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Ushering in
Genomic Medicine by
Bill Sardi Pharmacologists are scheming to classify all diseases by their genetic fingerprint, conduct massive genetic screening of the citizenry and then prescribe gene-controlling drugs. But as Big Pharma attempts to stake its claim for use of synthetic drug molecules to influence gene-controlled disease mechanisms, will nature trump the pharmacologists? The foods we eat, the drugs and dietary supplements we take, all provide molecules that affect the human genome – the 30,000 genes that are housed within the nucleus of each cell of the body. Genes, when activated, produce proteins, a process called gene expression. Gene-controlled protein making can also be down-regulated in the same manner. The influence of food, drugs and supplements over the entire genome can now be measured in what is called global gene microarray. Such gene array studies are in the process of changing the classification of diseases as well as therapies provided by modern medicine, and a battle is shaping up on which molecules will be employed to prevent or treat disease – naturally occurring molecules or man-made synthetics. Microarray technology allows investigators the opportunity to measure expression levels of thousands of genes simultaneously. [Functional Integral Genomics 2005 Jan; 5(1):32-9] Researchers employ laser scanning equipment to measure the expression of deoxyribonucleic acid (DNA) or messenger ribonucleic acid (RNA), which is the chemical blueprint for protein production. The genomic effect of diseases and certain treatments can be simultaneously monitored using this technology. The gene expression data is acquired and stored on a match-book sized "gene chip" that is produced on glass by high-speed robotics. In the past a pathologist might examine tissue slides of tumors from different patient’s that arise in the same part of the body and would not be able to distinguish that they are quite different in regard to their gene profile. With microarray technology, diseases once thought to have nothing in common now appear differently. "I’m shaking my head with disbelief that two genes would pop up in two diseases that have absolutely nothing in common," said Dr. Francis S. Collins, the director of the National Human Genome Research Institute. In the late 1990s, Todd Golub developed a technique that has revolutionized cancer diagnosis and treatment. He showed that DNA chips could discriminate between two similar leukemias because each cancer has a unique genetic fingerprint. [Molecular classification of cancer: class discovery and class prediction by gene expression monitoring. Science 1999 Oct 15; 286(5439):531-7] Mapping gene/disease fingerprints The first step in this genomic revolution is to reclassify diseases by their genomic profile. A landmark article in The New York Times by Andrew Pollack, entitled "Redefining disease, genes and all," ushers in a new era in modern medicine – the idea of defining disease by its genetic profile rather than by location, symptoms, markers or radiographic evidence. As researchers at George Mason University in Manassas, Virginia state: "Microarray technology presents the scientific community with a compelling approach that allows for simultaneous evaluation of all cellular processes at once. Cancer, being one of the most challenging diseases due to its polygenic nature, presents itself as a perfect candidate for evaluation by this approach." [Anticancer Research 2004 Mar-Apr; 24(2A):441-8] The current direction is to map the "diseasome," that is, the typical pattern of gene-derived proteins produced in a particular disease, for all diseases. [Redefining disease, genes and all, New York Times, May 6, 2008] Geneticists now claim the genetic landscape of human diseases can "robustly uncover causative genes with high accuracy for many people with certain genetic predispositions." [Molecular Systems Biology 4: 189, 2008] Gene microarray studies have already been launched to produce genetic profiles for certain diseases such as cancer. [Nature. 