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PubMed1979

An ethological view of human adolescence.

In modern times the essential "normality" of adolescence has been acknowledged. With its pan-cultural and functional perspective, ethology is in a position to elaborate a description of normal human adolescence. Ethologists attempt to elucidate four interrelated aspects of a given behavior: its survival function, evolution, development, and elicitation by internal and external factors. The basic research strategy is two-fold: to identify biologically based, or evolved, behaviors (chiefly by controlling for the effects of experience and seeing if a core of evolved behavior remains); and to discover their functions by isolating the necessary and sufficient ecological conditions for their evolution. Applying this evolutionary analysis to human adolescence, we find that two developments seem to be basic: reproductive maturation and gaining independence from parents. The remainder of the article is an interpretation of various behavioral, morphological, and cultural data in accordance with these two developmental functions. Puberty seems to be timed so as to promote these functions most effectively. Pubertal changes parallel somatic growth and are delayed by poor nutrition, disease, and psychological stress--patterns consistent with functional considerations. The influence of natural selection on the sequencing of pubertal events is also emphasized. The role of pubertal hormones in altering behavior as well as morphology is illustrated. The adolescent gains independence from his parents by means of maturation and sex differentiation. Males become specialized for vigorous exertion, and females for work near the settlement--although considerable overlap in morphological and behavioral tendencies exists between the sexes. Various examples of sex differentiation demonstrates how morphological, behavioral, and cultural factors complement each other. Adolescent initiation rites help channel boys and girls into appropriate adult roles, teach respect for one's culture, and favor the fittest individuals. Hopi rites of passage are described as an example. Reproductive maturation likewise involves adaptive morphological and behavioral changes that are reinforced by cultural mores. Males rely on intimidation more than females, in order to dominate other males and attract females; contrariwise, females employ an endearment strategy more than males do. Many sex differences in human reproductive behavior can be explained with reference to man's parental behavior pattern. These include the male's greater aggressiveness, the preponderance of polygyny over polyandry, and differences in the antecedents of jealousy. Lastly, the need for an ethological understanding of adolescence is underscored as promising to offer a useful perspective on the problems of U.S. youth.

Adolescent↗
PubMedDate not supplied

[The significance of digestive troubles of children in a psychosomatic perspective (author's transl)].

The description of digestive pathology in the child, seen through the psychosomatic angle, shows how this appears to be different from that in the adult. Aside from the rare cases in the scholar period, then later in the adolescent period, this pathology does not shed any light on the morbid entity clearly defined insofar as etiopathology. However, there are a series of alimentary and digestive symptoms. The value of these symptoms must always be understood through double optics of affective characteristics relative to the child of a given age and the characteristics of the personality of the parents, particularly the mother in the case of a very young child. The notion of a somatic basis favoring the trouble in the child appears indissociable from the psychosomatic concept. It is probably this fundamental factor which is of determining value and almost exclusively in the early onset of an ulcer in the child less than two years of age. The gastroenterologist should pay special attention to the affective development of the child; he can hardly predict the evolution towards a psychosomatic pathology insofar as the physiology as well as psychology are labile and plastic and that their alterations are a function of the different variables proper to the child and related to the conditions of the entourage which direct impact and interference are difficult to predict.

Adolescent↗
PubMed2004

Using bradykinin-potentiating peptide structures to develop new antihypertensive drugs.

Angiotensin I-converting enzyme (ACE) is a dipeptidyl-carboxypeptidase expressed in endothelial, epithelial and neuroepithelial cells. It is composed of two domains, known as N- and C-domains, and it is primarily involved in blood pressure regulation. Although the physiological functions of ACE are not limited to its cardiovascular role, it has been an attractive target for drug design due to its critical role in cardiovascular and renal disease. We examined natural structures based on bradykinin-potentiating peptides (BPPs) extracted from Bothrops jararaca venom for ACE inhibition. Modeling, docking and molecular dynamics were used to study the conserved residues in the S2', S1' and S1 positions that allow enzyme-substrate/inhibitor contacts. These positions are conserved in other oligopeptidases, and they form tight and non-specific contacts with lisinopril, enalapril and BPP9a inhibitors. The only specific inhibitor for human somatic ACE (sACE) was BPP9a, which is instable in the N-sACE-BPP9a complex due to repulsive electrostatic interactions between Arg P4-Arg 412 residues. Specificity for the C-terminal domain in human sACE inhibition was confirmed by electrostatic interaction with the Asp 1008 residue. Peptide-like BPP structures, naturally developed by snakes across millions of years of evolution, appear to be good candidates for the development of domain-selective ACE inhibitors with high stability and improved pharmacological profiles.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed2000

Sex, kings and serial killers and other group-selected human traits.

