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Biological Research

Special series on Microbial Interactions

The nine articles of this special issue of  Biological Research  address biochemical and genetic determinants of microbial response and tolerance to stressors in different biological models and environmental contexts. Individual articles provide a broad exploration of our current knowledge of response to stressors, with a special emphasis on metal metabolism and toxic compounds.

Special series on Antarctic Research

This special issue on Antarctic research in Biological Research comprises of recent studies, related to the discovery of several new enzymes and biotechnological applications that allow to expand the knowledge of Antarctic organisms and their potential applications.

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The crucial role of HFM1 in regulating FUS ubiquitination and localization for oocyte meiosis prophase I progression in mice

Authors: Chenyi Zhong, Huiyuan Wang, Xiong Yuan, Yuheng He, Jing Cong, Rui Yang, Wenjie Ma, Li Gao, Chao Gao, Yugui Cui, Jie Wu, Rongrong Tan and Danhua Pu

Distinct properties of putative trophoblast stem cells established from somatic cell nuclear-transferred pig blastocysts

Authors: Eunhye Kim, Lian Cai, Hyerin Choi, Mirae Kim and Sang-Hwan Hyun

Electroacupuncture attenuates neuropathic pain via suppressing BIP-IRE-1α-mediated endoplasmic reticulum stress in the anterior cingulate cortex

Authors: Lin-Wei Ma, Yu-Fan Liu, Hui Zhang, Chang-Jun Huang, Ang Li, Xin-Zhe Qu, Jia-Piao Lin, Yan Yang and Yong-Xing Yao

Effect of Cannabis sativa L. extracts, phytocannabinoids and their acetylated derivates on the SHSY-5Y neuroblastoma cells’ viability and caspases 3/7 activation

Authors: Elizabeth Tapia-Tapia, Pablo Aránguiz, Rodrigo Diaz, Luis Espinoza, Caroline R Weinstein-Oppenheimer and Mauricio Cuellar

The hepatoprotective effect of 4-phenyltetrahydroquinolines on carbon tetrachloride induced hepatotoxicity in rats through autophagy inhibition

Authors: Mohamed Hussein Abdelgalil, Reem H. Elhammamy, Hanan M. Ragab, Eman Sheta and Ahmed Wahid

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Awareness and current knowledge of breast cancer

Authors: Muhammad Akram, Mehwish Iqbal, Muhammad Daniyal and Asmat Ullah Khan

Stress and defense responses in plant secondary metabolites production

Authors: Tasiu Isah

Fate of nitrogen in agriculture and environment: agronomic, eco-physiological and molecular approaches to improve nitrogen use efficiency

Authors: Muhammad Anas, Fen Liao, Krishan K. Verma, Muhammad Aqeel Sarwar, Aamir Mahmood, Zhong-Liang Chen, Qiang Li, Xu-Peng Zeng, Yang Liu and Yang-Rui Li

Coping with drought: stress and adaptive mechanisms, and management through cultural and molecular alternatives in cotton as vital constituents for plant stress resilience and fitness

Authors: Aziz Khan, Xudong Pan, Ullah Najeeb, Daniel Kean Yuen Tan, Shah Fahad, Rizwan Zahoor and Honghai Luo

Biotechnological applications of archaeal enzymes from extreme environments

Authors: Ma. Ángeles Cabrera and Jenny M. Blamey

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Biological Research , formerly Archives of Experimental Medicine and Biology , was founded in 1964 and transferred to BioMed Central in 2014. An electronic archive of articles published between 1999 and 2013 can be found in the SciELO database.

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Editor’s profile

Manuel J Santos, Editor-in-Chief

Dr Santos is an Associate Professor in the Faculty of Biological Sciences and Medicine at the Pontificia Catholic University of Chile.

Dr Santos received his MD from the University of Chile and his PhD in Cell and Molecular Biology from the Pontificia Catholic University of Chile. He majored in Medical Genetics at The John Hopkins University (USA) and The René Descartes University of Paris (France), and held a post doctorate position in Cell Biology and Genetics at the Rockefeller University (USA).

His research has focused on the biogenesis of cellular organelles, particularly peroxisomes. A pioneer in this field, his research lead him to discover a new type of human genetic disease, the peroxisomal biogenesis disorders, which include Zellweger Syndrome. More recently his research has centered on studying the role of peroxisomes in Alzheimer’s disease, and he also works in the field of bioethics.

Over the span of his career, Dr Santos has published more than 70 peer reviewed papers and been the President of the Society of Biology of Chile, the Genetics Society of Chile and the Bioethical Society of Chile.

About the Society

The Chilean Biology Society (Sociedad de Biología de Chile), previously the Biological Society of Santiago, was founded in late 1928 as a subsidiary of The Societé de Biologie of Paris, France. For several years the summaries of its communications were published in Comps Rendú of the Societé de Biologie du Paris. The Society is currently a member of the International Union of Biological Sciences (IUBS).

The Chilean Biology Society promotes theoretical and experimental studies and research leading to advancement in and dissemination of the biological sciences for the benefit of the community. To accomplish this, the Society organizes periodic scientific meetings in which scientists communicate, comment and discuss research carried out in Chilean or foreign research laboratories. In addition, relations and cooperation with similar domestic and foreign institutions are stimulated, and communication by all appropriate means of biological research carried out in Chile. 

Members of the Society will receive a discount on Biological Research 's article-processing charge when they provide a discount code (which members can obtain by emailing the Society) during the submission process.  The discounted article-processing charge for Society members is £1150 in 2023.

The Society also publishes Revista Chilena de Historia Natural ( Chilean Journal of Natural History, founded in 1897).

Annual Journal Metrics

2022 Citation Impact 6.7 - 2-year Impact Factor 7.2 - 5-year Impact Factor 1.241 - SNIP (Source Normalized Impact per Paper) 1.294 - SJR (SCImago Journal Rank)

2023 Speed 25 days submission to first editorial decision for all manuscripts (Median) 155 days submission to accept (Median)

2023 Usage  489,080 downloads 731 Altmetric mentions 

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Page 1 of 24

Upregulated dual oxidase 1-induced oxidative stress and caspase-1-dependent pyroptosis reflect the etiologies of heart failure

Oxidative stress is implicated in the pathogenesis of heart failure. Dual oxidase 1 (DUOX1) might be important in heart failure development through its mediating role in oxidative stress. This study was design...

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Comparing chemical transfection, electroporation, and lentiviral vector transduction to achieve optimal transfection conditions in the Vero cell line

Transfection is an important analytical method for studying gene expression in the cellular environment. There are some barriers to efficient DNA transfection in host cells, including circumventing the plasma ...

High-fat diet enhances cell proliferation and compromises intestinal permeability in a translational canine intestinal organoid model

Emerging evidence underscores the responsiveness of the mammalian intestine to dietary cues, notably through the involvement of LGR5 + intestinal stem cells in orchestrating responses to diet-driven signals. H...

mTOR signaling pathway regulation HIF-1 α effects on LPS induced intestinal mucosal epithelial model damage

Sepsis-induced small-intestinal injury is associated with increased morbidity and mortality. Our previous study and other papers have shown that HIF-1α has a protective effect on intestinal mucosal injury in s...

Long non-coding RNA SOX2OT in tamoxifen-resistant breast cancer

Hormone receptor (HR)-positive breast cancer can become aggressive after developing hormone-treatment resistance. This study elucidated the role of long non-coding RNA (lncRNA) SOX2OT in tamoxifen-resistant (T...

Mice lacking DIO3 exhibit sex-specific alterations in circadian patterns of corticosterone and gene expression in metabolic tissues

Disruption of circadian rhythms is associated with neurological, endocrine and metabolic pathologies. We have recently shown that mice lacking functional type 3 deiodinase (DIO3), the enzyme that clears thyroi...

Optimization of seeding density of OP9 cells to improve hematopoietic differentiation efficiency

OP9 mouse stromal cell line has been widely used to induce differentiation of human embryonic stem cells (hESCs) into hematopoietic stem/progenitor cells (HSPCs). However, the whole co-culture procedure usuall...

Development of an in vitro human alveolar epithelial air-liquid interface model using a small molecule inhibitor cocktail

The alveolar epithelium is exposed to numerous stimuli, such as chemicals, viruses, and bacteria that cause a variety of pulmonary diseases through inhalation. Alveolar epithelial cells (AECs) cultured in vitr...

Mechanical stretch leads to increased caveolin-1 content and mineralization potential in extracellular vesicles from vascular smooth muscle cells

Hypertension-induced mechanical stress on vascular smooth muscle cells (VSMCs) is a known risk factor for vascular remodeling, including vascular calcification. Caveolin-1 (Cav-1), an integral structural compo...

Melatonin reduces lung injury in type 1 diabetic mice by the modulation of autophagy

In recent years, the role of autophagy has been highlighted in the pathogenesis of diabetes and inflammatory lung diseases. In this study, using a diabetic model of mice, we investigated the expression of auto...

TonEBP/NFAT5 expression is associated with cisplatin resistance and migration in macrophage-induced A549 cells

Macrophages promote angiogenesis, metastasis, and drug resistance in several cancers. Similarly, TonEBP/NFAT5 induces metastasis in renal carcinoma and colon cancer cells. However, the role of this transcripti...

Optimizing combination therapy in prostate cancer: mechanistic insights into the synergistic effects of Paclitaxel and Sulforaphane-induced apoptosis

Combination therapies in cancer treatment have demonstrated synergistic or additive outcomes while also reducing the development of drug resistance compared to monotherapy. This study explores the potential of...

CTC together with Shh and Nrf2 are prospective diagnostic markers for HNSCC

The lack of appropriate prognostic biomarkers remains a significant obstacle in the early detection of Head and Neck Squamous Cell Carcinoma (HNSCC), a cancer type with a high mortality rate. Despite considera...

Prioritization of Trypanosoma brucei editosome protein interactions interfaces at residue resolution through proteome-scale network analysis

Trypanosoma brucei is the causative agent for trypanosomiasis in humans and livestock, which presents a growing challenge due to drug resistance. While identifying novel drug targets is vital, the process is dela...

Sumoylation of SAP130 regulates its interaction with FAF1 as well as its protein stability and transcriptional repressor function

Fas-associated factor 1 (FAF1) is a multidomain protein that interacts with diverse partners to affect numerous cellular processes. Previously, we discovered two Small Ubiquitin-like Modifier (SUMO)-interactin...

Loss of Dec1 inhibits alcohol-induced hepatic lipid accumulation and circadian rhythm disorder

Chronic alcohol exposure increases liver damage such as lipid accumulation and hepatitis, resulting in hepatic cirrhosis. Chronic alcohol intake is known to disturb circadian rhythms in humans and animals. DEC...

Association between plasma L-carnitine levels and mitochondrial DNA copy number

Mitochondria are key cytoplasmic organelles in eukaryotic cells that generate adenosine triphosphate (ATP) through the electron transport chain and oxidative phosphorylation. Mitochondrial DNA (mtDNA) copy num...

Effect of Emi1 gene silencing on the proliferation and invasion of human breast cancer cells

Breast cancer is the most common malignant tumour in women. The early silk-splitting inhibitor protein 1 Emi1 is responsible for mediating ubiquitin protein degradation. The present study investigated the effe...

TNFα induces Caspase-3 activity in hematopoietic progenitor cells CD34+, CD33+, and CD41 + of myelodysplastic syndromes

Cytopenia is the primary feature of Myelodysplastic Syndrome, even in the presence of hypercellular bone marrow. TNFα is recognized as both a proinflammatory, and proapoptotic cytokine with a well established ...

From network analysis to experimental validation: identification of regulators of non-muscle myosin II contractility using the folded-gastrulation signaling pathway

The morphogenetic process of apical constriction, which relies on non-muscle myosin II (NMII) generated constriction of apical domains of epithelial cells, is key to the development of complex cellular pattern...

Simple, low-cost, and well-performing method, the outgrowth technique, for the isolation of cells from nasal polyps

Epithelial cells are an important part of the pathomechanism in chronic rhinosinusitis with nasal polyps. It is therefore essential to establish a robust method for the isolation and culture of epithelial cell...

Comprehensive brain tissue metabolomics and biological network technology to decipher the mechanism of hydrogen-rich water on Radiation-induced cognitive impairment in rats

Hydrogen-rich water (HRW) has been shown to prevent cognitive impairment caused by ionizing radiation. This study aimed to investigate the pharmacological effects and mechanisms of HRW on ionizing radiation by...

Mineral elements and adiposity-related consequences in adolescents with intellectual disabilities

Patients with intellectual disabilities are shown to have a limited capacity for cooperation, communication,and other biological consequences, which significantly require a specialized interest in healthcare p...

Glycyrrhizin inhibits LPS-induced inflammatory responses in goat ruminal epithelial cells in vitro

Inflammation plays a crucial role in the progression of Subacute Ruminal Acidosis (SARA). The experiment was designed to investigate anti-inflammatory effects of glycyrrhizin on goats ruminal epithelial cells ...

D-galactose-induced mitochondrial oxidative damage and apoptosis in the cochlear stria vascularis of mice

Age-related hearing loss, known as presbycusis, is the result of auditory system degeneration. Numerous studies have suggested that reactive oxygen species (ROS) and mitochondrial oxidative damage play importa...

Keratin 19 binds and regulates cytoplasmic HNRNPK mRNA targets in triple-negative breast cancer

Heterogeneous nuclear ribonucleoprotein K (HNRNPK) regulates pre-mRNA processing and long non-coding RNA localization in the nucleus. It was previously shown that shuttling of HNRNPK to the cytoplasm promotes ...

A computational peptide model induces cancer cells’ apoptosis by docking Kringle 5 to GRP78

Cells can die through a process called apoptosis in both pathological and healthy conditions. Cancer development and progression may result from abnormal apoptosis. The 78-kDa glucose-regulated protein (GRP78)...

BMP9 maintains the phenotype of HTR-8/Svneo trophoblast cells by activating the SDF1/CXCR4 pathway

Bone morphogenetic protein 9 (BMP9) has been shown to regulate processes such as angiogenesis, endothelial dysfunction, and tumorigenesis. However, the role of BMP9 in preeclampsia (PE) is unclear. The purpose...

Emodin and aloe-emodin, two potential molecules in regulating cell migration of skin cells through the MAP kinase pathway and affecting Caenorhabditis elegans thermotolerance

Emodin and aloe-emodin are two anthraquinones having positive effects in wound healing. However, their mechanism of action of wound healing is not fully understood. The MAP kinase family, which plays an active...

Knockdown of ELF4 aggravates renal injury in ischemia/reperfusion mice through promotion of pyroptosis, inflammation, oxidative stress, and endoplasmic reticulum stress

Renal ischemia/reperfusion (I/R) injury is a major cause of acute kidney injury (AKI). Dysfunction of E74-like ETS transcription factor 4 (ELF4) leads to inflammation. This research intended to look into the f...

Janus Kinase 3 phosphorylation and the JAK/STAT pathway are positively modulated by follicle-stimulating hormone (FSH) in bovine granulosa cells

Janus kinase 3 (JAK3) is a member of the JAK family of tyrosine kinase proteins involved in cytokine receptor-mediated intracellular signal transduction through the JAK/STAT signaling pathway. JAK3 was previou...

Genetic and protein interaction studies between the ciliary dyslexia candidate genes DYX1C1 and DCDC2

DYX1C1 (DNAAF4) and DCDC2 are two of the most replicated dyslexia candidate genes in genetic studies. They both have demonstrated roles in neuronal migration, in cilia growth and function and they both are cytosk...

SUMOylation of PDGF receptor α affects signaling via PLCγ and STAT3, and cell proliferation

The platelet-derived growth factor (PDGF) family of ligands exerts their cellular effects by binding to α- and β-tyrosine kinase receptors (PDGFRα and PDGFRβ, respectively). SUMOylation is an important posttra...

Myogenic differentiation of human myoblasts and Mesenchymal stromal cells under GDF11 on Poly-ɛ-caprolactone-collagen I-Polyethylene-nanofibers

For the purpose of skeletal muscle engineering, primary myoblasts (Mb) and adipogenic mesenchymal stem cells (ADSC) can be co-cultured and myogenically differentiated. Electrospun composite nanofiber scaffolds...

Computational analysis of missense variant CYP4F2*3 (V433M) in association with human CYP4F2 dysfunction: a functional and structural impact

Cytochrome P450 4F2 (CYP4F2) enzyme is a member of the CYP4 family responsible for the metabolism of fatty acids, therapeutic drugs, and signaling molecules such as arachidonic acid, tocopherols, and vitamin K...

Using RNA-seq to identify suitable housekeeping genes for hypoxia studies in human adipose-derived stem cells

Hypoxic culture conditions have been used to study the impact of oxygen deprivation has on gene expression in a number of disease models. However, hypoxia response elements present in the promoter regions of s...

SCAT8/miR-125b-5p axis triggers malignant progression of nasopharyngeal carcinoma through SCARB1

Nasopharyngeal carcinoma is a tumor with high malignancy and poor prognosis, which severely affects the health of the patients. LncRNAs and microRNAs are crucial for the occurrence and development of nasophary...

ARNTL2 upregulation of ACOT7 promotes NSCLC cell proliferation through inhibition of apoptosis and ferroptosis

Recent studies have reported that the circadian transcription factor aryl hydrocarbon receptor nuclear translocator like 2 (ARNTL2) promotes the metastatic progression of lung adenocarcinoma. However, the mole...

Evolutionary relevance of single nucleotide variants within the forebrain exclusive human accelerated enhancer regions

Human accelerated regions (HARs) are short conserved genomic sequences that have acquired significantly more nucleotide substitutions than expected in the human lineage after divergence from chimpanzees. The f...

The DNA demethylation-regulated SFRP2 dictates the progression of endometriosis via activation of the Wnt/β-catenin signaling pathway

Endometriosis cause decreases in life quality and pelvic pain in reproductive-age women. Methylation abnormalities played a functional role in the progression of endometriosis, this study aimed to explore the ...

Pre-treatment with IL-6 potentiates β-cell death induced by pro-inflammatory cytokines

Type I Diabetes mellitus (T1D) is characterized by a specific destruction of β-cells by the immune system. During this process pro-inflammatory cytokines are released in the pancreatic islets and contribute for β...

Role of the human solute carrier family 14 member 1 gene in hypoxia-induced renal cell carcinoma occurrence and its enlightenment to cancer nursing

Hypoxia is considered a critical contributor to renal cell carcinoma progression, including invasion and metastasis. However, the potential mechanisms by which it promotes invasion and metastasis have not yet ...

Cyclic tensile force modifies calvarial osteoblast function via the interplay between ERK1/2 and STAT3

Mechanical therapies, such as distraction osteogenesis, are widely used in dental clinics. During this process, the mechanisms by which tensile force triggers bone formation remain of interest. Herein, we inve...