2005 Jun 9; 435(7043):834-8] What is striking, when geneticists interconnected 1284 diseases, 867 had at least one link to other diseases and 516 diseases form one giant component, which suggests the genetic origins of most diseases are shared with other diseases! [The human disease network. Proceedings National Academy Science U S A. 2007 May 22; 104(21):8685-90] Researchers are hesitant to say this, but cure one and you might cure them all. The disease network can be viewed online here. Genetic connection between disease and drugs The second step in this genomic revolution is to connect drugs to the genes they activate, which has pharmacologists wringing their hands in anticipation. Todd Golub, now director of cancer genomics at the Broad Institute in Cambridge, Massachusetts, in collaboration with colleagues, has developed a "Connectivity Map," which profiles drugs by the genes they activate as a way to find new uses for existing drugs. Researchers at the Broad Institute and Harvard have already created an "interactome" composed of US Food & Drug Administration-approved drug molecules with gene targets. [Nature Biotechnology 2007 Oct; 25(10):1119-26; Science. 2006 Sep 29; 313(5795):1929-35] Dr. Peter J. Gillies, affiliated with the University of Toronto and DuPont USA, says "The pharmaceutical industry expects to leverage data from the Human Genome Project to develop new drugs based on the genetic constitution of the patient." [Journal American Dietetic Association 2003 Dec; 103(12 Supplement 2):S50-5] Nature versus man-made molecules: nutrigenomics But will man-made drugs conquer diseases or will pharmacologists be trumped by natural molecules found in foods and concentrated in dietary supplements? It’s difficult to imagine how the pharmaceutical industry is going to continue with their "drug deficiency" model of disease treatment because gene array technology is finally going to reveal which is superior, prescription drugs or functional foods and dietary supplements. Unless Big Pharma figures a way to sweep recent discoveries under the rug, it appears nature is going to win out over synthetic drugs. A less-heralded effort to usher in nutritional approaches to disease prevention and treatment is called nutrigenomics, which is a field of research based on the complete knowledge of the human genome and refers to the entire spectrum of human genes that determine the interactions of nutrition with the organism. Nutrigenetics is based on the inter-individual, genetically determined differences in metabolism. [Molecular Nutrition Food Research 2005 Oct; 49(10):908-17] The future of healthcare may belong to nutrigenomics. Stephen J. Genuis of the University of Alberta says it best:
Researchers at the DuPont Central Research & Development center in Wilmington, Delaware are calling for a "preemptive strike against chronic disease" by the development of functional foods and designer diets – a nutrigenomic approach to chronic disease. [Nutrition Reviews 2007 Dec; 65(12 Pt 2):S217-20] Inherited risk for disease (polymorphisms) It is difficult to fathom how the drug model of disease care is going to prevail in the coming world of nutrigenomics. The superiority of nutrients over drugs can be observed in segments of human populations that have genetic polymorphisms – a genetic trait exhibited in at least 1% of the population. Humans differ in their response to diet and many of these differences are attributed to genetic polymorphisms. Inherited trait: more skin pigmentation, less vitamin D For example, there are obvious inherited differences in genes for skin pigmentation. African Americans produce more melanin in their skin which reduces their production of vitamin D upon skin exposure to unfiltered solar ultraviolet radiation. The lack of vitamin D results in a weakened immune system and a greater tendency to develop cancer, particularly in northern climates where the UV component of sunlight is diminished in winter months. [Cancer Causes Control 2008 Jan 25] A lack of vitamin D is linked with many diseases ranging from rickets, osteoporosis, autoimmune disease (rheumatoid arthritis, lupus, multiple sclerosis, Crohn’s disease, Hashimoto’s thyroiditis), obesity, mental depression, heart failure, diabetes, to lack of muscle tone. Massive vitamin D food fortification and dietary supplement campaigns among individuals with darkly pigmented skin would compensate for this genetic difference. Genetic tests would not be required since skin pigmentation is an obvious observed trait. No new drug or gene test need be developed before such a program is implemented in the population at large. Inherited trait: more unbound iron = shortage of vitamin C Another example of genotypes that are prone to nutrient related disease is the Asian population that has an inherited flaw which results in greater risk for heart and arterial disease. Asians commonly produce lower amounts of haptoglobin, a protein that binds to iron as it is released from hemoglobin when red blood cells die off. This means more unbound iron is in play among Asians which results in oxidation of vitamin C. Typically Asians need more vitamin C to make up for this problem. [Clinical