Pre-molecular Era Research Articles

The T1/T2 Ratio is Associated With Resectability in Patients With Isocitrate Dehydrogenase-Mutant Astrocytomas Central Nervous System World Health Organization Grades 2 and 3.

Isocitrate dehydrogenase (IDH)-mutant astrocytomas central nervous system World Health Organization grade 2 and 3 show heterogeneous appearance on MRI. In the premolecular era, the discrepancy between T1 hypointense and T2 hyperintense tumor volume in absolute values has been proposed as a marker for diffuse tumor growth. We set out to investigate if a ratio of T1 to T2 tumor volume (T1/T2 ratio) is associated with resectability and overall survival (OS) in patients with IDH-mutant astrocytomas. Patient data from 2 centers (Sahlgrenska University Hospital, Center A; LMU University Hospital, Center B) were collected retrospectively. Inclusion criteria were as follows: pre and postoperative MRI scans available for volumetric analysis (I), diagnosis of an IDH-mutant astrocytoma between 2003 and 2021 (II), and tumor resection at initial diagnosis (III). Tumor volumes were manually segmented. The T1/T2 ratio was calculated and correlated with extent of resection, residual T2 tumor volume, and OS. The study comprised 134 patients with 65 patients included from Center A and 69 patients from Center B. The median OS was 134 months and did not differ between the cohorts (P = .29). Overall, the median T1/T2 ratio was 0.79 (range 0.15-1.0). Tumors displaying a T1/T2 ratio of 0.33 or lower showed significantly larger residual tumor volumes postoperatively (median 17.9 cm3 vs 4.6 cm3, P = .03). The median extent of resection in these patients was 65% vs 90% (P = .03). The ratio itself did not correlate with OS. In multivariable analyses, larger postoperative tumor volumes were associated with shorter survival times (hazard ratio 1.02, 95% CI 1.01-1.03, P < .01). The T1/T2 ratio might be a good indicator for diffuse tumor growth on MRI and is associated with resectability in patients with IDH-mutant astrocytoma. This ratio might aid to identify patients in which an oncologically relevant tumor volume reduction cannot be safely achieved.

Malignant peripheral nerve sheath tumor (MPNST) and MPNST-like entities are defined by a specific DNA methylation profile in pediatric and juvenile population

BackgroundMalignant peripheral nerve sheath tumors (MPNSTs) account for 3–10% of pediatric sarcomas, 50% of which occur in neurofibromatosis type 1 (NF1). Sporadic MPNSTs diagnosis may be challenging due to the absence of specific markers, apart from immunohistochemical H3K27me3 loss. DNA methylation (DNAm) profiling is a useful tool for brain and mesenchymal neoplasms categorization, and MPNSTs exhibit a specific DNAm signature. An MPNST-like group has recently been recognized, including pediatric tumors with retained H3K27me3 mark and clinical/histological features not yet well explored. This study aims to characterize the DNAm profile of pediatric/juvenile MPNSTs/MPNST-like entities and its diagnostic/prognostic relevance.ResultsWe studied 42 tumors from two groups. Group 1 included 32 tumors histologically diagnosed as atypical neurofibroma (ANF) (N = 5) or MPNST (N = 27); group 2 comprised 10 tumors classified as MPNST-like according to Heidelberg sarcoma classifier. We performed further immunohistochemical and molecular tests to reach an integrated diagnosis. In group 1, DNAm profiling was inconclusive for ANF; while, it confirmed the original diagnosis in 12/27 MPNSTs, all occurring in NF1 patients. Five/27 MPNSTs were classified as MPNST-like: Integrated diagnosis confirmed MPNST identity for 3 cases; while, the immunophenotype supported the change to high-grade undifferentiated spindle cell sarcoma in 2 samples. The remaining 10/27 MPNSTs variably classified as schwannoma, osteosarcoma, BCOR-altered sarcoma, rhabdomyosarcoma (RMS)-MYOD1 mutant, RMS-like, and embryonal RMS or did not match with any defined entity. Molecular analysis and histologic review confirmed the diagnoses of BCOR, RMS-MYOD1 mutant, DICER1-syndrome and ERMS. Group 2 samples included 5 high-grade undifferentiated sarcomas/MPNSTs and 5 low-grade mesenchymal neoplasms. Two high-grade and 4 low-grade lesions harbored tyrosine kinase (TRK) gene fusions.By HDBSCAN clustering analysis of the whole cohort we identified two clusters mainly distinguished by H3K27me3 epigenetic signature. Exploring the copy number variation, high-grade tumors showed frequent chromosomal aberrations and CDKN2A/B loss significantly impacted on survival in the MPNSTs cohort.ConclusionDNAm profiling is a useful tool in diagnostic work-up of MPNSTs. Its application in a retrospective series collected during pre-molecular era contributed to classify morphologic mimics. The methylation group MPNST-like is a ‘hybrid’ category in pediatrics including high-grade and low-grade tumors mainly characterized by TRK alterations.