Urine-derived mesenchymal stem cells-derived exosomes enhances survival and proliferation of aging retinal ganglion cells

This study was designed to investigate to test the effect of exosomes from urine-derived mesenchymal stem cells (USCs) on the survival and viability of aging retinal ganglion cells (RGCs), and explored the pre...

RPL11 promotes non-small cell lung cancer cell proliferation by regulating endoplasmic reticulum stress and cell autophagy

Abnormal biogenesis and ribosome free function of ribosomal proteins (RPs) is important for tumorgenesis and development. Ribosomal protein L11 (RPL11) is a component of ribosomal 60 S large subunit with diffe...

Sperm capacitation and transcripts levels are altered by in vitro THC exposure

Delta-9-tetrahydrocannabinol (THC) is the primary phytocannabinoid responsible for the psychoactive properties of cannabis and is known to interact with the endocannabinoid system, which is functionally presen...

The dual role of Nrf2 in melanoma: a systematic review

Melanoma is the most lethal type of skin cancer that originates from the malignant transformation of melanocytes. Although novel treatments have improved patient survival in melanoma, the overall prognosis rem...

Hyperoxia exposure upregulates Dvl-1 and activates Wnt/β-catenin signaling pathway in newborn rat lung

Bronchopulmonary dysplasia is a serious and lifelong pulmonary disease in premature neonates that influences around one-quarter of premature newborns. The wingless-related integration site /β-catenin signaling...

Circ-ATL1 silencing reverses the activation effects of SIRT5 on smooth muscle cellular proliferation, migration and contractility in intracranial aneurysm by adsorbing miR-455

Alterations in vascular smooth muscle cells (VSMCs) contribute to the pathogenesis of intracranial aneurysms (IAs). However, molecular mechanisms underlying these changes remain unknown. The present study aime...

HMGB1 mediates lipopolysaccharide-induced macrophage autophagy and pyroptosis

Autophagy and pyroptosis of macrophages play important protective or detrimental roles in sepsis. However, the underlying mechanisms remain unclear. High mobility group box protein 1 (HMGB1) is associated with...

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2022 Citation Impact 2.8 - 2-year Impact Factor 2.9 - 5-year Impact Factor 0.678 - SNIP (Source Normalized Impact per Paper) 0.775 - SJR (SCImago Journal Rank)

2023 Speed 24 days submission to first editorial decision for all manuscripts (Median) 143 days submission to accept (Median)

2023 Usage  582,382 downloads 193 Altmetric mentions 

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Page 1 of 6

Endothelial adherens junctions and the actin cytoskeleton: an 'infinity net'?

A recent paper in BMC Biology reports that actin stress fibers in adjacent cultured endothelial cells are linked through adherens junctions. This organization might provide a super-cellular network that could ena...

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Robust and specific inhibition of microRNAs in Caenorhabditis elegans

MicroRNAs (miRNAs) are small non-coding RNAs that regulate the expression of numerous target genes. Yet, while hundreds of miRNAs have been identified, little is known about their functions. In a recent report...

Genome of a songbird unveiled

An international collaborative effort has recently uncovered the genome of the zebra finch, a songbird model that has provided unique insights into an array of biological phenomena.

The mathematics of sexual attraction

Pollen tubes follow attractants secreted by the ovules. In a recent paper in BMC Plant Biology , Stewman and colleagues have quantified the parameters of this attraction and used them to calibrate a mathematical m...

Diversity lost: are all Holarctic large mammal species just relict populations?

Population genetic analyses of Eurasian wolves published recently in BMC Evolutionary Biology suggest that a major genetic turnover took place in Eurasian wolves after the Pleistocene. These results add to the gr...

Hybridization and speciation in angiosperms: arole for pollinator shifts?

The majority of convincingly documented cases of hybridization in angiosperms has involved genetic introgression between the parental species or formation of a hybrid species with increased ploidy; however, ho...

Evolution underground: shedding light on the diversification of subterranean insects

A recent study in BMC Evolutionary Biology has reconstructed the molecular phylogeny of a large Mediterranean cave-dwelling beetle clade, revealing an ancient origin and strong geographic structuring. It seems li...

A modern circadian clock in the common angiosperm ancestor of monocots and eudicots

The circadian clock enhances fitness through temporal organization of plant gene expression, metabolism and physiology. Two recent studies, one in BMC Evolutionary Biology , demonstrate through phylogenetic analys...

Scale-eating cichlids: from hand(ed) to mouth

Two recent studies in BMC Biology and Evolution raise important questions about a textbook case of frequency-dependent selection in scale-eating cichlid fishes. They also suggest a fascinating new line of researc...

Top dogs: wolf domestication and wealth

A phylogeographic analysis of gene sequences important in determining body size in dogs, recently published in BMC Biology , traces the appearance of small body size to the Neolithic Middle East. This finding stre...

No better time to FRET: shedding light on host pathogen interactions

Understanding the spatio-temporal subversion of host cell signaling by bacterial virulence factors is key to combating infectious diseases. Following a recent study by Buntru and co-workers published in BMC Biolo...

Making progress in genetic kin recognition among vertebrates

A recent study in BMC Evolutionary Biology has shown that genetically similar individual ring-tailed lemurs are also more similar in their scent composition, suggesting a possible mechanism of kin recognition. Th...

Regeneration review reprise

There have been notable advances in the scientific understanding of regeneration within the past year alone, including two recently published in BMC Biology . Increasingly, progress in the regeneration field is be...

Acoel and platyhelminth models for stem-cell research

Acoel and platyhelminth worms are particularly attractive invertebrate models for stem-cell research because their bodies are continually renewed from large pools of somatic stem cells. Several recent studies,...

Madm (Mlf1 adapter molecule) cooperates with Bunched A to promote growth in Drosophila

The TSC-22 domain family (TSC22DF) consists of putative transcription factors harboring a DNA-binding TSC-box and an adjacent leucine zipper at their carboxyl termini. Both short and long TSC22DF isoforms are ...

Bunched and Madm: a novel growth-regulatory complex?

By combining Drosophila genetics and proteomics Gluderer et al. report in this issue of Journal of Biology the isolation of a novel growth-regulatory complex consisting of Bunched and Madm. Future study of this c...

Q&A: What can microfluidics do for stem-cell research?

Regulation of metabolism in caenorhabditis elegans longevity.

The nematode Caenorhabditis elegans is a favorite model for the study of aging. A wealth of genetic and genomic studies show that metabolic regulation is a hallmark of life-span modulation. A recent study in BMC ...

Reprogramming of the non-coding transcriptome during brain development

A recent global analysis of gene expression during the differentiation of neuronal stem cells to neurons and oligodendrocytes indicates a complex pattern of changes in the expression of both protein-coding tra...

The THO complex as a key mRNP biogenesis factor in development and cell differentiation

The THO complex is a key component in the co-transcriptional formation of messenger ribonucleoparticles that are competent to be exported from the nucleus, yet its precise function is unknown. A recent study in B...

SnoPatrol: how many snoRNA genes are there?

Small nucleolar RNAs (snoRNAs) are among the most evolutionarily ancient classes of small RNA. Two experimental screens published in BMC Genomics expand the eukaryotic snoRNA catalog, but many more snoRNAs remain...

Sometimes one just isn't enough: do vertebrates contain an H2A.Z hyper-variant?

How much functional specialization can one component histone confer on a single nucleosome? The histone variant H2A.Z seems to be an extreme example. Genome-wide distribution maps show non-random (and evolutio...

Apical polarity in three-dimensional culture systems: where to now?

Delineation of the mechanisms that establish and maintain the polarity of epithelial tissues is essential to understanding morphogenesis, tissue specificity and cancer. Three-dimensional culture assays provide...

The water flea Daphnia - a 'new' model system for ecology and evolution?

Daphnia pulex is the first crustacean to have its genome sequenced. Availability of the genome sequence will have implications for research in aquatic ecology and evolution in particular, as addressed by a series...

Top ten in Journal of Biology in 2009: stem cells, influenza, pit bulls, Darwin, and more

The bacterial pathogen listeria monocytogenes : an emerging model in prokaryotic transcriptomics.

A major challenge in bacterial pathogenesis is understanding the molecular basis of the switch from saprophytism to virulence. Following a recent whole-genome transcriptomic analysis using tiling arrays, an ar...

Forward genetics in Tribolium castaneum : opening new avenues of research in arthropod biology

A recent paper in BMC Biology reports the first large-scale insertional mutagenesis screen in a non-drosophilid insect, the red flour beetle Tribolium castaneum . This screen marks the beginning of a non-biased, '...

Mapping the protistan 'rare biosphere'

The use of cultivation-independent approaches to map microbial diversity, including recent work published in BMC Biology , has now shown that protists, like bacteria/archaea, are much more diverse than had been re...

Scribble at the crossroads

Although proteins involved in determining apical-basal cell polarity have been directly linked to tumorigenesis, their precise roles in this process remain unclear. A recent report in BMC Biology clarifies the si...

Q&A: Quantitative approaches to planar polarity and tissue organization

Gene regulation, evolvability and the limits of genomics, the transcriptome of human monocyte subsets begins to emerge.

Human monocytes can be divided into subsets according to their expression or lack of the cell-surface antigen CD16. In papers published recently in the Journal of Proteome Research and in BMC Genomics , two groups...

Chromatin 'programming' by sequence - is there more to the nucleosome code than %GC?

The role of genomic sequence in directing the packaging of eukaryotic genomes into chromatin has been the subject of considerable recent debate. A new paper from Tillo and Hughes shows that the intrinsic therm...

Fishing for the signals that pattern the face

Zebrafish are a powerful system for studying the early embryonic events that form the skull and face, as a model for human craniofacial birth defects such as cleft palate. Signaling pathways that pattern the p...

Coordinated gene expression by post-transcriptional regulons in African trypanosomes

The regulation of gene expression in trypanosomes is unique. In the absence of transcriptional control at the level of initiation, a subset of Trypanosoma brucei genes form post-transcriptional regulons in which ...

Promoter architecture and the evolvability of gene expression

Evolutionary changes in gene expression are a main driver of phenotypic evolution. In yeast, genes that have rapidly diverged in expression are associated with particular promoter features, including the prese...

Adaptations of proteins to cellular and subcellular pH

Bioinformatics-based searches for correlations between subcellular localization and pI or charge distribution of proteins have failed to detect meaningful correlations. Recent work published in BMC Biology finds ...

TBP2 is a general transcription factor specialized for female germ cells

The complexity of the core promoter transcription machinery has emerged as an additional level of transcription regulation that is used during vertebrate development. Recent studies, including one published in BM...

Generalized immune activation as a direct result of activated CD4 + T cell killing

In addition to progressive CD4 + T cell immune deficiency, HIV infection is characterized by generalized immune activation, thought to arise from increased microbial exposure resulting from diminishing immunity.

Life and death as a T lymphocyte: from immune protection to HIV pathogenesis

Detailed analysis of T cell dynamics in humans is challenging and mouse models can be important tools for characterizing T cell dynamic processes. In a paper just published in Journal of Biology , Marques et al . s...

What we still don't know about AIDS

The gene complement of the ancestral bilaterian - was urbilateria a monster.

Expressed sequence tag analyses of the annelid Pomatoceros lamarckii , recently published in BMC Evolutionary Biology , are consistent with less extensive gene loss in the Lophotrochozoa than in the Ecdysozoa, but ...

The nature of cell-cycle checkpoints: facts and fallacies

The concept of checkpoint controls revolutionized our understanding of the cell cycle. Here we revisit the defining features of checkpoints and argue that failure to properly appreciate the concept is leading ...

An expanded evolutionary role for flower symmetry genes

CYCLOIDEA (CYC) -like TCP genes are critical for flower developmental patterning. Exciting recent breakthroughs, including a study by Song et al. published in BMC Evolutionary Biology , demonstrate that CYC -like ge...

Mechanisms of ubiquitin transfer by the anaphase-promoting complex

The anaphase-promoting complex (APC) is a ubiquitin-protein ligase required for the completion of mitosis in all eukaryotes. Recent mechanistic studies reveal how this remarkable enzyme combines specificity in...

Targeting TNF-α for cancer therapy

As the tumor vasculature is a key element of the tumor stroma, angiogenesis is the target of many cancer therapies. Recent work published in BMC Cell Biology describes a fusion protein that combines a peptide pre...

TEs or not TEs? That is the evolutionary question

Transposable elements (TEs) have contributed a wide range of functional sequences to their host genomes. A recent paper in BMC Molecular Biology discusses the creation of new transcripts by transposable element i...

Molecular machines or pleiomorphic ensembles: signaling complexes revisited

Signaling complexes typically consist of highly dynamic molecular ensembles that are challenging to study and to describe accurately. Conventional mechanical descriptions misrepresent this reality and can be a...

Ockham's broom: A new series

Adaptation by introgression.

Both selective and random processes can affect the outcome of natural hybridization. A recent analysis in BMC Evolutionary Biology of natural hybridization between an introduced and a native salamander reveals th...

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• v.28; Jan-Dec 2021

Cancer Biology, Epidemiology, and Treatment in the 21st Century: Current Status and Future Challenges From a Biomedical Perspective

Patricia piña-sánchez.

1 Oncology Research Unit, Oncology Hospital, Mexican Institute of Social Security, Mexico

Antonieta Chávez-González

Martha ruiz-tachiquín, eduardo vadillo, alberto monroy-garcía, juan josé montesinos, rocío grajales.

2 Department of Medical Oncology, Oncology Hospital, Mexican Institute of Social Security, Mexico

Marcos Gutiérrez de la Barrera

3 Clinical Research Division, Oncology Hospital, Mexican Institute of Social Security, Mexico

Hector Mayani

Since the second half of the 20th century, our knowledge about the biology of cancer has made extraordinary progress. Today, we understand cancer at the genomic and epigenomic levels, and we have identified the cell that starts neoplastic transformation and characterized the mechanisms for the invasion of other tissues. This knowledge has allowed novel drugs to be designed that act on specific molecular targets, the immune system to be trained and manipulated to increase its efficiency, and ever more effective therapeutic strategies to be developed. Nevertheless, we are still far from winning the war against cancer, and thus biomedical research in oncology must continue to be a global priority. Likewise, there is a need to reduce unequal access to medical services and improve prevention programs, especially in countries with a low human development index.

Introduction

During the last one hundred years, our understanding of the biology of cancer increased in an extraordinary way. 1 - 4 Such a progress has been particularly prompted during the last few decades because of technological and conceptual progress in a variety of fields, including massive next-generation sequencing, inclusion of “omic” sciences, high-resolution microscopy, molecular immunology, flow cytometry, analysis and sequencing of individual cells, new cell culture techniques, and the development of animal models, among others. Nevertheless, there are many questions yet to be answered and many problems to be solved regarding this disease. As a consequence, oncological research must be considered imperative.

Currently, cancer is one of the illnesses that causes more deaths worldwide. 5 According to data reported in 2020 by the World Health Organization (WHO), cancer is the second cause of death throughout the world, with 10 million deaths. 6 Clearly, cancer is still a leading problem worldwide. With this in mind, the objective of this article is to present a multidisciplinary and comprehensive overview of the disease. We will begin by analyzing cancer as a process, focusing on the current state of our knowledge on 4 specific aspects of its biology. Then, we will look at cancer as a global health problem, considering some epidemiological aspects, and discussing treatment, with a special focus on novel therapies. Finally, we present our vision on some of the challenges and perspectives of cancer in the 21 st century.

The Biology of Cancer

Cancer is a disease that begins with genetic and epigenetic alterations occurring in specific cells, some of which can spread and migrate to other tissues. 4 Although the biological processes affected in carcinogenesis and the evolution of neoplasms are many and widely different, we will focus on 4 aspects that are particularly relevant in tumor biology: genomic and epigenomic alterations that lead to cell transformation, the cells where these changes occur, and the processes of invasion and metastasis that, to an important degree, determine tumor aggressiveness.

Cancer Genomics

The genomics of cancer can be defined as the study of the complete sequence of DNA and its expression in tumor cells. Evidently, this study only becomes meaningful when compared to normal cells. The sequencing of the human genome, completed in 2003, was not only groundbreaking with respect to the knowledge of our gene pool, but also changed the way we study cancer. In the post-genomic era, various worldwide endeavors, such as the Human Cancer Genome Project , the Cancer Genome ATLAS (TCGA), the International Cancer Genome Consortium, and the Pan-Cancer Analysis Working Group (PCAWG), have contributed to the characterization of thousands of primary tumors from different neoplasias, generating more than 2.5 petabytes (10 15 ) of genomic, epigenomic, and proteomic information. This has led to the building of databases and analytical tools that are available for the study of cancer from an “omic” perspective, 7 , 8 and it has helped to modify classification and treatment of various neoplasms.

Studies in the past decade, including the work by the PCAWG, have shown that cancer generally begins with a small number of driving mutations (4 or 5 mutations) in particular genes, including oncogenes and tumor-suppressor genes. Mutations in TP53, a tumor-suppressor gene, for example, are found in more than half of all cancer types as an early event, and they are a hallmark of precancerous lesions. 9 - 12 From that point on, the evolution of tumors may take decades, throughout which the mutational spectrum of tumor cells changes significantly. Mutational analysis of more than 19 000 exomes revealed a collection of genomic signatures, some associated with defects in the mechanism of DNA repair. These studies also revealed the importance of alterations in non-coding regions of DNA. Thus, for example, it has been observed that various pathways of cell proliferation and chromatin remodeling are altered by mutations in coding regions, while pathways, such as WNT and NOTCH, can be disrupted by coding and non-coding mutations. To the present date, 19 955 genes that codify for proteins and 25 511 genes for non-coding RNAs have been identified ( https://www.gencodegenes.org/human/stats.html ). Based on this genomic catalogue, the COSMIC (Catalogue Of Somatic Mutations In Cancer) repository, the most robust database to date, has registered 37 288 077 coding mutations, 19 396 fusions, 1 207 190 copy number variants, and 15 642 672 non-coding variants reported up to August 2020 (v92) ( https://cosmic-blog.sanger.ac.uk/cosmic-release-v92/ ).

