Every week, it seems, we read new headlines about the discovery of yet another gene: the breast cancer gene, Alzheimer's gene, high-cholesterol gene, diabetes gene, and scores of others. But each of these discoveries raises serious questions. Is it possible that we nothing more than the sum of our genes? And has gene research ushered in a new era of medical fatalismÑthat our health is irrevocably cast in biology at conception?
The quick answer is this: the genes we inherit play a profound role in our health - we would not exist without them. Yet genes are far from the ultimate determinant of our health. Consider, as an example, the still unfolding story of the BRCA1 and BRCA2 "breast cancer" genes. Women who possess one or both of these genes have a very high risk of developing breast cancer. Yet only a small number of women with these genes actually develop breast cancer.
It turns out that the expression, or behavior, of genes is strongly influenced by a variety of factors. In fact, most genes seem to be good, or relatively neutral, until something turns them bad. Some chemicals, natural and synthetic, can damage and disrupt genes. So can good or bad nutritionÑand diet may be the most powerful influence on our genes. According to the latest research, you can foster the best of your genes by nourishing them with the right nutrients. Call it natural gene therapy, if you wish.
A Quick Course In Genes
What exactly are genes? How do they work? And what exactly do they do? Their function often gets lost in brief news stories that generalize genes as the "blueprint of life."
Every one of the 60 trillion cells in your body contains genes, which form a molecular code of instructions governing how that cell creates enzymes, proteins, and processes biochemicals. The alphabet for these instructions consists of sequences of molecules called nucleotides. Each nucleotide is built around one of four smaller molecules called bases: adenine (A), cytosine (C), guanine (G), and thymine (T).
When combined, these nucleotides form words in the genetic code (for example: TACCACCTGA), better known as deoxyribonucleic acid (DNA). The nucleotides in DNA form two corresponding strands in a spiral shape, kind of like the two railings of a circular staircase. Lengths of DNA with specific instructions, and separated by the biological equivalent of a period, form genes that define specific characteristics, such as the color of eyes or the efficiency of biochemical processes. These genes are further organized into chromosomesÑranging from a single chromosome in bacteria to 23 pairs in humans.
DNA conveys its instructions by transcribing its information to ribonucleic acid (RNA). The start of this process is called gene expressionÑessentially, the gene gets turned onÑand RNA executes the instructions and forms a protein or enzyme. It's analogous transcribing an audio tape into a manuscript, except for its incredible complexity. Human genes contain the blueprints for an estimated 60,000 proteins that promote biochemical reactions and build tissue.
A single strand of DNA and all its genes would stretch six miles, if it were possible to unravel it. That amounts to millions of nucleotidesÑand a lot of room for introducing errors, either when DNA is replicated during cell division or when it is transcribed to RNA.
Errors in genes are minimized through enzymes that travel up and down strands of proofread DNA, recognize bad DNA sequences (misspellings, so the speak), and fix them (essentially correcting biological typos). Incredibly, only three mistakes occur (on average) when 3 billion DNA bases are replicated during cell division. It's a record that any typist would be proud of, observed Daniel E. Koshland Jr., Ph.D., editor of the journal Science.
But this handful of DNA errors does accumulate and over the years, getting passed onto other cells during replication. When the errors become permanentÑunrepairableÑthey become known as DNA mutations. (A mutation is a permanent change.) Some of these mutations so alter a cell's behavior that they lead to uncontrolled proliferation, or cancer. In fact, many scientists see cancer as a model of how DNA goes bad; 80 to 90 percent of all human cancers result from DNA damage. Cancers aside, a lifetime of DNA mutations results in less efficient cell performance, what we recognize as aging.
Diet and DNA
The fundamental dependence of genes on nutrition, and their interaction with specific nutrients is inescapable. The raw material for your body's DNA comes from the protein you eat, which is broken down during digestion and reconstructed as your own distinctive DNA.
The production of your DNA and genes is dependent on B vitamins and amino acids. Thymine synthesis requires vitamins B3 and B6, guanine and adenine need folic acid, and cytosine depends on vitamin B6. Using eight essential dietary amino acids, DNA codes for the formation of all other amino acids, proteins, and enzymes. Geneticists often take nutrition for granted, but all of these substances are intertwined and interdependent.
