Good Genes Gone Bad
Scarcely a week goes by without coverage of a new discovery by scientists revealing that yet another disease is linked to one or another gene. The range of health conditions now known to be gene related is astonishing. Some are just what you would have expected 50 years ago: many cancers, birth defects, obscure metabolic disorders, and diabetes. Others are less obvious, for example, brain disorders like schizophrenia, Parkinson's disease, and Alzheimer's disease.
Most people react to this news -- disease linked to genes -- as yet another confirmation of life's capriciousness. Genes are what we got from our parents. If we're lucky, we get the good genes, and that means at least one health condition that won't burden us in life, compound the toll of growing old, or hurry us toward the grave. If we aren't lucky, well then, who ever said life is fair?
In the medical community and pharmaceutical industry, findings like these are fueling a rush in search of cures using “gene therapy.” If the experts can figure out what's wrong with a gene, well, perhaps a designer drug can fix it.
But one corner of science reacts quite differently, flipping the old “nature vs. nurture,” or “genes vs. environment” dichotomy on its head. In this corner, when a disease is linked to a gene, the research question shifts to a completely different perspective: What contaminants in the environment could be altering the behavior of that gene?
In other words, diseases linked to genes aren't simply the fatalistic results of inheritance. Diseases can also be the result of good genes gone bad because of interference from something in the environment. Rather than inviting exotic medical interventions, diseases caused by environmental interference with gene behavior may be preventable if the contaminant can be identified and the exposure eliminated. And please note that this isn't about mutation. The DNA sequence doesn't change. It isn't originally a “bad” gene, but rather one that's been hijacked.
This perspective does more than simply shift the boundaries of what is known as “environmentally caused disease.” It reframes the issue entirely. Classically, we have perceived diseases and disabilities as having distinctly genetic or environmental causes, or perhaps having a contribution from both due to mutation or some interaction between heredity and environment (as in some mental illnesses), and we have labored hard to sort out blame. This new perspective says something very different: Yes, we do inherit our genes from our parents, but the environment -- including diet, experience and contamination -- can alter how a specific gene behaves throughout life.
That new understanding holds immense promise for public health. It means that revelations by genetic research of “diseases linked to genes” aren't a litany of fatalism. Instead they are a compilation of diseases that may have environmental etiologies and can thus be candidates for prevention through exposure reduction. Not all diseases with a genetic basis will work this way, but the list will very likely be large and will include some profoundly important illnesses.
To make sense of this new framing -- what it means for a disease to be linked to a gene -- requires three pieces of information: two that form the core of modern molecular genetics, and a third that has emerged from new scientific discovery over the past two decades.
First, just as Gregor Mendel discovered in the late 1800s, you inherit genetic material from your parents. Decades of research during the 20th century then led to the discovery that genes are pieces of DNA in your chromosomes.
Second, genes aren't just passive strands of DNA but, instead, are part of nature's nanotechnology. They are tiny chemical manufacturing plants controlled by an intricate and dynamic set of chemical messengers that travel within and between cells to turn specific genes on, or off, at the proper time. When geneticists talk about gene behavior, they are referring to how a gene is turned on to set the steps in motion that lead to protein synthesis or other key changes in cell function. There are many variations of this process. In one scenario, involving hormones like testosterone and estrogen, the hormone molecule arrives from outside the cell, goes into the nucleus, and binds with another molecule called a receptor. This bound complex then controls the activity of the gene.
This process begins before conception in the formation of eggs and sperm and it continues through death. It is the molecular symphony of life, with 20,000-plus genes in each human cell, turning on and off as molecular signals reach the switch on a gene that controls its action. Different genes respond to different signals, yet the same gene in different tissues can also be programmed quite differently. That's why even though all the cells in a person's body have the same genes and we each have many different types of tissues, one body part takes on the characteristics of an eye and another a finger or a liver or a brain. And while changes in gene expression take place at the molecular level, they have a huge impact on a person's life. When working properly, those changes give you male or female sex organs, a functional brain, and an immune system that defends against disease. They regulate weight and protect you from cancers. In short, the right changes in gene expression as the fetus is growing are essential to a person's health and quality of life.