(Note: This unorthodox paper contains the first argument for heart disease being a programmed age change and promoted by the dramatic, post age-40 increases in the hormones FSH and hCG seen in some individuals.) A recent issue of Science suggests that the evolutionary purpose of sex is unknown. PARADOX: Surviving to adulthood implies a valuable gene combination which is destroyed by sexual recombination. This should be detrimental to offspring. PROPOSED: Sex is group-selected in prey to allow coalescence of beneficial, and disposal of detrimental, mutations in single individuals enabling rapid adaptation to novel predation. Group selection is a universal force driven by local inter-species (not intra-species) competition. Aging, metabolism, litter size, and fixed body size are directly linked. Sexual recombination and chromosomes destroy gene linkage and exist because mutations are usually detrimental, rarely positive, and occur in linked groups. In unevolving environments, sex is selected against and asexuality emerges. Periodic evolution of novel predators, like man, can explain the 'punctuated equilibria' fossil record. Genes inhibited by methylation or chromatin condensation, expressed at older ages in predation-minimized environments, allow for group selection. Stress increases mutation rates and beneficial mutation likelihood. Females select bigger, brighter, louder, or stronger males that can survive predator attention. Size approximates age and thus predator encounters; male traits represent predation-survival potential. Human male traits include, balding, acne, beard-length, wrinkling, graying, nose/ear growth. Progeria accelerates development of most male traits. Domination of groups by single males allows rapid predation-defense evolution: adolescent males are expelled, brave the wild, and expel another group's male to mate. If expelled and dominant males are culled by predation, males reaching puberty first will reproduce. Hormonal acceleration of puberty accelerates aging/population turnover, induces smaller bodies, larger litters. With a fixed group biomass, more, smaller, stressed individuals with faster aging/turnover, increase beneficial mutation likelihood. 'Kin selection', where dominant families are supported by celibate relatives, allow the best group genes to survive famine. Dominant families gorge while others starve. Equal food sharing results in group extinction leading to group-evolved human traits of social hierarchy, greed, king/queen/God worship. Menstrual hormone cycling parallels aging. FSH and DHT promote ovarian, hair, acne, dental, and arterial follicle development causing ovulation, hair growth, pimples, dental caries, and atherosclerotic soft plaques. Soft plaques contain macrophages and LDL plug; upper plaque layers thin and rupture, releasing LDL plug, causing thrombosis. FSH withdrawal or LH/hCG increases trigger ovulation and thrombosis. Artery narrowing atherosclerotic hard plaques are stress-induced through cortisol-promoted necrotic calcification. LH/hCG-induced apoptosis promotes ovulation and aging-related somatic atrophy. Long-term estradiol stimulates, while progesterone suppresses, gonadotropin levels. Estradiol protects by inhibiting gonadotropin bioactivity and has extracellular antioxidant, but intranuclear free radical, effects. Female X-linked gene mosaicism conserves evolved aging systems. Maternal age factors for chromosomal trisomy suggest menopause prevents human parthenogenesis. Homosexuality and serial killing inhibit genetic contribution by individuals evolutionarily perceived as stressed. Smoking during pregnancy may induce homosexual offspring. Nitric oxide, a free radical, stimulates cGMP, but not cAMP. cGMP likely first evolved as an antioxidant defense to free radicals. Human aging syndromes might reflect human evolution progression. AS#4 affects tissues evolved from plant ancestors, AS#5a - from predators, AS#5b-immune system, and AS#6-sex tissues. (ABSTRACT TRUNCA

Aging↗
PubMed1994

Mechanism of action and persistence of neuroprotection by cell-permeant Ca2+ chelators.