Not the Last Piece of the Puzzle: Niphargus Phylogeny in Hungary

The Palaearctic genus Niphargus is a promising model system to understand subterranean fauna genesis in Europe. The Pannonian Plain (mainly covered by Hungary) in Central Europe, once being the area of the Paratethys, is a key area for Niphargus diversification. However, our knowledge on Hungarian species of Niphargus is primarily based on sporadic taxonomical works from the pre-molecular era. Here, we studied 14 localities, covering the eight valid Hungarian species of Niphargus and including nine previously unstudied populations. Based on sequences of three gene fragments, we reconstructed their phylogeny using maximum likelihood and Bayesian approaches. We found that not all Hungarian species of Niphargus are closely related, and even species sampled at the same localities can belong to different clades. Some Hungarian species form monophyletic clades, while others are nested in various non-Hungarian lineages. The new populations are all genetically distinct from the known species. Our results suggest that the Hungarian Niphargus fauna has originated from seven unrelated clades and its diversity is underestimated due to unknown populations and cryptic species. The detection of genetically distinct species of Niphargus from non-carbonate regions calls for further research efforts. The high diversity and the number of putative new species in the N. tatrensis clade warrants further, high-resolution phylogenetic studies.

Genetic Knowledge: a Gift or a Curse?

The origins of genetic research in the molecular era are discussed along with the prospects for development of the system of the values underlying their legal regulation. Heredity and variability are included into a historically defined worldview as socially significant values respectively occupying alternate leading positions in archaic and modern societies. The article substantiates a connection between ideas about heredity and variability and the social structure, institutions and social practices of the two main types of the pre-molecular era societies. The article also discusses the significance of pre-scientific ideas concerning blood as a special substance ensuring biological, social and legal inheritance in the system of social action of the archaic society. Analysis is given to the conceptual foundations of the strategy of overcoming the ‘right of blood’ in modern societies, where the value of heredity is replaced by the value of variability to serve as a value-system basis for development and progress. Examples of coexisting worldviews and values inherent in both archaic and modern forms that still interact in present-day societies are presented and generalized. The example of the parascientific blood-type theory prevalent in today’s Japan is used to illustrate the ability of collective consciousness to integrate scientific ideas into deep underlying layers of pre-scientific thinking. The postmodern mixture of worldviews and values gives rise to ambiguity and uncertainty with regard to values in the era of discovery of the genetic mechanism of inheritance, creating additional difficulties for rule-makers (legislators) in course of forming a system for the legal regulation of genetic research. Finding a balance between prohibitions and permissions in the corpus of laws and by-laws regulating genetic knowledge development is all the more important given that the demarcation between representing and intervening in the research carried out by molecular biologists is losing its certainty (definiteness) even faster than in the physics of the microworld, let alone other subject areas of the modern science. Bioethics, which is currently providing a philosophical basis for the legal regulation of genetic research, requires theoretical elaboration and conceptualization. As one of the substantiation options, the article proposes the concept of supplementing instrumental rationality with social communication put forward by Jürgen Habermas within the framework of his theory of communicative action

Brain Gliomas and Ollier Disease: Molecular Findings as Predictive Risk Factors?