Chemistry 53: 1397-400, 2007] Here again, genetic tests need not be performed. Asian populations are generally clustered and food fortification programs would be more likely to make up for this nutrient deficiency than urging individual dietary supplement consumption. Inherited trait: the missing enzyme and loss of internal synthesis of vitamin C A universal genetic flaw is the mutation in the gene that controls the production of the gulonolactone oxidase enzyme. This enzyme converts blood sugar to ascorbate (vitamin C) in most animals except for humans, primates, fruit bats and guinea pigs. This gene, located in the liver, is a damaged gene that has lost all function. In 1979 Irwin Stone described the plight of humans, prone to develop scurvy and other health problems without adequate vitamin C in their diet. Dietary intake of vitamin C does not fully correct this genetic flaw. [Homo sapiens ascorbicus, a biochemically corrected robust human mutant. Medical Hypotheses. 1979 Jun; 5(6):711-21] Drs. Matthias Rath and Linus Pauling conclusively showed in 1990 that the lack of endogenous vitamin C synthesis results in heart disease in humans that is not observed in animals that internally produce their own vitamin C. [Proceedings National Academy Sciences 1990 Aug; 87(16):6204-7; 1990 Dec; 87(23):9388-90] Again, food fortification programs would eliminate this genetic vulnerability peculiar to humans and a few other species. Inherited trait: poor folic acid metabolism breeds birth defects, Alzheimer’s disease Another example of a genotype that is vulnerable to nutrient-related disease involves folic acid (vitamin B9). Folic acid is needed for DNA repair. A shortage of folic acid will produce breaks in DNA that are the same as if a person were exposed to ionizing radiation (i.e. gamma rays). [FASEB Journal 2004 Jan; 18(1):209-11] Shortages of folic acid will also produce birth defects (spina bifida) and raises homocysteine levels, an undesirable blood protein that is associated with greater incidence of Alzheimer’s disease. Humans vary in their ability to metabolize folic acid properly. Mutations in the gene for 5, 10-methylenetetrahydrofolate reductase enzyme results in folic acid becoming vulnerable to degradation by heat. Low folic acid levels result in high circulating levels of homocysteine, an undesirable blood protein, which generally affects 5-15% of the population. [Clinical Nutrition 24: 83-87, 2005] The two most common mutations of the gene that produces the enzyme to metabolize folic acid (polymorphisms 677C-T and 1298A-C) are particularly common in northern China (20%), southern Italy (26%), and Mexico (32%). [Atlas of Genetics and Cytogenetics in Oncology and Haematology] The C677T mutation ranges from 1% or less among Blacks from Africa and the United States to 20% or more among Italians and US Hispanics. [American Journal Epidemiology 2000 May 1; 151(9):862-77] Once again, folic acid food fortification and/or supplementation are called for, and folic acid from supplements is 20% more bioavailable than from foods. [American Journal Clinical Nutrition 2007 Feb; 85(2):465-73] Polymorphic gene disturbances of folic acid metabolism are too widespread to even think of universal testing and individual prescriptions. With such widespread nutritionally-related metabolic disturbances in human populations, is genotyping needed? A recent published report asked this very question: "Personalizing foods: is genotype necessary?" [Current Opinion Biotechnology 2008 Apr;19(2): 121-8] More doctoring or self-care? Doctors foresee a bonanza in the coming genomic age of medicine. Patients will come to their offices, be tested for genetic predispositions to disease and receive preventive or therapeutic drugs. But that isn’t the scenario painted in the above examples. Public health authorities would employ functional food and food fortification programs among the masses to blot out the occurrence of metabolic and age-related chronic disease altogether. In developing countries of the world, the cost of gene testing and drugs would be prohibitive. Prevent DNA strand breaks Dr. Michael Fenech, of Australia's Commonwealth Scientific and Industrial Research Organisation (CSIRO), says "It is becoming increasingly evident that (a) risk for developmental and degenerative disease increases with more DNA damage, which in turn is dependent on nutritional status, and (b) the optimal concentration of micronutrients for prevention of genome damage is also dependent on common genetic mutations (polymorphisms) that alter the function of genes involved required for DNA repair and DNA replication." [Proceedings Nutrition Society 2008 May; 67(2):146-56] Fenech along with colleagues at the Institute of Genetics in Shanghai report that folic acid deficiency produces chromosomal damage to white blood cells which is totally abolished by increasing folic acid concentrations. [Mutagenesis. 2006 Jan; 21(1):41-7] Fenech says diet is a key factor in determining genomic stability and is more important than previously imagined because we now know that it impacts on all relevant pathways, namely exposure to dietary carcinogens, activation/ detoxification of carcinogens and DNA repair. [Food Chemistry Toxicology 2002 Aug; 40(8):1113-7] Fenech goes on to say:
