSS Theory using age-standardized incidence rates (ASIRs) recording the levels of male- and female-bias in data obtained from different countries. The grand theory provides an evolutionary framework for explaining patterns of sex-biased trends in the prevalence of disease and health. Further exploration of women's vulnerability to social factors may help to facilitate new treatments for female-biased diseases.

Decoding 'Unnecessary Complexity': A Law of Complexity and a Concept of Hidden Variation Behind "Missing Heritability" in Precision Medicine.

The high hopes for the Human Genome Project and personalized medicine were not met because the relationship between genotypes and phenotypes turned out to be more complex than expected. In a previous study we laid the foundation of a theory of complexity and showed that because of the blind nature of evolution, and molecular and historical contingency, cells have accumulated unnecessary complexity, complexity beyond what is necessary and sufficient to describe an organism. Here we provide empirical evidence and show that unnecessary complexity has become integrated into the genome in the form of redundancy and is relevant to molecular evolution of phenotypic complexity. Unnecessary complexity creates uncertainty between molecular and phenotypic complexity, such that phenotypic complexity (CP) is higher than molecular complexity (CM), which is higher than DNA complexity (CD). The qualitative inequality in complexity is based on the following hierarchy: CP > CM > CD. This law-like relationship holds true for all complex traits, including complex diseases. We present a hypothesis of two types of variation, namely open and closed (hidden) systems, show that hidden variation provides a hitherto undiscovered "third source" of phenotypic variation, beside genotype and environment, and argue that "missing heritability" for some complex diseases is likely to be a case of "diluted heritability". There is a need for radically new ways of thinking about the principles of genotype-phenotype relationship. Understanding how cells use hidden, pathway variation to respond to stress can shed light on why two individuals who share the same risk factors may not develop the same disease, or how cancer cells escape death.

Origin of Sex-Biased Mental Disorders: An Evolutionary Perspective.

Sexual dimorphism or sex bias in diseases and mental disorders have two biological causes: sexual selection and sex hormones. We review the role of sexual selection theory and bring together decades of molecular studies on the variation and evolution of sex-biased genes and provide a theoretical basis for the causes of sex bias in disease and health. We present a Sexual Selection-Sex Hormone theory and show that male-driven evolution, including sexual selection, leads to: (1) increased male vulnerability due to negative pleiotropic effects associated with male-driven sexual selection and evolution; (2) increased rates of male-driven mutations and epimutations in response to early fitness gains and at the cost of late fitness; and (3) enhanced female immunity due to antagonistic responses to mutations that are beneficial to males but harmful to females, reducing female vulnerability to diseases and increasing the thresholds for disorders such as autism. Female-driven evolution, such as reproduction-related fluctuation in female sex hormones in association with stress and social condition, has been shown to be associated with increased risk of certain mental disorders such as major depression disorder in women. Bodies have history, cells have memories. An evolutionary framework, such as the Sexual Selection-Sex Hormone theory, provides a historical perspective for understanding how the differences in the sex-biased diseases and mental disorders have evolved over time. It has the potential to direct the development of novel preventive and treatment strategies.

Genes and genomes and unnecessary complexity in precision medicine.

The sequencing of the human genome heralded the new age of 'genetic medicine' and raised the hope of precision medicine facilitating prolonged and healthy lives. Recent studies have dampened this expectation, as the relationships among mutations (termed 'risk factors'), biological processes, and diseases have emerged to be more complex than initially anticipated. In this review, we elaborate upon the nature of the relationship between genotype and phenotype, between chance-laden molecular complexity and the evolution of complex traits, and the relevance of this relationship to precision medicine. Molecular contingency, i.e., chance-driven molecular changes, in conjunction with the blind nature of evolutionary processes, creates genetic redundancy or multiple molecular pathways to the same phenotype; as time goes on, these pathways become more complex, interconnected, and hierarchically integrated. Based on the proposition that gene-gene interactions provide the major source of variation for evolutionary change, we present a theory of molecular complexity and posit that it consists of two parts, necessary and unnecessary complexity, both of which are inseparable and increase over time. We argue that, unlike necessary complexity, comprising all aspects of the organism's genetic program, unnecessary complexity is evolutionary baggage: the result of molecular constraints, historical circumstances, and the blind nature of evolutionary forces. In the short term, unnecessary complexity can give rise to similar risk factors with different genetic backgrounds; in the long term, genes become functionally interconnected and integrated, directly or indirectly, affecting multiple traits simultaneously. We reason that in addition to personal genomics and precision medicine, unnecessary complexity has consequences in evolutionary biology.

