New evolutionary insight for cancer progression

By establishing the importance of non-clonal chromosomal aberrations (NCCAs), a non-recurrent type of genomic aberration that has been disregarded for decades in cancer research, we have demonstrated that genomic instability mediated stochastic genome aberrations are the key driving force in cancer progression and drug resistance.  The seminal discovery of the two phases of evolution (a punctuated stochastic phase responsible for macro-evolution and a stepwise gradual phase responsible for micro-evolution) in somatic cell evolution and its implications to organismal evolution is highly significant.  To push this concept and initiate a major paradigm shift, we have demonstrated that population diversity at the genome level rather than gene mutation level is a key index for tumorigenesis, and the degree of genome heterogeneity can be used in clinical diagnosis.  We have further established the evolutionary mechanism of cancer and its diverse relationship with a large number of individual molecular mechanisms.  Our findings and new concepts have received increasing attention.

J. B. Stevens, B. Y. Abdallah, S. D. Horne, G. Liu, S. W. Bremer, and H. H. Heng, "Genetic and epigenetic heterogeneity in cancer," eLS (2011). Wiley Online Library
H. H. Heng, J. B. Stevens, S. W. Bremer, G. Liu, B. Y. Abdallah, and C. J. Ye, "Evolutionary mechanisms and diversity in cancer," Adv Cancer Res 112, 217-253 (2011).
H. H. Heng, G. Liu, J. B. Stevens, S. W. Bremer, K. J. Ye, B. Y. Abdallah, S. D. Horne, and C. J. Ye, "Decoding the genome beyond sequencing: The new phase of genomic research," Genomics 98 (4), 242-252 (2011). PubMed
H. H. Heng, "Missing heritability and stochastic genome alterations," Nat Rev Genet 11 (11), 813 (2010). PubMed
H. H. Heng, J. B. Stevens, S. W. Bremer, K. J. Ye, G. Liu, and C. J. Ye, "The evolutionary mechanism of cancer," J Cell Biochem 109 (6), 1072-1084 (2010). PubMed
H. H. Heng, "Cancer genome sequencing: the challenges ahead," Bioessays 29 (8), 783-794 (2007). PubMed
H. H. Heng, J. B. Stevens, G. Liu, S. W. Bremer, K. J. Ye, P. V. Reddy, G. S. Wu, Y. A. Wang, M. A. Tainsky, and C. J. Ye, "Stochastic cancer progression driven by non-clonal chromosome aberrations," J Cell Physiol 208 (2), 461-472 (2006). PubMed

Online discussions of this research:

Advances in Cancer Research - Discussed by Dr. Mark D. Vincent, London Health Sciences Centre - Bernard Dugué  English Translation (According to Google)
- Cancer as a complex adaptive system
- The conflict between complex systems and reductionism

Linking instability mediated stochastic genome alterations to other common diseases

As many common and complex diseases share system problems as a key feature, focusing on genome instability mediated stochastic genome alterations will provide insight in the search for the common mechanisms.  By applying this principle, we have illustrated the linkage between Gulf War Illness and genome instability.  We have recently recieved support by the Department of Defense to study this issue.  Our Gulf War Illness studies have also implied relevance towards the study of other related diseases.  For example, we have begun to investigate whether genome instability also contributes to Chronic Fatigue and Immune Dysfunction Syndromes.

Dr. Henry H.Q. Heng awarded funding for Gulf War Illness genomic research - GenomeWeb
Dr. Henry H.Q. Heng on the Discovery Channel documentary "Conspiracy Test - Gulf War Illness"

Establishing the genome theory has solved the mystery of the main function of sexual reproduction

To solve an ever increasing number of surprises from genomic research that do not follow the gene theory, our group has established the genome theory with ten key principles including the concept of how genome reorganization rather than new gene formation defines new species.  According to the genome theory, genome level reorganizations create new species or systems (representing macro-evolution), while the gene or epigenetic levels of alteration modify the species (representing micro-evolution).

