Heterogeneity Mediated System Complexity: The Ultimate Challenge for Studying Common and Complex Diseases

Heng, Henry H.Q.; Horne, Steven D.; Stevens, Joshua B.; Abdallah, Batoul Y.; Guo, Liu; Chowdhury, Saroj K.; Bremer, Steven W.; Zhang, Kezhong; Ye, Christine J.

doi:10.1007/978-3-319-26221-5_9

Cited by 9 publications

(9 citation statements)

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“…A specific concept of "stress promoted, genetic variation mediated cellular evolution" has been proposed, using the genome theory to synthesize the current status of genomic medicine [8,11,13]. In brief, diseases are defined as genotype/environment-induced variants that are not compatible with a selected environment.…”

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confidence: 99%

Heterogeneity‐mediated cellular adaptation and its trade‐off: searching for the general principles of diseases

Heng

2016

Evaluation Clinical Practice

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Big-data-omics have promised the success of precision medicine. However, most common diseases belong to adaptive systems where the precision is all but difficult to achieve. In this commentary, I propose a heterogeneity-mediated cellular adaptive model to search for the general model of diseases, which also illustrates why in most non-infectious nonMendelian diseases the involvement of cellular evolution is less predictable when gene profiles are used. This synthesis is based on the following new observations/concepts: 1) the gene only codes "parts inheritance" while the genome codes "system inheritance" or the entire blueprint; 2) the nature of somatic genetic coding is fuzzy rather than precise, and genetic alterations are not just the results of genetic error but are in fact generated from internal adaptive mechanisms in response to environmental dynamics; 3) stress-response is less specific within cellular evolutionary context when compared to known biochemical specificities; and 4) most medical interventions have their unavoidable uncertainties and often can function as negative harmful stresses as trade-offs. The acknowledgment of diseases as adaptive systems calls for the action to integrate genome-(not simply individual gene-) mediated cellular evolution into molecular medicine.

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confidence: 99%

Heterogeneity‐mediated cellular adaptation and its trade‐off: searching for the general principles of diseases

Heng

2016

Evaluation Clinical Practice

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“…Recently, CIN has been linked to different types of human diseases, as elevated NCCAs have been detected from many common diseases [ 37 ]. Based on stress-elicited, genome alteration-mediated adaptation, and the trade-off of that gain versus the loss of genomic stability as pre-conditions for various diseases or illnesses, a general model was proposed of how genetic changes drive somatic cell evolution; this process can both improve cellular function but at the same time increase the risk of disease [ 97 - 99 ]. Under this realization, it is important to study all types of genomic variations and their impact on human variations and diseases.…”

Section: Contributions Of Molecular Cytogenetics/cytogenomics In Pre-mentioning

confidence: 99%

“…Taking this new framework into account changes previous perceptions of heterogeneity. Rather than simply “noise” that must be filtered out or disregarded, heterogeneity provides potential for evolution and represents a new layer of complexity [ 4 , 97 , 98 ]. In terms of complex tissues and organs, we have previously discussed the role of heterogeneity in performing complex functions while providing the robustness necessary to withstand the stress associated with those functions [ 90 ].…”

Section: Future Direction: Search For a New Conceptual Framework And mentioning

confidence: 99%

“…We recently examined the genome instability of GWI patients by comparing the degree of stochastic chromosomal aberrations from short-term lymphocyte cultures. Various karyotypic abnormalities were observed, and we demonstrated that genome instability was significantly elevated in GWI patients compared to controls [ 37 , 97 , 127 ]. Similar analysis was also performed in a Chronic Fatigue Syndrome (CFS) study, where again the overall level of genome instability was significantly higher in CFS patients than controls [ 37 ], (Ye et al , manuscript in preparation).…”

Section: Future Direction: Search For a New Conceptual Framework And mentioning

confidence: 99%

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A Postgenomic Perspective on Molecular Cytogenetics

Heng

Horne

Chaudhry

et al. 2018

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Background: The postgenomic era is featured by massive data collection and analyses from various large scale-omics studies. Despite the promising capability of systems biology and bioinformatics to handle large data sets, data interpretation, especially the translation of -omics data into clinical implications, has been challenging.Discussion: In this perspective, some important conceptual and technological limitations of current systems biology are discussed in the context of the ultimate importance of the genome beyond the collection of all genes. Following a brief summary of the contributions of molecular cytogenetics/cytogenomics in the pre- and post-genomic eras, new challenges for postgenomic research are discussed. Such discussion leads to a call to search for a new conceptual framework and holistic methodologies.Conclusion: Throughout this synthesis, the genome theory of somatic cell evolution is highlighted in contrast to gene theory, which ignores the karyotype-mediated higher level of genetic information. Since “system inheritance” is defined by the genome context (gene content and genomic topology) while “parts inheritance” is defined by genes/epigenes, molecular cytogenetics and cytogenomics (which directly study genome structure, function, alteration and evolution) will play important roles in this postgenomic era.

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“…Cancer evolution is driven by genome replacement, making system inheritance the most important inheritance while making gene-mediated parts inheritance become trivial. Interestingly, in cancer, the mechanism(s) maintaining various types of inheritance become less precise, forming a new type of inheritance, called fuzzy inheritance, which provides the mechanism to explain the high level of heterogeneity in cancer (Heng 2015;Heng et al, 2014;Abdallah et al, unpublished observations). Without the above understanding, and perhaps also due to the overemphasis on gene-based research, many key facts about chromosomal aberrations in cancer are not well known by most molecular cancer researchers.…”

Section: Genome Theory Emphasizes the Ultimate Importance Of Chromosomentioning

confidence: 99%

Insights on processes of evolutionary tumor growth

Horne¹,

Wexler²,

Stevens³

et al. 2017

Atlas of Genetics and Cytogenetics in Oncology and Haematology

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Application of traditional somatic evolutionary theory can offer an appropriate context for studying tumor growth at the molecular level. However, high degrees of heterogeneity (especially genome-level heterogeneity) within tumors coupled with a lack of common driver mutations have posed a challenge to the generally accepted stepwise concept of cancer evolution, where clonal expansion is the key. In order to account for multiple levels of heterogeneity and better understand tumor growth and progression, a new, holistic conceptual framework must be applied in cancer research. Herein, we discuss one such framework, the genome theory of cancer evolution, with respect to tumor growth. This includes detailing the ultimate importance of chromosome aberrations in cancer, the somatic cell evolutionary pattern, and single-cell/population growth dynamics. Under this new framework, tumor growth is a highly dynamic process where emergent outlier subpopulations can greatly influence the pattern of progression and the direction of evolution. Further, genome level changes have a greater impact on cancer evolution than individual gene mutations in most cancer types, as karyotype alteration often results in altered system inheritance which defines the network structure and even can change the meaning of individual genes (representing 'parts inheritance' by changing the gene context. Based on this analysis, we call for a focus shift back on cytogenetic and cytogenomic alterations (especially on non-clonal chromosomal aberrations) in monitoring population growth, identifying the emergence of new subpopulations and studying patterns of evolutionary dynamics. This new insight has implications in understanding cancer evolution in general as well as searching for new diagnostic and treatment strategies.

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Heterogeneity Mediated System Complexity: The Ultimate Challenge for Studying Common and Complex Diseases

Cited by 9 publications

References 43 publications

Heterogeneity‐mediated cellular adaptation and its trade‐off: searching for the general principles of diseases

Heterogeneity‐mediated cellular adaptation and its trade‐off: searching for the general principles of diseases

A Postgenomic Perspective on Molecular Cytogenetics

Insights on processes of evolutionary tumor growth

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