Simple SummaryAs reported in the recent Classification of the Tumors of the Central Nervous System (2021), the role of molecular markers in CNS tumor diagnosis and classification, and accordingly in the decision making of the therapeutic process, has become even more decisive. In this scenario, we performed an accurate literature review of patients with Ollier disease harboring brain gliomas, disclosing only thirty cases; our own case was also included. Most of the reported cases belong to the pre-molecular era. We found a strong relationship between an IDH mutation in the enchondroma of patients with Ollier disease and the occurrence of brain gliomas; this finding may allow an early diagnosis of brain glioma in these patients, detecting the tumor when still small and silent, thus allowing the neurosurgeon, oncologist, and radiotherapist to plan the best management. Background: Ollier disease (OD) is a rare nonhereditary type of dyschondroplasia characterized by multiple enchondromas, with typical onset in the first decade of life. Surgery is the only curative treatment for primary disease and its complications. Patients with OD are at risk of malignant transformation of enchondromas and of occurrence of other neoplasms. Methods: A wide literature review disclosed thirty cases of glioma associated with OD, most of them belonging to the pre-molecular era. Our own case was also included. Demographic, clinical, pathologic, molecular, management, and outcome data were analyzed and compared to those of sporadic gliomas. Results: Gliomas associated with OD more frequently occur at younger age, present higher rates of multicentric lesions (49%), brainstem localizations (29%), and significantly lower rates of glioblastomas (7%) histotype. The IDH1 R132H mutation was detected in 80% of gliomas of OD patients and simultaneously in enchondromas and gliomas in 100% of cases. Conclusions: The molecular data suggest a higher risk of occurrence of glioma in patients with enchondromas harboring the IDH1 R132H mutation than those with the IDH1 R132C mutation. Thus, we suggest considering the IDH1 R132H mutation in enchondromas of patients with OD as a predictive risk factor of occurrence of glioma.

Abemaciclib in metastatic or locally advanced anaplastic thyroid cancer.

TPS6112 Background: Anaplastic thyroid cancer (ATC) is a rare and lethal tumor of thyroid epithelium, with disease-specific mortality approaching 100%. ATC accounts for &gt; 50% of the 1200 annual deaths attributable to thyroid cancer. In the pre-molecular era, treatment options were largely ineffective, reflected in a median overall survival of 3-4 months following diagnosis. Outcomes have improved in BRAF V600E-mutated ATC with the FDA approval of dabrafenib and trametinib (Subbiah et al. JCO, 2018). However, a significant need exists for patients with BRAF wild-type tumors and patients with BRAF-mutated tumors who progress following treatment with BRAF-directed therapies. Abemaciclib is a CDK4/6 inhibitor currently FDA-approved in combination with endocrine therapy for hormone-positive breast cancer. Genomic analyses of ATC have indicated the presence of an intact Rb (Retinoblastoma) expression as well as the existence of CDKN2A (the gene encoding human p16) mutations in up to 32% of patients with ATC (Khan et al., Head Neck, 2019). Moreover, Lee et al. in 2008 reported undetectable p16 levels in 24 out of 27 (89%) patients with ATC. Low p16 levels would be expected to result in accelerated S phase entry, leading to uncontrolled ATC growth. Finally, studies in mouse xenograft models have demonstrated that ribociclib (a CDK4/6 inhibitor) slows proliferation and induces apoptosis of ATC cells (Lee et al., Cancer Letters, 2018). These molecular alterations and pre-clinical data provide a mechanistic rationale by which to evaluate CDK4/6 inhibitors in ATC and, to date, no CDK4/6 inhibitors have been evaluated in thyroid cancer. Methods: This multicenter, single-arm Phase 2 study will evaluate the safety and efficacy of treatment with abemaciclib in patients with histologically confirmed unresectable or metastatic ATC, using an optimal Simon two-stage design. Patients with BRAF V600E+ ATC must have progressed on or have an intolerance to dabrafenib and trametinib. The study intervention is abemaciclib 200 mg orally twice daily. The primary endpoint is overall response rate at eight weeks from the start of treatment. Secondary endpoints include progression-free survival and overall survival. Currently, 6 patients have been enrolled. Planned genomic analysis will be conducted to identify potential predictive biomarkers. Clinical trial information: NCT04552769.

WHO Grade Loses Its Prognostic Value in Molecularly Defined Diffuse Lower-Grade Gliomas.