Third, some environmental contaminants can interfere with gene expression, preventing genes from turning on when you need them, or turning them on when they should be silent. Take arsenic. At high levels, arsenic kills outright. At intermediate doses, arsenic is associated with a wide array of illnesses. At truly low doses -- 10 parts per billion, the new standard for drinking water in the United States -- experiments with cells indicate that arsenic can prevent some genes from being turned on by glucocorticoid hormones. These hormones control genes important for disease resistance, glucose metabolism, and a number of other vital processes. Some of these genes make proteins that are important for tumor suppression, for example. These effects were discovered as a result of experiments conducted using cells in a laboratory setting. Still, the results suggest that if the same processes are at work in people -- which is likely -- then people exposed to arsenic at that low dose may be ill-prepared to fight tumors. Arsenic in this case isn't causing illness directly, but it is instead setting the stage for illness to win over health. The arsenic's contribution undermines disease resistance by preventing protective genes from being turned on.
A key finding is that gene hijacking can take place at extremely low -- almost undetectable -- levels of exposure to some environmental chemicals. Exposure to high doses of many substances can be outright toxic -- poisonous in the classic sense. Historically, toxicologists have bowed to the mantra “the dose makes the poison.” But with low-dose exposures, the mechanism of action is different. It isn't a simple case of outright toxicity in which the more of a poison you take, the greater the toxic effect. Gene hijacking during fetal development can be like shifting the course of an ocean liner two degrees at the beginning of a voyage. Over a thousand-mile trip (or a 70-year life span), you wind up in a very different port. Or you may crash onto rocky shores. For example, in a fetus or infant, a subtle change in the path of development can lead to an immune system that can't resist common bacteria or that responds hyperactively, as in the case of asthma. A female fetus exposed in the womb can wind up with a uterus that isn't shaped properly; a male fetus may mature with a permanently low sperm count.
Our genes are vulnerable to hijacking throughout life. But fetal development and the period from childhood through puberty are the most vulnerable stages of life. This has taken on additional significance as work on gene hijacking has converged with another new field in the health sciences, “developmental origins of adult disease.” This work, which has roots in both animal and human studies, is revealing that many chronic illnesses and health conditions experienced by adults can have their origins in early development gone awry.
One early signal of the important role fetal events play in the onset of adult disease was revealed due to the discovery, in 1971, that young women who had been exposed in the womb to a drug called diethylstilbestrol, or des, developed a rare cancer in their late teens. Another came from research showing that adults whose mothers were starved in the third trimester of pregnancy are prone to obesity and other chronic problems, including heart disease, in adulthood. A third has emerged over the last decade as it has become clear that most cases of testicular cancer arise from failure of tissues within the fetal testes to differentiate properly. These undifferentiated tissues lie dormant for two to three decades and then turn into tumors. Research published in 2005 has even shown that a gene implicated in Alzheimer's, a disease of old age, may be vulnerable to hijacking around the time of birth. This work, done with rodents exposed to low levels of lead, shows that the gene behaves normally through adulthood, but in old age it's activated to an abnormally high level. The same study also showed that exposing an adult to the same low amount of lead doesn't have this effect.
The poster-child molecule for this reframing of links between environment and health is one that almost no one has heard of, but that almost everyone has in their tissues and fluids. That molecule is bisphenol A, invented in 1891 by the Russian chemist A.P. Dianin and discovered in 1936 to cause responses similar to those of the natural hormone estrogen. That discovery took place during the rush of pharmaceutical research to find synthetic estrogens, and bisphenol A, or BPA, lost out to its more powerful cousin, DES. While DES went on to be used by millions of women to control difficult pregnancies before it was outed as a cancer-causing agent, bisphenol A was put on the shelf until a polymer chemist discovered around 1950 that it could be combined in chains to make polycarbonate plastic and certain epoxy resins. Use since that discovery has skyrocketed, to the point that over six billion pounds are synthesized each year and the molecule is now included in countless consumer products.