Is menopause still evolving? Evidence from a longitudinal study of multiethnic populations and its relevance to women's health.

BACKGROUND: To reflect on the impact of changing patterns of delayed marriage and reproduction and to seek evidence as to whether menopause is still evolving, characteristics of the menopause transition were investigated within and between ethnic populations in this study. METHODS: A cross-sectional analysis was conducted using data on 747 middle-aged women obtained from the Study of Women's Health Across the Nation (SWAN) from 1996 to 2008. The ethnic groups included: Afro-American, Chinese, Japanese, Caucasian, and Hispanic. Perimenopause age and duration, menopause age, and hormonal indicators of menopause were examined across five ethnicities. RESULTS: We found a similar window of menopause age within populations, but no significant difference in perimenopause and menopause age between populations. The rate of increase of follicle-stimulating hormone and testosterone differed significantly in Hispanics and African-Americans during the menopause transition period. CONCLUSIONS: The broad window of variation in age at menopause within the population and the absence of significant differences between populations, in combination with population variation in menopause symptoms, suggest that menopause is a relatively recently evolved and still evolving trait. Under the mate choice theory of menopause, menopause is the result of the accumulation of infertility mutations in older women due to men's preference for younger mates. We propose a shifting mate choice-shifting menopause model which posits that, as the age of mate choice/marriage shifts to older ages, so will the age at menopause, and that menopause is a transient phase of female fertility; it can de-evolve, be delayed, if not disappear completely. Integrated longitudinal menopausal studies linked with genomics and hormonal studies on diverse ethnic populations can provide valuable information bearing on women's health and personalized medicine.

Mate Choice and the Persistence of Maternal Mortality.

Maternal mortality remains one of the leading causes of death in women of reproductive age in developing countries, and a major concern in some developed countries. It is puzzling why such a condition has not been reduced in frequency, if not eliminated, in the course of evolution. Maternal mortality is a complex phenomenon caused by several physiological and physical factors. Among the physical factors, maternal mortality due to fetopelvic disproportion remains controversial. Several explanations including evolution of bipedal locomotion, rapid brain growth, and nutritional changes and life style changes in settler communities have been proposed. The influences of human reproductive biology and sexual selection have rarely been considered to explain why maternal mortality persisted through human evolution. We entertain the hypothesis that irrespective of the causes, the risks of all factors causing maternal mortality would be aggravated by disassortative mating, specifically male preference for younger females who are generally small statured and at higher risk of obstetric complications. Maternal mortality arising due to sexual selection and mate choice would have the long-term effect of driving widowers toward younger women, often resulting in "child marriage," which still remains a significant cause of maternal mortality globally. Evolutionarily, such a male driven mating system in polygamous human populations would have prolonged the persistence of maternal mortality despite selection acting against it. The effects may extend beyond maternal mortality because male-mate choice driven maternal mortality would reduce average reproductive life spans of women, thus influencing the evolution of menopause.

Rotation of sex combs in Drosophila melanogaster requires precise and coordinated spatio-temporal dynamics from forces generated by epithelial cells.

The morphogenesis of sex combs (SCs), a male trait in many species of fruit flies, is an excellent system in which to study the cell biology, genetics and evolution of a trait. In Drosophila melanogaster, where the incipient SC rotates from horizontal to a vertical position, three signal comb properties have been documented: length, final angle and shape (linearity). During SC rotation, in which many cellular processes are occurring both spatially and temporally, it is difficult to distinguish which processes are crucial for which attributes of the comb. We have used a novel approach combining simulations and experiments to uncover the spatio-temporal dynamics underlying SC rotation. Our results indicate that 1) the final SC shape is primarily controlled by the inhomogeneity of initial cell size in cells close to the immature comb, 2) the final angle is primarily controlled by later cell expansion and 3) a temporal sequence of cell expansion mitigates the malformations generally associated with longer rotated SCs. Overall, our work has linked together the morphological diversity of SCs and the cellular dynamics behind such diversity, thus providing important insights on how evolution may affect SC development via the behaviours of surrounding epithelial cells.

LC-MS/MS method for the simultaneous quantification of luteolin, wedelolactone and apigenin in mice plasma using hansen solubility parameters for liquid-liquid extraction: Application to pharmacokinetics of Eclipta alba chloroform fraction.