To prevent chromosome damage, Fenech says the intake levels of folic acid must exceed current recommended intake levels for folic acid – 700 micrograms of folic acid and 7 micrograms of vitamin B12 are required. Many multivitamins do not provide this amount of B vitamins. [Mutation Research 2001 Apr 18; 475(1-2):57-67] Ensuring levels of disease or health Current efforts, now underway at international CODEX proceedings, attempting to limit ("harmonize") nutrient levels in foods and supplements worldwide would appear to be an effort to lock in levels of disease for doctors and drug companies to treat. Setting nutrient intake levels below the amount needed to stabilize the genome would be a way to ensure the medical industrial complex never runs out of customers. Drugs would represent inappropriate therapy that would only address symptoms, not causes of disease, resulting in perpetual treatment for perpetual disease. Disease is not inevitable: epigenetics Genes do nothing on their own. Genes are activated or downregulated by molecules in foods or drugs and environmental factors. This is called epigenetics, a term biologists use to describe changes in gene expression that can be produced by various biological stressors – heat, sunlight, food deprivation, overeating, for example. Food researchers at the Nestle Research Centre in Lausanne, Switzerland, know that disease is not inevitable due to genetic predilection. [Current Opinion Biotechnology 2008 Apr; 19(2):121-8] Epigenetics is a frontier of its own. Hormesis Among biological stressors are so-called hormetic effects, the idea that a small amount of biological stressing agent can upregulate powerful gene-controlled defenses in the human body. The production of vitamin D in response to skin exposure to solar ultraviolet radiation is an obvious example. The human body activates an army of white blood cells in response to vitamin D, thinking a person has just experienced a severe sunburn. This protective mechanism can be activated by "sunlight in a bottle," vitamin D pills, without exposure to harsh sun rays. Calorie restricted diets (food deprivation) have been studied and it has been shown that a 50% reduction in calories doubles the lifespan of all organisms (yeast cells, roundworms, fruit flies, mice). [Ageing Research Reviews 2007 Sep 4] The failing of gene-targeted drugs Hormetic agents are of great interest because they influence a broad range of genes. The broad gene array approach is a departure from single-gene-targeted drugs that have been employed with great fanfare, but are only marginally effective. For example, while single-gene targeted anti-cancer drugs have been introduced (herceptin, erbitux, gleevec, iressa), cancer involves thousands of genes. Bernard Weinstein and colleagues at Columbia University claim "it is a gross oversimplification to speak of ‘the’ cancer gene, or to assume that multistage cancer simply involves a successive series of random gene mutations." [Multistage carcinogenesis involves multiple genes and multiple mechanisms. Journal Cellular Physiology Supplement 3: 127-37, 1984] Bryan Roth, a biochemist at Case Western Reserve University in Cleveland, says "magic shotguns" rather than "magic bullets" are what’s needed. Simon Frantz, writing the lead article in an issue of Nature Magazine, says: "Forget drugs carefully designed to hit one particular molecule – a better way of treating complex diseases such as cancer may be to aim for several targets at once." [Nature 437: 942-43, 2005] Researchers at the MD Anderson Cancer Center in Houston, Texas, report that "most chronic illnesses such as cancer, cardiovascular and pulmonary diseases, neurological diseases, diabetes, and autoimmune diseases exhibit dysregulation of multiple gene pathways, most which are linked to inflammation. Therapies targeted at single genes over the past two decades have proven to be unsafe, ineffective and expensive." [Cell Cycle 2008 Feb 15; 7(8)] "Natural compounds (rather