"And yet the last five years, in Olson's view, have been "a period of a great grinding of gears, kind of shifting of gears." In the terms of the science historian Thomas Kuhn, it's been "a period of consolidation and more normal science." Others, such as Sydney Brenner of the Salk Institute, the Nobel Prize-winning pioneer of the worm, Caenorhabditis elegans, go further, worrying that the genome sequence and the growing lists of sequences and proteins and protein interactions and functional elements don't get very deep into such core problems of biology as the operations of the cell, of development from egg to adult, or the problem of consciousness. "We've become very geno-centric," says Brenner. "The cell must become the focus."
What vexes many thousands of colleagues around the world most is that genomics hasn't yet moved into the "real world" of medical relevance."
Bio-IT World Microarrays Decipher Disease
"Interstitial lung diseases represent both a diagnostic and therapeutic challenge because the clinical features of the disease are often nonspecific. “The classifications of the disease changes every few years so it’s very hard to diagnose,” says Naftali Kaminski, director of the Dorothy P. and Richard P. Simmons Center for Interstitial Lung Disease (ILD) and associate professor of medicine, pathology, and human genetics at the University of Pittsburgh Medical Center.
Kaminski and Moises Selman from Mexico City set out to ascertain whether gene expression patterns could help determine differences between various interstitial lung disease types, including idiopathic pulmonary fibrosis (IPF), hypersensitivity pneumonitis (HP), and nonspecific interstitial pneumonia (NSIP)."
"Using custom oligonucleotide arrays designed by Eos Biotechnology and Affymetrix, Kaminski and Selman and their collaborators found a functional genetic signature to distinguish between IPF and HP. “We found that the genes that distinguish HP from IPF were genes related to inflammation,” says Kaminski."
The New York Review of Books How Sick Is Modern Medicine?
"Basic science came to be dominated by molecular genetics. The discovery of DNA spawned new technologies that led to research into genetic engineering, genetic screening, and gene therapy. Naive investors, often ignorant about the wafer-thin credibility of the research they were paying for, poured millions into biotechnology companies. The result, according to Le Fanu, has been that "the impression of progress has not been vindicated by anything resembling the practical benefits originally anticipated."
Worse, gene therapy has largely turned out to be "not only expensive but useless." Why has the new genetics so far failed medicine? Le Fanu answers that "genetics is not a particularly significant factor in human disease." And, in any case, genes are "complex," "unpredictable," and "perverse." They are not amenable to easy understanding. Their involvement in disease is largely "incomprehensible.""
The New England Journal Of Medicine: Correspondence Will Genetics Revolutionize Medicine?
"Neither we nor our critics defined a revolution in medicine. We mean a paradigm shift in theory or practice. Sotos and Rienhoff's plea for "precise diagnosis" epitomizes the current paradigm. In most of those who will have common disorders, the interaction of genetic, environmental, and behavioral factors makes the quest for precise diagnosis illusive. "
"The revolution in medicine will come with the recognition, based in part on genetic research, that the quest for single causes for common diseases will seldom be fruitful and that a new paradigm of a causal web must be adopted. Interventions must be directed at the most vulnerable points in the web. Sometimes this will involve biomedical interventions. At other times, it will involve modifying aspects of our social structure, lifestyle, or environment that increase the risk of disease."The New England Journal Of Medicine Will Genetics Revolutionize Medicine?redux [11.02.00]
"On both sides of the Atlantic, revolutionary claims have been made about the ultimate impact of genetics on clinical medicine. John Bell at Oxford has asserted that "within the next decade genetic testing will be used widely for predictive testing in healthy people and for diagnosis and management of patients.... The excitement in the field has shifted to the elucidation of the genetic basis of the common diseases." (1) And in the United States the director of the National Human Genome Research Institute, Francis Collins, has stated that the good that would come from mapping the human genetic terrain "would include a new understanding of genetic contributions to human disease and the development of rational strategies for minimizing or preventing disease phenotypes altogether." (2)
Statements like these clothe medicine in a genetic mantle. The result of efforts to identify genes that have a role in common diseases suggests a different picture: the genetic mantle may prove to be like the emperor's new clothes. In this article we argue that the new genetics will not revolutionize the way in which common diseases are identified or prevented. Mapping and sequencing the human genome will lead to the identification of more genes causing mendelian disorders and to the development of diagnostic and predictive tests for them. The development of safe and effective treatments, however, will usually lag behind, (3) although occasionally a treatment does precede the discovery of the disease-causing allele, as was the case for hemochromatosis. (4) Furthermore, only a small proportion of the population has mendelian disorders, and this will limit the ultimate impact of the Human Genome Project.
Our doubts stem from the incomplete penetrance of genotypes for common diseases, the limited ability to tailor treatment to genotypes, and the low magnitude of risks conferred by various genotypes for the population at large. Consequently, most people will have little interest in learning their genotypes."
The Centers for Disease Control The Future of Genetic Studies of Complex Human Diseases: An Epidemiologic Perspective
"With advances in the human genome project and the increasing availability of DNA markers scattered throughout the genome such as simple sequence polymorphisms, variable number tandem repeats, and short sequence repeat polymorphisms, it has become increasingly possible to search for the genetic basis of complex human diseases using genomic wide screening methods. Linkage analysis using LOD score analysis in large pedigrees has been the traditional tool to identify gene loci for human disorders both for single gene disorders (e.g. Huntington) and for complex chronic diseases (e.g. bipolar disease). Recently, Risch and Merikangas have argued that the future of genetic studies of complex human disease may depend, to a large extent, on applications of new "association" type methods to family-based data. The main method of interest is the transmission disequilibrium test (TDT) in which alleles at a given locus for a person with a specific disease are compared with parental non transmitted alleles, to look for evidence of deviation from expectations in the absence of linkage. The TDT has been shown to be a valid test of linkage in the presence of linkage disequilibrium (which creates associations with specific alleles). They showed that the TDT has more power than traditional linkage analysis for disease genes with weak to moderate effects on disease risks.