To demonstrate the power of the genome theory, we have applied its concepts to the century old mystery of why sex is a dominant form of reproduction despite its cost when compared to asexual reproduction.  When discussing the main function of sexual reproduction, a generally accepted viewpoint states that asexual reproduction produces identical copies and that the main function of sexual reproduction is to provide diversity necessary for evolutionary progress.  By treating a species as a system, we realized that mixing genes will not change a given system (species), so sexual reproduction promotes the continuation of a species by maintaining the chromosome-defined boundary or framework of a species and that the main result of sexual reproduction is the preservation of the identity of a given genome rather than the promotion of genetic diversity as is commonly thought.  This viewpoint differs fundamentally from conventional models as chromosomal aberrations cannot survive the very process of sexual reproduction itself.  Interestingly, our discovery serves as an important example of the conflict between the gene and the genome.

R. Gorelick and H. H. Heng, "Sex reduces genetic variation: a multidisciplinary review," Evolution 65 (4), 1088-1098 (2011). PubMed
"Sex, cancer, and evolution - a sneak preview of a member's hot upcoming GENOME article."  PDF
H. H. Heng, "The genome-centric concept: resynthesis of evolutionary theory," Bioessays 31 (5), 512-525 (2009). PubMed
H. H. Heng, "Elimination of altered karyotypes by sexual reproduction preserves species identity," Genome 50 (5), 517-524 (2007). PubMed

Online discussions of this research: - Bernard Dugué
    English translation (According to Google)
Shanghai Science News 7.26.2011

Beijing News 7.24.2011

Establishing a novel system to monitor mitotic death

Cell death plays a key role in both cancer progression and the response to treatment.  We have recently characterized chromosome fragmentation, a new type of cell death that takes place in mitosis.  It occurs spontaneously or can be induced by treatment with chemotherapeutics and is observable within cell lines, tumors and lymphocytes of cancer patients.  The process of chromosome fragmentation results in loss of viability, but is apparently non-apoptotic and further differs from death defined by mitotic catastrophe.  Chromosome fragmentation is linked to genomic instability, serving as a method to eliminate genomically unstable cells.  Paradoxically, this process could result in genome aberrations common in cancer.  Chromosome fragmentation represents an efficient means of induced cell death and is a clinically relevant biomarker of mitotic cell death as we have detected high levels of chromosome fragmentation from cancer patient samples.  The characterization of chromosome fragmentation may also shed light on the mechanism of chromosomal pulverization.  Interestingly, chromosome fragmentation is one important form of non-clonal chromosome aberration essential for cancer evolution.  Our recent work further links various individual molecular mechanisms to common system stress, which leads to genome instability through centrosome abnormalities, and triggers mitotic cell death.  The concept of chromosome fragmentation mediated cell death is receiving increasing attention within the field.

J. B. Stevens, B. Y. Abdallah, G. Liu, C. J. Ye, S. D. Horne, G. Wang, S. Savasan, M. Shekhar, S. A. Krawetz, M. Huttemann, M. A. Tainsky, G. S. Wu, Y. Xie, K. Zhang, and H. H. Heng, "Diverse system stresses: common mechanisms of chromosome fragmentation," Cell Death Dis 2, e178 (2011). PubMed
J. B. Stevens, B. Y. Abdallah, S. M. Regan, G. Liu, S. W. Bremer, C. J. Ye, and H. H. Heng, "Comparison of mitotic cell death by chromosome fragmentation to premature chromosome condensation," Mol Cytogenet 3, 20 (2010). PubMed
J. B. Stevens, G. Liu, S. W. Bremer, K. J. Ye, W. Xu, J. Xu, Y. Sun, G. S. Wu, S. Savasan, S. A. Krawetz, C. J. Ye, and H. H. Heng, "Mitotic cell death by chromosome fragmentation," Cancer Res 67 (16), 7686-7694 (2007). PubMed