"Diet and genetics interact in numerous ways to influence chronic disease risk," observed Gregory D. Miller, Ph.D., and Susan M. Groziak, Ph.D., in the Journal of the American College of Nutrition. "Genetics influences the absorption, excretion, and metabolism of nutrients. Genetics also influences the human body's physiological response to diet. Diet, in turn, may influence the expression of genes related to specific chronic diseases."
In fact, nutrient deficiencies often lead to DNA damage and impaired repair. Researchers at the Bhabha Atomic Research Centre, Bombay, India, reported that laboratory rats deficient in only vitamin B2 suffered a high rate of DNA damage after exposure to aflatoxin (a cancer-causing fungus). Supplementation with vitamin B2 reduced the rate of DNA damage to normal. A cell-culture study, conducted at the University of Kentucky, Lexington, found that low levels of vitamin B3 interfered with the activity of p53, a key cancer-suppressing gene. The researchers noted in the FASEB Journal that supplementation of vitamin B3 might prevent cancer.
Still other DNA damage can occur because of vitamin deficiencies interfere with routine DNA repair. For example, when cells cannot make thymine (because of deficiencies in vitamin B3 or B6 or other reasons), the thymine is replaced with uracil, an RNA nucleotide base. The presence of uracil in DNA can lead to mutations. Often, DNA repair enzymes recognize that uracil in the wrong place and remove it, but end up leaving breaks in single strands of DNA.
According to Bruce N. Ames, Ph.D., a leading molecular biologist at the University of California, Berkeley, when a person is deficient in folic acid, large numbers of uracil deposits are made, and their removal by DNA-repair enzymes increases the risk of more serious double-strand DNA breaks. Double-strand DNA breaks (i.e., the same damage in both DNA strands) is far more difficult to repair than single-strand DNA breaks.
How serious is the problem with folic acid deficiency? In an article in the Proceedings of the National Academy of Sciences of the USA, Ames noted that folic acid deficiency affects about 10 percent of the U.S. population overall and about one-half of adolescents, elderly, and low-income African Americans. The long-term affect, he wrote, may be to increase to risk of cancer, heart disease, and Alzheimer's disease. After giving folic acid supplements to people deficient in the vitamin, the amount of uracil in DNA decreased significantly.
Recent research, described in the journal Carcinogenesis, indicates that supplemental folic acid and vitamin B12 can actually slow the rate of chromosome damage in healthy young adults. Michael Fenech, Ph.D., a researcher at Australia's Commonwealth Scientific and Industrial Research Organization, gave 64 men and women, ages 18-35, plain bran cereals or cereals fortified with 700 mcg of folic acid and 7 mcg of vitamin B12 (roughly 3.5 times the Australian recommended daily allowance).
Fenech found that the supplements reduced chromosome damage to below initial values among people consuming the extra B vitamins. However, still larger amounts of folic acid and B12 (10 times recommended levels) had no further benefit, at least not among these young healthy adults. In addition, chromosome damage correlated with elevated homocysteine levels, indicating that elevated homocysteine may be a marker of genetic damage (as well as coronary heart disease risk). An earlier study by Fenech found that chromosome damage correlated with low vitamin B12 levels in men ages 50-70.
Antioxidants Protect DNA
Damage to DNA (and subsequently to genes and chromosomes) can also be caused by unstable molecules known as free radicals. Radiation, including ultraviolet radiation from sunlight, generates free radicals in human cells. Additional free radicals are found in tobacco smoke and other types of air pollution or are produced in the body as byproducts of metabolism.
Free radical damage is highly unpredictable, according to Denham Harman, M.D., Ph.D., professor emeritus at the University of Nebraska, Omaha, who conceived the free radical theory of aging. Free radicals can attack cell membranes, proteins, and DNA. Damage to DNA may be the most serious, because it can induce mutations. Aging and age-related degenerative diseases, says Harman, are largely the accumulation of such DNA mutations.