In this paper, we argue that the future of the genetic study of complex disorders will rely increasingly on the classical epidemiologic "association" paradigm. We show that on the long run, improvements in study designs and in adjusting for population stratification using interviews and genetics markers will lead to a new era of population-based incident case-control studies that could have more power and lead to more detailed information not only on the presence or absence of a disease susceptibility gene but define the magnitude of risks and gene-environment interaction- a crucial first step to disease prevention and health promotion."
British Medical Journal Single gene disorders or complex traits: lessons from the thalassaemias and other monogenic diseases
"As a result of the revolution in the biological sciences following the development of recombinant DNA technology and the sequencing of most of the human genome, the role of genetics in the pathogenesis of human disease now dominates biomedical research. There is every sign that the rapidly evolving technology of the post genome era will unravel the function of the human genome and explain how the 50 000 to 100 000 genes interact with one another and the environment to make us what we are.
The central question for the medical sciences is the extent to which it will be possible to relate events at the molecular level with the clinical findings or phenotypes of patients with particular diseases. This problem will permeate every aspect of medical research and practice in the future. It will dominate predictive genetics and genetic counselling. It will also be of major importance for clinical decision making as new and novel approaches to the treatment of disease become available, particularly those involving genetic manipulation. Further exploration of the genome may also provide information on some of the common killers of Western society, such as heart disease, stroke, diabetes, and psychiatric disease, leading to a new form of pharmacology in which drugs are tailored to an individual's genetic make up. Even more important, and certainly more complex, will be relating genotype to phenotype. Many of our most important diseases almost certainly reflect varying susceptibility, due to the action of many different genes and a wide variety of environmental factors and to the ill understood biology of ageing."
"Is there any way of guessing the likely levels of complexity that will be encountered as the genetic basis of disease is explored with the new technology?"
The New York Times Genes May Cause 25% of 3 Major Cancers
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"Genes may cause more than one-quarter of three major types of cancer, more than previously thought, a group of researchers says.
Scandinavian researchers concluded that genes account for 42 percent of the risk for prostate cancer, 35 percent for colorectal cancer and 27 percent for breast cancer.
The rest of the cases are caused by what people do, such as smoking and diet, or what happens to them, such as on-the-job hazards or viral infections, the researchers said."
"...the conclusion runs contrary to the widespread belief that scientists "will find solutions or cures to all diseases in the genes," Dr. Lichtenstein said. "That won't be the case."
BioMedCentral Simplifying genetic disorders
"Simple genetic diseases, such as cystic fibrosis and thalassaemia are just that — simple. A single gene underlies them. Finding it is like climbing a steep hill — hard work but straightforward. Complex disorders, such as asthma and type 2 diabetes, by contrast, have many components, which makes finding a cause more like scaling Everest — far harder, requiring more specialist equipment and the strong possibility of failure.
In work published in the October issue of Nature Genetics, University of Chicago researchers have cleared a path to studying the genetic foundation of type 2, or non-insulin-dependent diabetes mellitus (NIDDM). In a study of a Mexican-American population and two white populations (Finns and Germans) they have found that small genetic variations, called single-nucleotide polymorphisms (SNPs), in a particular gene tend to occur more often in diabetics than in healthy relatives. Although finding a common genetic variation in family groups affected by simple genetic disorders is implicit, a gene implicated in a population with a complex disease could provide a potential new target for gene therapy. "Variation in this gene is associated with a threefold increased risk in the groups studied," explains lead researcher Graeme Bell. "
"The research does represent a shift in the landscape of genetic diseases. "Studies are not going to be easy," says Bell "but they are not impossible and each locus will present its own challenges." Kruglyak feels the path is clearer, if only because of the 'psychological factor' of showing it can succeed. How important it will be in the overall problem of diabetes, or how often this kind of success will occur in other diseases, will emerge in time. "
The New England Journal Of Medicine The Triple Helix: Gene, Organism, and Environment
""Like any large construction project in the public domain, sequencing the human genome has been a subject of discussion and controversy. Major issues have been the cost of the project, its scientific merit, and the effects of the knowledge gained on human affairs. The concern about cost subsided as the project proved viable and attracted private funding. That leaves the other two questions: What will we learn from this sequence, and how will it affect our lives? With fame and fortune to be made in the genome business, one can only be skeptical of the wondrous claims made by the project's protagonists. The Triple Helix examines these questions from a critical and biologically informed angle."
"In Lewontin's triple helix, the genes are placed in their natural context, where history and geography shape the nature of organisms and the genes they contain. His differences with the most modern of molecular and cellular biologists are irreconcilable and reflect the ever-widening gulf between biologists who have an affinity for what goes on outside the laboratory and those for whom the differences between individuals and between species represent "an annoyance [to be] ignored whenever possible." In many laboratories, organisms are now studied under conditions in which genetic variation is eliminated and the environment held constant. It is only under these special conditions, where neither variation nor natural selection is tolerated, that the triple helix collapses into the double helix and genes appear to be paramount.""
“Bioinformatics will be at the core of biology in the 21st century. In fields ranging from structural biology to genomics to biomedical imaging, ready access to data and analytical tools are fundamentally changing the way investigators in the life sciences conduct research and approach problems. Complex, computationally intensive biological problems are now being addressed and promise to significantly advance our understanding of biology and medicine. No biological discipline will be unaffected by these technological breakthroughs.”BIOINFORMATICS IN THE 21st CENTURY
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