BackgroundWhile molecular insights to diffuse lower-grade glioma (dLGG) have improved the basis for prognostication, most established clinical prognostic factors come from the pre-molecular era. For instance, WHO grade as a predictor for survival in dLGG with isocitrate dehydrogenase (IDH) mutation has recently been questioned. We studied the prognostic role of WHO grade in molecularly defined subgroups and evaluated earlier used prognostic factors in the current molecular setting.Material and MethodsA total of 253 adults with morphological dLGG, consecutively included between 2007 and 2018, were assessed. IDH mutations, codeletion of chromosomal arms 1p/19q, and cyclin-dependent kinase inhibitor 2A/B (CDKN2A/B) deletions were analyzed.ResultsThere was no survival benefit for patients with WHO grade 2 over grade 3 IDH-mut dLGG after exclusion of tumors with known CDKN2A/B homozygous deletion (n=157) (log-rank p=0.97). This was true also after stratification for oncological postoperative treatment and when astrocytomas and oligodendrogliomas were analyzed separately. In IDH-mut astrocytomas, residual tumor volume after surgery was an independent prognostic factor for survival (HR 1.02; 95% CI 1.01–1.03; p=0.003), but not in oligodendrogliomas (HR 1.02; 95% CI 1.00–1.03; p=0.15). Preoperative tumor size was an independent predictor in both astrocytomas (HR 1.03; 95% CI 1.00–1.05; p=0.02) and oligodendrogliomas (HR 1.05; 95% CI 1.01–1.09; p=0.01). Age was not a significant prognostic factor in multivariable analyses (astrocytomas p=0.64, oligodendrogliomas p=0.08).ConclusionOur findings suggest that WHO grade is not a robust prognostic factor in molecularly well-defined dLGG. Preoperative tumor size remained a prognostic factor in both IDH-mut astrocytomas and oligodendrogliomas in our cohort, whereas residual tumor volume predicted prognosis in IDH-mut astrocytomas only. The age cutoffs for determining high risk in patients with IDH-mut dLGG from the pre-molecular era are not supported by our results.

Quantification of Target Volume Changes on Radiation Planning MRI in IDH-Wildtype Glioblastoma

IDH-wildtype glioblastoma (GBM) has an exceptionally poor prognosis due to its rapid growth. Delaying post-operative radiation therapy (RT) more than 6 weeks after surgery negatively impacts prognosis. Post-operative magnetic resonance imaging (MRI) is commonly used to assess the extent of surgical resection followed by a delayed MRI for RT planning. In a heterogeneous population of high-grade gliomas treated in the pre-molecular era, significant resolution of edema and a trend towards increase in surgical cavity sizes were observed. Post-operative volumetric changes in IDH-wildtype GBM have not been described and we suspect these tumors may demonstrate higher rates of recurrence or regrowth during the latent period before the initiation of RT.30 patients with IDH-wildtype GBM treated with post-operative RT from our institution were identified. Patients with RT planning MRIs obtained between 3-6 weeks after biopsy or surgical resection were included. RT target volumes were contoured and compared between post-operative and RT planning MRIs. Volumetric changes in GTV2 (surgical cavity + residual enhancing disease) and GTV1 (edema + GTV2) were calculated. Progression-free survival (PFS) and overall survival (OS) were measured.The mean time between post-operative and RT planning MRI was 29.4 days (range: 21-42 days). When comparing post-operative and RT planning MRIs, the mean decrease in GTV1 was 25.8cc or 14.7% (P = 0.011) and the mean increase in GTV2 was 10.21cc or 39.6% (P = 0.0013). GTV1 decreased at an average rate of 0.5% per day and GTV2 increased at an average rate of 1.4% per day. The proportional growth was similar to a rate of historical controls of mixed high-grade gliomas. Median PFS and OS in our group were 5.6 and 11.2 months, respectively. A delay of more than one month between post-operative and planning MRI was associated with worse median OS of 8.0 months compared with 11.5 months (P = 0.044).To our knowledge, this is the largest volumetric study of the impact of post-operative MRIs in a uniform group of IDH-wildtype GBM. RT planning MRIs performed 3-6 weeks after biopsy or surgical resection of IDH-wildtype GBM demonstrate significant volumetric changes. Similar to previously published data on a heterogenous population of high-grade gliomas, decreases in GTV1 signify a resolution of edema, however, increases in GTV2 imply recurrence or regrowth of disease over a relatively short time. While this was not statistically significant in a previously published analysis of a heterogeneous population of high-grade gliomas, our analysis of a homogeneous population of IDH-wildtype GBM demonstrates a statistically significant increase in GTV2. Delaying planning MRI more than one month post-operatively was associated with worse OS. These findings support the need for RT planning MRIs and confirm the association between delayed treatment and worse survival. Radiomic analysis of cavity regression vs. tumor regrowth is forthcoming.J.B. Bell: None. B.J. Rich: None. I.B. Mihaylov: Research Grant; Philips Radiation Oncology Systems, NIH.C. Benjamin: None. E.A. Mellon: None. M.C. Abramowitz: None. G. Azzam: None. M. Guillermo Prieto Ei: None. M. De La Fuente: None. M. Butkus: None. T. Diwanji: None.

Historical aspects of muscle research in the Dubowitz Neuromuscular Centre: the Hammersmith days

Historical aspects of muscle research in the Dubowitz Neuromuscular Centre: the Hammersmith days

Growth failure: 'idiopathic' only after a detailed diagnostic evaluation.