The genomic approach has accelerated the development of new cancer drugs. Indeed, two of the most relevant initiatives in recent years are ATOM (Accelerating Therapeutics for Opportunities in Medicine), which groups industry, government and academia, with the objective of accelerating the identification of drugs, 13 and the Connectivity Map (CMAP), a collection of transcriptional data obtained from cell lines treated with drugs for the discovery of functional connections between genes, diseases, and drugs. The CMAP 1.0 covered 1300 small molecules and more than 6000 signatures; meanwhile, the CMAP 2.0 with L1000 assay profiled more than 1.3 million samples and approximately 400 000 signatures. 14

The genomic study of tumors has had 2 fundamental contributions. On the one hand, it has allowed the confirmation and expansion of the concept of intratumor heterogeneity 15 , 16 ; and on the other, it has given rise to new classification systems for cancer. Based on the molecular classification developed by expression profiles, together with mutational and epigenomic profiles, a variety of molecular signatures have been identified, leading to the production of various commercial multigene panels. In breast cancer, for example, different panels have been developed, such as Pam50/Prosigna , Blue Print , OncotypeDX , MammaPrint , Prosigna , Endopredict , Breast Cancer Index , Mammostrat, and IHC4 . 17

Currently, the genomic/molecular study of cancer is more closely integrated with clinical practice, from the classification of neoplasms, as in tumors of the nervous system, 18 to its use in prediction, as in breast cancer. 17 Improvement in molecular methods and techniques has allowed the use of smaller amounts of biological material, as well as paraffin-embedded samples for genomic studies, both of which provide a wealth of information. 19 In addition, non-invasive methods, such as liquid biopsies, represent a great opportunity not only for the diagnosis of cancer, but also for follow-up, especially for unresectable tumors. 20

Research for the production of genomic information on cancer is presently dominated by several consortia, which has allowed the generation of a great quantity of data. However, most of these consortia and studies are performed in countries with a high human development index (HDI), and countries with a low HDI are not well represented in these large genomic studies. This is why initiatives such as Human Heredity and Health in Africa (H3Africa) for genomic research in Africa are essential. 21 Generation of new information and technological developments, such as third-generation sequencing, will undoubtedly continue to move forward in a multidisciplinary and complex systems context. However, the existing disparities in access to genomic tools for diagnosis, prognosis, and treatment of cancer will continue to be a pressing challenge at regional and social levels.

Cancer Epigenetics

Epigenetics studies the molecular mechanisms that produce hereditable changes in gene expression, without causing alterations in the DNA sequence. Epigenetic events are of 3 types: methylation of DNA and RNA, histone modification (acetylation, methylation, and phosphorylation), and the expression of non-coding RNA. Epigenetic aberrations can drive carcinogenesis when they alter chromosome conformation and the access to transcriptional machinery and to various regulatory elements (promoters, enhancers, and anchors for interaction with chromatin, for example). These changes may activate oncogenesis and silence tumor-suppressor mechanisms when they modulate coding and non-coding sequences (such as micro-RNAs and long-RNAs). This can then lead to uncontrolled growth, as well as the invasion and metastasis of cancer cells.

While genetic mutations are stable and irreversible, epigenetic alterations are dynamic and reversible; that is, there are several epigenomes, determined by space and time, which cause heterogeneity of the “epigenetic status” of tumors during their development and make them susceptible to environmental stimuli or chemotherapeutic treatment. 22 Epigenomic variability creates differences between cells, and this creates the need to analyze cells at the individual level. In the past, epigenetic analyses measured “average states” of cell populations. These studies revealed general mechanisms, such as the role of epigenetic marks on active or repressed transcriptional states, and established maps of epigenetic composition in a variety of cell types in normal and cancerous tissue. However, these approaches are difficult to use to examine events occurring in heterogeneous cell populations or in uncommon cell types. This has led to the development of new techniques that permit marking of a sequence on the epigenome and improvement in the recovery yield of epigenetic material from individual cells. This has helped to determine changes in DNA, RNA, and histones, chromatin accessibility, and chromosome conformation in a variety of neoplasms. 23 , 24

In cancer, DNA hypomethylation occurs on a global scale, while hypermethylation occurs in specific genomic loci, associated with abnormal nucleosome positioning and chromatin modifications. This information has allowed epigenomic profiles to be established in different types of neoplasms. In turn, these profiles have served as the basis to identify new neoplasm subgroups. For example, in triple negative breast cancer (TNBC), 25 and in hepatocellular carcinoma, 26 DNA methylation profiles have helped to the identification of distinct subgroups with clinical relevance. Epigenetic approaches have also helped to the development of prognostic tests to assess the sensitivity of cancer cells to specific drugs. 27

Epigenetic traits could be used to characterize intratumoral heterogeneity and determine the relevance of such a heterogeneity in clonal evolution and sensitivity to drugs. However, it is clear that heterogeneity is not only determined by genetic and epigenetic diversity resulting from clonal evolution of tumor cells, but also by the various cell populations that form the tumor microenvironment (TME). 28 Consequently, the epigenome of cancer cells is continually remodeled throughout tumorigenesis, during resistance to the activity of drugs, and in metastasis. 29 This makes therapeutic action based on epigenomic profiles difficult, although significant advances in this area have been reported. 30

During carcinogenesis and tumor progression, epigenetic modifications are categorized by their mechanisms of regulation ( Figure 1A ) and the various levels of structural complexity ( Figure 1B ). In addition, the epigenome can be modified by environmental stimuli, stochastic events, and genetic variations that impact the phenotype ( Figure 1C ). 31 , 32 The molecules that take part in these mechanisms/events/variations are therapeutic targets of interest with potential impact on clinical practice. There are studies on a wide variety of epidrugs, either alone or in combination, which improve antitumor efficacy. 33 However, the problems with these drugs must not be underestimated. For a considerable number of epigenetic compounds still being under study, the main challenge is to translate in vitro efficacy of nanomolar (nM) concentrations into well-tolerated and efficient clinical use. 34 The mechanisms of action of epidrugs may not be sufficiently controlled and could lead to diversion of the therapeutic target. 35 It is known that certain epidrugs, such as valproic acid, produce unwanted epigenetic changes 36 ; thus the need for a well-established safety profile before these drugs can be used in clinical therapy. Finally, resistance to certain epidrugs is another relevant problem. 37 , 38

Epigenetics of cancer. (A) Molecular mechanisms. (B) Structural hierarchy of epigenomics. (C) Factors affecting the epigenome. Modified from Refs. 31 and 32 .

As we learn about the epigenome of specific cell populations in cancer patients, a door opens to the evaluation of sensitivity tests and the search for new molecular markers for detection, prognosis, follow-up, and/or response to treatment at various levels of molecular regulation. Likewise, the horizon expands for therapeutic alternatives in oncology with the use of epidrugs, such as pharmacoepigenomic modulators for genes and key pathways, including methylation of promoters and regulation of micro-RNAs involved in chemoresponse and immune response in cancer. 39 There is no doubt that integrated approaches identifying stable pharmagenomic and epigenomic patterns and their relation with expression profiles and genetic functions will be more and more valuable in our fight against cancer.

Cancer Stem Cells

Tumors consist of different populations of neoplastic cells and a variety of elements that form part of the TME, including stromal cells and molecules of the extracellular matrix. 40 Such intratumoral heterogeneity becomes even more complex during clonal variation of transformed cells, as well as influence the elements of the TME have on these cells throughout specific times and places. 41 To explain the origin of cancer cell heterogeneity, 2 models have been put forward. The first proposes that mutations occur at random during development of the tumor in individual neoplastic cells, and this promotes the production of various tumor populations, which acquire specific growth and survival traits that lead them to evolve according to intratumor mechanisms of natural selection. 42 The second model proposes that each tumor begins as a single cell that possess 2 functional properties: it can self-renew and it can produce several types of terminal cells. As these 2 properties are characteristics of somatic stem cells, 43 the cells have been called cancer stem cells (CSCs). 44 According to this model, tumors must have a hierarchical organization, where self-renewing stem cells produce highly proliferating progenitor cells, unable to self-renew but with a high proliferation potential. The latter, in turn, give rise to terminal cells. 45 Current evidence indicates that both models may coexist in tumor progression. In agreement with this idea, new subclones could be produced as a result of a lack of genetic stability and mutational changes, in addition to the heterogeneity derived from the initial CSC and its descendants. Thus, in each tumor, a set of neoplastic cells with different genetic and epigenetic traits may be found, which would provide different phenotypic properties. 46

The CSC concept was originally presented in a model of acute myeloid leukemia. 47 The presence of CSCs was later proved in chronic myeloid leukemia, breast cancer, tumors of the central nervous system, lung cancer, colon cancer, liver cancer, prostate cancer, pancreatic cancer, melanoma, and cancer of the head and neck, amongst others. In all of these cases, detection of CSCs was based on separation of several cell populations according to expression of specific surface markers, such as CD133, CD44, CD24, CD117, and CD15. 48 It is noteworthy that in some solid tumors, and even in some hematopoietic ones, a combination of specific markers that allow the isolation of CSCs has not been found. Interestingly, in such tumors, a high percentage of cells with the capacity to start secondary tumors has been observed; thus, the terms Tumor Initiating Cells (TIC) or Leukemia Initiating Cells (LIC) have been adopted. 46

A relevant aspect of the biology of CSCs is that, just like normal stem cells, they can self-renew. Such self-renewal guarantees the maintenance or expansion of the tumor stem cell population. Another trait CSCs share with normal stem cells is their quiescence, first described in chronic myeloid leukemia. 49 The persistence of quiescent CSCs in solid tumors has been recently described in colorectal cancer, where quiescent clones can become dominant after therapy with oxaliplatin. 50 In non-hierarchical tumors, such as melanoma, the existence of slow-cycling cells that are resistant to antimitogenic agents has also been proved. 51 Such experimental evidence supports the idea that quiescent CSCs or TICs are responsible for both tumor resistance to antineoplastic drugs and clinical relapse after initial therapeutic success.

In addition to quiescence, CSCs use other mechanisms to resist the action of chemotherapeutic drugs. One of these is their increased numbers: upon diagnosis, a high number of CSCs are observed in most analyzed tumors, making treatment unable to destroy all of them. On the other hand, CSCs have a high number of molecular pumps that expulse drugs, as well as high numbers of antiapoptotic molecules. In addition, they have very efficient mechanisms to repair DNA damage. In general, these cells show changes in a variety of signaling pathways involved in proliferation, survival, differentiation, and self-renewal. It is worth highlighting that in recent years, many of these pathways have become potential therapeutic targets in the elimination of CSCs. 52 Another aspect that is highly relevant in understanding the biological behavior of CSCs is that they require a specific site for their development within the tissue where they are found that can provide whatever is needed for their survival and growth. These sites, known as niches, are made of various cells, both tumor and non-tumor, as well as a variety of non-cellular elements (extracellular matrix [ECM], soluble cytokines, ion concentration gradients, etc.), capable of regulating the physiology of CSCs in order to promote their expansion, the invasion of adjacent tissues, and metastasis. 53

It is important to consider that although a large number of surface markers have been identified that allow us to enrich and prospectively follow tumor stem cell populations, to this day there is no combination of markers that allows us to find these populations in all tumors, and it is yet unclear if all tumors present them. In this regard, it is necessary to develop new purification strategies based on the gene expression profiles of these cells, so that tumor heterogeneity is taken into account, as it is evident that a tumor can include multiple clones of CSCs that, in spite of being functional, are genetically different, and that these clones can vary throughout space (occupying different microenvironments and niches) and time (during the progression of a range of tumor stages). Such strategies, in addition to new in vitro and in vivo assays, will allow the development of new and improved CSC elimination strategies. This will certainly have an impact on the development of more efficient therapeutic alternatives.

Invasion and Metastasis

Nearly 90% of the mortality associated with cancer is related to metastasis. 54 This consists of a cascade of events ( Figure 2 ) that begins with the local invasion of a tumor into surrounding tissues, followed by intravasation of tumor cells into the blood stream or lymphatic circulation. Extravasation of neoplastic cells in areas distant from the primary tumor then leads to the formation of one or more micrometastatic lesions which subsequently proliferate to form clinically detectable lesions. 4 The cells that are able to produce metastasis must acquire migratory characteristics, which occur by a process known as epithelial–mesenchymal transition (EMT), that is, the partial loss of epithelial characteristics and the acquirement of mesenchymal traits. 55

Invasion and metastasis cascade. Invasion and metastasis can occur early or late during tumor progression. In either case, invasion to adjacent tissues is driven by stem-like cells (cancer stem cells) that acquire the epithelial–mesenchymal transition (EMT) (1). Once they reach sites adjacent to blood vessels, tumor cells (individually or in clusters) enter the blood (2). Tumor cells in circulation can adhere to endothelium and extravasation takes place (3). Other mechanisms alternative to extravasation can exist, such as angiopelosis, in which clusters of tumor cells are internalized by the endothelium. Furthermore, at certain sites, tumor cells can obstruct microvasculature and initiate a metastatic lesion right there. Sometimes, a tumor cells that has just exit circulation goes into an MET in order to become quiescent (4). Inflammatory signals can activate quiescent metastatic cells that will proliferate and generate a clinically detectable lesion (5).

Although several of the factors involved in this process are currently known, many issues are still unsolved. For instance, it has not yet been possible to monitor in vivo the specific moment when it occurs 54 ; the microenvironmental factors of the primary tumor that promote such a transition are not known with precision; and the exact moment during tumor evolution in which one cell or a cluster of cells begin to migrate to distant areas, is also unknown. The wide range of possibilities offered by intra- and inter-tumoral heterogeneity 56 stands in the way of suggesting a generalized strategy that could resolve this complication.

It was previously believed that metastasis was only produced in late stages of tumor progression; however, recent studies indicate that EMT and metastasis can occur during the early course of the disease. In pancreatic cancer, for example, cells going through EMT are able to colonize and form metastatic lesions in the liver in the first stages of the disease. 52 , 57 Metastatic cell clusters circulating in peripheral blood (PB) are prone to generate a metastatic site, compared to individual tumor cells. 58 , 59 In this regard, novel strategies, such as the use of micro-RNAs, are being assessed in order to diminish induction of EMT. 60 It must be mentioned, however, that the metastatic process seems to be even more complex, with alternative pathways that do not involve EMT. 61 , 62

A crucial stage in the process of metastasis is the intravasation of tumor cells (alone or in clusters) towards the blood stream and/or lymphatic circulation. 63 These mechanisms are also under intensive research because blocking them could allow the control of spreading of the primary tumor. In PB or lymphatic circulation, tumor cells travel to distant parts for the potential formation of a metastatic lesion. During their journey, these cells must stand the pressure of blood flow and escape interaction with natural killer (NK) cells . 64 To avoid them, tumor cells often cover themselves with thrombocytes and also produce factors such as VEGF, angiopoietin-2, angiopoietin-4, and CCL2 that are involved in the induction of vascular permeability. 54 , 65 Neutrophils also contribute to lung metastasis in the bloodstream by secreting IL-1β and metalloproteases to facilitate extravasation of tumor cells. 64

The next step in the process of metastasis is extravasation, for which tumor cells, alone or in clusters, can use various mechanisms, including a recently described process known as angiopellosis that involves restructuring the endothelial barrier to internalize one or several cells into a tissue. 66 The study of leukocyte extravasation has contributed to a more detailed knowledge of this process, in such a way that some of the proposed strategies to avoid extravasation include the use of integrin inhibitors, molecules that are vital for rolling, adhesion, and extravasation of tumor cells. 67 , 68 Another strategy that has therapeutic potential is the use of antibodies that strengthen vascular integrity to obstruct transendothelial migration of tumor cells and aid in their destruction in PB. 69

Following extravasation, tumor cells can return to an epithelial phenotype, a process known as mesenchymal–epithelial transition and may remain inactive for several years. They do this by competing for specialized niches, like those in the bone marrow, brain, and intestinal mucosa, which provide signals through the Notch and Wnt pathways. 70 Through the action of the Wnt pathway, tumor cells enter a slow state of the cell cycle and induce the expression of molecules that inhibit the cytotoxic function of NK cells. 71 The extravasated tumor cell that is in a quiescent state must comply with 2 traits typical of stem cells: they must have the capacity to self-renew and to generate all of the cells that form the secondary tumor.

There are still several questions regarding the metastatic process. One of the persisting debates at present is if EMT is essential for metastasis or if it plays a more important role in chemoresistance. 61 , 62 It is equally important to know if there is a pattern in each tumor for the production of cells with the capacity to carry out EMT. In order to control metastasis, it is fundamental to know what triggers acquisition of the migratory phenotype and the intrinsic factors determining this transition. Furthermore, it is essential to know if mutations associated with the primary tumor or the variety of epigenetic changes are involved in this process. 55 It is clear that metastatic cells have affinity for certain tissues, depending on the nature of the primary tumor (seed and soil hypothesis). This may be caused by factors such as the location and the direction of the bloodstream or lymphatic fluid, but also by conditioning of premetastatic niches at a distance (due to the large number of soluble factors secreted by the tumor and the recruitment of cells of the immune system to those sites). 72 We have yet to identify and characterize all of the elements that participate in this process. Deciphering them will be of upmost importance from a therapeutic point of view.

Epidemiology of Cancer

Cancer is the second cause of death worldwide; today one of every 6 deaths is due to a type of cancer. According to the International Agency for Research on Cancer (IARC), in 2020 there were approximately 19.3 million new cases of cancer, and 10 million deaths by this disease, 6 while 23.8 million cases and 13.0 million deaths are projected to occur by 2030. 73 In this regard, it is clear the increasing role that environmental factors—including environmental pollutants and processed food—play as cancer inducers and promoters. 74 The types of cancer that produce the greatest numbers of cases and deaths worldwide are indicated in Table 1 . 6

Total Numbers of Cancer Cases and Deaths Worldwide in 2020 by Cancer Type (According to the Global Cancer Observatory, IARC).

Data presented on this table were obtained from Ref. 6.

As shown in Figure 3 , lung, breast, prostate, and colorectal cancer are the most common throughout the world, and they are mostly concentrated in countries of high to very high human development index (HDI). Although breast, prostate, and colorectal cancer have a high incidence, the number of deaths they cause is proportionally low, mostly reflecting the great progress made in their control. However, these data also reveal the types of cancer that require further effort in prevention, precise early detection avoiding overdiagnosis, and efficient treatment. This is the case of liver, lung, esophageal, and pancreatic cancer, where the difference between the number of cases and deaths is smaller ( Figure 3B ). Social and economic transition in several countries has had an impact on reducing the incidence of neoplasms associated with infection and simultaneously produced an increase in the types related to reproductive, dietary, and hormonal factors. 75

Incidence and mortality for some types of cancer in the world. (A) Estimated number of cases and deaths in 2020 for the most frequent cancer types worldwide. (B) Incidence and mortality rates, normalized according to age, for the most frequent cancer types in countries with very high/& high (VH&H; blue) and/low and middle (L&M; red) Human Development Index (HDI). Data include both genders and all ages. Data according to https://gco.iarc.fr/today , as of June 10, 2021.

