Biological Foundations Research Articles

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Obesity-Associated Heart Failure as a Theoretical Target for Treatment With Mineralocorticoid Receptor Antagonists

ImportanceDespite their clinical benefits, mineralocorticoid receptor antagonists are greatly underprescribed by most practitioners who treat patients with chronic heart failure. A novel approach to encouraging the use of these drugs is to enhance awareness about the intimate link between aldosterone and obesity.ObservationsThere is a strong association between abdominal obesity and circulating levels of aldosterone, and markers of abdominal obesity identify patients most likely to benefit from mineralocorticoid receptor antagonism. In a trial of patients with heart failure and a reduced ejection fraction, patients with an increased waist circumference exhibited an approximately 50% reduction in the risk of a primary end point. The magnitude of benefit was more than twice as great in patients with abdominal obesity than in those with a normal waist circumference, and patients with abdominal obesity tolerated treatment better than nonobese patients. Similarly, in a trial of patients with heart failure and a preserved ejection fraction, those who were most likely to have abdominal obesity (identified by their level of natriuretic peptides) were most likely to demonstrate a benefit of treatment with spironolactone, exhibiting an approximately 80% reduction in the risk of a primary end point (based on a small number of events).Conclusions and RelevanceAlthough these analyses are post hoc, their concordance and strong biological foundation suggests that abdominal obesity may identify patients who respond most favorably to mineralocorticoid receptor antagonism. Given the easy availability of its measurement, targeting patients with an increased waist circumference could enhance the adoption of these important drugs for the treatment of chronic heart failure in clinical practice.

Serine/Threonine Ligation: Origin, Mechanistic Aspects, and Applications.

Synthetic proteins are expected to go beyond the boundary of recombinant DNA expression systems by being flexibly installed with site-specific natural or unnatural modification structures during synthesis. To enable protein chemical synthesis, peptide ligations provide effective strategies to assemble short peptide fragments obtained from solid-phase peptide synthesis (SPPS) into long peptides and proteins. In this regard, chemoselective peptide ligation represents a simple but powerful transformation realizing selective amide formation between the C-terminus and N-terminus of two side-chain-unprotected peptide fragments. These reactions are highly chemo- and regioselective to tolerate the side-chain functionalities present on the unprotected peptides, highly reactive to work with millmolar or submillimolar concentrations of the substrates, and operationally simple with mild conditions and accessible building blocks. This Account focuses on our work in the development of serine/threonine ligation (STL), which originates from a chemoselective reaction between an unprotected peptide with a C-terminal salicylaldehyde (SAL) ester and another unprotected peptide with an N-terminal serine or threonine residue. Mechanistically, STL involves imine capture, 5- endo-trig ring-chain tautomerization, O-to- N [1,5] acyl transfer to afford the N, O-benzylidene acetal-linked peptide, and acidolysis to regenerate the Xaa-Ser/Thr linkage (where Xaa is the amino acid) at the ligation site. The high abundance of serine and threonine residues (12.7%) in naturally occurring proteins and the good compatibility of STL with various C-terminal residues provide multiple choices for ligation sites. The requisite peptide C-terminal SAL esters can be prepared from the peptide fragments obtained from both Fmoc-SPPS and Boc-SPPS through four available methods (a safety-catch strategy based on phenolysis, direct coupling, ozonolysis, and the n + 1 strategy). In the synthesis of proteins (e.g., ACYP enzyme, MUC1 glycopeptide 40-mer to 80-mer, interleukin 25, and HMGA1a with variable post-translational modification patterns), both C-to- N and N-to- C sequential STL strategies have been developed through selection of temporal N-terminal protecting groups and proper design of the switch-on/off C-terminal SAL ester surrogate, respectively. In the synthesis of cyclic peptide natural products (e.g., daptomycin, teixobactin, cyclomontanin B, yunnanin C) and their analogues, intramolecular head-to-tail STL has been implemented on linear peptide SAL ester precursors containing four to 10 amino acid residues with good efficiency and minimized oligomerization. As a thiol-independent chemoselective ligation complementary to native chemical ligation, STL provides an alternative tool for the chemical synthesis of homogeneous proteins with site-specific and structure-defined modifications and cyclic peptide natural products, which lays foundation for chemical biology and medicinal studies of those molecules with biological importance and therapeutic potential.