Novel features of the chromatin loop domain and genome architecture

1)  Development of a novel experimental system to study chromosome structure and its impact on genetic recombination and gene expression.  By using transgenic mice and DNA-protein in situ co-visualization approaches, it has been discovered that the loop size regulation of meiotic chromosomes is determined by chromosomal location and overall AT/GC content rather than by specific DNA sequences, and that the telomeric region has special control of chromatin formation at the high order level.  This new concept and the experimental system will have a great impact in the field of chromosomal research, as well as applications in gene therapy.
2)  Established the concept of the dynamic use of chromatin loop anchors that are defined by nuclear matrix association sequences.  Our review article (Heng et al., 2001) has been referred as "a good starting signal for chromosomics," a new field.
3)  Discovered that GC and AT-rich sequences for different sized chromatin loops, which reconcile the inconsistency between mitotic and meiotic chromosomes (the inconsistency between the physical and genetic distances) (manuscript in preparation).

H. H. Heng, S. Goetze, C. J. Ye, G. Liu, J. B. Stevens, S. W. Bremer, S. M. Wykes, J. Bode, and S. A. Krawetz, "Chromatin loops are selectively anchored using scaffold/matrix-attachment regions," J Cell Sci 117 (Pt 7), 999-1008 (2004). PubMed
H. H. Heng, J. Chamberlain, X. M. Shi, B. Spyropoulos, L-C. Tsui, and P. B. Moens, "Regulation of meiotic chromatin loop size by chromosomal position," Proc Natl Acad Sci USA 93, 2795-2800 (1996). PubMed
H. H. Heng, L-C. Tsui, and P. B. Moens, "Organization of heterologous DNA inserts on the mouse meiotic chromosome core," Chromosome 103, 401-407 (1994) (featured on cover) PubMed

Methodology development for cytogenomics

1)  Pioneered high resolution FISH on released chromatin fibers that have revolutionized the FISH field.  This system, now known as Fiber FISH, has been extensively used for gene cloning, physical mapping, DNA replication, and chromosome and genome structure studies.  This achievement has been referred to as one of the four major contributions to molecular cytogenetic approaches.
2)  Developed the multiple color DNA-protein in situ co-detection methods that have been extensively used in chromosomal research.
3)  Solved the mystery of non-reproducible banding patterns during FISH detection and provided a reliable method of FISH detection on banded chromosomes.  Additionally, set up new FISH methods for small cDNA detection (as small as a few hundred base pairs).  This approach is valuable for the detection of expanded trinucleotide repeats in patients, to study genome evolution and to compare the insertion sites of transgenes, especially when transferring mapping information among different species (such as from human to mouse to rat).

C. J. Ye, L. Lawrenson, G. Liu, J. B. Stevens, K. J. Ye, S. W. Bremer, and H. H. Heng, Chapter 19: Simultaneous fluorescence immunostaining and FISH.  In Liehr edited: Fluorescence in situ hybridization (FISH) - Application.  Springer Publishing.  193-216 (2009).
B. Beatty and H. H. Heng, Gene mapping by fluorescence in situ hybridization.  In Meyer R ed Encyclopedia of Molecular Cell Biology and Molecular Medicine.  Wiley-VCH. Vol 5, 137-171 (2004).
H. H. Q. Heng, B. Spyropoulos, and P. Moens, "FISH technology in chromosome and genome research," Bioessays 19, 75-84 (1997). PubMed
H. H. Q. Heng and L-C. Tsui, "Modes of DAPI banding and simultaneous in situ hybridization," Chromosome 102, 325-332 (1993) (featured on cover).  PubMed
E. Pennisi, "Science news of the week: Now in vivid color, details of DNA," Science News 144, 164 (1993).  PDF
J. B. Lawrence, K. C. Carter, and M. J. Gerdes, "Extending the capabilities of interphase chromatin mapping," Nature Genetics 2, 171-172 (1992).  PDF
H. H. Q. Heng, J. Squire, and L-C. Tsui, "High resolution mapping of mammalian genes by in situ hybridization to free chromatin," Proc Natl Acad Sci USA 89, 9509-9513 (1992) (featured by Science News and Nature Genetics). PubMed