In the past 3 decades, cancer mortality rates have fallen in high HDI countries, with the exception of pancreatic cancer, and lung cancer in women. Nevertheless, changes in the incidence of cancer do not show the same consistency, possibly due to variables such as the possibility of early detection, exposure to risk factors, or genetic predisposition. 76 , 77 Countries such as Australia, Canada, Denmark, Ireland, New Zealand, Norway, and the United Kingdom have reported a reduction in incidence and mortality in cancer of the stomach, colon, lung, and ovary, as well as an increase in survival. 78 Changes in modifiable risk factors, such as the use of tobacco, have played an important role in prevention. In this respect, it has been estimated that decline in tobacco use can explain between 35% and 45% of the reduction in cancer mortality rates, 79 while the fall in incidence and mortality due to stomach cancer can be attributed partly to the control of Helicobacter pylori infection. 80 Another key factor in the fall of mortality rates in developed countries has been an increase in early detection as a result of screening programs, as in breast and prostate cancer, which have had their mortality rates decreased dramatically in spite of an increase in their incidence. 76

Another important improvement observed in recent decades is the increase in survival rates, particularly in high HDI countries. In the USA, for example, survival rates for patients with prostate cancer at 5 years after initial diagnosis was 28% during 1947–1951; 69% during 1975–1977, and 100% during 2003–2009. Something similar occurred with breast cancer, with a 5-year survival rate of 54% in 1947–1951, 75% in 1975–1977, and 90% in 2003–2009. 81 In the CONCORD 3 version, age-standardize 5-year survival for patients with breast cancer in the USA during 2010–2014 was 90%, and 97% for prostate cancer patients. 82 Importantly, even among high HDI countries, significant differences have been identified in survival rates, being stage of disease at diagnosis, time for access to effective treatment, and comorbidities, the main factors influencing survival in these nations. 78 Unfortunately, survival rates in low HDI countries are significantly lower due to several factors, including lack of information, deficient screening and early detection programs, limited access to treatment, and suboptimal cancer registration. 82 It should be noted that in countries with low to middle HDI, neoplasms with the greatest incidence are those affecting women (breast and cervical cancer), which reflects not only a problem with access to health services, but also a serious inequality issue that involves social, cultural, and even religious obstacles. 83

Up to 42% of incident cases and 47% of deaths by cancer in the USA are due to potentially modifiable risk factors such as use of tobacco, physical activity, diet, and infection. 84 It has been calculated that 2.4 million deaths by cancer, mostly of the lung, can be attributed to tobacco. 73 In 2020, the incidence rate of lung cancer in Western Africa was 2.2, whereas in Polynesia and Eastern Asia was 37.3 and 34.4, respectively. 6 In contrast, the global burden of cancer associated with infection was 15.4%, but in Sub-Saharan Africa it was 30%. 85 Likewise, the incidence of cervical cancer in Eastern Africa was 40.1, in contrast with the USA and Canada that have a rate of 6.2. This makes it clear that one of the challenges we face is the reduction of the risk factors that are potentially modifiable and associated with specific types of cancer.

Improvement of survival rates and its disparities worldwide are also important challenges. Five-year survival for breast cancer—diagnosed during 2010-2014— in the USA, for example, was 90%, whereas in countries like South Africa it was 40%. 82 Childhood leukemia in the USA and several European countries shows a 5-year survival of 90%, while in Latin-American countries it is 50–76%. 86 Interestingly, there are neoplasms, such as pancreatic cancer, for which there has been no significant increase in survival, which remains low (5–15%) both in developed and developing countries. 82

Although data reported on global incidence and mortality gives a general overview on the epidemiology of cancer, it is important to note that there are great differences in coverage of cancer registries worldwide. To date, only 1 out of every 3 countries reports high quality data on the incidence of cancer. 87 For the past 50 years, the IARC has supported population-based cancer registries; however, more than one-third of the countries belonging to the WHO, mainly countries of low and middle income (LMIC), have no data on more than half of the 18 indicators of sustainable development goals. 88 High quality cancer registries only cover 4% of the population in Africa, 8% in Asia, and 7% in Latin America, contrasting with 83% in the USA and Canada, and 33% in Europe. 89 In response to this situation, the Global Initiative for Cancer Registry Development was created in 2012 to generate improved infrastructure to permit greater coverage and better quality registries, especially in countries with low and middle HDI. 88 It is expected that initiatives of this sort in the coming years will allow more and better information to guide strategies for the control of cancer worldwide, especially in developing regions. This will enable survival to be measured over longer periods of time (10, 15, or 20 years), as an effective measure in the control of cancer. The WHO has established as a target for 2025 to reduce deaths by cancer and other non-transmissible diseases by 25% in the population between the ages of 30–69; such an effort requires not only effective prevention measures to reduce incidence, but also more efficient health systems to diminish mortality and increase survival. At the moment, it is an even greater challenge because of the effects of the COVID-19 pandemic which has negatively impacted cancer prevention and health services. 90

Oncologic Treatments

A general perspective.

At the beginning of the 20th century, cancer treatment, specifically treatment of solid tumors, was based fundamentally on surgical resection of tumors, which together with other methods for local control, such as cauterization, had been used since ancient times. 91 At that time, there was an ongoing burst of clinical observations along with interventions sustained on fundamental knowledge about physics, chemistry, and biology. In the final years of the 19 th century and the first half of the 20th, these technological developments gave rise to radiotherapy, hormone therapy, and chemotherapy. 92 - 94 Simultaneously, immunotherapy was also developed, although usually on a smaller scale, in light of the overwhelming progress of chemotherapy and radiotherapy. 95

Thus began the development and expansion of disciplines based on these approaches (surgery, radiotherapy, chemotherapy, hormone therapy, and immunotherapy), with their application evolving ever more rapidly up to their current uses. Today, there is a wide range of therapeutic tools for the care of cancer patients. These include elements that emerged empirically, arising from observations of their effects in various medical fields, as well as drugs that were designed to block processes and pathways that form part of the physiopathology of one or more neoplasms according to knowledge of specific molecular alterations. A classic example of the first sort of tool is mustard gas, originally used as a weapon in war, 96 but when applied for medical purposes, marked the beginning of the use of chemicals in the treatment of malignant neoplasms, that is, chemotherapy. 94 A clear example of the second case is imatinib, designed specifically to selectively inhibit a molecular alteration in chronic myeloid leukemia: the Bcr-Abl oncoprotein. 97

It is on this foundation that today the 5 areas mentioned previously coexist and complement one another. The general framework that motivates this amalgam and guides its development is precision medicine, founded on the interaction of basic and clinical science. In the forecasts for development in each of these fields, surgery is expected to continue to be the fundamental approach for primary tumors in the foreseeable future, as well as when neoplastic disease in the patient is limited, or can be limited by applying systemic or regional elements, before and/or after surgical resection, and it can be reasonably anticipated for the patient to have a significant period free from disease or even to be cured. With regards to technology, intensive exploration of robotic surgery is contemplated. 98

The technological possibilities for radiotherapy have progressed in such a way that it is now possible to radiate neoplastic tissue with an extraordinary level of precision, and therefore avoid damage to healthy tissue. 99 This allows administration of large doses of ionizing radiation in one or a few fractions, what is known as “radiosurgery.” The greatest challenges to the efficacy of this approach are related to radio-resistance in certain neoplasms. Most efforts regarding research in this field are concentrated on understanding the underlying biological mechanisms of the phenomenon and their potential control through radiosensitizers. 100

“Traditional” chemotherapy, based on the use of compounds obtained from plants and other natural products, acting in a non-specific manner on both neoplastic and healthy tissues with a high proliferation rate, continues to prevail. 101 The family of chemotherapeutic drugs currently includes alkylating agents, antimetabolites, anti-topoisomerase agents, and anti-microtubules. Within the pharmacologic perspective, the objective is to attain a high concentration or activity of such molecules in specific tissues while avoiding their accumulation in others, in order to achieve an increase in effectiveness and a reduction in toxicity. This has been possible with the use of viral vectors, for example, that are able to limit their replication in neoplastic tissues, and activate prodrugs of normally nonspecific agents, like cyclophosphamide, exclusively in those specific areas. 102 More broadly, chemotherapy also includes a subgroup of substances, known as molecular targeted therapy, that affect processes in a more direct and specific manner, which will be mentioned later.

There is no doubt that immunotherapy—to be explored next—is one of the therapeutic fields where development has been greatest in recent decades and one that has produced enormous expectation in cancer treatment. 103 Likewise, cell therapy, based on the use of immune cells or stem cells, has come to complement the oncologic therapeutic arsenal. 43 Each and every one of the therapeutic fields that have arisen in oncology to this day continue to prevail and evolve. Interestingly, the foreseeable future for the development of cancer treatment contemplates these approaches in a joint and complementary manner, within the general framework of precision medicine, 104 and sustained by knowledge of the biological mechanisms involved in the appearance and progression of neoplasms. 105 , 106

Immunotherapy

Stimulating the immune system to treat cancer patients has been a historical objective in the field of oncology. Since the early work of William Coley 107 to the achievements reached at the end of the 20 th century, scientific findings and technological developments paved the way to searching for new immunotherapeutic strategies. Recombinant DNA technology allowed the synthesis of cytokines, such as interferon-alpha (IFN-α) and interleukin 2 (IL-2), which were authorized by the US Food and Drug Administration (FDA) for the treatment of hairy cell leukemia in 1986, 108 as well as kidney cancer and metastatic melanoma in 1992 and 1998, respectively. 109

The first therapeutic vaccine against cancer, based on the use of autologous dendritic cells (DCs), was approved by the FDA against prostate cancer in 2010. However, progress in the field of immunotherapy against cancer was stalled in the first decade of the present century, mostly due to failure of several vaccines in clinical trials. In many cases, application of these vaccines was detained by the complexity and cost involved in their production. Nevertheless, with the coming of the concept of immune checkpoint control, and the demonstration of the relevance of molecules such as cytotoxic T-lymphocyte antigen 4 (CTLA-4), and programmed cell death molecule-1 (PD-1), immunotherapy against cancer recovered its global relevance. In 2011, the monoclonal antibody (mAb) ipilimumab, specific to the CTLA-4 molecule, was the first checkpoint inhibitor (CPI) approved for the treatment of advanced melanoma. 110 Later, inhibitory mAbs for PD-1, or for the PD-1 ligand (PD-L1), 111 as well as the production of T cells with chimeric receptors for antigen recognition (CAR-T), 112 which have been approved to treat various types of cancer, including melanoma, non-small cell lung cancer (NSCLC), head and neck cancer, bladder cancer, renal cell carcinoma (RCC), and hepatocellular carcinoma, among others, have changed the paradigm of cancer treatment.

In spite of the current use of anti-CTLA-4 and anti-PD-L1 mAbs, only a subgroup of patients has responded favorably to these CPIs, and the number of patients achieving clinical benefit is still small. It has been estimated that more than 70% of patients with solid tumors do not respond to CPI immunotherapy because either they show primary resistance, or after responding favorably, develop resistance to treatment. 113 In this regard, it is important to mention that in recent years very important steps have been taken to identify the intrinsic and extrinsic mechanisms that mediate resistance to CPI immunotherapy. 114 Intrinsic mechanisms include changes in the antitumor immune response pathways, such as faulty processing and presentation of antigens by APCs, activation of T cells for tumor cell destruction, and changes in tumor cells that lead to an immunosuppressive TME. Extrinsic factors include the presence of immunosuppressive cells in the local TME, such as regulatory T cells, myeloid-derived suppressor cells (MDSC), mesenchymal stem/stromal cells (MSCs), and type 2 macrophages (M2), in addition to immunosuppressive cytokines.

On the other hand, classification of solid tumors as “hot,” “cold,” or “excluded,” depending on T cell infiltrates and the contact of such infiltrates with tumor cells, as well as those that present high tumor mutation burden (TMB), have redirected immunotherapy towards 3 main strategies 115 ( Table 2 ): (1) Making T-cell antitumor response more effective, using checkpoint inhibitors complementary to anti-CTLA-4 and anti-PD-L1, such as LAG3, Tim-3, and TIGT, as well as using CAR-T cells against tumor antigens. (2) Activating tumor-associated myeloid cells including monocytes, granulocytes, macrophages, and DC lineages, found at several frequencies within human solid tumors. (3) Regulating the biochemical pathways in TME that produce high concentrations of immunosuppressive molecules, such as kynurenine, a product of tryptophan metabolism, through the activity of indoleamine 2,3 dioxygenase; or adenosine, a product of ATP hydrolysis by the activity of the enzyme 5’nucleotidase (CD73). 116

Current Strategies to Stimulate the Immune Response for Antitumor Immunotherapy.

Abbreviations: TME, tumor microenvironment; IL, interleukin; TNF, Tumor Necrosis Factor; TNFR, TNF-receptor; CD137, receptor–co-stimulator of the TNFR family; OX40, member number 4 of the TNFR superfamily; CD27/CD70, member of the TNFR superfamily; CD40/CD40L, antigen-presenting cells (APC) co-stimulator and its ligand; GM-CSF, granulocyte-macrophage colony-stimulating factor; IFN, interferon; STING, IFN genes-stimulator; RIG-I, retinoic acid inducible gene-I; MDA5, melanoma differentiation-associated protein 5; CDN, cyclic dinucleotide; ATP, adenosine triphosphate; HMGB1, high mobility group B1 protein; TLR, Toll-like receptor; HVEM, Herpes virus entry mediator; GITR, glucocorticoid-induced TNFR family-related gene; CTLA4, cytotoxic T lymphocyte antigen 4; PD-L1, programmed death ligand-1; TIGIT, T-cell immunoreceptor with immunoglobulin and tyrosine-based inhibition motives; CSF1/CSF1R, colony-stimulating factor-1 and its receptor; CCR2, Type 2 chemokine receptor; PI3Kγ, Phosphoinositide 3-Kinase γ; CXCL/CCL, chemokine ligands; LFA1, lymphocyte function-associated antigen 1; ICAM1, intercellular adhesion molecule 1; VEGF, vascular endothelial growth factor; IDO, indolamine 2,3-dioxigenase; TGF, transforming growth factor; LAG-3, lymphocyte-activation gene 3 protein; TIM-3, T-cell immunoglobulin and mucin-domain containing-3; CD73, 5´nucleotidase; ARs, adenosine receptors; Selectins, cell adhesion molecules; CAR-T, chimeric antigen receptor T cell; TCR-T, T-cell receptor engineered T cell.

Apart from the problems associated with its efficacy (only a small group of patients respond to it), immunotherapy faces several challenges related to its safety. In other words, immunotherapy can induce adverse events in patients, such as autoimmunity, where healthy tissues are attacked, or cytokine release syndrome and vascular leak syndrome, as observed with the use of IL-2, both of which lead to serious hypotension, fever, renal failure, and other adverse events that are potentially lethal. The main challenges to be faced by immunotherapy in the future will require the combined efforts of basic and clinical scientists, with the objective of accelerating the understanding of the complex interactions between cancer and the immune system, and improve treatment options for patients. Better comprehension of immune phenotypes in tumors, beyond the state of PD-L1 and TME, will be relevant to increase immunotherapy efficacy. In this context, the identification of precise tumor antigenicity biomarkers by means of new technologies, such as complete genome sequencing, single cell sequencing, and epigenetic analysis to identify sites or subclones typical in drug resistance, as well as activation, traffic and infiltration of effector cells of the immune response, and regulation of TME mechanisms, may help define patient populations that are good candidates for specific therapies and therapeutic combinations. 117 , 118 Likewise, the use of agents that can induce specific activation and modulation of the response of T cells in tumor tissue, will help improve efficacy and safety profiles that can lead to better clinical results.

Molecular Targeted Therapy

For over 30 years, and based on the progress in our knowledge of tumor biology and its mechanisms, there has been a search for therapeutic alternatives that would allow spread and growth of tumors to be slowed down by blocking specific molecules. This approach is known as molecular targeted therapy. 119 Among the elements generally used as molecular targets there are transcription factors, cytokines, membrane receptors, molecules involved in a variety of signaling pathways, apoptosis modulators, promoters of angiogenesis, and cell cycle regulators. 120

Imatinib, a tyrosine kinase inhibitor for the treatment of chronic myeloid leukemia, became the first targeted therapy in the final years of the 1990s. 97 From then on, new drugs have been developed by design, and today more than 60 targeted therapies have been approved by the FDA for the treatment of a variety of cancers ( Table 3 ). 121 This has had a significant impact on progression-free survival and global survival in neoplasms such as non-small cell lung cancer, breast cancer, renal cancer, and melanoma.

FDA Approved Molecular Targeted Therapies for the Treatment of Solid Tumors.

Abbreviations: mAb, monoclonal antibody; ALK, anaplastic lymphoma kinase; CDK, cyclin-dependent kinase; CTLA-4, cytotoxic lymphocyte antigen-4; EGFR, epidermal growth factor receptor; FGFR, fibroblast growth factor receptor; GIST, gastrointestinal stroma tumor; mTOR, target of rapamycine in mammal cells; NSCLC, non-small cell lung carcinoma; PARP, poli (ADP-ribose) polimerase; PD-1, programmed death protein-1; PDGFR, platelet-derived growth factor receptor; PD-L1, programmed death ligand-1; ER, estrogen receptor; PR, progesterone receptor; TKR, tyrosine kinase receptors; SERM, selective estrogen receptor modulator; TKI, tyrosine kinase inhibitor; VEGFR, vascular endothelial growth factor receptor. Modified from Ref. [ 127 ].

Most drugs classified as targeted therapies form part of 2 large groups: small molecules and mAbs. The former are defined as compounds of low molecular weight (<900 Daltons) that act upon entering the cell. 120 Targets of these compounds are cell cycle regulatory proteins, proapoptotic proteins, or DNA repair proteins. These drugs are indicated based on histological diagnosis, as well as molecular tests. In this group there are multi-kinase inhibitors (RTKs) and tyrosine kinase inhibitors (TKIs), like sunitinib, sorafenib, and imatinib; cyclin-dependent kinase (CDK) inhibitors, such as palbociclib, ribociclib and abemaciclib; poli (ADP-ribose) polimerase inhibitors (PARPs), like olaparib and talazoparib; and selective small-molecule inhibitors, like ALK and ROS1. 122

As for mAbs, they are protein molecules that act on membrane receptors or extracellular proteins by interrupting the interaction between ligands and receptors, in such a way that they reduce cell replication and induce cytostasis. Among the most widely used mAbs in oncology we have: trastuzumab, a drug directed against the receptor for human epidermal growth factor-2 (HER2), which is overexpressed in a subgroup of patients with breast and gastric cancer; and bevacizumab, that blocks vascular endothelial growth factor and is used in patients with colorectal cancer, cervical cancer, and ovarian cancer. Other mAbs approved by the FDA include pembolizumab, atezolizumab, nivolumab, avelumab, ipilimumab, durvalumab, and cemiplimab. These drugs require expression of response biomarkers, such as PD-1 and PD-L1, and must also have several resistance biomarkers, such as the expression of EGFR, the loss of PTEN, and alterations in beta-catenin. 123

Because cancer is such a diverse disease, it is fundamental to have precise diagnostic methods that allow us to identify the most adequate therapy. Currently, basic immunohistochemistry is complemented with neoplastic molecular profiles to determine a more accurate diagnosis, and it is probable that in the near future cancer treatments will be based exclusively on molecular profiles. In this regard, it is worth mentioning that the use of targeted therapy depends on the existence of specific biomarkers that indicate if the patient will be susceptible to the effects of the drug or not. Thus, the importance of underlining that not all patients are susceptible to receive targeted therapy. In certain neoplasms, therapeutic targets are expressed in less than 5% of the diagnosed population, hindering a more extended use of certain drugs.