ENABLE 2017, the First European PhD and Post-Doc Symposium. Session 1: Building the Foundations of Biology: Synthetic and Cellular Research.

The European Academy for Biomedical Science (ENABLE) is an initiative funded by the European Union Horizon 2020 program involving four renowned European Research Institutes (Institute for Research in Biomedicine—IRB Barcelona, Spain; Radboud Institute for Molecular Life Sciences—RIMLS, the Netherlands; Novo Nordisk Foundation Center for Protein Research—NNF CPR, Denmark; European School of Molecular Medicine—SEMM, Italy) and an innovative science communication agency (Scienseed). With the aim of promoting biomedical science of excellence in Europe, ENABLE organizes an annual three-day international event. This gathering includes a top-level scientific symposium bringing together leading scientists, PhD students, and post-doctoral fellows; career development activities supporting the progression of young researchers and fostering discussion about opportunities beyond the bench; and outreach activities stimulating the interaction between science and society. The first European PhD and Postdoc Symposium, entitled “Breaking Down Complexity: Innovative Models and Techniques in Biomedicine”, was hosted by the vibrant city of Barcelona. The scientific program of the conference was focused on the most recent advances and applications of modern techniques and models in biomedical research and covered a wide range of topics, from synthetic biology to translational medicine. Overall, the event was a great success, with more than 200 attendees from all over Europe actively participating in the symposium by presenting their research and exchanging ideas with their peers and world-renowned scientists.

Successful Targeted Therapies for Breast Cancer: the Worcester Foundation and Future Opportunities in Women's Health.

The signing of the National Cancer Act in 1971 was designed to take laboratory discoveries rapidly from the bench to the bedside. A "war on cancer" had been declared. Combination cytotoxic chemotherapy was predicted to cure all cancers, based on the stunning success in treating childhood leukemia. Breast cancer treatments were primitive; radical mastectomy and radiation were standard of care for disease that had not spread. Ablative endocrine surgery (oophorectomy, hypophysectomy, and adrenalectomy) was a palliative last option for metastatic breast cancer. However, only 30% responded, surviving for only 1 or 2 years: every patient soon died. The discovery of the estrogen receptor (ER) and translation to breast cancer treatment triggered a revolution in women's health. Two important but interconnected events occurred in 1972 at the Worcester Foundation for Experimental Biology (WFEB) that would exploit the breast tumor ER as the first target to save lives and prevent breast cancer development. Two new groups of medicines-selective ER modulators (SERMs) and aromatase inhibitors (AIs)-would continue the momentum of research at the WFEB to improve women's health. Here, we recount the important progress made in women's health based on knowledge of the endocrinology of breast cancer. We propose future opportunities in SERM therapeutics to "refresh" the current standards of care for breast cancer treatment. The opportunity is based on emerging knowledge about acquired resistance to long-term adjuvant AI therapy used to treat breast cancer.

Between-group pathogen transmission: From processes to modeling

Pathogen transmission is a key process in epidemiology and its mathematical form plays a pivotal role when modeling pathogen spread. Much work has been devoted to the transmission function applied to a homogeneous population structure. However, between-group transmission functions, required when different groups are identified to account for a distinct epidemiological risk, are much less documented. The aim of this study is to detail the mathematical form of five between-group transmission functions and to assess its influence on predictions in epidemiological modeling. Simulations with a two-group model were carried out so as to generate prediction differences among between-group transmission functions for a large range of situations, defined by the within-group transmission pattern, the basic reproduction number, the proportion of the whole transmission due to between-group transmission and the ratio of population sizes. Pathogen spread simulations highlighted differences in prevalence among four transmission functions (frequency-dependent, density-dependent and functions representing either a temporary mixing or a proportion of visitors exposed to infectious individuals). The differences could be seen either in long-term or in transient simulated dynamics. The fifth one, representing limited interactions at a gate, was shown to be equivalent to the density-dependent function in our parametrization when keeping constant group sizes. When considering population dynamics, particularly with increasing group sizes, this function and the density-dependent one were shown to behave opposite from each other and to differ from the other functions. This work highlights the need to carefully define the between-group transmission function when modeling pathogen spread in a heterogeneous structure. Our work brings insight into the biological grounds that could guide the choice of such a function.