Cell-permeant Ca2+ chelators such as 1,2-bis-(2-aminophenoxy)ethane- N,N,N',N'-tetraacetic acid acetoxymethyl ester (BAPTA-AM) have been reported to protect neurons in experimental focal cerebral ischemia. However, their in vivo actions are uncertain, and their protective efficacy is proven only in brief cerebral ischemia paradigms. Here we examine their mechanism of action in vitro and duration of efficacy in vivo. Electrophysiological studies were made in CA1 neurons in rat hippocampal slices. When superfused with BAPTA-AM (30-50 microM), CA1 somatic field potential recordings showed attenuation of the population spike amplitude, and intracellular recordings showed reduced excitatory postsynaptic potentials, indicating inhibition of excitatory synaptic transmission. Also, Ca(2+)-dependent accommodation and post-spike-train hyperpolarizations were reduced, indicating Ca2+ chelation hear the internal cell membrane surface. To determine whether Ca2+ chelators reduce the size of cerebral infarction rather than simply delaying its evolution, we studied the effects of BAPTA-AM treatment on infarction size 24 h after permanent middle cerebral artery occlusion. Fischer rats (n = 8 per group) were pretreated with saline, BAPTA-AM (20 mg/kg), or MK-801 (0.5 mg/kg). Infarction volumes in animals treated with BAPTA-AM were reduced by 50.5% compared with controls (p = 0.018), whereas animals treated with MK-801 experienced a statistically insignificant infarct volume reduction (26%; p = 0.27). These data show a persistence of neuroprotection by the Ca2+ chelator at 24 h and indicate that it may act by attenuating synaptic transmission and subplasma membrane Ca2+ excess.

Animals↗
PubMed2002

A hormone-based characterization and taxonomy of stress: possible usefulness in management.

"Stress" is being increasingly implicated in the pathogenesis of a variety of psychological and somatic disturbances. Because responses to stress can vary widely, the absence of a suitable, pathophysiologically based taxonomy of stress responses has hindered physicians in their efforts to devise treatments tailored to deal with specific stress-related problems. It is proposed herein that classical endocrinologic criteria be employed to characterize stress responses in terms of the associated hormonal secretion ratios and their temporal evolution. Ratios of the responses to stressors of the sympathoadrenal system (SA) and the hypothalamo-pituitary-adrenal (HPA) axis can be either unity (ratio = 1) or dissociated in varying degree, with SA or HPA dominance and for more or less prolonged periods. Published reports of studies in both laboratory animals and patients with stress-associated illnesses (eg, post-traumatic stress disorder [PTSD]) suggest that such hormone-secretion ratios together with their temporal patterns can be used to characterize the particular stress response under examination, thereby providing strong support for further study of the proposed taxonomy. Such a classification of responses to stress stimuli will make it possible to test the overall concept by establishing a correspondence between the suggested hormonal profile and the associated clinical/psychological picture, as well as enable assessment of the benefit of a therapeutic strategy designed to fit the particular category of stress response exhibited by the patient.

Hormones↗
PubMed2004

Conditional use of sex and parthenogenesis for worker and queen production in ants.

The near-ubiquity of sexual reproduction in animal species has long been considered a paradox because sexually reproducing individuals transmit only half of their genome to their progeny. Here, we show that the ant Cataglyphis cursor circumvents this cost by using alternative modes of reproduction for the production of reproductive and nonreproductive offspring. New queens are almost exclusively produced by parthenogenesis, whereas workers are produced by normal sexual reproduction. By selectively using sex for somatic growth and parthenogenesis for germline production, C. cursor has taken advantage of the ant caste system to benefit from the advantages of both sexual and asexual reproduction.

Alleles↗
PubMed2002

Allelic variation of a Beauveria bassiana (Ascomycota: Hypocreales) minisatellite is independent of host range and geographic origin.

The minisatellite locus, BbMin1, was isolated from a partial Beauveria bassiana genomic library that consisted of poly(GA) flanked inserts. Polymerase chain reaction (PCR) of the BbMin1 repeat demonstrated allele size variation among 95 B. bassiana isolates. Amplification was also observed from single isolates of Beauveria amorpha, Beauveria brongniartii, and Beauveria caledonica. Eight alleles were identified at the haploid locus, where repeat number fluctuated between one and fourteen. AMOVA and theta (Fst) indicated that fixation of repeat number has not occurred within pathogenic ecotypes or geographically isolated samples of B. bassiana. Selective neutrality of allele size, the rate of BbMin1 mutation, and the age of the species may contribute to host and geographic independence of the marker. Presence of alleles with a large number of repeat units may be attributed to the rare occurrence of somatic recombination or DNA replication error. The molecular genetic marker was useful for the identification of genetic types of B. bassiana and related species.

Analysis of Variance↗
PubMed1985

Nucleotide sequence preservation of human mitochondrial DNA.