The identification of biomarkers and the use of new generation sequencing on tumor cells has shown predictive and prognostic relevance. Likewise, mutation analysis has allowed monitoring of tumor clone evolution, providing information on changes in canonic gene sequences, such as TP53, GATA3, PIK3CA, AKT1, and ERBB2; infrequent somatic mutations developed after primary treatments, like SWI-SNF and JAK2-STAT3; or acquired drug resistance mutations such as ESR1. 124 The study of mutations is vital; in fact, many of them already have specific therapeutic indications, which have helped select adequate treatments. 125

There is no doubt that molecular targeted therapy is one of the main pillars of precision medicine. However, it faces significant problems that often hinder obtaining better results. Among these, there is intratumor heterogeneity and differences between the primary tumor and metastatic sites, as well as intrinsic and acquired resistance to these therapies, the mechanisms of which include the presence of heterogeneous subclones, DNA hypermethylation, histone acetylation, and interruption of mRNA degradation and translation processes. 126 Nonetheless, beyond the obstacles facing molecular targeted therapy from a biological and methodological point of view, in the real world, access to genomic testing and specific drugs continues to be an enormous limitation, in such a way that strategies must be designed in the future for precision medicine to be possible on a global scale.

Cell Therapy

Another improvement in cancer treatment is the use of cell therapy, that is, the use of specific cells as therapeutic agents. This clinical procedure has 2 modalities: the first consists of replacing and regenerating functional cells in a specific tissue by means of stem/progenitor cells of a certain kind, 43 while the second uses immune cells as effectors to eliminate malignant cells. 127

Regarding the first type, we must emphasize the development of cell therapy based on hematopoietic stem and progenitor cells. 128 For over 50 years, hematopoietic cell transplants have been used to treat a variety of hematologic neoplasms (different forms of leukemia and lymphoma). Today, it is one of the most successful examples of cell therapy, including innovative modalities, such as haploidentical transplants, 129 as well as application of stem cells expanded ex vivo . 130 There are also therapies that have used immature cells that form part of the TME, such as MSCs. The replication potential and cytokine secretion capacity of these cells make them an excellent option for this type of treatment. 131 Neural stem cells can also be manipulated to produce and secrete apoptotic factors, and when these cells are incorporated into primary neural tumors, they cause a certain degree of regression. They can even be transfected with genes that encode for oncolytic enzymes capable of inducing regression of glioblastomas. 132

With respect to cell therapy using immune cells, several research groups have manipulated cells associated with tumors to make them effector cells and thus improve the efficacy and specificity of the antitumor treatment. PB leckocytes cultured in the presence of IL-2 to obtain activated lymphocytes, in combination with IL-2 administration, have been used in antitumor clinical protocols. Similarly, infiltrating lymphocytes from tumors with antitumor activity have been used and can be expanded ex vivo with IL-2. These lymphocyte populations have been used in immunomodulatory therapies in melanoma, and pancreatic and kidney tumors, producing a favorable response in treated patients. 133 NK cells and macrophages have also been used in immunotherapy, although with limited results. 134 , 135

One of the cell therapies with better projection today is the use of CAR-T cells. This strategy combines 2 forms of advanced therapy: cell therapy and gene therapy. It involves the extraction of T cells from the cancer patient, which are genetically modified in vitro to express cell surface receptors that will recognize antigens on the surface of tumor cells. The modified T cells are then reintroduced in the patient to aid in an exacerbated immune response that leads to eradication of the tumor cells ( Figure 4 ). Therapy with CAR-T cells has been used successfully in the treatment of some types of leukemia, lymphoma, and myeloma, producing complete responses in patients. 136

CAR-T cell therapy. (A) T lymphocytes obtained from cancer patients are genetically manipulated to produce CAR-T cells that recognize tumor cells in a very specific manner. (B) Interaction between CAR molecule and tumor antigen. CAR molecule is a receptor that results from the fusion between single-chain variable fragments (scFv) from a monoclonal antibody and one or more intracellular signaling domains from the T-cell receptor. CD3ζ, CD28 and 4-1BB correspond to signaling domains on the CAR molecule.

Undoubtedly, CAR-T cell therapy has been truly efficient in the treatment of various types of neoplasms. However, this therapeutic strategy can also have serious side effects, such as release of cytokines into the bloodstream, which can cause different symptoms, from high fever to multiorgan failure, and even neurotoxicity, leading to cerebral edema in many cases. 137 Adequate control of these side effects is an important medical challenge. Several research groups are trying to improve CAR-T cell therapy through various approaches, including production of CAR-T cells directed against a wider variety of tumor cell-specific antigens that are able to attack different types of tumors, and the identification of more efficient types of T lymphocytes. Furthermore, producing CAR-T cells from a single donor that may be used in the treatment of several patients would reduce the cost of this sort of personalized cell therapy. 136

Achieving wider use of cell therapy in oncologic diseases is an important challenge that requires solving various issues. 138 One is intratumor cell heterogeneity, including malignant subclones and the various components of the TME, which results in a wide profile of membrane protein expression that complicates finding an ideal tumor antigen that allows specific identification (and elimination) of malignant cells. Likewise, structural organization of the TME challenges the use of cell therapy, as administration of cell vehicles capable of recognizing malignant cells might not be able to infiltrate the tumor. This results from low expression of chemokines in tumors and the presence of a dense fibrotic matrix that compacts the inner tumor mass and avoids antitumor cells from infiltrating and finding malignant target cells.

Further Challenges in the 21st Century

Beyond the challenges regarding oncologic biomedical research, the 21 st century is facing important issues that must be solved as soon as possible if we truly wish to gain significant ground in our fight against cancer. Three of the most important have to do with prevention, early diagnosis, and access to oncologic medication and treatment.

Prevention and Early Diagnosis

Prevention is the most cost-effective strategy in the long term, both in low and high HDI nations. Data from countries like the USA indicate that between 40-50% of all types of cancer are preventable through potentially modifiable factors (primary prevention), such as use of tobacco and alcohol, diet, physical activity, exposure to ionizing radiation, as well as prevention of infection through access to vaccination, and by reducing exposure to environmental pollutants, such as pesticides, diesel exhaust particles, solvents, etc. 74 , 84 Screening, on the other hand, has shown great effectiveness as secondary prevention. Once population-based screening programs are implemented, there is generally an initial increase in incidence; however, in the long term, a significant reduction occurs not only in incidence rates, but also in mortality rates due to detection of early lesions and timely and adequate treatment.

A good example is colon cancer. There are several options for colon cancer screening, such as detection of fecal occult blood, fecal immunohistochemistry, flexible sigmoidoscopy, and colonoscopy, 139 , 140 which identify precursor lesions (polyp adenomas) and allow their removal. Such screening has allowed us to observe 3 patterns of incidence and mortality for colon cancer between the years 2000 and 2010: on one hand, an increase in incidence and mortality in countries with low to middle HDI, mainly countries in Asia, South America, and Eastern Europe; on the other hand, an increase in incidence and a fall in mortality in countries with very high HDI, such as Canada, the United Kingdom, Denmark, and Singapore; and finally a fall in incidence and mortality in countries like the USA, Japan, and France. The situation in South America and Asia seems to reflect limitations in medical infrastructure and a lack of access to early detection, 141 while the patterns observed in developed countries reveal the success, even if it may be partial, of that which can be achieved by well-structured prevention programs.

Another example of success, but also of strong contrast, is cervical cancer. The discovery of the human papilloma virus (HPV) as the causal agent of cervical cancer brought about the development of vaccines and tests to detect oncogenic genotypes, which modified screening recommendations and guidelines, and allowed several developed countries to include the HPV vaccine in their national vaccination programs. Nevertheless, the outlook is quite different in other areas of the world. Eighty percent of the deaths by cervical cancer reported in 2018 occurred in low-income nations. This reveals the urgency of guaranteeing access to primary and secondary prevention (vaccination and screening, respectively) in these countries, or else it will continue to be a serious public health problem in spite of its preventability.

Screening programs for other neoplasms, such as breast, prostate, lung, and thyroid cancer have shown outlooks that differ from those just described, because, among other reasons, these neoplasms are highly diverse both biologically and clinically. Another relevant issue is the overdiagnosis of these neoplasms, that is, the diagnosis of disease that would not cause symptoms or death in the patient. 142 It has been calculated that 25% of breast cancer (determined by mammogram), 50–60% of prostate cancer (determined by PSA), and 13–25% of lung cancer (determined by CT) are overdiagnosed. 142 Thus, it is necessary to improve the sensitivity and specificity of screening tests. In this respect, knowledge provided by the biology of cancer and “omic” sciences offers a great opportunity to improve screening and prevention strategies. All of the above shows that prevention and early diagnosis are the foundations in the fight against cancer, and it is essential to continue to implement broader screening programs and better detection methods.

Global Equity in Oncologic Treatment

Progress in cancer treatment has considerably increased the number of cancer survivors. Nevertheless, this tendency is evident only in countries with a very solid economy. Indeed, during the past 30 years, cancer mortality rates have increased 30% worldwide. 143 Global studies indicate that close to 70% of cancer deaths in the world occur in nations of low to middle income. But even in high-income countries, there are sectors of society that are more vulnerable and have less access to cancer treatments. 144 Cancer continues to be a disease of great social inequality.

In Europe, the differences in access to cancer treatment are highly marked. These treatments are more accessible in Western Europe than in its Eastern counterpart. 145 Furthermore, highly noticeable differences between high-income countries have been detected in the cost of cancer drugs. 146 It is interesting to note that in many of these cases, treatment is too costly and the clinical benefit only marginal. Thus, the importance of these problems being approached by competent national, regional, and global authorities, because if these new drugs and therapeutic programs are not accessible to the majority, progress in biomedical, clinical and epidemiological research will have a limited impact in our fight against cancer. We must not forget that health is a universal right, from which low HDI countries must not be excluded, nor vulnerable populations in nations with high HDI. The participation of a well-informed society will also be fundamental to achieve a global impact, as today we must fight not only against the disease, but also against movements and ideas (such as the anti-vaccine movement and the so-called miracle therapies) that can block the medical battle against cancer.

Final Comments

From the second half of the 20th century to the present day, progress in our knowledge about the origin and development of cancer has been extraordinary. We now understand cancer in detail in genomic, molecular, cellular, and physiological terms, and this knowledge has had a significant impact in the clinic. There is no doubt that a patient who is diagnosed today with a type of cancer has a better prospect than a patient diagnosed 20 or 50 years ago. However, we are still far from winning the war against cancer. The challenges are still numerous. For this reason, oncologic biomedical research must be a worldwide priority. Likewise, one of the fundamental challenges for the coming decades must be to reduce unequal access to health services in areas of low- to middle income, and in populations that are especially vulnerable, as well as continue improving prevention programs, including public health programs to reduce exposure to environmental chemicals and improve diet and physical activity in the general population. 74 , 84 Fostering research and incorporation of new technological resources, particularly in less privileged nations, will play a key role in our global fight against cancer.

Declaration of Conflicting Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding: The author(s) received no financial support for the research, authorship, and/or publication of this article.

Hector Mayani https://orcid.org/0000-0002-2483-3782

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The human auditory system uses amplitude modulation to distinguish music from speech

Roles Conceptualization, Data curation, Formal analysis, Funding acquisition, Investigation, Methodology, Project administration, Resources, Software, Visualization, Writing – original draft, Writing – review & editing

* E-mail: [email protected]

Affiliation Department of Psychology, New York University, New York, New York, United States of America

Roles Conceptualization, Formal analysis, Methodology, Writing – original draft, Writing – review & editing

Affiliation Department of Psychology, Chinese University of Hong Kong, Hong Kong SAR, China

Affiliation Instituto de Neurobiología, Universidad Nacional Autónoma de México, Juriquilla, Querétaro, México

Roles Conceptualization, Data curation, Formal analysis, Funding acquisition, Investigation, Methodology, Project administration, Resources, Supervision, Writing – original draft, Writing – review & editing

Affiliations Department of Psychology, New York University, New York, New York, United States of America, Ernst Struengmann Institute for Neuroscience, Frankfurt am Main, Germany, Center for Language, Music, and Emotion (CLaME), New York University, New York, New York, United States of America, Music and Audio Research Lab (MARL), New York University, New York, New York, United States of America

• Andrew Chang, 
• Xiangbin Teng, 
• M. Florencia Assaneo, 
• David Poeppel

• Published: May 28, 2024
• https://doi.org/10.1371/journal.pbio.3002631
• Reader Comments

Music and speech are complex and distinct auditory signals that are both foundational to the human experience. The mechanisms underpinning each domain are widely investigated. However, what perceptual mechanism transforms a sound into music or speech and how basic acoustic information is required to distinguish between them remain open questions. Here, we hypothesized that a sound’s amplitude modulation (AM), an essential temporal acoustic feature driving the auditory system across processing levels, is critical for distinguishing music and speech. Specifically, in contrast to paradigms using naturalistic acoustic signals (that can be challenging to interpret), we used a noise-probing approach to untangle the auditory mechanism: If AM rate and regularity are critical for perceptually distinguishing music and speech, judging artificially noise-synthesized ambiguous audio signals should align with their AM parameters. Across 4 experiments ( N = 335), signals with a higher peak AM frequency tend to be judged as speech, lower as music. Interestingly, this principle is consistently used by all listeners for speech judgments, but only by musically sophisticated listeners for music. In addition, signals with more regular AM are judged as music over speech, and this feature is more critical for music judgment, regardless of musical sophistication. The data suggest that the auditory system can rely on a low-level acoustic property as basic as AM to distinguish music from speech, a simple principle that provokes both neurophysiological and evolutionary experiments and speculations.

Citation: Chang A, Teng X, Assaneo MF, Poeppel D (2024) The human auditory system uses amplitude modulation to distinguish music from speech. PLoS Biol 22(5): e3002631. https://doi.org/10.1371/journal.pbio.3002631

Academic Editor: Manuel S. Malmierca, Universidad de Salamanca, SPAIN

Received: October 15, 2023; Accepted: April 17, 2024; Published: May 28, 2024

Copyright: © 2024 Chang et al. This is an open access article distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Data Availability: All stimuli, experimental programs, raw data, and analysis codes have been deposited at a publicly available OSF repository ( https://doi.org/10.17605/OSF.IO/RDTGC ).

Funding: A.C. was supported by a Ruth L. Kirschstein Postdoctoral Individual National Research Service Award, National Institute on Deafness and Other Communication Disorders/National Institutes of Health (F32DC018205) and Leon Levy Scholarships in Neuroscience, Leon Levy Foundation/New York Academy of Sciences. X.T. was supported by Improvement on Competitiveness in Hiring New Faculties Funding Scheme, the Chinese University of Hong Kong (4937113). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Competing interests: The authors have declared that no competing interests exist.

Introduction

Music and speech, two complex auditory signals, are frequently compared across many levels of biological sciences, ranging from system and cognitive neuroscience to comparative and evolutionary biology. As acoustic signals, they exhibit a range of interesting similarities (e.g., temporal structure [ 1 , 2 ]) and differences (e.g., music, but not speech, features discrete pitch intervals). In the brain, they are processed by both shared [ 3 – 6 ] and specialized [ 7 – 10 ] neural substrates. However, which acoustic information underpins a sound to be perceived as music or speech remains an open question.

One way to address the broader question of how music and speech are organized in the human mind/brain is to capitalize on ecologically valid, “real” signals, a more holistic approach. That strategy has the advantage of working with stimulus materials that are naturalistic and, therefore, engage the perceptual and neural systems in a typical manner (e.g., [ 11 , 12 ]). The disadvantage of adopting such an experimental attack is that it can be quite challenging to identify and isolate the components and processes that underpin perception. Here, we pursue the alternative reductionist approach: parametrically generating and manipulating ambiguous auditory stimuli with basic, analytically tractable amplitude modulation (AM) features. If the auditory system distinguishes music and speech according to the low-level acoustic parameters, the music/speech judgment on artificially noise-synthesized ambiguous audio signals should align with their AM parameters, even if no real music or speech is contained in the signal.

In the neural domain, AM is a basic acoustic feature that drives auditory neuronal circuits and underlying complex communicative functions across both humans and nonhuman animals. At the micro- and meso-levels, single-cell and population recording of auditory cortex neurons in nonhuman animals demonstrated various mechanisms to encode AM features (e.g., [ 13 , 14 ]). At the macro-level, human neuroimaging studies showed that the acoustic AM synchronizes the neural activities at auditory cortex and correlated with perception and speech comprehensions (e.g., [ 15 – 18 ]). A critical but underexplored gap is the mechanism of how low-level AM features affect a sound to be processed as a complex high-level signal such as music and speech.

Our experiments tested the hypothesis that a remarkably basic acoustic parameter can, in part , determine a sound to be perceptually judged as music or speech. The conjecture is that AM ( Fig 1 ) is one crucial acoustic factor to distinguish music and speech. Previous studies that quantified many hours and a wide variety of music and speech recordings showed distinct peak AM rates in the modulation spectrum: music peaks at 1 to 2 Hz and speech peaks at 3.5 to 5.5 Hz [ 19 – 21 ]. Consistent with those findings, these rate differences are also observed in spontaneous speech and music production [ 22 ]. Next, temporal regularity of AM could also be important, as music is often metrically organized with an underlying beat, whereas speech is not periodic and is better considered quasirhythmic [ 20 , 23 ]. Also, supporting the relevant role played by AM, neuroimaging evidence showed that temporally scrambled but spectrally intact signals weaken neural activity in speech- or music-related cortical clusters [ 9 , 24 ]. Finally, a preliminary study ( n = 12) showed that listeners were able to near-perfectly categorize 1-channel noise-vocoded realistic speech and music excerpts [ 19 ]. However, the noise-vocoding approach was insufficient to mechanistically pinpoint the degree to which AM rate and regularity contribute to music/speech distinction, as this manipulation preserved all the envelope temporal features above and beyond rate and regularity. For example, onset sharpness of speech envelope is encoded by the spoken language cortical network (superior temporal gyrus) and critical to comprehension [ 25 – 27 ]; also, the onset sharpness of the music envelope is crucial for timbre perception, e.g., a piano tone typically has a sharper onset than violin. We therefore build on the notion that the AM distinction between music and speech signals appears to be acoustically robust. However, in order to advance our understanding of potential mechanisms, we ask what aspects of the AM influence listeners to make this perceptual distinction. How acoustically reduced and simple can a signal be and still be judged to be speech or music?