Eclipta alba (Bhringraj) in ayurveda has been widely used as a traditional medicine for its multi-therapeutic properties for ages. Luteolin (LTL), wedelolactone (WDL) and apigenin (APG) are the three main bioactive phytochemicals present in Eclipta alba extract. However there was a lack of sensitive bioanalytical method for the pharmacokinetics of these free compounds in plasma which majorly contributes for their activities after oral administration of Eclipta alba. The present study aims to develop a sensitive, rapid and reliable liquid chromatography tandem mass spectrometry (LC-MS/MS) method for the simultaneous estimation of mice plasma concentrations of LTL, WDL and APG using quercetin as an internal standard for the pharmacokinetic analysis. Analytes were separated on Phenomenex Luna C18 (150 × 4.6 mm, 3.0 µm) column with mobile phase containing methanol: acetonitrile (90: 10, v/v) and 0.1% formic acid in 10 mM ammonium formate buffer in the ratio of 70: 30 (v/v) in isocratic mode. Liquid-liquid extraction was optimized using Hansen solubility parameters and diethyl ether finalized as an extraction solvent for the recovery ranging from 61 to 76% for all analytes in mice plasma. The validated method has an accuracy and precision over the linearity range of 0.1-200 ng/mL with a correlation coefficient (r2) of ≥0.997. The intra and inter-day assay accuracy was between 98.17 and 107% and 95.83-107.89% respectively and the intra and inter day assay precision ranged from 0.37-6.05% and 1.85-10.76%, respectively for all the analytes. This validated method can be used for future clinical investigation studies of Eclipta alba extracts.

Genomic portrait of population of Jharkhand, India, drawn with 15 autosomal STRs and 17 Y-STRs.

We analysed 15 autosomal STRs in 200 unrelated individuals (102 males and 98 females) and 17 Y-STRs in 102 unrelated males living in Jharkhand, India, to establish parameters of forensic interest. The examined autosomal STRs revealed high combined power of exclusion (CPE) and combined power of discrimination (CPD) as equal to 0.9999 and greater than 0.99999, respectively. The combined probability of match (CPm) and combined paternity index (CPI) for all 15 autosomal STR loci were found to be 5.15 × 10-18 and 6.83 × 105, respectively. A total of 97 unique haplotypes were obtained, of which 93 were observed only once. The haplotype diversity, discrimination capacity and matching probability for 17 Y-STR loci were 0.999, 0.951 and 1.09 × 10-2, respectively. The highest gene diversity values at the single copy locus DYS635 and multi-copy locus DYS385 a/b were 0.785 and 0.823, respectively.

Science beyond boundary: are premature discoveries things of the past?

Mendel's name more than of any other draws our attention to the personal side in terms of success and failure in science. Mendel lived 19 years after presenting his research findings and died without receiving any recognition for his work. Are premature discoveries things of the past, you may ask? I review the material basis of science in terms of science boundary and field accessibility and analyze the possibility of premature discoveries in different fields of science such as, for example, physics and biology. I conclude that science has reached a stage where progress is being made mostly by pushing the boundary of the known from inside than by leaping across boundaries. As more researchers become engaged in science, and as more publications become open access, on-line, and interactive, the probability of an important discovery remaining buried and going unrecognized would become exceedingly small. Of course, as examples from physics show, a new theory or an important idea can always lie low, unrecognized until it becomes re-discovered and popularized by other researchers. Thus, premature discoveries will become less likely but not forbidden.

A Theory for the Origin of Human Menopause.

A complete and compelling evolutionary explanation for the origin of human menopause is wanting. Menopause onset is defined clinically as the final menses, confirmed after 1 year without menstruation. The theory proposed herein explains at multiple levels - ultimately genetic but involving (1) behavioral, (2) life history, and (3) social changes - the origin and evolution of menopause in women. Individuals in Lower Paleolithic human populations were characterized by short lifespans with diminished late-age survival and fertility, similar to contemporary chimpanzees, and thence were subject to three changes. (1) A mating behavior change was established in which only young women reproduced, thereby rendering as effectively neutral female-specific late-onset fertility-diminishing mutations, which accumulated subsequently. (2) A lifespan increase was manifested adaptively, revealing the reproductive senescence phenotype encoded in late-onset fertility-diminishing mutation genotypes, which, heretofore, had been unexpressed in the shorter lifespan. (3) A social interaction change emerged exaptively, when older non-reproductive women exclusively started assisting in rearing grandchildren rather than giving birth to and caring for their own children, ultimately leading to menstrual cycle cessation. The changes associate in a one-to-one manner with existing, non-mutually exclusive hypotheses for the origin of human menopause. Evidence for each hypothesis and its associated change having occurred are reviewed, and the hypotheses are combined in a synthetic theory for the origin of human menopause. The new theory simultaneously addresses the main theoretical problem with each hypothesis and yields predictions for future testing.