Recombinant DNA techniques have been used to quantitate the amount of nucleotide sequence divergence in the mitochondrial DNA population of individual normal humans. Mitochondrial DNA was isolated from the peripheral blood lymphocytes of five normal humans and cloned in M13 mp11; 49 kilobases of nucleotide sequence information was obtained from 248 independently isolated clones from the five normal donors. Both between- and within-individual differences were identified. Between-individual differences were identified in approximately 1/200 nucleotides. In contrast, only one within-individual difference was identified in 49 kilobases of nucleotide sequence information. This high degree of mitochondrial nucleotide sequence homogeneity in human somatic cells is in marked contrast to the rapid evolutionary divergence of human mitochondrial DNA and suggests the existence of mechanisms for the concerted preservation of mammalian mitochondrial DNA sequences in single organisms.

Adult↗
PubMed2000

Physiological non-equivalence of the two isoforms of angiotensin-converting enzyme.

The structurally related somatic and germinal isoforms of angiotensin-converting enzyme (ACE) contain the same catalytic active center and are encoded by the same gene, whose disruption causes renal atrophy, hypotension, and male sterility. The reason for the evolutionary conservation of both isozymes is an enigma, because, in vitro, they have very similar enzymatic properties. Despite the common enzymatic properties, discrete expression of both isoforms is maintained in alternate cell types. We have previously shown that sperm-specific expression of transgenic germinal ACE in Ace -/- male mice restores fertility without curing their other abnormalities (Ramaraj, P., Kessler, S. P., Colmenares, C. & Sen, G. C. (1998) J. Clin. Invest. 102, 371-378). In this report we tested the biological equivalence of somatic ACE and germinal ACE utilizing an in vivo isozymic substitution approach. Here we report that restoration of male fertility was not achieved by the transgenic expression of enzymatically active, somatic ACE in the sperm of Ace -/- mice. Therefore, the requisite physiological functions of the two tissue-specific isozymes of ACE are not interchangeable.

Animals↗
PubMed1978

Environmental carcinogenesis: an integrative model.

An integrative theory is proposed in which environmental carcinogenesis is viewed as a process by which the genetic control of cell division and differentiation is altered by carcinogens. In this theory, carcinogens include physical, chemical, and viral "mutagens," as well as chemical and viral gene modulators. Existing explanations of carcinogenesis can be considered either as somatic mutation theories or as epigenetic theories. Evidence seems to support the hypothesis that both mutations and epigenetic processes are components of carcinogenesis. The mutational basis of cancer is supported by the clonal nature of tumors, the mutagenicity of most carcinogens, high mutation frequencies in cells of cancer-prone human fibroblasts lacking DNA repair enzymes, the correlation of in vitro DNA damage and in vitro mutation and transformation frequencies with in vivo tumorigenesis, age-related incidences of various hereditary tumors, and the correlation between photoreactivation of DNA damage and the biological amelioration of UV-induced neoplasms. Since both mutagens and gene modulators can be carcinogenic it may be that carcinogens affect genes which control cell division. An integration of the mutation and epigenetic theories of cancer with the "two-stage" theory and Comings's general theory of carcinogenesis is proposed. This integrative theory postulates that carcinogens can affect regulatory genes which control a series of "transforming genes." A general hypothesis is advanced that involves a common mechanism of somatic mutagenesis via error-prone repair of DNA damage which links carcinogenesis, teratogenesis, atherosclerosis and aging. Various concepts are presented to provide a framework for evaluating the scientific, medical, and social implications of cancer.

Aging↗
PubMed1990

The evolution of heteromorphic sex chromosomes.

The facts and ideas which have been discussed lead to the following synthesis and model. 1. Heteromorphic sex chromosomes evolved from a pair of homomorphic chromosomes which had an allelic difference at the sex-determining locus. 2. The first step in the evolution of sex-chromosome heteromorphism involved either a conformational or a structural difference between the homologues. A structural difference could have arisen through a rearrangement such as an inversion or a translocation. A conformational difference could have occurred if the sex-determining locus was located in a chromosomal domain which behaved as a single control unit and involved a substantial segment of the chromosome. It is assumed that any conformational difference present in somatic cells would have been maintained in meiotic prophase. 3. Lack of conformational or structural homology between the sex chromosomes led to meiotic pairing failure. Since pairing failure reduced fertility, mechanisms preventing it had a selective advantage. Meiotic inactivation (heterochromatinization) of the differential region of the X chromosome in species with heterogametic males and euchromatinization of the W in species with heterogametic females are such mechanisms, and through them the pairing problems are avoided. 4. Structural and conformational differences between the sex chromosomes in the heterogametic sex reduced recombination. In heterogametic males recombination was reduced still further by the heterochromatinization of the X chromosome, which evolved in response to selection against meiotic pairing failure. 5. Suppression of recombination resulted in an increase in the mutation rate and an increased rate of fixation of deleterious mutations in the recombination-free chromosome regions. Functional degeneration of the genetically isolated regions of the Y and W was the result. In XY males this often led to further meiotic inactivation of the differential region of the X chromosome, and in this way an evolutionary positive-feedback loop may have been established. 6. Structural degeneration (loss of material) followed functional degeneration of Y or W chromosomes either because the functionally degenerate genes had deleterious effects which made their loss a selective advantage, or because shorter chromosomes were selectively neutral and became fixed by chance. 7. The evolutionary routes to sex-chromosome heteromorphism in groups with female heterogamety are more limited than in those with male heterogamety. Oocytes are usually large and long-lived, and are likely to need the products of X- or Z-linked genes. Meiotic inactivation of these chromosomes is therefore unlikely. In the oocytes of ZW females, meiotic pairing failure is avoided through euchromatinization of the W rather than heterochromatinization of the Z chromosome.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1987