Biological and Psychosocial Processes in the Development of Children's Appetitive Traits: Insights from Developmental Theory and Research.

There has been increasing concern expressed about children’s food intakes and dietary patterns. These are closely linked to children’s appetitive traits (such as disinhibited eating and food fussiness/neophobia). Research has examined both biological and psychosocial correlates or predictors of these traits. There has been less focus on possible processes or mechanisms associated with children’s development of these traits and research that links biological and psychosocial factors. There is an absence of research that links biological and psychosocial factors. In the present article, we outline a model intended to facilitate theory and research on the development of appetitive traits. It is based on scholarship from developmental theory and research and incorporates biological factors such as genetic predispositions and temperament as well as psychosocial factors in terms of parent cognitions, feeding styles and feeding practices. Particular attention is directed to aspects such as emotional eating and feeding, self-regulation of energy intake, and non-shared family environments. We highlight the opportunity for longitudinal research that examines bidirectional, transactional and cascade processes and uses a developmental framework. The model provides a basis for connecting the biological foundations of appetitive traits to system-level analysis in the family. Knowledge generated through the application of the model should lead to more effective prevention and intervention initiatives.

DIFFERENT HUMAN IMAGES AND ANTHROPOLOGICAL COLISSIONS OF POST-MODERNISM EPOCH: BIOPHILOSOPHICAL INTERPRETATION

Purpose. The research is aimed at substantiation of the process of formation of various human images in the postmodernism era in the context of biophilosophy, taking into account the need to find an adequate response to historical challenges and the production of new value orientations reflecting succession of civilization development. Theoretical basis. The author in his theoretical constructs proceeds from the need of taking into account the biophilosophical aspect of postmodern man, as the one who, remaining a representative of the species Homo sapiens, began to dynamically change, losing (weakening) its own natural and functional qualities, acquiring to a large extent the socio-technology-related qualities. The thesis that in the postmodern society the moral and legal foundations of existence of human being, as the subject of actions and responsibility for these actions, practically coincide with the biological foundations is taken as initial argument. New biological knowledge, as well as the related technologies, orient the public consciousness towards production of fundamentally new or modernization of the existing bio-philosophical ideas. The author's vision of the anthropological collision of the Post-Modernism era is caused by the fact that the issues of a postmodern man acquire a special urgency at the end of the ХХ – early XXI century. A progressive disproportion between a human being, whose abilities as a representative of the species Homo sapiens are biologically limited, and the human community, which sees no limits in its information and technological expansion, is of current interest. Originality. The author reveals the key features of the Post-Modernism era, in which a fundamentally different civilizational space originates, and where a new type of person emerges in its internal culture, which is called the postmodern man. The postmodern man was considered through the prism of bio-philosophy. Its interest in man is caused by his or her place in nature, the prospects of development at the individual, population and species levels. Conclusions. In the process of development of bio-philosophy, its research field will be naturally expanded with the use of philosophical means of perception of life as such and filling the bio-philosophy with philosophical and biological issues. In contemporary conditions, the study of the boundaries of biological reality and its previously unknown properties, definition of new horizons of theoretical knowledge in the science of life, the critical rethinking of the concepts of biocentrism and anthropocentrism in the space of modern scientific knowledge, the definition of perspective trends in the study of man, his or her place and role in the planetary being is of great importance.