than man-made drugs) offer a less specific but perhaps more effective strategy for cancer therapy by inducing combinations of effects that may counteract the metabolic alterations related to cancer promotion," says Paolo Signorelli and Riccardo Ghidoni, researchers at the San Paolo University Hospital, School of Medicine, University of Milan. [Journal Nutritional Biochemistry 16: 449-66, 2005] Here is where nature trumps pharmacology. Naturally occurring molecules exert a broader effect upon the genome than drugs. Microarray of nutrients Only a few naturally occurring molecules have already undergone microarray analysis. DNA microarray experiments confirm that omega-3 fatty acids (fish oil) regulate the expression of many genes and gene pathways involving oxidative stress response and antioxidant capacity; cell proliferation; cell growth and cell turnover (apoptosis); cell signaling and cell transduction. [Current Opinion Clinical Nutrition Metabolic Care. 2004 Mar; 7(2):151-6] Gene array studies have been conducted with astaxanthin, a powerful antioxidant carotenoid supplement. In the mouse genome of 30,000 genes, which is about the size of the human genome, about 3.1% of genes were significantly affected by astaxanthin among diabetic mice. [International Journal Molecular Medicine 2006 Oct; 18(4):685-95] When a study compared the gene expression of 12,423 genes from brain (cerebral cortex) tissue samples from young (4-month-old) and old (27-month-old) male mice, only 25 of these genes changed significantly, meaning a small number of genes may control brain aging. The provision of melatonin as a dietary supplement reversed 13 of the 25 genes altered with age. [Journal Pineal Research 2004 Apr; 36(3):165-70] Surprisingly, some highly promoted dietary supplements, like coenzyme Q10 and lipoic acid, had no impact upon longevity or tumor patterns of laboratory mice, whereas a calorie restricted diet increased maximum life span by 13% and reduced tumor incidence. [Free Radical Biology Medicine 2004 Apr 15; 36(8):1043-57] The health genome While geneticists are mapping the "diseasome," what is the gene profile for health and longevity? The pharmaceutical model aims at treating disease after it occurs. The nutraceutical model prevents disease altogether and more appropriately addresses the cause of disease. Calorie restricted diets are the model against which any intervention can be compared since it is the unequivocal way to promote health and longevity. [Ageing Research Review 2008 Jan; 7(1):43-8] Drug, diet or nutraceutical-centered interventions need to be compared against a proven standard of health and longevity, in this case, calorie restriction. Has the "healthsome" been mapped? Richard Weindruch, Tom Prolla and colleagues at Lifegen Technologies in Madison, Wisconsin, have already conducted gene array studies for muscle, brain and heart tissues among calorie restricted mice and primates. [Archives Neurology 2002 Nov; 59(11):1712-4; Proceedings National Academy Science U S A. 2002 Nov 12; 99(23):14988-93; Mechanics Ageing Development 2002 Jan;123(2-3):177-93; Journal Gerontology A Biology Science Medicine Science 2001 Mar;56(3):B116-22] Lifegen Technologies has the microarray database needed for comparison of diets, foods or supplements with the "healthsome." The mouse genome has more than 90 percent of the coding sequences of the human genome and has a relatively short lifespan (~3 years) which facilitates longevity studies. Combining nutrigenomics with longevity studies is a natural extension and promises to help identify mechanisms whereby nutrients affect the aging process, life span, and, with the incorporation of age-dependent functional measures, health span. [Methods Molecular Biology 2007; 371:111-41] The overall physiologic influence of a calorie-restricted diet is similar between species (mice, rats, pigs, monkeys, yeast, and flies). So, animal studies closely parallel human genomics. [Journal Nutrition 2005 Jun; 135(6):1343-6] It is interesting to note that when laboratory mice are shifted from a calorie-restricted diet to a standard lab chow, 90% of the gene expression produced by calorie restriction is reversed within 8 weeks. [Proceedings National Academy Science U S A. 2004 Apr 13; 101(15):5524-9] A molecular calorie restriction mimic Possibly one of the biggest breakthroughs in biology was recently announced with the discovery that calorie restriction activates the Sirtuin 1 DNA-repair "survival" gene, a genetic mechanism that can be mimicked with a red wine molecule called resveratrol. Instead of humans having to deprive themselves of food to live longer and