MISCELLANIA

• CHELATION THERAPY FOR CORONARY ARTERY DISEASE : US NATIONAL INSTITUTES HEALTH INITIATES A MAJOR STUDY

The National Center for Complementary and Alternative Medicine (NCCAM) and the National Heart, Lung, and Blood Institute (NHLBI), both components of the National Institutes of Health (NIH), have launched the Trial To Assess Chelation Therapy (TACT). TACT is the first large-scale, multicenter study to determine the safety and efficacy of EDTA chelation therapy for individuals with coronary artery disease.

Chelation is a chemical process in which a substance is used to bind molecules, such as metals or minerals, and hold them tightly so that they can be removed from a system, such as the body. In medicine, chelation has been scientifically proven to rid the body of excess or toxic metals. For example, a person who has lead poisoning may be given chelation therapy in order to bind and remove excess lead from the body before it can cause damage.In the case of EDTA chelation therapy, the substance that binds and removes metals and minerals is EDTA (ethylene diamine tetra-acetic acid), a synthetic, or man-made, amino acid that is delivered intravenously (through the veins). EDTA was first used in the 1940s for the treatment of heavy metal poisoning. EDTA chelation removes heavy metals and minerals from the blood, such as lead, iron, copper, and calcium, and is approved by the U.S. Food and Drug Administration (FDA) for use in treating lead poisoning and toxicity from other heavy metals. Although it is not approved by the FDA to treat CAD, some physicians and alternative medicine practitioners have recommended EDTA chelation as a way to treat this disorder.

When used as approved by the FDA (at the appropriate dose and infusion rate) for treatment of heavy metal poisoning, chelation with EDTA has a low occurrence of side effects. The most common side effect is a burning sensation experienced at the site where the EDTA is delivered into the veins. Rare side effects can include fever, hypotension (a sudden drop in blood pressure), hypocalcemia (abnormally low calcium levels in the blood), headache, nausea, vomiting, and bone marrow depression (meaning that blood cell counts fall). Injury to the kidneys has been reported with EDTA chelation therapy, but it is rare. Other serious side effects can occur if EDTA is not administered by a trained health professional.

Several theories have been suggested by those who recommend this form of treatment. One theory suggests that EDTA chelation might work by directly removing calcium found in fatty plaques that block the arteries, causing the plaques to break up. Another is that the process of chelation may stimulate the release of a hormone that in turn causes calcium to be removed from the plaques or causes a lowering of cholesterol levels. A third theory is that EDTA chelation therapy may work by reducing the damaging effects of oxygen ions (oxidative stress) on the walls of the blood vessels. Reducing oxidative stress could reduce inflammation in the arteries and improve blood vessel function. None of these theories has been well tested in scientific studies.

There is a lack of adequate prior research to verify EDTA chelation therapy's safety and effectiveness for CAD. The bulk of the evidence supporting the use of EDTA chelation therapy is in the form of case reports and case series. Some patients who have undergone chelation therapy and the physicians who prescribed it claim improvement in CAD. In addition, there are approximately 12 published descriptive studies and 5 randomized controlled clinical trials regarding the use of EDTA chelation for CAD. Although each descriptive study did report a reduction in angina, they were uncontrolled clinical observations or retrospective data, typically with a small number of participants. Of the five clinical trials in which patients were randomly selected to receive chelation therapy or a placebo (a dummy solution), the most rigorous way of assessing a new treatment, three trials involved so few people that only a dramatic improvement could have been detected. Studies need a larger number of participants to detect more mild benefits of a treatment. The fourth study was never published in final form, so its conclusions are uncertain. Finally, the fifth study reported that EDTA chelation was associated with an improvement in ability to exercise, but it had only 10 participants.

It is estimated by the American College for Advancement in Medicine (ACAM), a professional association that supports the use of chelation therapy, that more than 800,000 visits for chelation therapy were made in the United States in 1997 alone. CAD is the leading cause of death among men and women in the United States. In spite of effective standard therapies, such as lifestyle modifications, medications, and surgical procedures, some patients with CAD seek out EDTA chelation therapy as a treatment option.

Therefore, NCCAM and NHLBI saw a public health need to conduct a large-scale, well-designed clinical trial that could determine more clearly whether EDTA chelation therapy is indeed an effective and safe alternative for treating CAD. However, there are professional organizations that are of the opinion that a large study of EDTA chelation therapy should not be carried out because of the lack of scientific evidence supporting its effectiveness.