A large body of research supports the role of antioxidants in preventing, or reducing, free radical damage to DNA. In a cell-culture experiment, V. J. McKelvey-Martin, Ph.D., of the University of Ulster, Northern Ireland, found that vitamins C and E protected against free radical damage. Vitamin C protected against radicals generated by x-rays, and vitamin E protected against radicals generated by hydrogen peroxide.
In a German study, researchers assessed baseline levels of DNA strand breaks and free radical damage in 23 healthy men on their normal diets and on variations of a high-carotenoid diet. The high-carotenoid diet consisted of daily servings of tomato juice (rich in lycopene), carrot juice (beta- and alpha-carotene), or a spinach-containing (lutein) beverageÑeach for two weeks. The carotenoid-rich foods reduced the number of DNA strand breaks, but only carrots resulted in a substantial decrease in DNA oxidation.
Herbs, which contain large amounts of polyphenolic antioxidants, can also reduce serious genetic damage. In a study, French and Armenian researchers noted that cleanup workers exposed to high levels of radiation at the Chernobyl nuclear reactor site had levels of chromosome damage 10 times above normal in their blood cells. Because Ginkgo biloba extract EGb 761 reduced chromosome damage in cell-culture studies, the researchers gave 120 mg of EGb 761 daily to 30 former Chernobyl workers for two months. Chromosome damage was reduced to near normal levels, with the benefits lasting in two-thirds of the men for one year after supplementation ceased. In one-third of the men, chromosome damage returned to higher levels, suggesting that continued supplementation might be needed to counter genetic damage.
Promoting Normal Gene Expression
Other research and clinical experiences suggest that vitamin supplements can, to some extent, compensate for genetic diseases. For example, cystic fibrosis interferes with fat absorption, but several studies have found that high supplemental doses of fat-soluble nutrients (e.g., vitamin E and beta-carotene) can overcome this problem. Some of the most remarkable work in the treatment of genetic diseases was conducted by the late Henry Turkel, M.D., who used a vitamin supplement program to treat children with Down syndrome. The supplements, of course, could not correct the genetic defect characteristic of this disorder. However, children taking the supplements were more intelligent and had fewer "mongoloid" physicial features, particularly if they began taking supplements at a young age. It's not clear yet whether the supplements promoted more normal gene expression, despite the defects, or helped bypass the defective gene to promote more normal biochemical activities.
Currently, many molecular biologists are focusing on how free radicals and antioxidants actually turn on and off genes. Indeed, the protective effects of antioxidants on normal gene expression may eventually be recognized as more important than their ability to quench free radicals.
Several teams of researchers have confirmed that free radicals activate two gene transcription factors, NF-kappa B and activator protein-1 (AP-1), and likely others. NF-kappa B influences the immune response to infection and AP-1 controls cell proliferation. However, over-expression of NF-kappa B and AP-1 is involved in the progression of AIDS, cancer, heart disease, and diabetes, according to Chandan K. Sen, Ph.D., and Lester Packer, Ph.D., of the University of California, Berkeley. A variety of antioxidantsÑincluding vitamin E, N-acetylcysteine, flavonoids, and carotenoidsÑhave been shown to inhibit the activation of NF-kappa B or to halt the expression of other deleterious gene factors.
Antioxidants also appear to regulate the biological clocks of cells, which time the replication of DNA and cell division. In fact, antioxidants can turn off abnormal cell clocks in cancer cells. Rajesh Agarwal, Ph.D., of the AMC Cancer Research Center, Denver, reported in Cancer Research that silymarin, an antioxidant complex found in milk thistle (Silybum marianum), stopped the replication of breast cancer cells in vitro by interrupting the cell-cycle clock.
This research justifies the use of vitamins and antioxidants in making the most of your DNA and genes, and it provides a sound explanation for their benefits in terms of molecular biology. Such research, however, is overwhelmed by the millions of research dollars being spent identifying specific genes involved in disease processes and ways to remake defective genes.
This situation, as always, leaves a person's ultimate decisions about disease prevention squarely in his own hands, and any doctor will tell you that it's far better to prevent than to treat a disease. The future may include a natural form of gene therapy, using vitamins and antioxidants to inexpensively maintain the normal behavior of your genes. It only makes sense to preserve the genes you've got.
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