healthier they could just take a red wine pill. [Nature 2003 Sep 11; 425(6954):191-6] Doctors Signorelli and Ghidoni single out resveratrol, a red wine molecule, for its unique ability to favorably control hundreds of genes at one time. [Journal Nutritional Biochemistry 16: 449-66, 2005] Dr. John Pezzutto of the University of Illinois, describes resveratrol’s overwhelming effect upon the genome as "a whiff that induces a biologically specific tsunami." [Cancer Biology Therapy 2004 Sep; 3(9):889-90] With such a broad effect upon the human genome, imagine how many drugs resveratrol might replace? The list is dazzling. In doses achievable with dietary supplements, resveratrol is a potent anti-inflammatory (COX-inhibitor) agent, blood thinner, cholesterol controller, antioxidant, mineral chelator, liver detoxifier, brain plaque cleanser, blood sugar normalizer, bone builder, cell adhesion inhibitor, anti-depressant, as well as an anti-bacterial, anti-viral and anti-fungal agent. The pharmaceutical model of a drug for every disease is abolished. One pill for all. Furthermore, resveratrol pre-conditions the brain and heart against damage caused by strokes or heart attacks. [Cell Cycle. 2008 Feb 15; 7(8)] Resveratrol inhibits weight gain by two mechanisms – inhibition of fatty acid synthase, an enzyme needed to convert sugars into fat, and by reduction of insulin levels which reduce hunger. Current Medicinal Chemistry 2006; 13(8):967-77; Life Science. 2008 Feb 13; 82(7-8):430-5] In a remarkable experiment conducted at the Cardiovascular Research Center at the University of Connecticut, resveratrol overcame an animal model of heart failure where the first blood vessel outside the heart (the aorta) was restricted with a band, inducing the heart to pump harder against intentional resistance. This usually results in thickening of the ventricle (chamber) walls of the heart and reduced expulsion of blood (ejection fraction). However, these effects were abolished in resveratrol-treated animals. [Current Opinion Investigational Drugs. 2008 Apr; 9(4):371-8] Because resveratrol also exists as an unpatentable dietary supplement, it stands directly in the way of plans by Big Pharma to control the emerging field of genomic medicine. By itself, resveratrol could completely "harmonize" modern pharmacology – a universal pill for all disease. Will Big Pharma ever allow such a pill to stand on its own? A proprietary resveratrol pill is currently undergoing human clinical testing for diabetes but company executives claim it will only be used as a co-drug, such as with metformin, an anti-diabetic drug, or with a statin cholesterol-lowering drug. [Current Opinion Investigative Drugs. 2008 Apr; 9(4):371-8; Journal Molecular Cell Cardiology 2007 Mar; 42(3):508-16] But Big Pharma may be losing control of resveratrol. This proprietary resveratrol drug appears to be a knock-off of an existing brand of resveratrol supplement designed to enhance stability and bioavailability, and improve absorption (Longevinex® – United States Patent application 20050158376, first filing October 25, 2004). The fact resveratrol is both a dietary supplement and an investigative medicine creates a public blur in what constitutes an FDA approved drug. Adoption of genomic medicine The public is naïve and not savvy to manipulation in the medical marketplace. Doctors with Mayo Clinic diplomas will forever be trusted. The public may run for this latest advance out of desperation, given the continuing collapse of conventional medicine – the Vioxx scandal, the ineffective liver-toxic statin drugs, the huge drop in breast cancer since hormone replacement therapy has been largely abandoned, problematic vaccines, and now admissions that modern medicines are often ineffective due to inherited gene polymorphisms. The public isn’t likely to run to adopt genomic medicine; it will have to be ushered in by doctors and paid for by insurance plans. Just exactly what tissues would be supplied for genetic testing is unclear, but patients may undergo testing without their knowledge and be confronted with a prescription for yet another problematic anti-inflammatory drug, since inflammation is universal to all disease processes.
May 15, 2008 Bill Sardi [send him mail] is author of the new book: You Don’t Have To Be Afraid Of Cancer Anymore. Copyright © 2008 Bill Sardi Word of Knowledge Agency, San Dimas, California. Not intended for commercial use or posting on other websites. Permission to reprint should be obtained from the author. (Bill Sardi has a commercial interest in resveratrol pills – Longevinex.)
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