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https://doi.org/10.1371/journal.pbio.3002631.g001

Based on the literature, we hypothesized that stimuli with a lower-in-modulation-frequency and narrower-in-variance peak (i.e., higher temporal regularity, more isochrony) in the AM spectrum would be judged as music, while those with higher and broader peaks (i.e., lower temporal regularity) as speech. If these hypotheses are plausible, artificial sounds synthesized with the designated AM properties should be perceptually categorized accordingly. This noise-probing approach is conceptually similar to the reverse-correlation approach in studies seeking to understand what features are driving the “black-box” perceptual system (e.g., [ 28 , 29 ]). In short, we synthesized stimuli with specific AM parameters by “reversing” a pipeline for analyzing realistic, naturalistic music and speech recordings ( Fig 1B ). First, we used a lognormal function that resembles the empirically determined AM spectra reported in previous studies [ 19 , 20 ]; this function permits the independent manipulation of peak frequency and temporal regularity parameters. Next, after transforming each AM spectrum into a time-domain AM signal (inverse Fourier transform), that signal was used to modulate a flat white noise (i.e., low-noise noise) carrier to generate a 4-s duration experimental stimulus. This approach, importantly, eliminates typical spectral features of both music and speech. In our 4 online experiments, participants were told that each stimulus came from a real music or speech recording but was synthesized with noise, and their task was to judge whether it was music or speech. Although none of the stimuli sounded like real music or speech, participants’ judgments revealed how well each stimulus matched their internal representation of one or the other perceptual category.

In Experiment 1, we manipulated peak AM frequency while σ (the regularity parameter, or the width of the peak of the AM spectrum; see Methods ) was fixed at 0.35 (the value was chosen as it sounded the most “natural” or “comfortable” according to the informal feedback from colleagues in the lab). Stimuli were presented one at a time, and participants were requested to judge whether a stimulus is music or speech. Data from 129 participants were included in the analyses. The overall responses are presented in Fig 2A . To investigate the effect of peak frequencies, each participant’s responses (speech = 1, music = 0) were linearly regressed on the peak frequencies (mean ± standard error of R 2 = 0.53 ± 0.03; Fig 2B ). The response slopes were significantly above 0 ( Fig 2C ; t (128) = 7.70, p < 10 −11 , Cohen’s d = 0.68), suggesting that people judge sounds with a higher peak AM frequency as speech and sounds with a lower peak AM frequency as music. We then explored the association of this judgment with participants’ musical sophistication and found that the participants with a higher General Musical Sophistication score (Gold-MSI [ 30 ]; see Methods ) were more likely to have a higher response slope ( r (127) = 0.17, p = 0.056; but after removing 1 outlier: r (126) = 0.20, p = 0.023; Fig 2D ). We further split the participants by slope at 0 and performed an unequal-variance 2-sample t test without removing that 1 outlier. This analysis confirmed that the participants with a positive response slope have higher General Musical Sophistication scores than the participants with a negative slope ( t (57.25) = 2.96, p = 0.005, Cohen’s d = 0.57). We further correlated the response slope with each subscale of the musical sophistication index, but none of them were significant (unsigned r (127) < 0.16, p > 0.075). While null effects should be interpreted with caution, this suggests that general musical sophistication, rather than a specific musical aspect, is driving the outcome. In short, the findings show that the sounds with a higher peak AM frequency are more likely to be judged as speech and lower as music, and this tendency is positively associated with participants’ general musical sophistication.

( A ) The music vs. speech judgment response of each participant at different levels of AM peak frequencies. ( B ) Fitted regression lines of each participant’s response. ( C ) Each dot represents the response slope on peak frequencies of a participant, and the bar and the error bars represent the mean ± standard error. The participants’ response slopes were significantly above 0, suggesting that the participants tend to judge the stimuli with a higher peak AM frequency as speech and lower as music. ( D ) The response slopes and the General Musical Sophistication score of the participants were positively correlated, suggesting that the musically more sophisticated participants are more likely to judge the stimuli with a higher peak AM frequency as speech and a lower peak frequency as music. Note that the gray circle marks the outlier, and the regression line and the p -value reported on the figure were based on the analysis without the outlier. Underlying data and scripts are available at https://doi.org/10.17605/OSF.IO/RDTGC and in S1 Data .

https://doi.org/10.1371/journal.pbio.3002631.g002

Note that we attempted to fit the data with a logistic psychometric function. Although the findings were consistent as the fitted slopes of the logistic model were also significantly above 0 ( t (128) = 6.85, p < 10 −9 ), suggesting the sounds with a higher peak AM frequency are more likely to be judged as speech over music, the R 2 of the logistic model were much lower than the linear model (mean R 2 difference: 0.19), so did the following experiments (see Methods for more details), suggesting that the linear model was a more appropriate model. Therefore, only the linear models were interpreted.

To investigate the effect of temporal regularity, in Experiment 2, we manipulated AM temporal regularity (σ) at 3 peak AM frequencies (1, 2.5, and 4 Hz, which roughly correspond to the AM range of music, a midpoint, and speech). The procedure was identical to Experiment 1, and data from 48 participants were included. The overall responses are presented in Fig 3A . Each participant’s responses were linearly regressed on the σ under each peak frequency ( R 2 = 0.37 ± 0.02; Fig 3B ). The response slopes were significantly above 0 for the peak frequency at 1 Hz ( t (47) = 6.19, p < 10 −6 , Cohen’s d = 0.89) and 2.5 Hz ( t (47) = 6.37, p < 10 −7 , Cohen’s d = 0.92), suggesting that listeners tend to judge sounds with lower temporal regularity (higher σ) as speech and higher regularity as music ( Fig 3C ). Note that this pattern was the opposite for the peak frequency at 4 Hz, with a lower effect size ( t (47) = −3.34, p = 0.016, Cohen’s d = 0.48). It suggests that the association between temporal regularity and the music judgment is conditional on the low-to-mid peak AM frequency range, and the influence of temporal regularity is weaker when peak AM frequency is in the AM range of speech. We also examined the associations between participants’ musical sophistication levels and response slope, but no correlation was significant ( Fig 3D ; unsigned r (46) < 0.13, p = 0.404).

( A ) The music vs. speech judgment response of each participant at different levels of temporal regularity (σ). ( B ) Fitted regression lines of each participant’s response. ( C ) The participants’ response slopes on σ were significantly above 0 for the peak AM frequencies at 1 and 2.5 Hz but not 4 Hz. This suggests that participants tend to judge the temporally more regular stimuli as music and irregular as speech, but this tendency was not observed when the peak frequency was as high as 4 Hz. ( D ) The response slopes and the General Musical Sophistication scores were not correlated at any peak AM frequencies. Underlying data and scripts are available at https://doi.org/10.17605/OSF.IO/RDTGC and in S1 Data . n . s ., nonsignificant.

https://doi.org/10.1371/journal.pbio.3002631.g003

The dichotomy of the behavioral judgment that our task imposes could be a concern because it only allows a stimulus to be judged as music or speech, while ignoring other possible categories. It is, to be sure, reasonable to directly contrast music and speech, as these are arguably among the most dominant high-level auditory forms in human cognition, sharing many commonalities (cf., [ 1 , 9 ]), and a discrimination task between two categories is usually considered psychophysically more powerful than two separate detection tasks on each category [ 31 ]. However, other auditory categories, such as animal calls and environmental sounds, are critical in human perception as well. Therefore, we tested the robustness of the findings of Experiments 1 and 2 by replicating them with detection tasks, and we investigated whether there were effects specific to music or speech.

In Experiment 3, peak AM frequency was manipulated with σ fixed at 0.35; 80 participants were included in the analyses. In the “music detection” task, participants were instructed that 50% of the stimuli were music and 50% were not music (“others”), and they were asked to judge whether it was music or something else. For the “speech detection” task, the task was analogous. The 50% instruction was added to prevent participants with a strong response bias. Each participant performed both tasks with the same stimuli. The overall responses are presented in Fig 4A . Each participant’s responses (music or speech = 1, others = 0) were linearly regressed on peak frequency for each task ( R 2 = 0.68 ± 0.02; Fig 4B ). For the speech task, the response slopes were significantly above 0 ( t (79) = 12.79, p < 10 −20 , Cohen’s d = 1.43; Fig 4C ), suggesting that the sounds with a higher peak AM frequencies are more likely to be judged as speech over others. Musical sophistication did not correlate with the speech response slope ( r (78) = 0.04, p = 0.717; Fig 4D ). For the music task, the response slope was not significantly different from 0 ( t (79) = 0.49, p = 0.628, Cohen’s d = 0.05; Fig 4C ). Interestingly, there was a significant correlation suggesting that the more musically sophisticated participants are more likely to judge the sound with a lower peak AM frequency as music ( r (78) = −0.28, p = 0.011; Fig 4D ), and this is again confirmed by the unequal-variance 2-sample t test between split-data at slope equals to 0 ( t (72.57) = 2.66, p = 0.010, Cohen’s d = 0.58). We also correlated the response slope with each subscale; however, once again, none of them passed the Bonferroni-corrected statistical threshold at 0.01 (unsigned r (78) < 0.28, p > 0.013). Together, the effect of peak AM frequency reported in Experiment 1 is robustly replicated for the speech judgment, but the music judgment was conditional on participants’ general musical sophistication.

Results of Experiments 3 (A-D) and 4 (E-H). ( A ) The “music vs. others” and “speech vs. others” judgment response of each participant at different levels of peak AM frequencies. ( B ) The fitted regression line of each participant’s response. ( C ) The participants’ response slopes on peak frequencies were significantly above 0 for the speech task but not for the music task, suggesting that the participants tend to judge the stimuli with a higher peak AM frequency as speech. ( D ) The response slopes and the General Musical Sophistication scores of the participants were positively correlated for the music task but not for the speech task, suggesting that the musically more sophisticated participants are more likely to judge the stimuli with a lower peak AM frequency as music. ( E - H ) The same format as above, but at different levels of temporal regularity (σ). The participants tend to judge the stimuli with a higher temporal regularity as music. Underlying data and scripts are available at https://doi.org/10.17605/OSF.IO/RDTGC and in S1 Data . n . s ., nonsignificant.

https://doi.org/10.1371/journal.pbio.3002631.g004

In Experiment 4, AM temporal regularity was manipulated while the peak AM frequency was fixed at 2 Hz (equally likely to be judged as music or speech, according to the previous experiments). The tasks were as in Experiment 3, and data from 78 participants were included. The overall responses are shown in Fig 4E . Each participant’s responses were linearly regressed on σ for each task ( R 2 = 0.32 ± 0.02; Fig 4F ). For the music task, the response slope was significantly below 0 ( t (77) = -4.95, p < 10 −5 , Cohen’s d = 0.56; Fig 4G ), suggesting that people tend to judge the sounds with higher temporal regularity (lower σ) as music. For the speech task, the response slopes were slightly above 0 but not reaching the statistical threshold ( t (77) = 1.89, p = 0.063, Cohen’s d = 0.21; Fig 4G ). We did not observe any associations between participants’ musical sophistication and response slope (unsigned r (76) < 0.13, p > 0.293; Fig 4H ). Together, the effect of AM temporal regularity reported in Experiment 2 was robustly replicated for music but only a trend was observed for speech.

These surprising findings and their replications show that listeners use acoustic amplitude modulations in sounds, one of the most basic features, fundamental to human auditory perception, to judge whether a sound is “like” music or speech, even when spectral features are eliminated. We show that peak AM frequency can affect high-level categorization: Sounds with a higher peak AM frequency tend to be judged as speech, those with a lower peak as music, especially among musically sophisticated participants. This pattern is consistent with previous quantifications of natural music recordings showing that the peak AM frequency of music is lower than speech [ 19 ]. This result might arise because of participants’ (implicit) knowledge of this acoustic feature. We note that, while the effect of peak AM frequency in Experiment 1 was robustly replicated in the speech task in Experiment 3, in the music task, the effect was more salient among musically sophisticated participants but not visible when pooling all participants. In other words, peak AM frequency is a universal cue for speech but not for music. A possible explanation is that this effect depends on listeners’ experience or sophistication with music or speech sounds. While our participants exhibited a ceiling effect for speech (as university students, every listener can be classified as an “expert” in speech), their musical sophistication scores appeared lower than the norm (Experiment 3 versus Müllensiefen and colleagues [ 30 ]: 71.39 versus 81.58, Cohen’s d = 0.49; but it is similar to other studies (e.g., [ 32 , 33 ])). The potential effect of speech expertise would need to be examined, for example, in future developmental studies in which expertise can be more carefully controlled.

Temporal regularity (and, in the extreme, isochrony, if σ = 0) of AM also has an effect: Sounds with more regular modulation are more likely to be judged as music than speech. This is consistent with the fact that Western music is usually metrically organized while speech is quasirhythmic [ 20 , 23 ]. There are a few aspects worth discussing. First, this effect is more relevant to music than to speech. The detection tasks in Experiment 4 show that the effect of temporal regularity is only robustly observed for music but not for speech. It appears that temporal regularity is a more prevalent principle than peak AM frequency to judge a sound as music as this effect does not depend on the listener’s musical sophistication. Second, in Experiment 2, the effect of temporal regularity was slightly opposite when the peak AM frequency was at 4 Hz. A possible explanation is that temporal regularity might be less critical for distinguishing music and speech when peak AM frequency is already in the canonical speech range 3.5 to 5.5 Hz [ 19 – 21 ]. Last but not least, while temporal regularity in the current parameter range did not drastically influence the auditory judgments, the current data demonstrate a clear pattern across participants: A sound with a more temporally regular AM is more like music.

AM is one of the most fundamental building blocks for auditory perception, and especially so for human speech. While frequency/spectral information is critical for auditory object identification, pitch perception, and timbre, AM is considered a key information-bearing component and critical for speech intelligibility [ 34 , 35 ]. AM, especially around the 2-4 Hz, is faithfully encoded by neurons in the primary auditory cortex [ 14 , 36 ]. While previous studies have demonstrated that temporal envelope information alone is arguably sufficient for speech perception (e.g., [ 37 ]), the current findings further show that AM rate can be used to identify a sound as speech or not (i.e., Fig 4C ). Relatedly, AM rate helps identify music, at least among musically sophisticated listeners. This could be for different reasons. First, music has salient features in both time and frequency domains. A recent survey showed that adults explicitly consider both AM regularity (rhythm/beat) and melody (frequency/spectral domain), but not AM rate, as being the primary acoustic features for distinguishing speech and song [ 38 ]. This is consistent with the current finding that people rely on AM regularity more than rate to identify music. Second, the association between AM rate and music perception might require musical experience. This is consistent with the neural entrainment studies showing that the fidelity of auditory cortex entraining to music rhythm is positively associated with the musical expertise of the listeners [ 25 , 39 ]. Together, our data provide the empirical advance that AM rate or regularity alone, regardless of the fine temporal features (e.g., onset sharpness) preserved by the noise-vocoded approach [ 19 ], have an effect on the music/speech judgment. Given that the AM rate and regularity are processed early in the auditory cortex [ 14 ], notably prior to superior temporal gyrus encoding of speech onset (e.g., [ 26 , 27 ]), AM rate or regularity should have more decisive roles than temporal envelope features for distinguishing music and speech at an early stage of the auditory cortical pathway.

The current study has four noteworthy limitations. First, the lognormal function can resemble the average AM spectrum of many hours of music or speech recordings [ 19 ], but it does not necessarily approximate individual recordings well. Second, the current forced-choice task design can only demonstrate how acoustic features affect the auditory judgments , but whether participants subjectively experienced the percepts of our stimuli as “reduced” forms of music or speech is unclear, as the rich spectral and timbral features of typical music or speech were by design eliminated from the stimuli. Third, while the current experimental design only showed the influences of AM rate and regularity on distinguishing music and speech, we did not compare their influences to those of other acoustic features. Although spectral or frequency modulation, orthogonal to AM, is another promising acoustic feature fundamental to auditory perception, the current study focuses on only the AM aspect as it has been demonstrated distinct between music and speech acoustics while the spectral aspect has not. Lastly, the factors that contributed to the substantial individual differences in music-related tasks remain unclear, and musical sophistication only partially accounts for it. Other perceptual and cognitive factors (e.g., preference for fast or slow music, unawareness of hearing loss among young adults) and experimental factors (e.g., whether the participants were exposed to any specific music or speech in the environment while performing our experiment online, remotely, and on their own) likely contributed to the individual differences as well. Nevertheless, our reductionist approach demonstrates the striking fact that music or speech judgment starts from basic acoustic features such as AM.

A related phenomenon that builds on the role of temporal structure can be illuminated by these data. The speech-to-song illusion demonstrates that, by looping a (real) speech excerpt, the perceptual judgment can gradually shift from speech toward song [ 40 – 42 ]. The effects reported here are consistent with the speech-to-song illusion: The low frequency power of the AM spectrum would emerge from the repeating-segment periodicity and, therefore, bias the judgment toward music. Supporting this view, this illusion disappears if speech is temporally jumbled in every repetition [ 40 ], which eliminates low-frequency periodicity across repetitions. Furthermore, consistent with our findings, the strength of the illusion is also positively associated with beat regularity and participants’ musical expertise [ 41 , 43 – 45 ].

The properties of AM that support the distinction of music and speech merit consideration in the context of human evolution and neurophysiology. Group cohesion and interpersonal interaction have been hypothesized as one primary function of music [ 46 – 53 ]. If music serves as an auditory cue for coordinating group behaviors, predictable temporal regularity at the optimal rate for human movements and audiomotor synchronization (1 to 2 Hz; [ 54 – 56 ]) would be important. And, in fact, motor brain networks are involved while processing auditory rhythms (e.g., [ 57 – 64 ]). The AM rate of speech, analogously, has been attributed to the neurophysiological properties of the specialized auditory-motor oscillatory network for speech perception and production, as well as the associated biomechanics of the articulatory movements [ 17 , 20 , 65 , 66 ]. Consistent with these data patterns, perceptual studies have also shown a general pattern that music versus speech task performance is optimal with rates ranging around 0.5 to 6.7 and 2 to 9 Hz, respectively [ 67 , 68 ].

The experimental results we present demonstrate that human listeners can use a basic acoustic feature fundamental to auditory perception to judge whether a sound is like music or speech. These data reveal a potential processing principle that invites both neurophysiological and evolutionary experiments and speculations that could further address the long-lasting questions on the comparison between music and speech in both the humanities and the sciences.