National Centre for Complementary and Alternative Medicine
National Institutes of Health
Washington DC, USA

• DIET TIPS FOR A HEALTHY HEART

• Eat a diet low in saturated fat, especially animal fats and palm and coconut oils.
• Add foods to your diet that are high in monounsaturated fats, such olive oil, canola oil, and seafood.
• Eat foods containing polyunsaturated fats found in plants and seafood. Safflower oil and corn oil are high in polyunsaturated fats.
• Choose a diet moderate in salt and sodium.
• Maintain or improve your weight.
• Eat plenty of grain products, fruits and vegetables.

Eating this way does not mean you have to spend more money on food. You can still eat many foods that cost the same or less than what you're eating now.

Instead of ...	Do this ...
Whole or 2 percent milk, and cream	Use 1 percent or skim milk.
Fried foods	Eat baked, steamed, boiled, broiled, or microwaved foods.
Cooking with lard, butter, palm and coconut oils, and shortenings made with these oils	Cook with these oils only: corn, safflower, sunflower, soybean, cottonseed, olive, canola, peanut, sesame, or shortenings made from these oils.
Smoked, cured, salted and canned meat, poultry and fish	Eat unsalted fresh or frozen meat, poultry and fish.
Fatty cuts of meat, such as prime rib	Eat lean cuts of meat or cut off the fatty parts of meat.
One whole egg in recipes	Use two egg whites.
Sour cream and mayonnaise	Use plain low-fat yogurt, low-fat cottage cheese, or low-fat or "light" sour cream and mayonnaise.
Sauces, butter and salt	Season vegetables, including potatoes, with herbs and spices.
Regular hard and processed cheeses	Eat low-fat, low-sodium cheeses.
Crackers with salted tops	Eat unsalted or low-sodium whole-wheat crackers.
Regular canned soups, broths and bouillons and dry soup mixes	Eat sodium-reduced canned broths, bouillons and soups, especially those with vegetables.
White bread, white rice, and cereals made with white flour	Eat whole-wheat bread, brown rice, and whole-grain cereals.
Salted potato chips and other snacks	Choose low-fat, unsalted tortilla and potato chips and unsalted pretzels and popcorn.

• WHAT IS GENETIC DISEASE?

To type "OMIM" into any search engine reaches the database Online Mendelian Inheritance in Man, maintained by the National Institutes of Health. A mass of data emerges. At the last count, 10,000 distinct genetic conditions were listed, by recessive (needing two flawed genes, one from each parent), dominant (a single gene doing the damage), and sex-linked loci (those carried on the X chromosome), with others due to many genes of small effect. That number is large indeed. Most perinatal mortality has some genetic basis, and most long-term mental patients have conditions that can be ascribed to genes. All cancers, too, involve genetic changes, in body cells, in the germ line, or in both.

Although most of the illnesses listed are rare, the incidence of genetic damage as a whole is quite high. In populations of European descent, about one child in 2,500 is born with cystic fibrosis. Certain populations are at even higher risk: in parts of West Africa, one person in three carries a single copy of the sickle-cell allele, and by 2050 one child in 15, worldwide, will bear one or more copies of genes associated with abnormal red blood cells.

Mendel's rules show that there are far more copies of recessive alleles hidden within normal people than are ever exposed. One in 25 Europeans carries a single copy of the cystic fibrosis gene. This "genetic load" is reflected in the greater incidence of ill health among the offspring of relatives. Marriages between cousins suggest that every person bears, on average, a single copy of a gene that if present in double copy would be lethal. Damaged genes are not exceptional, but normal.

• WHAT IS NOT GENETIC DISEASE?

Ill health runs in families. Usually, this has rather little to do with genes. The best predictor is simple: class. Tuberculosis and lung cancer (like rickets in the 19th century) may soon be diseases of the poor, and even for conditions such as cancer, the chances of survival are related to income. Wealth and poverty are inherited, and most people born poor stay that way. In Britain, the difference in life span between the most and the least affluent is 11 years, which dwarfs anything that DNA might do. As familiar as all this is, and as important to public health as it might be, nobody sees this as falling within the province of genetics.

In the 1930s, pellagra--a deficiency of vitamin B--was identified as a "Mendelian" illness because it was passed from parents to children. When its real cause was discovered, the genetic hypothesis was abandoned. Today's nutritional problems are involved more with excess than with lack, but such illnesses still run in families. Obesity, coronary artery disease, and diabetes are concentrated among those with poor diets--the poor themselves. Heritable though such conditions are, to change eating habits would do more to improve health than could the most optimistic molecular biologist. The boundaries between "external" and "internal" causes of illness are far from simple.