Specific chromosome aberration in human renal cell carcinoma.

Using G-banding technique, the chromosomes were studied in short-term cultures of 25 primary renal-cell carcinomas (RCC). Phytohaemagglutinin-stimulated peripheral blood lymphocytes or normal kidney cells of the same patients growing in primary cultures were analysed to define the constitutional karyotype. The modal chromosome number of 23 RCC's was found to be pseudo-diploid or near-diploid with only few structural rearrangements, 22 of the RCC's showed an aberration of chromosome 3, deletion of 3p, or translocation of different chromosome segments to the deleted chromosome 3, leading to the loss of variable segments of chromosome 3. The break-points in rearrangements of chromosome 3 clustered in the region 3p11.2-p13. Shortest-region overlap analysis localized a consistent change to a small area of 3p13-pter. In 8 of the 25 RCCs, the rearrangement of chromosome 3 was the only karyotype change determined, and 4 other tumours had only one chromosomal rearrangement in addition to the aberration of chromosome 3. These results suggest that the aberration of chromosome 3 is the first cytogenetic event in the clonal evolution of RCCs. Translocation 3;5 was preferentially involved in the rearrangements between chromosome 3p and other chromosomes. The breakpoint on chromosome 3 was constant at p13, but the breaks on chromosome 5 varied between bands q11.2 and q22. Monosomy 14 was observed in 10 cases and loss of Y chromosome was detected in 6 of 14 tumours obtained from male patients. Since the normal somatic cells were free of chromosomal aberrations, one may conclude that the loss of 3p13-pter segment is an acquired, consistent chromosomal aberration which marks human RCCs.

Adult↗
PubMed2006

AID in somatic hypermutation and class switch recombination.

Somatic hypermutation and class-switch-recombination are initiated by the deamination of deoxycytosine in DNA by activation-induced-deaminase, AID. Recently, there has been much research into how AID targets double-stranded DNA in sub-regions of Ig genes, the involvement of co-factors and posttranslational modifications in this process, the co-option of DNA 'repair' mechanisms and AID evolution.

Animals↗
PubMed2026

Immune dysregulatory disorders: perspective from solving a diagnostic odyssey.

PURPOSE OF REVIEW: Inborn errors of immunity (IEIs), once considered rare disorders characterized primarily by recurrent infections, are now recognized as a rapidly expanding group of diseases encompassing autoimmunity, autoinflammation, allergy, malignancy, and immune dysregulation. Advances in next-generation sequencing, functional immunology, and systems biology have revealed overlap between traditionally distinct disease categories and highlighted the complexity of genotype-phenotype relationships. RECENT FINDINGS: While this evolution has led to the discovery of hundreds of previously unrecognized disorders, it has also challenged conventional diagnostic paradigms and demonstrated how patients may have care spread across multiple specialties, without a clear medical home. These discoveries have also highlighted ongoing challenges translating scientific findings to the clinic including difficulties in accessing genomic testing, interpretation of variants of uncertain significance, impacts of incomplete penetrance and somatic mosaicism, and limited availability of specialized functional assays. Emerging computational approaches, including artificial intelligence, offer opportunities to accelerate diagnosis but cannot replace comprehensive clinical evaluation or longitudinal physician-patient relationships. SUMMARY: This perspective examines how the diagnostic odyssey for immune dysregulatory disorders has evolved, side-by-side with the changing framework for diagnosing rare immune diseases. We propose an integrated approach combining clinical phenotyping, genomics, functional validation, and multidisciplinary expertise to unite ongoing discovery between clinicians and scientists, diagnostics, and patient outcomes.

diagnostic odyssey↗
PubMedDate not supplied

[Various biosociological aspects of women during childhood].