Resource availability

All stimuli, experimental programs, raw data, and analysis codes have been deposited at a publicly available OSF repository ( https://doi.org/10.17605/OSF.IO/RDTGC ).

Participants

The participants were students at New York University who signed up for the studies via the SONA online platform and received course credit for completing the experiments. The local Institutional Review Board (New York University’s Committee on Activities Involving Human Subjects) approved all protocols (IRB-FY2016-1357), in complete adherence to the principles outlined in the Declaration of Helsinki. All participants provided informed consent via an online form. Participants had self-reported normal hearing, were at least 18 years old, and reported no cognitive, developmental, neurological, psychiatric, or speech-language disorders. The total number of online participants was 488, and the data of 335 participants (208 females, 122 males, 5 other/prefer not to say, age range: 18 to 25) were included for analysis (see Quantification and statistical analysis for exclusion criteria, and Results for the sample size of each experiment).

The pipeline to generate audio stimuli with a designated peak AM frequency and temporal regularity parameters is composed of the following steps (resembling an inverse pipeline for analyzing audio recordings), which are conceptually illustrated in Fig 1 .

• An inverse fast Fourier transformation with random phases was applied to an AM spectrum to generate a 20-s time-domain signal with a 44.1-kHz sampling rate, and then it was transformed to an amplitude envelope [ 69 , 70 ].
• The resulting amplitude envelope was used to modulate a 20- to 20,000-Hz low-noise noise (LNN) carrier sound. The LNN is a white noise with a flat amplitude envelope [ 71 , 72 ], which ensures that the amplitude fluctuations of the final stimuli were not caused by the carrier signal.
• The middle 4-s segment of each 20-s amplitude-modulated LNN was extracted as a stimulus.
• There were 100, 50, 50, and 50 stimuli generated for each condition of Experiments 1 to 4, respectively, and the root-mean-square values of all the stimuli were equalized within each experiment. All steps were performed using MATLAB R2020a.

The experiments were programmed on PsychoPy Builder (v2020.1.2) and executed on the Pavlovia.org platform.

The participants were required to perform the experiment using a browser on their personal computer, in a quiet environment with headphones on, and each listener could set the audio volume at a comfortable level. First, only those participants who passed a headphone screening task (see below) could proceed. Next, the practice phase included 4 trials; the AM parameters of these stimuli were within the range of, but not identical to, the parameter values used in the subsequent testing phase. On each practice trial, a stimulus was presented, and then participants were asked to make a binary judgment by clicking a button on the screen, without time limit. After the response, the next trial started. A probe trial was inserted in the practice phase, which presented 1 to 4 brief tones without warning in a 2-s window with random stimulus-onset asynchronies, and the participants were requested to indicate the number of tones by pressing the corresponding key. Participants could repeat the practice phase until they felt comfortable to proceed to the testing phase. Only in Experiments 3 and 4, a practice phase was inserted prior to each of the first music and speech blocks.

In the testing phase, for Experiments 1 and 2, for each participant, a set of 150 unique stimuli (15 or 10 per condition in Experiments 1 or 2, respectively) were randomly drawn from the stimulus pool, and they were randomly ordered within each of the first and second half of the experiment, resulting in a total of 300 testing trials. There was no cue between two halves of the experiment. The participants were not instructed regarding the occurrence rates of “music” or “speech.”

For Experiments 3 and 4, within each of the first and second halves of the experiment, there were 1 music block and 1 speech block, randomly ordered. Within each block, there were 75 unique stimuli (15 per condition) randomly drawn from the stimulus pool, and the same set of stimuli was used for all 4 blocks for each participant, resulting in a total of 150 trials for each task and, therefore, totaling 300 testing trials for the entire experiment. Before and during each block, there were text and visual cues on the screen to remind the participants of the current block type. The participants were instructed that 50% of the trials were music or speech and 50% were not music or speech (“others”), respectively, for each block type.

For all the experiments, the procedure of each testing trial was identical to the practice trial. A self-paced break was inserted every 10 trials, and the percentage of progress in the experiment was shown on the screen during the break. Twelve probe trials were mixed with roughly even spaces with the testing trials.

After the experiment, participants were directed to another webpage to anonymously fill out demographic information, the Goldsmiths musical sophistication index, and other background and task-related questions (not analyzed).

Headphone screening task.

The participants were requested to perform a headphone screening task prior to the main task, to ensure that they used headphones to complete our online experiments [ 73 ]. On each trial, participants were asked to identify the quietest tone (3-alternative forced choice) among three 1-s duration 200 Hz pure tones (with 100 ms ramps), including a binaurally in-phase loud tone, an antiphase loud tone, and an in-phase quiet tone of (−6 dB). Stimuli were presented sequentially with counterbalanced orders across 6 trials. Because the antiphase loud tone would be attenuated by phase cancelation in the air if it was played through loudspeakers, the quietest tone can only be correctly identified with headphones. Participants had to perform at least 5 out of 6 trials correctly to proceed.

Goldsmith musical sophistication index (Gold-MSI).

The Gold-MSI is one of the most common and reliable indices and for assessing musicality [ 30 ]. It is composed of 39 questions to assess multiple aspects of music expertise, including active engagement, perceptual abilities, musical training, singing abilities, and emotional responses. The General Musical Sophistication subscale is a general index that covers all the aspects of Gold-MSI, which ranges from 18 to 126; the mean and the standard deviation of the norm (147,633 participants) are 81.58 and 20.62, and the reliability α is 0.926.

Quantification and statistical analysis

Since all participants completed the study online without supervision, we used several exclusion criteria to ensure data quality. (1) The participants who did not complete both the experiment and the questionnaire, who did not pass the headphone screening task, admitted not using headphones throughout the experiment, made the same response for all the trials, or whose probe trial accuracy below 90%, were excluded. These criteria excluded 41, 19, 31, and 23 participants from Experiments 1, 2, 3, and 4. (2) Since the participants were instructed that the occurrence rate of music/speech was 50% in Experiments 3 and 4, the participants whose response biases exceeded 50 ± 15% in any task were excluded. This criterion excluded 16 and 23 participants from Experiments 3 and 4. Statistical test significance was assessed with α = .05, two-tailed. The specific tests used are reported in the Results section. The computations were performed on MATLAB R2020a and R2021b.

Power analysis and sample sizes

As the effect size of this task was unknown, in the Experiment 1, we recruited more than 100 participants to reduce the risk of being underpowered and to estimate the statistical power for the following experiments. Based on the data of Experiment 1, a power analysis showed that the required number of participants was 20 when alpha level was set at 0.05 and statistical power at 0.8, and 36 when alpha level was set at 0.01 and statistical power at 0.9. Therefore, we targeted the sample size of Experiment 2 to be slightly above those levels ( n > 40). Although the tasks of Experiments 3 and 4 were similar to Experiments 1 and 2, the judgment of “speech versus others” and “music versus others” might have a lower statistical power than “music versus speech,” as “others” is not a well-defined category. Therefore, we set the target sample sizes to be double ( n ≈ 80) as the required sample size of alpha at 0.01 and power at 0.9.

Supporting information

S1 data. data underlying the plots in fig 2 – 4 ..

https://doi.org/10.1371/journal.pbio.3002631.s001

Acknowledgments

We thank the Poeppel Lab members at New York University, Max Planck Institute for Empirical Aesthetics, Ernst Struengmann Institute for Neuroscience, and Benjamin Morillon for their comments and support.

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The ESMTB Award Committee unanimously recommend the article titled "Pulled, pushed or failed: the demographic impact of a gene drive can change the nature of its spatial spread" by Lena Kläy, Léo Girardin, Vincent Calvez and Florence Débarre for the Karl-Peter Hadeler prize 2023.

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The Karl-Peter Hadeler Prize Winner 2022

The ESMTB Award Committee unanimously recommend the article titled "Spatial ecology, optimal control and game theoretical fishing problems" by Idriss Mazari and Domènec Ruiz-Balet for the Karl-Peter Hadeler prize 2022. The mathematical results presented in this article are interesting and well-integrated with the underlying ecological problem, of which they genuinely support a more in-depth theoretical understanding. Both authors are young researchers at an early stage of their academic careers and will thus certainly benefit from being awarded the KPH prize.

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150 Actual Biology Research Paper Topics

Table of contents

• 1 What Is Biology? What Topics Might Biologists Study?
• 2 How to Choose a Topic for Biology Research Paper?
• 3.1 15 Developmental Biology Topics For Research
• 3.2 15 Immune System Biology Research Topics
• 3.3 15 Cell Biology Research Topics
• 3.4 15 DNA Research Topics
• 3.5 15 Molecular Biology Research Topics
• 3.6 15 Neurobiology Research Topics
• 3.7 15 Abortion, Human cloning, and Genetic Researches Topics
• 3.8 15 Environmental and Ecology Topics for Your Research
• 3.9 15 Plant Pathology Biology Research Topics
• 3.10 15 Animals Biology Research Topics
• 3.11 15 Marine Biology Research Topics
• 3.12 15 Zoology Research Topics
• 3.13 15 Genetics Research Topics
• 3.14 15 Biotechnology Research Topics
• 3.15 15 Evolutionary Biology Research Topics

Biology is one of the most magnetic fields of study these days. If you want to be a biologist or scientist in the future, there is no better time to start than right now. Biology research topics covered in this article will keep you busy and interested. Writing a research paper is one of the best ways to dip your toes into the field. Before doing that, you need to know some good topics for the research paper . They should be suitable for biology students rather than cutting-edge researchers. On Papersowl.com , we provide as many biology research paper examples as possible so that you have a huge choice.

What Is Biology? What Topics Might Biologists Study?

Biology is simply the study of everything that has a form of life. It includes investigations on plants, animals, and everything found in the environment. It is about studying how life forms grow, develop, and interact with each other. Biology essay topics for research encompass all these and more.

This science uncovers many fields where various life forms are studied. It makes sense to look through these fields to help you decide which suits you the best.

Plant Biology research topics are about studying the plants around us. They disclose information about their existence as a part of the ecosystem, their life cycle, resources they can give us, their ability to preserve them from climate changes, and so on. There are many ideas to choose from, but you must focus on a specific one.

Human Biology research topics are all about us. These topics focus on different body parts, such as the human brain, the human immunological system, the nervous system, etc. In addition, you can discuss DNA modifications in humans and explain why genetic disorders occur in your research projects. Various cell research is also common today.

Biology research topics on the environment are in great demand too. For example, climate change is becoming a more significant threat every day. By studying environmental topics in biology for projects and research, we can come up with ways to combat them and preserve ecosystems.

Microbiology research topics delve into things we can’t see. There are trillions of microbes and bacteria all around us. Knowing about them is essential to understanding what makes us sick and how to fight against them. All microbiology research paper topics are pretty complicated yet very engaging to include in your paper research.

Molecular biology topics dive even deeper into the level of atoms and molecules. The various medicines and drugs we take were all created through molecular-biology research. It is one of the areas full of ideas, but there is yet to be much evidence. Science is advancing in this realm but still needs a lot of time. Topics of molecular biology will need days for research only.

Keep in mind that there are more ideas and variations of this science. We offer more examples in further sections of the article about developmental biology, marine biology, evolutionary biology, etc. Explore them and make your writing appealing and meaningful in the eyes of a professor.

How to Choose a Topic for Biology Research Paper?

When choosing a biology project topic, you must be aware of one or more fields of science. Biology research is critical to the present world. By doing research, we can learn more about genetic disorders, immune disorders, mental health, natural disease resistance, etc. Knowing about each of these could save lives in the future.

For those who may not have the time or resources to do their own research, there are research paper writing services that can provide assistance with the project. And we are always here to help you find your own topic among interesting biology research topics. Here we prepared some useful tips to follow.

• Tip 1: The level of interest matters Pay attention to one that interests you, and you might have ideas on how to develop the topic. Passion is fundamental in research, after all.
• Tip 2: Explore the topic Try to narrow things down a bit. If the topic is too broad, you may not be able to cover all aspects of it in one research paper. If it is too narrow, the paper could end up too short. Analyze the topic and the ways to approach it. By doing so, you can strike a balance between the two.
• Tip 3: Discover the recent developments To make your research paper touchable with the present day, you must explore the latest developments in the field. You can find out what kind of research has been done recently by looking at journals. Check out research papers, topics, research articles, and other sources.
• Tip 4: Ensure to get enough resources When choosing a topic, make sure it has plenty of resources available. For example, a research paper on xenobiology or cutting-edge nanobiology might sound attractive. Still, you might have difficulties getting data and resources for those unless you are a researcher at a government lab. Data, resources, complex numbers, and statistics are all invaluable to writing a paper about these topics.

That is why we have selected a range of biological topics. The topics on this list are all hopefully exciting topics for research you could write an excellent paper on. We should also add that easy biology topics to research are rare, and a writer usually needs days to prepare and start writing. Yes, biology research topics for high school students are a bit easier, but still, they need time to explore them.

On the other hand, biology research topics for college students are far more complex and detailed. Some people prefer evolutionary biology research paper topics, and we can agree with this claim. These research areas do have a lot of potential and a lot of data to support the claims. Others prefer cell biology research topics that are a bit specific and fun. Anyway, with this article’s list of easy biology research topics, you will surely find the one matching your interest.

For those who may not have the time or resources to do their own research, there are provide assistance with the project.

Top Research Biology Paper Topics

This section contains a large selection of research biology paper topics. You will be able to find one that will suit you the best. The only thing left is to decide what variation of science you prefer. Whether you’re interested in microbiology, genetics, or any other type of science, you’ll find a topic to get you started. If you’re ever stuck or need some extra help, you can always pay someone to write your paper for you. So, take a look, and choose the perfect topic for your project!

15 Developmental Biology Topics For Research

Exploring the processes of how cells grow and develop is exciting. The human body contains millions of cells, and it’s interesting to research their behavior under different conditions. If you feel like writing about it, you can find some interesting biology topics below.

• How do stem cells form different tissues?
• How are tumors formed?
• Duplication of genomes
• Plasticity of development
• Different birth defects
• Interactions between genes and the environment
• Anticancer drugs mixtures
• Developmental diseases: Origin
• Drosophila Oogenesis
• Most deadly viruses
• Most deadly bacteria in the world
• How do germs affect cells?
• How does leukemia start?
• Development of the cardiovascular system in children
• How do autoimmune diseases start and affect the human body?

15 Immune System Biology Research Topics

For decades, many scientists and immunologists have studied the human immune system and tried to explain its reaction to various pathogens. This area allows you to deepen into it and reveal how a body protects itself from harmful impact. Look over the biology research questions below and find your match-up.

• How does the human body’s immune system work?
• The human immune system: How to strengthen it?
• What makes the immunological system weaker?
• The notion of auto-immune diseases and their effect on the body’s immune system
• The global HIV/aids epidemic
• What methods are used to prevent the spread of hives?
• Living with auto-immune diseases
• Genetics and the immune system: effects and consequences
• How do immune disorders affect the body, and what causes them?
• Are allergies signs of worrying about an immune disorder?
• DNA modification in solving immune disorders
• Stress as the biggest ruiner of the immunological system
• Vaccines as strong supporters of the immunological system
• The perception of vaccines in society
• Why do some people refuse vaccines and put others around them in danger?

15 Cell Biology Research Topics

Cell study might seem challenging yet very engaging. It will be a good idea to compare various types of cells and compare them in animals and plants. Make your choice from the list of cell biology research topics below.

• The structure of an animal cell
• Mitochondria and its meaning in cell development
• Cells classification and their functions
• Red blood cells and their function in transporting oxygen
• White blood cells and their responsibility to fight diseases
• How are plant cells different from animal cells?
• What would it be if animals had a function to photosynthesize?
• Single-celled organisms: What is it, and how do they work?
• What processes do cells go through in division?
• Invasion of bacteria into the body
• Viruses – alive or not?
• Fungi: their reproduction and distribution
• Cancer cells: Why are they so dangerous?
• What methods are used to kill cancer cells?
• The role of stem cells and their potential in a body

15 DNA Research Topics

The variety of biology research topics for college students might impress you a lot. This is a science with a large field of investigation, disclosing much scientific information to use in your project. The notion of DNA and its gist are also excellent options to write about.

• The structure of the human DNA
• The main components of a DNA chain
• Why does DNA have a double-helix spiral structure?
• The purpose of chromosomes
• MRNA and its relation to DNA
• Do single-celled organisms have DNA?
• Do viruses have DNA?
• What happens if you have too many or too few chromosomes?
• Analyzing the structure of DNA using computers
• Uses for the DNA of extinct organisms like mammoths and dinosaurs
• Storing non-genetic information in DNA
• Can you write a computer program into human DNA?
• How does radiation affect DNA?
• Modifying DNA to treat aids
• Can we fight cancer through DNA modification?

15 Molecular Biology Research Topics

Do you prefer to research molecules’ chemical and physical composition? We gathered some molecular biology research topics to make your choice easier.

• The structure and components of a gene
• How do molecules move in and out of a cell?
• The basic building blocks of life
• How are drugs designed for humans?
• How is a vaccine designed to target a specific disease?
• Dominant genes vs. recessive genes
• Prion disease – why is it so dangerous?
• Hormones and their function in the body
• Developing artificial hormones from other animals
• How to carry out a western blot?
• Testing and analyzing DNA using PCR
• The three-dimensional structure of a molecule
• What is DNA transcription, and how is it used?
• The structure of a prion
• What is the central dogma of molecular biology?

15 Neurobiology Research Topics

The more you dive into science, the more exciting things you find. That’s about biology. Here, you can choose biology research topics for high school and try to reveal more simply.

• Nervous system: its structure and function
• Neurons as unique cells playing a central role in the nervous system
• What is the maximum reaction speed in a human?
• Reaction speed: how to improve it?
• Research on Organic Farming
• What are the symptoms of Alzheimer’s disease?
• Why do we feel happy or sad?
• Headaches in terms of Neurobiology
• What are the reasons for neurobiological degeneration?
• Myths and reality of Amnesia
• What causes Alzheimer’s Disease, and what are the consequences of the disease?
• What is the treatment for Spinal Cord Injury?
• Studies on Narcolepsy and Insomnia: What are the causes?
• Is there a connection between Mental Health and Neurobiology?
• Emotions in terms of their reflection in the brain

15 Abortion, Human cloning, and Genetic Researches Topics

There are so many scientific researches and theories that society accepts or neglects. You can operate different notions and try to explain them, reflecting their advantages and downsides for a human being. We gathered some enticing life science research topics for high school students that might interest you.