Susceptibility rather than certainty is coded into the DNA. Vitamin supplements given to women who have had one child with a neural tube defect reduce their risk of having another, although genes are involved in the condition. If everyone smoked, lung cancer would be a genetic disease. The interaction between nature and nurture makes it hard, as a result, to exclude any illness from the territory of genetics. More and more inherited weaknesses are emerging, and more and more genes that respond to environmental stress are being tracked down. The new genetics reminds us of what medicine has always known: that nurture and nature work together. Genetics allows us to understand that interaction with greater precision and to identify those most at risk.

• THE ALLURE OF TECHNOLOGY

To complete the map of DNA was a triumph of genetics as a science. Its success as a technology, however, has yet to be established. It can be hard to translate theory into practice.

Vesalius worked out the anatomy of the heart in 1543. Eighty years later, William Harvey sorted out blood circulation, but the first heart transplant was not performed until 1967. The double helix was discovered less than half a century ago. Since then, genetics has been transformed. Its techniques range from novel staining methods for chromosomes to the polymerase chain reaction that has revolutionized gene sequencing. The Southern blot matches a DNA sequence with others suitably labeled. In this way, a gene can quickly be tracked down. That idea has been developed into the "DNA chip," in which tens of thousands of targets are put onto a plate and used to search for mutations. Such technology means that medicine is now able to work from the bottom up (from gene to receptor protein to potential drug, for example) rather than, as in earlier times, starting with a disease and trying to infer its basis.

Genetics is the first science to accelerate by going into reverse. To find out what genes do no longer depends on the existence of an inherited abnormality. As a result, much of medical research has become genetic research, and large parts of medicine have, somewhat to physicians' surprise, become genetics. Without difference, there could be no genetics, and a start has been made on mapping variation among people and populations. About one DNA base in 1,000 varies from person to person, and a world map of variable sites is now being drawn. To understand the relation between the inheritance of DNA variations and patterns of disease is a crucial step toward identifying wayward genes. There is now a free market of genes, with the potential of moving DNA from any organism to any other. Genetic engineering is used by agribusiness and pharmaceutical companies. Some proclaim that the 21st century as the "post-genomic era": the time when the language of the genes will be translated, and we will understand what every gene does and how it interacts with others on the journey from egg to adult. But it is worth remembering how little impact most of this science has had on the practice of medicine.

Although the treatment of inherited diseases has improved, genetics has not played much of a part. The error behind sickle-cell anemia has been known for 50 years, but what treatments are available have emerged from empirical medicine. The same is true for cystic fibrosis. The genes for Huntington's disease and muscular dystrophy were among the first to be identified, but these discoveries, too, have not led to treatments. In the same way, many inherited cancers are no more curable than they were before their genes were discovered. The value of discoveries in genetics to medical practice has yet to be established.

• THE SEARCH FOR CURES : THERAPY, CLONES AND XENOTRANSPLANTS

The idea of repairing damaged DNA has been around for a long time. The first claims were made in the 1980s, but the idea remains more a hope than a reality. Supposed successes with, for example, the replacement of the enzyme lacked by children with severe combined immunodeficiency (the "boy in a bubble" syndrome) are complicated by the fact that (with one exception reported in early 2000) children treated with this therapy are receiving other treatments as well. Likewise, the many attempts to reduce the severity of cystic fibrosis with DNA-based medicaments have had equivocal results complicated by unwelcome side effects.

Other claims of success in the treatment of various cancers and other inherited diseases are too premature to be assessed. Adding to the confusion is the use of the term gene therapy in a sense much wider than its original, to include, for example, the treatment of heart disease with proteins that stimulate the formation of capillaries. Those involved in such research still disagree about which delivery method is best, as well as about a host of other practical and theoretical issues. At least for the time being, this technology seems unlikely to play a large part in medicine. The situation might change, and there are real prospects in some areas--for example, drugs designed to target cancer cells. But, for now, gene therapy (however defined) has a marginal role in the clinic no matter how exciting its prospects in the laboratory.