The terms ‘idiopathic short stature’ (ISS) and ‘small for gestational age’ (SGA) were first used in the 1970s and 1980s. ISS described non-syndromic short children with undefined aetiology who did not have growth hormone (GH) deficiency, chromosomal defects, chronic illness, dysmorphic features or low birth weight. Despite originating in the pre-molecular era, ISS is still used as a diagnostic label today. The term ‘SGA’ was adopted by paediatric endocrinologists to describe children born with low birth weight and/or length, some of whom may experience lack of catch-up growth and present with short stature. GH treatment was approved by the FDA for short children born SGA in 2001, and by the EMA in 2003, and for the treatment of ISS in the US, but not Europe, in 2003. These approvals strengthened the terms ‘SGA’ and ‘ISS’ as clinical entities. While clinical and hormonal diagnostic techniques remain important, it is the emergence of genetic investigations that have led to numerous molecular discoveries in both ISS and SGA subjects. The primary message of this article is that the labels ISS and SGA are not definitive diagnoses. We propose that the three disciplines of clinical evaluation, hormonal investigation and genetic sequencing should have equal status in the hierarchy of short stature assessments and should complement each other to identify the true pathogenesis in poorly growing patients.

The Dimensions of Primary Mitochondrial Disorders.

The concept of a mitochondrial disorder was initially described in 1962, in a patient with altered energy metabolism. Over time, mitochondrial energy metabolism has been discovered to be influenced by a vast number of proteins with a multitude of functional roles. Amongst these, defective oxidative phosphorylation arose as the hallmark of mitochondrial disorders. In the premolecular era, the diagnosis of mitochondrial disease was dependent on biochemical criteria, with inherent limitations such as tissue availability and specificity, preanalytical and analytical artifacts, and secondary effects. With the identification of the first mitochondrial disease-causing mutations, the genetic complexity of mitochondrial disorders began to unravel. Mitochondrial dysfunctions can be caused by pathogenic variants in genes encoded by the mitochondrial DNA or the nuclear DNA, and can display heterogenous phenotypic manifestations. The application of next generation sequencing methodologies in diagnostics is proving to be pivotal in finding the molecular diagnosis and has been instrumental in the discovery of a growing list of novel mitochondrial disease genes. In the molecular era, the diagnosis of a mitochondrial disorder, suspected on clinical grounds, is increasingly based on variant detection and associated statistical support, while invasive biopsies and biochemical assays are conducted to an ever-decreasing extent. At present, there is no uniform biochemical or molecular definition for the designation of a disease as a “mitochondrial disorder”. Such designation is currently dependent on the criteria applied, which may encompass clinical, genetic, biochemical, functional, and/or mitochondrial protein localization criteria. Given this variation, numerous gene lists emerge, ranging from 270 to over 400 proposed mitochondrial disease genes. Herein we provide an overview of the mitochondrial disease associated genes and their accompanying challenges.

The frequency of thelytokous parthenogenesis in European-derived Apis mellifera virgin queens

Thelytokous parthenogenesis is the asexual production of female progeny. In the honey bee, Apis mellifera, thelytoky is unknown from mated queens, but can occur in virgin queens that have been induced to lay. We used microsatellite markers to quantify theltyoky in virgin A. mellifera queens of European origin that were sham inseminated with saline and/or narcotised with carbon dioxide. Of 20 queens, 17 (85%) produced at least one daughter thelytokously during an 8-week period. One exceptional queen produced 19% thelytokous progeny, though few total offspring (20 daughters in 107 pupae). The average proportion of thelytokous progeny among the remaining queens was 0.9% (range 0–3.5%), with the balance being males. These results are consistent with observations from the pre-molecular biology era that virgin honey bee queens of non-African subspecies regularly produce thelytokous offspring at low frequency and indicate that there is significant natural variation in the capacity for thelytoky among these queens.

Myopathology of Congenital Myopathies: Bridging the Old and the New

Congenital myopathies (CM) are a genetically heterogeneous group of neuromuscular disorders most commonly presenting with neonatal/childhood-onset hypotonia and muscle weakness, a relatively static or slowly progressive disease course, and originally classified into subcategories based on characteristic histopathologic findings in muscle biopsies. This enduring concept of disease definition and classification based on the clinicopathologic phenotype was pioneered in the premolecular era. Advances in molecular genetics have brought into focus the increased blurring of the original seemingly "watertight" categories through broadening of the clinical phenotypes in existing genes, and continuous identification of novel genetic backgrounds. This review summarizes the histopathologic landscape of the 4 "classical" subtypes of CM-nemaline myopathies, core myopathies, centronuclear myopathies, and congenital fiber type disproportion and some of the emerging and novel genetic diseases with a CM presentation.

