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Saturday, February 26, 2011

[AlternativeAnswers] The Human Genome Project 10 Years Out: Reviewing the Past, Present, and Future o

 


This review from the largest conference ever had on Genomic Medicine
permits you to know what the experts feel has been useful to date and what the
future of genetic based research might hold! Of course, some like Bruce
Lipton with his book The Biology of Belief puts all this into perspective by
pointing out that genes only express themselves in an environment that permits
that expression. Thus BRCA 1 and 2 positive do not need breast removal if
patients learn the Kobayashi program, which tests for increased cancer
burden long before lumps or bumps appear, permitting life style changes that
stop the development of the tumor even in genetically susceptible individuals.

Now that Johnson and Johnson will soon have their new blood test for
cancer in the peripheral blood more of you will want to learn all about making
cancer cells in peripheral blood disappear with non-toxic life style based
medicine combined with nutrient support and
detoxification daily for life.

There clearly is some controversy among the experts in this report about
just how much progress the human genome project has made. But it is useful
to review this so you can accurately understand what the proponents feel has
been learned to date although there are molecular biologists like Bruce
Lipton who will challenge them. Interesting to me is the subject of
Epigenetics covered briefly here and the issue of methylation support, which I feel
has become so essential today for most of us. I feel that just the research
on Bisphenol A and the need for methylation support documented by Dr Randy
Jirtle at Duke on Agouti mice is why I designed my BioEn'R-G'y C to be a
vitamin C delivery system. I made it with Trimethyl Glycine and Methyl
Sulfono Methane (MSM) along with aloe and ribose, as my contribution to
maintaining optimal health with the most advanced oral vitamin C product available
anywhere at any price short of the IV form that is still available today
from Apothecure in Dallas.

I also highly recommend to most of my patients additional methylation
support, as Beyond B12 with Methylcobalamin and methyl folic acid in a potent
sublingual form. I feel that BPA has produced epigenetic changes that make
much of this genetic research too superficial, too little and too late.

Garry F. Gordon MD,DO,MD(H)
President, Gordon Research Institute
www.gordonresearch.com

http://www.medscape.com/viewarticle/735196?src=mp&spon=2

Medscape Medical News from the:

American Society of Human Genetics (ASHG) 60th Annual Meeting
From Medscape Genomic Medicine

The Human Genome Project 10 Years Out: Reviewing the Past, Present, and
Future of Genomic Medicine
Shelley D. Smith, PhD
Posted: 01/04/2011

The 60th Annual Meeting of the American Society of Human Genetics held in
Washington, DC, was the largest meeting of this Society ever held.

The meeting was flanked by the Distinguished Speakers' Symposium
highlighting scientific progress since the completion of the Human Genome Project[1]
and a Special Symposium on the future of the National Institutes of Health
(NIH).[2] In between, the 7200 registrants attended more than 400 platform
presentations and viewed more than 2700 posters, many of which focused on
research advances in the inheritance of complex disorders. This review will
summarize key points from the bookend symposia and focus on a few key
presentations that might help clinicians appreciate how genetic research
affects our understanding -- and ultimately our management -- of disease.

The Human Genome Project: Where Are We Now?
As part of a Distinguished Speakers' Symposium, Eric Lander,[1] President
of the Broad Institute at the Massachusetts Institute of Technology and
Harvard University, reviewed some of the advances made in the 10 years since
the announcement of the completion of the human genome sequence.

Although there has been some public perception that expected gains in
diagnosis and treatment haven't been realized, Dr. Lander outlined the
tremendous gains that have been made and illustrated how they are leading to a more
comprehensive knowledge of gene function and regulation.

Sequencing of the human genome has led to major advances in the
identification of genes contributing to Mendelian and non-Mendelian disorders. In
1990, only 70 genes causing dominant or recessive disorders had been cloned;
by 2000, this increased to 1300, and currently more than 2900 genes have
been identified.

The increase has been even more striking for non-Mendelian traits, which
include most common disorders. In 2000, only about 25 genes contributing to
common disorders were known, including the contribution of APOE4 to
Alzheimer disease. Since then, genome-wide association studies have identified
more than 1100 disease-associated genes, including those influencing diabetes,
age-related macular degeneration, inflammatory bowel disease, and heart
disease. Cancer genetics has made similar strides, starting from 12 genes in
1990 known to influence the development or progression of cancer, 80 in
2000, and now at least 240. Although individual genes identified for common
disorders might have only a small effect on the variance of the disorder
(implying that the individual genes do not have much clinical meaning), Dr.
Lander emphasized that the "missing heritability" is probably in the greater
effects produced by the interactions of genes (termed epistasis) than from
each gene acting alone. Moreover, the identification of individual genes and
pathways is critical to understanding the biology of a disorder, which is
much more important clinically than is accounting for the total variance.