Ironically, one of the most conspicuous of these uses is the transparent plastic water bottles, often tinted bright colors, which are wild favorites on campuses, strapped to countless backpacks of health-conscious Generation X members who've been told the material is safe because it is rigid and doesn't smell like plastic or leach dioxin. True, these bottles don't leach dioxin. That was never the concern. But they do leach bisphenol A because the chemical bonds that create the polymer easily degrade in water -- and they do so even faster if the plastic gets hot or is exposed to alcohol, soaps, or acids. BPA exposure comes from many other sources, for example, in a resin used to line metal food cans, from which it also leaches.
Today almost all people sampled in the developed world have bisphenol A in their body at trace levels (in the low parts per billion), including in amniotic fluid, umbilical cord blood, and placental tissue. A Centers for Disease Control study in 2005 detected low amounts of BPA in the urine of 95 percent of Americans sampled. Twenty years ago scientists would have looked at those levels and scoffed: too low to make a difference. Indeed, back then these levels were too low to even measure. But since 1997, well over 200 articles have been published in the peer-reviewed scientific literature showing that BPA has a biological impact on cells and animals at levels beneath the current federal standards, which were based on data gathered in the early 1980s. In cells, BPA has been shown to alter vital genetic signaling pathways at under one part per trillion. In animals, effects have been reported at less than one part per billion.
Significantly, all of the reports of major effects come from government or academic studies, while none of the 12 studies funded by industry has reported harm. And independent analyses of those 12 reveal not only fatal flaws in experimental design, but outright misrepresentation of data. As recently as January 2006, industry scientists used these very studies and misrepresentations to argue during a hearing convened by the California legislature that BPA is safe. One “product-defense” firm testifying in those hearings, the D.C.-based Weinberg Group, was revealed by an investigative report published in February 2006 to have its roots in defending tobacco and aggressively soliciting business from companies whose materials are under attack because of health and safety concerns. One of the firm's most recent clients is a company that manufactures a Teflon chemical judged by an EPA science advisory board in early 2006 to be a likely human carcinogen.
The list of diseases and adverse health conditions now plausibly linked to bisphenol A by animal and cell research is large and reflects disease trends in the human population. It runs from reduced sperm count to spontaneous miscarriages; from prostate and breast cancers to degenerative brain diseases; from attention deficit disorders to obesity and insulin resistance, which links it to Type 2 diabetes. “Plausibly” is a long way from “certainly.” Even if it accounts for only some percentage, say 10 percent or 20 percent, of cases, these “plausibly linked” conditions have been caused by exposure to BPA. And those are cases that could have been prevented and health-care costs that could have been avoided.
How does one molecule contribute to so much suffering? Research shows that BPA alters the behavior of over 200 genes, more than one percent of all human genes. The genes affected aren't controlling minor traits like eye color. They are genes involved centrally in how cells multiply, how stem cells become more specialized, how metabolism is regulated, and how the brain gets wired as a fetus grows. It is not at all surprising, therefore, to see so many potential links to health problems.
Because of the extremely low levels at which BPA has demonstrable effects, this molecule is at the center of the debate over low-level contamination, gene expression, and human health, but it is by no means alone. It is but one of hundreds of synthetic chemicals that have been found to alter gene behavior. Some are compounds that have been of concern for decades, like dioxins, polychlorinated biphenyls (PCBs), and certain pesticides. Others, like phthalates, Teflon-related chemicals, and brominated flame retardants, have been attracting attention more recently, especially because they are present in consumer products in every home in America; hence, exposure is ubiquitous. The United States has made good -- but incomplete -- progress on the former, but for too many, particularly in the latter group, the work has barely begun.