• The controversy around abortion: legal or not?
• Can abortion be safe?
• Human cloning – reality vs. science-fiction
• The goals of cloning humans
• Are human cloning and transplantation ethical?
• Having a “perfect child” through gene therapy: Is it a myth?
• How far has gene therapy gone in genetic research?
• Advantages and disadvantages of gene therapy
• How gene therapy can help beat cancer
• How gene therapy can eliminate diabetes
• The opportunity to edit genes by CRISPR
• DNA modifications in humans to enhance our abilities – an ethical dilemma
• Will expensive gene therapy widen the gap between the rich and the poor?
• Cloning: the good and the Bad for a Generation
• The disadvantages of cloning
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15 Environmental and Ecology Topics for Your Research

The nature around us is so enormous and includes many branches to investigate. If you are keen on the environment and how ecology affects it, the list of follow-up biology paper topics might be helpful to you.

• The theory of evolution
• How does natural selection work?
• How do living organisms adapt to their environment?
• The concept of divergent and convergent evolution
• Building a sustainable environment
• Development of environment-friendly cities
• How to control population growth?
• Why have recycling resources become so essential in the modern world?
• The effect of plastic on the environment
• What are the global consequences of deforestation?
• What can we expect when losing biodiversity?
• Ecological damage: How to prevent it?
• How can GMO products affect ecology?
• Cloning endangered or extinct species: Is it a good idea?
• Is climate change the main reason for disrupting ecology?

15 Plant Pathology Biology Research Topics

Many factors impact human health and the quality of food products matters. These easy biology research topics will be useful if you want to describe the connection between those two concepts.

• How do plants protect themselves from diseases?
• How to increase the plant’s resistance to diseases?
• Diseases distribution among plants
• The banana pandemic
• How do herbicides influence plants?
• Corn blight
• Can any plant diseases affect humans?
• The issue of stem rust and its impact on wheat
• What approaches are used to struggle against invasive plants and affected weeds?
• Fertilizers: their pros and cons on plants
• Plant disease genetics: its system and structure
• What is the connection between ecological changes and plant diseases?
• Modifications on food production because of plant diseases
• How do fungal and viral diseases appear in plants?
• The sweet potato virus

15 Animals Biology Research Topics

It’s hard to find someone who doesn’t like animals. If you are curious about animals scientifically, here you are with biology research paper topics in this field.

• Classification of animals
• Land-based life: its evolution history
• Controversies about keeping animals as pets
• Is it ethical to test drugs and products on animals?
• Why do nature reserves against zoos?
• Evidence on prehistoric aquatic animals growing giant
• What species of animals are vegan?
• Animals and their social behavior
• Primate behavior
• How intelligent can other primates be?
• Are wolves and dogs intelligent?
• Domesticating animals
• Hibernation in animals
• Why animals migrate
• Should we bring back extinct animals?

15 Marine Biology Research Topics

The marine theme is engaging as it reveals so many interesting facts about life forms dwelling under the water. You can make your paper look captivating using biology topics in marine below.

• How acidification affects aquatic environments
• Evolution in the deep sea
• What’s the meaning of camouflage mechanism in sea life?
• Consequences of oil spills on marine life
• Oldest marine species
• How do whales communicate with each other?
• How blind fish navigate
• Are marine shows and aquariums ethical?
• The biology and life cycle of seabirds
• How jellyfish are immortal
• Plankton ecology
• Difference between freshwater and seawater marine life
• Coral reefs: their importance and evolution
• Saving and restoring coral reefs
• Life in the deep-sea ocean trenches

15 Zoology Research Topics

Zoology can be an excellent choice to write about if you are close to animal studies. Look at biology topics to research and choose the one that fits your interest most.

• Asian elephants and human speech patterns
• Oyster genomes and adaptation
• Darwin’s work in the Galápagos Islands
• Asian carp: Invasive species analysis
• Giant squids: Fact vs. fiction
• Coyote and wolf hybrid species in the United States
• Parasites and disease
• Migration patterns of killer bees
• The treatment of species in Melville’s Moby Dick
• Biodiversity and plankton
• The role of camels and the development of Africa and the Middle East
• Muskellunge and adaptive creek mechanisms to small water
• Ants and cooperative behavior among species
• Animal communication and the origin of language
• Speech in African Gray Parrots

15 Genetics Research Topics

Writing about modifications caused on the gene level is pretty challenging but very fascinating. You can select one among the biological questions for research and bring up a meaningful paper.

• Genetics and its role in cancer studies
• Can genetic code be confidential?
• Is it possible to choose the sex of a person before birth?
• Genetics as a ray of hope for children with an intellectual disability
• What factors in human genetics affect behavior?
• Is it somehow possible to improve human personality through genetics?
• Are there any living cells in the gene?
• Fighting HIV with gene mutations
• Genetic mutations
• How addictive substances affect genes
• Genetic testing: is it necessary?
• Cloning: positive or negative outcome for future generations
• Pros and cons of genetic engineering
• Is the world ready for the bioethics revolution?
• The linkage between genetics and obesity

15 Biotechnology Research Topics

The way scientists conduct research today is magnificent. Implementing high-tech innovations in biology research brings new opportunities to study the world. What are these opportunities? Explore biotechnology research topics for college students and disclose the best options for you.

• Biotechnology used in plant research
• What is the contribution of biotechnology to food?
• Pharmacogenetics: What is it, and how it works?
• How are anti-cancer drugs produced to be effective?
• Nanotechnology in DNA: How to isolate it?
• Recent nanotechnology used in HIV treatment
• What biotech apps are used to detect foodborne pathogens in food systems?
• Genotypes research: Why are they tolerant and sensitive to heavy metal?
• High-tech solutions in diagnosing cancer
• Forensic DNA and its latest developments
• Metabolic changes at the level of cells
• Nanotechnology in improving treatments for respiratory viruses
• The latest biotech discoveries
• Digital evolution: bioresearch and its transformation
• The concept of vaccine development

15 Evolutionary Biology Research Topics

Knowing how life forms started their existence is fundamental. And more interesting is to look through the evolution of many processes. If you find this trend of research more engaging, we outlined evolutionary biology research paper topics to diversify your choice.

• Darwin’s concept’s impact on science
• The evolution concept by Lamarck
• Origins of the evolutionary theory
• Evolution acceptance: a belief vs. a theory?
• Evolutionary in microbiology
• Development of robotics
• Revealing differences: human brain & animal brain
• Preservation of biological resources
• Transformations in aging
• Adaptive genetic system
• Morphometrics’ history
• Developmental theory and population genomics
• Bacteria ecology’s evolution
• Biological changes: impact and evolution
• Infectious diseases and their profession

The world of science and biology is vast, making research tedious. Use our list of interesting biology research topics to choose the best issue to write your own paper.

However, it is still hard to prepare a high-quality biology research paper, even with a brilliant topic. Not all college students can do it. Do you feel like you need some help? Then buy biology paper from our professional writers! Our experts will choose the best biology experimental research topics for you and can bring up top-level papers within the shortest time. Additionally, if you need help with a statistics project related to biology, our team of experienced professionals is equipped to provide you with the utmost quality of research and analysis.

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Guest Essay

The Long-Overlooked Molecule That Will Define a Generation of Science

By Thomas Cech

Dr. Cech is a biochemist and the author of the forthcoming book “The Catalyst: RNA and the Quest to Unlock Life’s Deepest Secrets,” from which this essay is adapted.

From E=mc² to splitting the atom to the invention of the transistor, the first half of the 20th century was dominated by breakthroughs in physics.

Then, in the early 1950s, biology began to nudge physics out of the scientific spotlight — and when I say “biology,” what I really mean is DNA. The momentous discovery of the DNA double helix in 1953 more or less ushered in a new era in science that culminated in the Human Genome Project, completed in 2003, which decoded all of our DNA into a biological blueprint of humankind.

DNA has received an immense amount of attention. And while the double helix was certainly groundbreaking in its time, the current generation of scientific history will be defined by a different (and, until recently, lesser-known) molecule — one that I believe will play an even bigger role in furthering our understanding of human life: RNA.

You may remember learning about RNA (ribonucleic acid) back in your high school biology class as the messenger that carries information stored in DNA to instruct the formation of proteins. Such messenger RNA, mRNA for short, recently entered the mainstream conversation thanks to the role they played in the Covid-19 vaccines. But RNA is much more than a messenger, as critical as that function may be.

Other types of RNA, called “noncoding” RNAs, are a tiny biological powerhouse that can help to treat and cure deadly diseases, unlock the potential of the human genome and solve one of the most enduring mysteries of science: explaining the origins of all life on our planet.

Though it is a linchpin of every living thing on Earth, RNA was misunderstood and underappreciated for decades — often dismissed as nothing more than a biochemical backup singer, slaving away in obscurity in the shadows of the diva, DNA. I know that firsthand: I was slaving away in obscurity on its behalf.

In the early 1980s, when I was much younger and most of the promise of RNA was still unimagined, I set up my lab at the University of Colorado, Boulder. After two years of false leads and frustration, my research group discovered that the RNA we’d been studying had catalytic power. This means that the RNA could cut and join biochemical bonds all by itself — the sort of activity that had been thought to be the sole purview of protein enzymes. This gave us a tantalizing glimpse at our deepest origins: If RNA could both hold information and orchestrate the assembly of molecules, it was very likely that the first living things to spring out of the primordial ooze were RNA-based organisms.

That breakthrough at my lab — along with independent observations of RNA catalysis by Sidney Altman at Yale — was recognized with a Nobel Prize in 1989. The attention generated by the prize helped lead to an efflorescence of research that continued to expand our idea of what RNA could do.

In recent years, our understanding of RNA has begun to advance even more rapidly. Since 2000, RNA-related breakthroughs have led to 11 Nobel Prizes. In the same period, the number of scientific journal articles and patents generated annually by RNA research has quadrupled. There are more than 400 RNA-based drugs in development, beyond the ones that are already in use. And in 2022 alone, more than $1 billion in private equity funds was invested in biotechnology start-ups to explore frontiers in RNA research.

What’s driving the RNA age is this molecule’s dazzling versatility. Yes, RNA can store genetic information, just like DNA. As a case in point, many of the viruses (from influenza to Ebola to SARS-CoV-2) that plague us don’t bother with DNA at all; their genes are made of RNA, which suits them perfectly well. But storing information is only the first chapter in RNA’s playbook.

Unlike DNA, RNA plays numerous active roles in living cells. It acts as an enzyme, splicing and dicing other RNA molecules or assembling proteins — the stuff of which all life is built — from amino acid building blocks. It keeps stem cells active and forestalls aging by building out the DNA at the ends of our chromosomes.

RNA discoveries have led to new therapies, such as the use of antisense RNA to help treat children afflicted with the devastating disease spinal muscular atrophy. The mRNA vaccines, which saved millions of lives during the Covid pandemic, are being reformulated to attack other diseases, including some cancers . RNA research may also be helping us rewrite the future; the genetic scissors that give CRISPR its breathtaking power to edit genes are guided to their sites of action by RNAs.

Although most scientists now agree on RNA's bright promise, we are still only beginning to unlock its potential. Consider, for instance, that some 75 percent of the human genome consists of dark matter that is copied into RNAs of unknown function. While some researchers have dismissed this dark matter as junk or noise, I expect it will be the source of even more exciting breakthroughs.

We don’t know yet how many of these possibilities will prove true. But if the past 40 years of research have taught me anything, it is never to underestimate this little molecule. The age of RNA is just getting started.

Thomas Cech is a biochemist at the University of Colorado, Boulder; a recipient of the Nobel Prize in Chemistry in 1989 for his work with RNA; and the author of “The Catalyst: RNA and the Quest to Unlock Life’s Deepest Secrets,” from which this essay is adapted.

The Times is committed to publishing a diversity of letters to the editor. We’d like to hear what you think about this or any of our articles. Here are some tips . And here’s our email: [email protected] .

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Langmead, Salzberg distinguished at RECOMB 2024

Ben Langmead took home the Best Paper Award while Steven Salzberg was one of five distinguished keynote speakers at the annual International Conference on Research in Computational Molecular Biology.

• Awards and Honors

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Department faculty were recognized for their contributions to the field of computational biology at the 28th Annual International Conference on Research in Computational Molecular Biology held April 26 through May 2 in Cambridge, Massachusetts. RECOMB is a leading international conference on algorithmic computational biology, bridging computational, mathematical, statistical, and biological sciences.

Ben Langmead , an associate professor of computer science, and Li Song , an alumnus of the department and now an assistant professor at Dartmouth College, won this year’s Best Paper Award for their work, “ Centrifuger: Lossless compression of microbial genomes for efficient and accurate metagenomic sequence classification.” Available in Genome Biology ,  the paper presents Centrifuger, an efficient taxonomic classification method that compares sequencing reads against a microbial genome database. With its lossless compression and unconstrained match length, Centrifuger achieves greater accuracy than competing methods at lower taxonomic levels.

On April 30, Steven Salzberg , Bloomberg Distinguished Professor of Biomedical Engineering, Computer Science, and Biostatistics, was invited to give one of five distinguished keynotes. His talk “The status of the human genome catalogue: Where are we now, and how do we finish it?” reviewed the course of the Human Genome Project and described recent efforts to use large RNA sequencing resources to create a comprehensive human gene database.

Johns Hopkins teams additionally presented the following posters at the main conference:

• “Compressed Indexing for Pangenome Substring Queries” by Stephen Hwang, Nathaniel Brown, Omar Ahmed , Katharine Jenike, Sam Kovaka, Michael Schatz , and Ben Langmead—also selected for a short talk at RECOMB-Seq , a satellite workshop on biological sequence analysis held prior to the main conference
• “Combining DNA and protein alignments to improve genome annotation with LiftOn” by Kuan-Hao Chao , Jakob M. Heinz, Celine Hoh, Alan Mao, Alaina Shumate, Mihaela Pertea, and Steven Salzberg—also selected for a short talk at RECOMB-Seq
• “Detecting differential transcript usage in complex diseases with SPIT” by Beril Erdogdu, Ales Varabyou, Stephanie Hicks, Steven Salzberg, and Mihaela Pertea
• “Quality assessment of splice site annotation based on conservation across multiple species” by Ilia Minkin and Steven Salzberg—also an Overlay Track talk at RECOMB-Seq

Hopkins researchers also presented the following work at RECOMB-Seq :

• “Movi: A fast and cache-efficient full-text pangenome index” by Mohsen Zakeri , Nathaniel Brown, Omar Ahmed, Travis Gagie, and Ben Langmead—one of six proceedings papers published in the workshop
• “ Mumemto: Efficient maximal matching across multiple genomes” by Vikram Shivakumar and Ben Langmead—selected for a short talk

College of Agricultural and Environmental Sciences

A Drying Salton Sea Pollutes Neighboring Communities

Research finds higher particulate pollution after water diverted to san diego.

• by Emily C. Dooley
• May 29, 2024

When desert winds stir up dust from the Salton Sea’s exposed lakebed, nearby communities suffer from increased air pollution. The deterioration coincides with reduced flows into California’s largest lake, a new research paper in the American Journal of Agricultural Economics finds. 

Disadvantaged communities have been affected more than others in the areas near the Salton Sea, which has been shrinking for years, said the paper’s co-leading author Eric Edwards. He is an assistant professor of agricultural economics at University of California, Davis, who did the research while at North Carolina State University. 

“We have a dusty area, and any time there is wind, it’s going to pick up dust and move it around,” Edwards said. “We think this new dust is increasing the amount of pollution faced by disadvantaged communities in the region surrounding the lake.”

An overflowing river

The Salton Sea formed in 1905 after the Colorado River overflowed its banks and the floodwaters settled into what was known as the Salton Sink. It was primarily fed by water runoff from agricultural operations for almost a century. As the southern part of California struggled to meet growing water demand, the Imperial Irrigation District agreed to send water to San Diego for urban use. 

Imperial, which supplies water to vast desert farms as well as seven towns and two special districts, is the largest user of Colorado River water. The agreement with San Diego required agricultural water users to increase efficiency and reduce their water consumption, which reduced water running into the Salton Sea, Edwards said. 

The reductions increased the lake’s salt content, which is higher than in the Pacific Ocean . This also harmed wildlife habitats and created localized air pollution. The area is the subject of many environmental restoration projects. 

Studying implications

Edwards and others used a particle transport model to study the effects of changing water diversions on particulate pollution.

They found that the paths of fine particulate matter – which can cause asthma, heart and respiratory issues when inhaled – were associated with higher air pollution readings after Imperial began reducing runoff water to the Salton Sea around 2011 in order to transfer it to San Diego, a practice that continues today. 

Researchers modeled lakebed exposure by dividing the lake’s shoreline into 1-square-kilometer grids and collected air pollution data daily for over 20 years, from 1998 to 2018. They added data about the exposed lakebed, or playa, and used a sophisticated physics model called HYSPLIT to factor in wind levels and particle size to track the movement of dust over time. State health screening information available by ZIP Code added more to the story by pinpointing disadvantaged areas, asthma rates and other vulnerabilities. 

Lake levels were higher in 1998 before the transfers, so the change was not evident until later years, when the lakebed became more exposed. 

“We show that during that post-2011, there is an increase in particles going through disadvantaged communities relative to non-disadvantaged communities, which are farther away from the sea,” Edwards said.

In the paper, the pollution paths are depicted on a map of the state. The Salton Sea is marked with a black dot, and red lines radiate from there to distances of 100 miles or more. 

“From every exposed grid cell you have these paths predicting where the particles are going based on physics,” Edwards said. “That’s the path of emissions.” 

Prior research suggests that dust particles from newly exposed playa are more susceptible to wind erosion. 

“There’s lots of evidence that playa is particularly emissive in terms of dust,” Edwards said. “If it’s dry, those particles get picked up readily by the wind and create dust—and at rates higher than areas that have been exposed to the wind over long periods of time.” 

Informing decision makers

Edwards said policymakers and regulators should consider the health and environmental impacts of water diversions in their decision making.

“The drying up of the Salton Sea has serious health consequences that have generally fallen on more disadvantaged populations, who may not be well equipped to advocate for policies that improve their health,” he said. “Policymakers need to think about how to facilitate the movement of water via market transactions, which are essential, while also accounting for potential negative effects on the environment.”

Ryan Abman from San Diego State University and Dana Hernandez-Cortes from Arizona State University contributed equally with Edwards to the research and journal article. 

The U.S. Department of Agriculture’s National Institute of Food and Agriculture supported this research. 

Media Resources

• Eric Edwards, Department of Agricultural and Resource Economics,  [email protected]
• Emily C. Dooley, College of Agricultural and Environmental Sciences, 530-650-6807,  [email protected]  
• Kat Kerlin, UC Davis News and Media Relations, 530-750-9195, [email protected]
• Susanne Clara Bard, San Diego State University Strategic Communications and Public Affairs, 202-441-8976,  [email protected]  

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