Biological Pathways and Epistasis
These 2 themes of the clinical value of understanding biological pathways
and epistasis were carried through in many of the individual sessions. For
example, Jo Knight[3] of King's College in London, presenting on behalf of
the Genetic Analysis of Psoriasis Consortium, noted the discovery of several
new genes contributing to psoriasis, and the kind of gene-gene interaction
that Dr. Lander predicted. Together, the genes helped define the genetic
pathways behind the functions of the skin in pathogen detection,
inflammation, and antigen processing, as well as their role in the pathogenesis of
psoriasis.
The themes of biological pathways and gene-gene interaction were addressed
again in later sessions: Lars Alfredsson[4] of the Karolinska Institute
demonstrated gene-gene and gene-environment (ie, smoking) interactions for
both rheumatoid arthritis and multiple sclerosis, and Braxton Mitchell[5] of
the University of Maryland demonstrated an interaction between the gene
ANRIL, smoking, and stroke. Of note, ANRIL produces a noncoding RNA; the
functions of such genes were themselves the subject of other sessions describing
the role of noncoding RNAs in gene regulation.[6]

The challenge of testing all possible single nucleotide polymorphism (SNP)
interactions on a genome-wide scale was highlighted by Marylyn Ritchie[7]
of Vanderbilt University: Just testing 3 SNPs at a time from a 500,000-SNP
array -- small by today's standards -- results in 2 x 1016 tests, which
strains most computational systems: Analysis of 5 SNPs at a time, given 1
second of computing time per test, would take more than 8 x 1018 years! A
practical solution is to test candidate genes for epistatic effects, but the
selection of candidates depends on some knowledge of the underlying biology of
the disorder, which too often is still unknown.

New Technologies and Gene Identification
"Next-generation" massively parallel sequencing has made sequencing of a
full genome much cheaper and faster than it was in the days when the human
genome was being sequenced, but the cost is still out of the range of most
research and clinical studies. Some have suggested extracting the "exome,"
or protein-coding regions, and sequencing only this much smaller amount of
DNA. Alternatively, linkage or SNP association studies of a disorder can
identify genomic regions that are likely to contain important genes -- and
sequencing just these regions is probably more affordable.

These new technologies have enabled researchers to identify a wide range
of genes for complex disorders that help to shed light on the pathogenesis
of disease. Examples include the identification of 3 genes that influence
stuttering, all of which are in lysosomal pathways and thus may be amenable
to therapy[8]; identification of mutations in the gene coding for the
connective protein fibrillin 1 in thoracic aortic aneurysms and dissection,
independent of its causation of Marfan syndrome[9]; identification of a
dinucleotide repeat in the promoter of the gene DYPSL2 that confers risk for
schizophrenia through its effects on axon growth[10]; and mutations of the
X-linked gene PTCHD1 in families with autism or intellectual disability that is
in the Hedgehog pathway of developmental signaling genes.[11]

Type 2 diabetes, otherwise known as "the geneticists' nightmare," has had
at least 42 risk loci identified through genome-wide association studies,
and, as Michael Boehnke[12] of the University of Michigan noted on behalf of
his colleagues, these studies have contributed to the knowledge of the
biology of this disorder by demonstrating that most of the genes are involved
in pancreatic B-cell dysfunction rather than insulin function.

Finally, further illustrating the advances in gene identification made
possible by these new technologies, Mark Hannibal and colleagues of the
University of Washington in Seattle used exome sequencing to discover the MLL2
gene that underlies most cases of Kabuki syndrome. MLL2 is a histone
methyltransferase and is therefore involved in the epigenetic regulation of other
genes. This finding confirms the autosomal dominant nature of the syndrome
and provides a means of molecular diagnosis. Further studies will define the
genes that are regulated by MLL2 and that cause the craniofacial features
and
developmental delays associated with Kabuki syndrome.