What do these results mean for human health? Scientists aren't certain because despite 50 years of growing use of BPA in commerce, there have been almost no human studies. The chemical industry takes the “absence of proof of harm in humans” as evidence of safety rather than simply a result of the fact that almost no one has investigated the matter, even though there is extensive evidence of harm in other animals. The preceding list of plausible links includes conditions that have become epidemics over the past several decades, the same time frame during which exposure to BPA became virtually unavoidable. Those trends are what you would predict from the animal studies, but a lot of other things in our world have also changed, so the congruence of trends proves nothing by itself. Definitive human studies can take decades to complete, especially if the focus is on something as complex as adult diseases caused by developmental exposure. Only one study has attempted to test predictions based on the recent animal research involving BPA, and it confirmed the prediction, but the study was small and needs to be repeated.
The National Institute of Child Health and Human Development has spent tens of millions of dollars over the past five years planning a study that would track 100,000 subjects from conception to age 21. Patterned after a famous and highly productive study of cardiovascular health called the Framingham Heart Study, the National Children's Study would examine many different factors affecting development, including environmental chemicals and diet. This sweeping scale of research is required scientifically to reach firm conclusions about which products are safe and which are not. Unfortunately, President Bush's proposed budget for 2007 has eliminated funding.
The United States has already demonstrated an ability to reduce harmful exposures dramatically through stronger public-health standards. Exposure to lead, PCBs, hexachlorobenzene, and other contaminants is now at much lower levels than it was 40 years ago. The newer contaminants, like BPA (in principle), are no less amenable to policy intervention, but corporations and their “product defense” consultants are now far more sophisticated about battling government efforts to strengthen public-health standards, making it ever harder for agencies to keep the standards up-to-date with current science. For example, BPA's current standard is based upon data gathered in the mid-1980s.
Two new sources of opportunities to reduce harmful exposure are “green chemistry” and the marketplace for safer products. By paying attention to the molecular detail of how contaminants cause harm, chemists can invent new materials that are harmless by molecular design. BPA causes harm because of coincidence: Its shape fits into the estrogen receptor. Minor changes in that structure should yield a molecule that can be used to make similar plastics, but that won't alter gene expression. Entrepreneurial companies, seeing potential profits in inherently safe products, are actively involved in bringing such products to market.
Until the early 20th century, the United States was wracked with waves of epidemics, mostly of infectious diseases. Most of those were finally controlled through public-health interventions, especially better water treatment, not through antibiotics or even vaccines. Huge public investments were made, even though the science wasn't definite. Those investments changed the face of public health in this country. We have clean drinking water, and sewage systems that work (most of the time). And today very few people die from waterborne diseases in the United States.
Today's epidemics are very different. They involve cancers, cardiovascular problems, and metabolic syndrome (obesity and Type 2 diabetes), and in the young they include some serious behavioral problems like attention disorders and autism. These epidemics have obvious human costs, and they burden the economy. The medical conditions that would have been studied by the National Children's Study cost the United States $640 billion annually.
If today's epidemics continue along the trend lines that have emerged over the past 30 years, it is likely that this generation of children will be the first in modern history to have less healthy adult lives than those of their parents. Changes in gene expression play a significant role in virtually all of them. It is highly likely that some percentage is caused by exposure to contaminants. Those epidemics, in principle, can be prevented. As this science advances, and as people, government, and companies act upon these developments, it is possible to envision a transformation in public health just as radical, and positive, as that achieved when society cleaned its water of infectious-disease agents.
Pete Myers is founder, CEO, and chief scientist of Environmental Health Sciences in Charlottesville, Virginia. Former director of the W. Alton Jones Foundation, he is a coauthor of Our Stolen Future (1996), which explores the threats posed by man-made chemical contaminants to fetal development and human health. For more, see www.EnvironmentalHealthNews.org.
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