Several biosociocultural characteristics that define the woman's form of evolution during her first stages of growth and uterine development are analyzed. In order to outstand these features, a comparison is established between the events that take place in the woman and those that occur in men. For instance, the apparent immunologic deviation in the female sex and the greater incidence of certain congenital anomalies and metabolic diseases in man. On the other hand, the somatic differences are stressed, apparently as a result of metabolic peculiarities of one or the other sex, together with the unique behavior of women from a very early age in life. Finally, the behavior of the Mexican before the birth of a female is outlined in this statement, the series of sociocultural restrictions confronting women from the initial stages of her growth and development are pointed out.

Child Development↗
PubMed1994

Quantitative study of tyrosine hydroxylase protein levels within the somatic area of the rat locus coeruleus during postnatal development.

To date only global dosages of tyrosine hydroxylase (TH) protein have been realized in the locus coeruleus (LC) without discriminating the enzyme contained in the cell body area from the one in the surrounding neuropil. The preceding immunohistochemical study (Bezin et al., 1994) revealed a dramatic plasticity of the cellular expression of TH in the LC during the postnatal development of the rat. It was therefore necessary to develop a quantitative biochemical approach, strengthened by a great anatomical resolution, to follow the developmental evolution of TH levels exactly in the space containing the coerulean TH-immunoreactive perikarya. In the present work two biochemical parameters necessary for precisely defining the phenotypic characterization of TH expression within the rat LC have been established during the postnatal development at six different stages: postnatal day 4 (PND4), PND10, PND14, PND21, PND30, and PND42. TH tissue concentration and content were precisely determined along the caudorostral extent of the LC within the previously (Bezin et al., 1994) defined spaces delimited by the TH-containing perikarya. TH tissue concentration remained quite stable during the postnatal development. TH quantity exhibited few age-related variations with a transient peak at PND10 and followed the same evolution as the volume containing the TH-expressing perikarya. The mean cell contribution to the total quantity of TH measured in the whole LC showed important age-related fluctuations with a dramatic peak at PND10 followed by a drastic decrease until PND21.(ABSTRACT TRUNCATED AT 250 WORDS)

Aging↗
PubMed1994

Historical origins of current concepts of carcinogenesis.

The first attempts to understand the causes of cancer were based on generalizations of what might now be termed a "holistic" nature, and hereditary influences were recognized at an early stage; these views survive principally through a supposed positive connection between psychological factors such as stress and diminished ability to combat the progressive development of tumors through some form of immunologically mediated rejection of potentially cancerous cells. While evidence for immunosurveillance is generally accepted, it is now widely regarded as almost wholly confined to instances where tumor viruses are involved as causative agents. The earliest theorists drew an analogy between the processes of carcinogenesis and of evolution; the cancer cells acquired the ability to outstrip their normal counterparts in their capacity for proliferation. This was even before evolution had been interpreted as involving a continuous succession of mutations. Evidence was already to hand before the end of the 18th century that exogenous agents, notably soot, a product of the "industrial revolution," could cause skin cancer. Somewhat over 100 years later, another industrial innovation, the manufacture of synthetic dyestuffs, implicated specific chemical compounds that could act systemically to cause bladder cancer. Meanwhile, the 19th century saw the establishment of the fundamentals of modern medical science; of particular relevance to cancer was the demonstration that it involved abnormalities in the process of cell division. The commencement of the 20th century was marked by a rediscovery of the concept of mutation; and it was proposed that cancer originated through uncontrolled division of somatically mutated cells. At around this time, two further important exogenous causative agents were discovered: X-rays and tumor viruses. In the late 1920s, x-radiation became the first established exogenous cause of mutagenesis. The discoverer of this phenomenon, H. J. Muller, suggested that while mutation in a single cell was the primary causative mechanism in carcinogenesis, its generally observed logarithmic increase in incidence with age reflected a "multihit" process, and that multiple successive mutations were required in the progeny of the original mutants. He also recognized that the rate of proliferation of potentially cancerous cells would markedly influence the probability of their subsequent mutation. These considerations are essentially the foundation of the generally accepted view of carcinogenesis that now seems unlikely to be superseded. However, this acceptance did not come about unopposed. The analogy between carcinogenesis and evolution was disliked by many biologists because it embodied the concept that cancer was an inevitable consequence of our evolutionary origins.(ABSTRACT TRUNCATED AT 400 WORDS)

Alkylation↗