Derek M. Jones, The biological foundations of action

Derek M. Jones, The biological foundations of action

The Nature of Parenthood

In the wake of Obergefell v. Hodges, courts and legislatures claim in principle to have repudiated the privileging of different-sex over same-sex couples and men over women in the legal regulation of the family. But as struggles over assisted reproductive technologies (ART) demonstrate, in the law of parental recognition such privileging remains. Those who break from traditional norms of gender and sexuality — women who separate motherhood from biological ties (for instance, through surrogacy), and women and men who form families with a same-sex partner — often find their parent-child relationships discounted. This Article explores what it means to fully vindicate gender and sexual-orientation equality in the law of parental recognition. It does so by situating the treatment of families formed through ART within a longer history of parentage. Inequalities that persist in contemporary law are traceable to earlier eras. In initially defining parentage through marriage, the common law embedded parenthood within a gender-hierarchical, heterosexual order. Eventually, courts and legislatures repudiated the common-law regime and protected biological parent-child relationships formed outside marriage. While this effort to derive parental recognition from biological connection was animated by egalitarian impulses, it too operated within a gender-differentiated, heterosexual paradigm. Today, the law increasingly accommodates families formed through ART, and, in doing so, recognizes parents on not only biological but also social grounds. Yet, as courts and legislatures approach the parental claims of women and same-sex couples within existing frameworks organized around marital and biological relationships, they reproduce some of the very gender- and sexuality-based asymmetries embedded in those frameworks. With biological connection continuing to anchor nonmarital parenthood, unmarried gays and lesbians face barriers to parental recognition. With the gender-differentiated, heterosexual family continuing to structure marital parenthood, the law organizes the legal family around a biological mother. Against this backdrop, nonbiological mothers in different-sex couples, as well as nonbiological fathers in same-sex couples, struggle for parental recognition. To protect the parental interests of women and of gays and lesbians, this Article urges greater emphasis on parenthood’s social dimensions. Of course, as our common law origins demonstrate, the law has long recognized parental relationships on social and not simply biological grounds. But today, commitments to equality require reorienting family law in ways that ground parental recognition more fully and evenhandedly in social contributions. While this Article focuses primarily on reform of family law at the state level, it also contemplates eventual constitutional oversight.

Shigella Phages Isolated during a Dysentery Outbreak Reveal Uncommon Structures and Broad Species Diversity.

In 2016, Michigan experienced the largest outbreak of shigellosis, a type of bacillary dysentery caused by Shigella spp., since 1988. Following this outbreak, we isolated 16 novel Shigella-infecting bacteriophages (viruses that infect bacteria) from environmental water sources. Most well-known bacteriophages infect the common laboratory species Escherichia coli and Salmonella enterica, and these phages have built the foundation of molecular and bacteriophage biology. Until now, comparatively few bacteriophages were known to infect Shigella spp., which are close relatives of E. coli We present a comprehensive analysis of these phages' host ranges, genomes, and structures, revealing genome sizes and capsid properties that are shared by very few previously described phages. After sequencing, a majority of the Shigella phages were found to have genomes of an uncommon size, shared by only 2% of all reported phage genomes. To investigate the structural implications of this unusual genome size, we used cryo-electron microscopy to resolve their capsid structures. We determined that these bacteriophage capsids have similarly uncommon geometry. Only two other viruses with this capsid structure have been described. Since most well-known bacteriophages infect Escherichia or Salmonella, our understanding of bacteriophages has been limited to a subset of well-described systems. Continuing to isolate phages using nontraditional strains of bacteria can fill gaps that currently exist in bacteriophage biology. In addition, the prevalence of Shigella phages during a shigellosis outbreak may suggest a potential impact of human health epidemics on local microbial communities.IMPORTANCEShigella spp. bacteria are causative agents of dysentery and affect more than 164 million people worldwide every year. Despite the need to combat antibiotic-resistant Shigella strains, relatively few Shigella-infecting bacteriophages have been described. By specifically looking for Shigella-infecting phages, this work has identified new isolates that (i) may be useful to combat Shigella infections and (ii) fill gaps in our knowledge of bacteriophage biology. The rare qualities of these new isolates emphasize the importance of isolating phages on "nontraditional" laboratory strains of bacteria to more fully understand both the basic biology and diversity of bacteriophages.

OpenHiCAMM: High-Content Screening Software for Complex Microscope Imaging Workflows

SummaryHigh-content image acquisition is generally limited to cells grown in culture, requiring complex hardware and preset imaging modalities. Here we report an open source software package, OpenHiCAMM (Open Hi Content Acquisition for μManager), that provides a flexible framework for integration of generic microscope-associated robotics and image processing with sequential workflows. As an example, we imaged Drosophila embryos, detecting the embryos at low resolution, followed by re-imaging the detected embryos at high resolution, suitable for computational analysis and screening. The OpenHiCAMM package is easy to use and adapt for automating complex microscope image tasks. It expands our abilities for high-throughput image-based screens to a new range of biological samples, such as organoids, and will provide a foundation for bioimaging systems biology.

Typological thinking: Then and now.