Neither is cloning, in its usual sense, likely to have much practical impact. Claims that human cloning is imminent are hard to take seriously. Even without legal prohibitions, its many difficulties (a low success rate, with a high incidence of birth defects in cloned animals) means that this technology will not soon affect human reproduction or medicine. Less ambitious forms of cloning, however--such as cloning cells to replace missing white blood cells or to make sheets of skin cells that match a donor--are much more feasible.

Stem cells (very early embryonic cells together with cells from a few adult tissues) differentiate into particular tissues, and might even be persuaded to make whole organs or parts thereof. Because such cells may be obtained from surplus embryos created through artificial fertilization, objections have been raised to the research, but it has much promise. And xenotransplantation, in which immunological cues are altered to prevent, for example, the rejection of a pig's heart transplanted into a human body, is also under investigation. The potential risk of transfer of viruses between species seems less important than it did. If the method succeeds, a new weapon will be added to the surgeon's armory and geneticists will be drawn into a new field of medicine.

In other areas, too, genetics is involved in the practice of medicine. Already, in vitro fertilization has a success rate per attempt higher than does conventional sex. Egg and sperm donation are widespread (as is surrogate motherhood), and early embryos can be checked for liability to genetic disease before implantation.

• THE UBIQUITY OF ERROR

Everyone, in the end, dies, and genes are often involved in that unpleasant process. Nobody escapes from the fate coded in DNA: aging takes place as mutations build up in cell lineages, and cancer is a genetic disease of body cells. Ancestry changes the risk of illness. Cystic fibrosis, common among Europeans, is not found in Africans. Finns have many genetic diseases unknown elsewhere. Mediterraneans are of particular risk of thalassemias, while some Jewish groups have a high incidence of Tay-Sachs disease.

To suffer from a genetic disease at some time of life or to be a carrier of a gene that in double copy causes severe illness is not rare, but universal. That is the greatest challenge of genetics. To map the genes should, perhaps, make it easy to test those at risk of inherited illness, and many feel that a new era of certainty has dawned. The truth is, alas, less simple.

• LIFE GOES WRONG IN MANY WAYS

There are two problems in applying Mendel to mankind. First, for most Mendelian illnesses, any gene can be damaged in a number of different places. Every population--sometimes, every family--may have its own mutation within a structure that may be tens of thousands of bases long. As a result, a test that detects an inherited error in one group or family may not work for others. To speak of "the" test for, say, cystic fibrosis means less than it seems.

In addition, the accidents of history mean that there is a great variety of damaged genes. Some mutations happened long ago and have spread to millions. Others have taken place recently and are found in only a few. In hemophilia, for example, almost every affected family has its own variant. Some genes (such as those responsible for some breast cancers) carry a mixture of ancient and modern mutations.

In general, the older a mutation is, the more widely it has spread and the easier it is to generate a useful test. But for the hundred or so most frequent Mendelian diseases the news is not particularly good: most have high mutational diversity, most individual mutations are rare, and the majority, most probably, have appeared within the past 2,000 or so years. All this means that to establish carrier status is not easy. Cystic fibrosis may arise from more than 1,000 different errors, some common and some rare. One is responsible for 70 percent of the cases in western Europe, but, 2,000 miles to the east, that mutation causes only a small fraction of cases. In Jewish populations in the United States it is involved in only about a third of cases, but among North African Jews quite a different mutation is most common. A single illness, the result of errors in a single gene, has a multiplicity of causes. The accuracy of tests will no doubt increase. Multiple mutations mean, nevertheless, that screening will remain ambiguous and that a negative result does not mean safety. A general screening for all common genetic diseases is, for the time being, not feasible.

• DNA IS SIMPLE, BUT ILLNESS IS COMPLICATED

Many ailments that at one time appeared to be single diseases have been subdivided. "Fever" was one single disorder with a single treatment, and much the same was true of "cancer." Such views began to change long before genetics, but advances in genetic science have speeded up the process. Nobody doubts that cystic fibrosis is a single illness. However, most inherited diseases are not due to errors in a single (or even a few) genes: instead, they are symptoms of a great constellation of failures.

Sometimes a single error is involved in certain cases but not others; sometimes, inherited changes whose individual effects are imperceptible may together produce a disease. The genes at fault may differ from place to place or from family to family. Often, a genetic problem may not show itself until it is exposed to a particular challenge. Because some conditions (heart disease and many more) have a largely environmental origin in some patients and a mainly genetic one in others, to unravel the causes will not be easy. Even then, it is not clear how useful the information will be.