Anti-breast tumor activity of Eclipta extract in-vitro and in-vivo: novel evidence of endoplasmic reticulum specific localization of Hsp60 during apoptosis.

Major challenges for current therapeutic strategies against breast cancer are associated with drug-induced toxicities. Considering the immense potential of bioactive phytochemicals to deliver non-toxic, efficient anti-cancer therapeutics, we performed bio-guided fractionation of Eclipta alba extract and discovered that particularly the chloroform fraction of Eclipta alba (CFEA) is selectively inducing cytotoxicity to breast cancer cells over non-tumorigenic breast epithelial cells. Our unbiased mechanistic hunt revealed that CFEA specifically activates the intrinsic apoptotic pathway by disrupting the mitochondrial membrane potential, upregulating Hsp60 and downregulating the expression of anti-apoptotic protein XIAP. By utilizing Hsp60 specific siRNA, we identified a novel pro-apoptotic role of Hsp60 and uncovered that following CFEA treatment, upregulated Hsp60 is localized in the endoplasmic reticulum (ER). To our knowledge, this is the first evidence of ER specific localization of Hsp60 during cancer cell apoptosis. Further, our LC-MS approach identified that luteolin is mainly attributed for its anti-cancer activities. Moreover, oral administration of CFEA not only offers potential anti-breast cancer effects in-vivo but also mitigates tumor induced hepato-renal toxicity. Together, our studies offer novel mechanistic insight into the CFEA mediated inhibition of breast cancer and may potentially open up new avenues for further translational research.

Female Choice or Male Sex Drive? The Advantages of Male Body Size during Mating in Drosophila Melanogaster.

The mating success of larger male Drosophila melanogaster in the laboratory and the wild has been traditionally been explained by female choice, even though the reasons are generally hard to reconcile. Female choice can explain this success by virtue of females taking less time to mate with preferred males, but so can the more aggressive or persistent courtships efforts of large males. Since mating is a negotiation between the two sexes, the behaviors of both are likely to interact and influence mating outcomes. Using a series of assays, we explored these negotiations by testing for the relative influence of male behaviors and its effect on influencing female courtship arousal threshold, which is the time taken for females to accept copulation. Our results show that large males indeed have higher copulation success compared to smaller males. Competition between two males or an increasing number of males had no influence on female sexual arousal threshold;-females therefore may have a relatively fixed 'arousal threshold' that must be reached before they are ready to mate, and larger males appear to be able to manipulate this threshold sooner. On the other hand, the females' physiological and behavioral state drastically influences mating; once females have crossed the courtship arousal threshold they take less time to mate and mate indiscriminately with large and small males. Mating quicker with larger males may be misconstrued to be due to female choice; our results suggest that the mating advantage of larger males may be more a result of heightened male activity and relatively less of female choice. Body size per se may not be a trait under selection by female choice, but size likely amplifies male activity and signal outputs in courtship, allowing them to influence female arousal threshold faster.

Maternal effect and speciation: maternal effect contributes to the evolution of hybrid inviability between Drosophila simulans and Drosophila mauritiana.

Haldane's rule has been the basis of speciation research during the last 30 years. Most studies have focused on the nature of incompatibilities in the hybrid male, but not much attention has been given to the genetic basis of fertility and inviability in hybrid females. Hybridizations between Drosophila simulans and Drosophila mauritiana produce fertile females and sterile males. Here, we re-examined the level of fertility in reciprocal F1 females of these two species and looked for the presence of maternal effects. Our results show that the reciprocal F1 females of D. simulans and D. mauritiana hybridizations are fully fertile and in fact show a significant level of heterosis in the rate of oviposition but display reduced egg hatching in one direction. Reduced egg hatching was observed in the progenies of F1 hybrid females with D. mauritiana as mother, the same cross that showed a stronger negative effect on F1 male fertility. A review of the literature on the hybridizations in Lepidoptera also showed a maternal effect on inviability when reciprocal crosses produced asymmetric results. Our findings point to the importance of maternal effects in the evolution of embryo inviability and thus enhancing the process of speciation through the evolution of hybrid inviability.

Evolutionary Consequences of Male Driven Sexual Selection and Sex-Biased Fitness Modifications in Drosophila melanogaster and Members of the simulans Clade.