A popular narrative about the history of modern biology has it that Ernst Mayr introduced the distinction between “typological thinking” and “population thinking” to mark a contrast between a metaphysically problematic and a promising foundation for (evolutionary) biology, respectively. This narrative sometimes continues with the observation that, since the late‐20th century, typological concepts have been making a comeback in biology, primarily in the context of evolutionary developmental biology. It is hard to square this narrative with the historical and philosophical literature on the typology/population distinction from the last decade or so. The conclusion that emerges from this literature is that the very distinction between typological thinking and population thinking is a piece of mere rhetoric that was concocted and rehearsed for purely strategic, programmatic reasons. If this is right, it becomes hard to make sense of recent criticisms (and sometimes: espousals) of the purportedly typological underpinnings of certain contemporary research programs. In this article, I offer a way out of this apparent conflict. I show that we can make historical and philosophical sense of the continued accusations of typological thinking by looking beyond Mayr, to his contemporary and colleague George Gaylord Simpson. I show that before Mayr discussed the typology/population distinction as an issue in scientific metaphysics, Simpson introduced it to mark several contrasts in methodology and scientific practice. I argue that Simpson's insightful discussion offers useful resources for classifying and assessing contemporary attributions of typological thinking.

A pragmatic approach to the possibility of de-extinction

A number of influential biologists are currently pursuing efforts to restore previously extinct species. But for decades, philosophers of biology have regarded “de-extinction” as conceptually incoherent. Once a species is gone, it is gone forever. We argue that a range of metaphysical, biological, and ethical grounds for opposing de-extinction are at best inconclusive and that a pragmatic stance that allows for its possibility is more appealing.

Transdermal immunomodulation: Principles, advances and perspectives.

Immunomodulation, manipulation of the immune responses towards an antigen, is a promising strategy to treat cancer, infectious diseases, allergies, and autoimmune diseases, among others. Unique features of the skin including the presence of tissue-resident immune cells, ease of access and connectivity to other organs makes it a unique target organ for immunomodulation. In this review, we summarize advances in transdermal delivery of agents for modulating the immune responses for vaccination as well as tolerization. The biological foundation of skin-based immunomodulation and challenges in its implementation are described. Technological approaches aimed at enhancing the delivery of immunomodulatory therapeutics into skin are also discussed in this review. Progress made in the treatment of several specific diseases including cancer, infections and allergy are discussed. Finally, this review discusses some practical considerations and offers some recommendations for future studies in the field of transdermal immunomodulation.

Abstract P1-02-05: The effect of obesity and metabolic factors on genomic assays for risk of recurrence

Abstract Background: Obesity and other factors contributing to metabolic syndrome (MS) have become increasingly prolific in today's population. They are also known risk factors or comorbidities in many disease states including breast cancer (BC). While obesity and MS are known to increase the risk of developing BC, the effect on the risk of distant recurrence is uncertain. This substudy evaluated the relationship of BMI, blood pressure, cholesterol, triglyceride, diabetic status, and MS on the risk of recurrence in early BC patients. Methods: The effect of these metabolic factors on MammaPrint (MP) and Oncotype DX (ODX) risk of recurrence assays was compared. Additionally, gene expression analysis was performed to elucidate the differences between obese patients who were MP high risk (HR) vs. low risk (LR), and MP HR patients who were obese vs. not-obese. This subanalysis included patients from the PROMIS (n=198) and IMPACt (n=382) studies for whom metabolic characteristics were captured with informed consent. From the IMPACt study, 98 patients also reported ODX results (RS range 0-69). Results: By BMI, 1% of patients were classified as underweight (BMI <18.5), 22% normal (18.5≤ BMI <25), 31% overweight (25≤ BMI <30), and 46% as obese (BMI ≥30). To be classified as having MS, the patient had to exhibit any 3 of the 5 metabolic factors. In the full cohort, having MS was significantly associated with ethnicity (p < 0.05) and menopausal status (p < 0.001), but not histopathological tumor type, histological grade, tumor stage, or lymph node status (p > 0.05). 36% (207/580) of patients were considered as having MS in the full cohort, similarly 36% (35/98) had MS in the ODX subset. Of the patients with MS, MP classified 52% (108/207) as HR. For the subset of ER-positive patients with an ODX result, ODX classified the 11% (4/35) as HR whereas MP classified 57% (20/35) of the same patients as HR. Conclusions: Patients with obesity as measured by BMI and with MS were more frequently classified as HR by MP, in contrast to ODX which classified nearly all patients as intermediate or LR, confirming previous findings by Robinson, et. al (SABCS 2012 and 2014). Understanding the biological foundation of how obesity and metabolic factors affect risk of recurrence in breast cancer will improve both the treatment and care of patients. Citation Format: Soliman H, Treece T, Audeh W, IMPACt Investigators Group I. The effect of obesity and metabolic factors on genomic assays for risk of recurrence [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P1-02-05.