Epigenetic Regulation
The role of epigenetic regulation in clinical disorders, an emerging area
of intense interest, was highlighted in several other sessions. Epigenetic
regulation refers to regulatory processes that are not mediated by DNA
codes but that are carried out through mechanisms such as methylation of DNA or
histone modification, which presumably affect the access of transcription
mechanisms to coding DNA.
In a session highlighting the effects of epigenetic mechanisms on such
disorders as schizophrenia, bipolar illness, and addiction, Ezra Susser[13] of
Columbia University described his research on the long-term effects of
prenatal famine on the later development of schizophrenia, as documented by
follow-up studies of the 1945 "Hunger Winter" in The Netherlands during World
War II and the1959-1961 famine in the Anhui and Guangxi provinces of
China. Preliminary data indicate an association of schizophrenia in exposed
individuals with decreased methylation of an insulin growth factor gene (IGF2);
presumably, this altered methylation was affected by the effects of the
famine in utero, and was maintained into adulthood. Additional work to detect
other epigenetic changes is in progress. However, the methylation changes
were seen in peripheral blood cells, which may not necessarily reflect the
regulatory patterns in tissues in the brain.
Mouse models of human disease can circumvent this problem, as demonstrated
by a study of the addiction process by Eric Nestler[14] of the Mount Sinai
School of Medicine in New York. Using mice addicted to cocaine, the
researchers focused on the deltaFosB gene, which affects histone methylation and
acetylation in the nucleus accumbens, and found that exposure to cocaine
caused increased expression of a particular isoform of the gene. This was
associated with an overall decrease in gene repression, an increase in the
number of dendritic synapses, and an increase in addictive behaviors. Some of
the epigenetic changes persisted even after withdrawal from cocaine.
Determination of the genes that are regulated by these histone changes may
provide targets for therapy.

Expanding Research Avenues and Technologie
The translation of basic science knowledge into clinical science and
therapeutic strategies was a major focus of the closing talk by Francis
Collins,[15] Director of the NIH.
Dr. Collins described the new initiatives being taken by the NIH to
facilitate movement through the drug development pipeline: from gene discovery as
a target for therapeutic intervention, through the testing and optimization
of small molecule compounds that might serve as drugs against these
targets, and finally the very risky and expensive venture of clinical testing.

Four NIH Molecular Library Centers are available for high-throughput
testing of 350,000 potentially therapeutic compounds, and the NIH Therapeutics
for Rare and Neglected Diseases (TRND) program facilitates further testing.
This program can support collaborations between researchers outside of the
NIH and the NIH laboratories to move through the pipeline to the point
where external funding sources are willing to take the risks for further
development.

There are currently 5 projects supported by TRND: 1 on hookworm and 4 for
genetic disorders, namely Neimann-Pick type C, hereditary inclusion body
myopathy, chronic lymphocytic leukemia, and sickle cell anemia.

Clinical testing of therapies can be coordinated through institutions with
NIH-supported Clinical Translational Service Awards and drug development
can be further enhanced by the Cures Accelerated Network, authorized by the
new Healthcare Affordability Act, which would provide new and flexible
mechanisms to fund this research.

An important part of the development of new therapeutics is comparative
effectiveness research, also supported by the new healthcare legislation.
Treatment comparisons can be facilitated by the NIH, and Dr. Collins
envisioned the combination of efficacy testing with personalized medicine, in which
genomic information could be used to determine the best therapies for
individuals with different genotypes.

Dr. Collins also noted some challenges for biomedical research in the
future, including the relatively flat federal funding for research, the
increase in direct-to-consumer genetic testing and its lack of regulation, and the
uncertain legal status of stem cell research and patents on human genomic
DNA sequences.

The NIH has been particularly active in addressing the challenges raised
by the latter 2 issues. The challenge of poorly regulated direct-to-consumer
testing is being addressed through a proposed voluntary registry of
laboratories and companies providing molecular diagnostic testing, although Dr.
Collins recognized that this proposal has been somewhat contentious, and the
American Society of Human Genetics has formally questioned its need given
the currently available and curated GeneTests Website. On the gene
patenting front, the NIH participated in an amicus brief in the currently pending
appeal of the ruling that found that DNA sequences should not be patentable.
The brief made the distinction between human-engineered DNA sequences,
which should be patentable, and genomic DNA sequences, which should be
considered a product of nature and thus not subject to patents. It is hoped that
this change will facilitate research into different means of molecular
diagnosis and treatment.

Finally, Dr. Collins turned to the allegations cited by Dr. Lander in his
opening talk[1] that claimed there has been a lack of progress in human
genetics in the 10 years after completion of the Human Genome Project.

Dr. Collins also refuted those claims, saying that after reading one such
article making this claim, he had immediately come up with 29 recent
advancements that affected peoples' lives.

Advances produced by the Human Genome Project have been most visible to
biomedical researchers, however, and he urged researchers and clinicians to
make themselves available to media representatives to be sure that accurate
information is available. At the same time, he cautioned us to not let our
enthusiasm lead us to overpromise or oversell the consequences of our own
research because failure to deliver on those promises can lead to cynicism
toward research progress later.

Although it is important to convey our passion for our science, he
concluded, this must be balanced by the recognition that the process of going from
an insight to a clinically relevant treatment is very difficult. "It is a
long and expensive and failure-prone road, but it is the best hope we have,
and I don't think we should be shy to describe how this affects our hopes
for the future, for all those people who need that hope, because right now
they don't have what they need."

[Non-text portions of this message have been removed]

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