Diabetes mellitus is a state of glucose intolerance. The cause, a loss of control of blood sugar, seems simple. It leads to kidney damage, nerve destruction, and death and, in the United States, costs $100 billion a year to treat. The disease comes in two flavors. One, the insulin-dependent form, results from a failure of the secretory glands of the pancreas. Juvenile diabetes, as it is often called, affects about one child in 1,000, appears early, and can be treated with insulin. The other variety, non-insulin-dependent diabetes mellitus (NIDDM), is milder, appears later, and is resistant to that treatment. At least 6 million Americans have the illness without knowing it, and it is becoming more common. The diseases, similar though they seem, present medicine with quite different problems.

Genetics shows not only that "diabetes mellitus" is actually two or more distinct diseases but that some are influenced by inheritance and some not. It was once thought that insulin-dependent diabetes was caused by viruses, or by diet, or even by living in towns. None of those ideas was sustained. Genes are involved, in particular those of the immune system. Siblings of diabetics have a risk of the disease 20 times higher than does the general population.

Even those without relatives known to have the disease, but with certain combinations of cell-surface antigens, face a tenfold increase in risk. Early-onset diabetes, is, it appears, an autoimmune disease. Variation in one gene explains a third of the family clustering. At least 20 others--some involved in the insulin machinery and others at work in unrelated parts of the cell--confer a predisposition to the disease. As identical twins have only a one-in-three chance of both being affected, an unknown environmental agent is also involved. This form of diabetes is, it seems, a disease in which the underlying variable, insulin production, and the threshold at which illness sets in, vary from person to person. Because the genetic component may sometimes be strong, a DNA test can be used to identify some children at risk and to begin treatment before any damage is done. But, most patients--those with genes of minor effect, or those exposed to the unknown environmental stress--will not be helped by a genetic test. NIDDM is even more complicated. Genes play a part, but they separate populations rather than individuals and manifest their effects only in certain conditions.

The disease is common among those of Pacific Islander, Native American, or Asian ancestry. Although the illness runs strongly in families, no single gene accounts for more than a tenth of individual susceptibility. Many genes, scattered through the genome, are involved, but we have little clue regarding how they lead to illness. A search in the United States for the 11 genes thought to be involved in NIDDM in the British population turned up only two. The most striking aspect of NIDDM is the power of the environment. The illness is rare in Native Americans living in rural Mexico but common among their descendants in the United States. A difference in diet is to blame. Native Americans are genetically less able to cope with carbohydrates than are Europeans, but those living in the United States consume much more of that material than do their relatives in Mexico, and the illness follows. In this group, one gene has a relatively large effect and might be used as a test for those most at risk, but for non-insulin-dependent diabetes genetics as a whole is a much less effective predictor than is diet. A change in lifestyle would benefit the whole population, whatever their genetic predisposition.

Is diabetes--once thought of as a single disease--two, or more, or many, each of which may require a different treatment? Certain patients may be detected before symptoms appear, but others will be missed by any screening program. Drug therapies help some but not others. A few people will develop diabetes whatever their diet, while others may, despite an inherited susceptibility, avoid the illness because of the way they live. In the end, it seems, genetics has little relevance to the treatment of NIDDM; banning cheeseburgers would do far more.

Many, perhaps most, diseases are rather like this. Breast cancer kills thousands of American women. Two genes, BRCA1 and BRCA2, are implicated in about one case in 20, but the majority of cases cannot be attributed to specific genes at all. What is more, one in five of all carriers of the BRCA variants do not develop the illness. The case is similar for Alzheimer's disease: most sufferers have no overt genetic predisposition, although homozygosity for the Apo E4 allele may bring the probable date of first symptoms forward by almost 20 years.

Cardiovascular disease is likewise complicated, with both genes and environment involved. Some families inherit a tendency toward high levels of blood cholesterol, but almost 200 different genotypes can generate the effect. As a result, such families can be more readily identified with a simple blood-cholesterol test than with DNA analysis. The best predictors--smoking, obesity, and a family history of heart disease--need no technology at all.

The problems of multiple loci, multiple alleles, and unknown environmental factors mean that research on the genetics of common illnesses has been plagued with findings that cannot be replicated. The many claims that genes are associated with mental illnesses such as schizophrenia and depression have for the most part not been sustained. Icelandic researchers' claim to have discovered genes predisposing to multiple sclerosis was soon retracted. Despite plans for huge (and expensive) sweeps through the DNA undergrowth the chances of success in tracking down genes for such conditions are not high.