Flies and Yaws: Molecular Studies Provide New Insight

Flies and Yaws: Molecular Studies Provide New Insight

New frontiers for an ancient disease: genetics of atrial fibrillation

Atrial fibrillation (AF) is the commonest sustained arrhythmia in clinical practice, but its treatment is still a challenge for modern cardiology. During the last decade new insights regarding AF genetic background have been achieved. Familial aggregation suggesting a potential heritability was well known in the pre-molecular era. Now, research on the molecular basis of the disease is providing evidence that familial AF is mostly autosomal, both dominant and recessive, and genetically heterogeneous. Mutations in several disease genes with different functional effects may be associated with AF. Early results encourage family studies and monitoring. In addition, genome-wide association studies have recently identified common polymorphisms associated with an increased risk of AF in different large populations. These studies are contributing to provide early answers, but also raise new questions. In this review we analyze existing knowledge on genetics of AF and related potential clinical impact.

Follow your lead

Probe molecules with systemic activity remain rare, and, as was realized in the pre-molecular era, even their off-target activity can illuminate biology. A study reporting a screen of over 600 kinase inhibitors found nine with bromodomain inhibitory activity and has implications for mechanism and compound optimization.

Systems oncology: A new paradigm in cancer research.

Systems oncology: A new paradigm in cancer research.

A Century of Cell Adhesion: From the Blastomere to the Clinic Part 1: Conceptual and Experimental Foundations and the Pre-Molecular Era

The historical roots of cell adhesion research stretch back over a hundred years, commencing with fundamental questions from the advent of experimental embryology in the late nineteenth century. The transition of embryology from a descriptive to an experimentally driven and mechanistic branch of the biological sciences included investigations focused on the interactions of the first cells of the newly developing embryo, the blastomeres, and followed the movement, interactions and fate of these cells as the tissues and organs of the growing embryo took form. Of special interest to early investigators were cell-cell contacts, which were obviously dynamic but of an obscure nature. This historical review, the first of a series, explores the early years of the cell adhesion field, including the work of Roux, Wilson, Galtsoff, Just and Holtfreter, and discusses the classical experiments, observations and conceptual developments that formed the cornerstone of cell adhesion research during its premolecular era.

Origins, evolution, and phenotypic impact of new genes

Ever since the pre-molecular era, the birth of new genes with novel functions has been considered to be a major contributor to adaptive evolutionary innovation. Here, I review the origin and evolution of new genes and their functions in eukaryotes, an area of research that has made rapid progress in the past decade thanks to the genomics revolution. Indeed, recent work has provided initial whole-genome views of the different types of new genes for a large number of different organisms. The array of mechanisms underlying the origin of new genes is compelling, extending way beyond the traditionally well-studied source of gene duplication. Thus, it was shown that novel genes also regularly arose from messenger RNAs of ancestral genes, protein-coding genes metamorphosed into new RNA genes, genomic parasites were co-opted as new genes, and that both protein and RNA genes were composed from scratch (i.e., from previously nonfunctional sequences). These mechanisms then also contributed to the formation of numerous novel chimeric gene structures. Detailed functional investigations uncovered different evolutionary pathways that led to the emergence of novel functions from these newly minted sequences and, with respect to animals, attributed a potentially important role to one specific tissue--the testis--in the process of gene birth. Remarkably, these studies also demonstrated that novel genes of the various types significantly impacted the evolution of cellular, physiological, morphological, behavioral, and reproductive phenotypic traits. Consequently, it is now firmly established that new genes have indeed been major contributors to the origin of adaptive evolutionary novelties.

Historical perspective on mitochondrial medicine

In this review, we trace the origins and follow the development of mitochondrial medicine from the premolecular era (1962-1988) based on clinical clues, muscle morphology, and biochemistry into the molecular era that started in 1988 and is still advancing at a brisk pace. We have tried to stress conceptual advances, such as endosymbiosis, uniparental inheritance, intergenomic signaling and its defects, and mitochondrial dynamics. We hope that this historical review also provides an update on mitochondrial medicine, although we fully realize that the speed of progress in this area makes any such endeavor akin to writing on water.