Full genetic analysis for genome-wide association study of Fangji: a powerful approach for effectively dissecting the molecular architecture of personalized traditional Chinese medicine.

Elucidation of the systems biology foundation underlying the effect of Fangji, which are multi-herbal traditional Chinese medicine (TCM) formulas, is one of the major aims in the field. The numerous bioactive ingredients of a Fangji deal with the multiple targets of a complex disease, which is influenced by a number of genes and their interactions with the environment. Genome-wide association study (GWAS) is an unbiased approach for dissecting the genetic variants underlying complex diseases and individual response to a given treatment. GWAS has great potential for the study of systems biology from the point of view of genomics, but the capacity using current analysis models is largely handicapped, as evidenced by missing heritability. Recent development of a full genetic model, in which gene-gene interactions (dominance and epistasis) and gene-environment interactions are all considered, has addressed these problems. This approach has been demonstrated to substantially increase model power, remarkably improving the detection of association of GWAS and the construction of the molecular architecture. This analysis does not require a very large sample size, which is often difficult to meet for a GWAS of treatment response. Furthermore, this analysis can integrate other omic information and allow for variations of Fangji, which is very promising for Fangjiomic study and detection of the sophisticated molecular architecture of the function of Fangji, as well as for the delineation of the systems biology of personalized medicine in TCM in an unbiased and comprehensive manner.

On the Biological Foundations of Language: Recent Advances in Language Acquisition, Deterioration, and Neuroscience Begin to Converge

In this paper, experimental results on the study of language loss in pro- dromal Alzheimer’s disease (AD) in the elderly are linked to experimen- tal results from the study of language acquisition in the child, via a tran- sitional stage of Mild Cognitive Impairment (MCI). Recent brain imag- ing results from a pilot study comparing prodromal AD and normal ag- ing are reported. Both, behavioral results and their underlying neural underpinnings, identify the source of language deficits in MCI as break- down in syntax–semantics integration. These results are linked to inde- pendent discoveries regarding the ontogeny of language in the child and their neural foundations. It is suggested that these convergent results ad- vance our understanding of the true nature of maturational processes in language, allowing us to reconsider a “regression hypothesis” (e.g., Ribot 1881), wherein later acquisition predicts earliest dissolution.

Justifications for a Discontinuity Theory of Language Evolution

In Chapter 6 of Biological Foundations of Language, Lenneberg argues against continuity theories of language evolution, which claim that language evolved from simpler communication systems. Although Lenneberg was pessimistic about even discontinuity theories explaining how language evolved, discontinuity has become significant in the Minimalist program, which posits that our species’ acquisition of Merge was the key discontinuity that made language possible. On the basis of a unified description of natural communication systems, I show that language is indeed based upon a cognitive discontinuity, which is moreover specific to linguistic ability. However, I argue that even Minimalist theories must recognise this discontinuity as the sensorimotor interface with syntax, rather than syntax itself. This ultimately supports the view that syntactic structures are structures of thought, but taking this claim seriously means reimagining how syntax relates to semantics and morphology, as the traditional ‘lexical item’ is no longer a tenable primitive of generative theory.

Hukum Minimum Liebig - Sebuah Ulasan dan Aplikasi Dalam Biologi Kontemporer

Optimum plant growth depends on numerous ecological factors. In relation to this theme, there is an old law called Law of the Minimum Liebig. The postulate discussed the growth of the plant that is determined by the scarcest environmental factors. It is one of the oldest ecological postulate proposed more than one and a half-century ago. It has become one of the most important foundations for agriculture and biology, even the in contemporary biology. This short review will provide the history, principles, development and criticism, and applications in some recent biological sciences, including evolution, conservation, ecological indicator and even climate change.