@Wayne State University
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). PubMed
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
http://ecolonews.blog.fr
- Bernard Dugué English
Translation (According to Google)
http://www.dbusiness.com
http://emergentfool.com
- Cancer as a complex adaptive system
http://emergentfool.com
- 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:
Forumdesforums.com
- Bernard Dugué
English
translation (According to Google)
Shanghai
Science News 7.26.2011
Beijing
News 7.24.2011
DiscoverMagazine.com
ScienceDaily.com
ScienceNewsLine.com
Physorg.com
eScienceNews.com
EurekaAlert.org
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, 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