Males have evolved a variety of behavioral, morphological, and physiological traits to manipulate their mates in order to maximize their chances of success. These traits are bound to influence how females respond to male behaviors and influence the nature of sexual selection/conflict. A common consequence of aggressive male mating strategies in Drosophila melanogaster is the reduction of female lifespan. Our study shows that this is common across members of the simulans clade. Reduced life expectancy of females implies that female contribution to a population is less than that of males per generation. Fitness differences between the sexes in every generation will invariably affect overall population fitness. How natural selection responds to the female deaths and thereby the unequal fitness of the sexes has rarely been addressed. We shed light on this issue and provide evidence, which suggests that additional gains of fitness by males due to their longevity and continued mating may provide one explanation as to why the loss of female fitness may be "invisible" (effectively neutral) to natural selection. Male driven sexual selection and additional, transgenerational gains of male fitness can be an important force of evolutionary change and need to be tested with other organisms.

Limits of imagination: the 150th Anniversary of Mendel's Laws, and why Mendel failed to see the importance of his discovery for Darwin's theory of evolution.

Mendel is credited for discovering Laws of Heredity, but his work has come under criticism on three grounds: for possible falsification of data to fit his expectations, for getting undue credit for the laws of heredity without having ideas of segregation and independent assortment, and for being interested in the development of hybrids rather than in the laws of heredity. I present a brief review of these criticisms and conclude that Mendel deserved to be called the father of genetics even if he may not, and most likely did not, have clear ideas of segregation and particulate determiners as we know them now. I argue that neither Mendel understood the evolutionary significance of his findings for the problem of genetic variation, nor would Darwin have understood their significance had he read Mendel's paper. I argue that the limits to imagination, in both cases, came from their mental framework being shaped by existing paradigms-blending inheritance in the case of Darwin, hybrid development in the case of Mendel. Like Einstein, Darwin's natural selection was deterministic; like Niels Bohr, Mendel's Laws were probabilistic-based on random segregation of trait-determining "factors". Unlike Einstein who understood quantum mechanics, Darwin would have been at a loss with Mendel's paper with no guide to turn to. Geniuses in their imaginations are like heat-seeking missiles locked-in with their targets of deep interests and they generally see things in one dimension only. Imagination has limits; unaided imagination is like a bird without wings--it goes nowhere.

Serum microRNA profiling to distinguish papillary thyroid cancer from benign thyroid masses.

OBJECTIVES: Papillary thyroid cancer (PTC) is increasing in incidence. Fine needle aspiration is the gold standard for diagnosis, but results can be indeterminate. Identifying tissue and serum biomarkers, like microRNA, is therefore desirable. We sought to identify miRNA that is differentially expressed in the serum of patients with PTC. METHODS: Serum miRNA was quantified in 31 female thyroidectomy patients: 13 with benign disease and 18 with PTC. qPCR results were compared for significant fold-changes in 175 miRNAs, against a pooled control. RESULTS: 128 miRNA qualified for analysis. There were identifiable fold-changes in miRNA levels between benign and control, and between PTC and control. There were statistically significant fold changes in the level of four miRNAs between benign and PTC: hsa-miR-146a-5p and hsa-miR-199b-3p were down-regulated, while hsa-let7b-5p and hsa-miR-10a-5p were up-regulated. CONCLUSIONS: MicroRNA is differentially expressed in the serum of patients with PTC. Serum miRNA has the potential to aid in thyroid cancer diagnosis.

Darwin's legacy II: why biology is not physics, or why it has taken a century to see the dependence of genes on the environment.

Genes and environment make the organism. Darwin stood firm in his denial of any direct role of environment in the modification of heredity. His theory of evolution heralded two debates: one about the importance and adequacy of natural selection as the main mechanism of evolution, and the other about the role of genes versus environment in the modification of phenotype and evolution. Here, I provide an overview of the second debate and show that the reasons for the gene versus environment battle were twofold: first, there was confusion about the role of environment in modifying the inheritance of a trait versus the evolution of that trait, and second, there was misunderstanding about the meaning of environment and its interaction with genes in the production of phenotypes. It took nearly a century to see that environment does not directly affect the inheritance of a phenotype (i.e., its heredity), but it is nevertheless the primary mover of phenotypic evolution. Effects of genes and environment are not separate but interdependent. One cannot separate the effect of genes from that of environment, or nature from nurture. To answer the question posed in the title, it is partly because the 20th century has been a century of unending progress in genetics. But also because unlike physics, biology is not colorblind; progress in biology has often been delayed beyond the Kuhnian paradigm change due to built-in interest in negating the influence of environment. Those who are against evolution, of course, cannot be expected to understand the role of environment in evolution. Those for it, many biologists included, believing in the supremacy of genes empowers them by giving adaptation a solely gene-directed (self-driven) "teleological" interpretation.