If you can imagine that a fetus’s genome is a cake recipe, it’s easy to see how a mother can tweak it subtly. She’s saying something like slip in more egg yolk. Reduce the lemon zest. Bake ten minutes less. Her tweaks are like directions written on sticky notes in that they’re not part of the recipe itself. The master recipe is intact. Nothing is erased or permanently altered; the ingredients are the same. But the final product is different from what it would have been under other circumstances.
Tweaking the genomic “recipe” is what epigenetics—altering the activity of genes without changing their underlying DNA sequence—is all about. In technical terms, the foods we eat can contain organic compounds called methyl groups that attach themselves to our unborn baby’s genes and change their behavior, especially early in development. Adding methyl groups turns gene expression down (methylate) and removing them turns it up (demethylate), like turning the volume higher or lower, on or off. The result can be as dramatic as slightly altering a recipe for a spongy, bright-yellow cake so that it comes out dense and nut brown.
In a way, that’s exactly what happened when scientists at Duke University and Baylor College of Medicine experimented on a species of mouse called agouti. The photos accompanying their study show two agouti mice, one obese and bright yellow (considered normal for this lab breed) and the other compact and nut brown. As radically different in appearance as the two rodents were, they were as genetically similar as identical twins. If you looked at their DNA alone, you’d see the exact same code in both. The only difference between them is that two weeks before conception and throughout pregnancy and lactation, the mother of the compact brown mouse ate chow supplemented with chemicals that donate methyl groups to genes—in this case, B-complex vitamins such as vitamin B12, folic acid, choline, and betaine. Early in the embryonic development of the brown mouse, those methyl groups attached themselves near the sites of genes that normally promote yellow pigment and obesity (linked to diabetes and cancer) in agouti mice and silenced them.
It was an astonishing experiment. Here was an animal whose predisposition to obesity, diabetes, cancer, and yellow fur was overcome by maternal diet alone. The mother was fed only three times as many supplements as found in normal mouse chow—the human equivalent of an extra dose of vitamins. Foods that contain these nutrients are meat, liver, shellfish, milk ( for vitamin B12), leafy veggies, sunflower seeds, baker’s yeast ( for folic acid), egg yolk, liver, soy ( for vitamin B6 and choline), and beets, wheat, spinach, and shellfish ( for betaine).
Later studies found that genistein, a weak estrogenic chemical found in soy products, had the same Cinderella effect, transforming homely mice with a genetic predisposition to obesity and cancer into stunningly healthy brown ones. Isn’t it interesting, the researchers point out, that Asians, the population that consumes the most soy in the world—2,050 times more per capita than in the West—have the lowest risk of breast, colon, and prostate cancers? And isn’t it telling that Asians conceived and raised in the East enjoy increased protection from breast cancer while their daughters, raised on a Western diet, do not? Genistein in soy seems to prevent genes from overexpressing themselves and causing cancers.
This reminds me of what we say about kids when they act up. It’s not the genes themselves that are bad, it’s the way they behave. And diet affects a gene’s behavior.
Parents who are aspiring for a baby genius may be intrigued by choline, another B complex vitamin that is essential for brain development. A methyl-bearing chemical found in eggs, liver, salmon, and organ meats, choline has epigenetic properties too. When expectant mother rats were fed four times their usual intake of choline in late pregnancy, their offspring had visual and auditory memories vastly superior to those of pups whose mothers ate a normal diet. In old age, these brainy rats also escaped the usual fate of rodent senility and had fewer tumors. Choline appears to affect the behavior of genes that alter the timing, placement, and behavior of neurons in the hippocampus, the memory center of the brain. In humans, development of the hippocampus may continue for years after birth, suggesting that we should stuff ourselves with eggs not only when we’re pregnant but also if we’re breast feeding. Two eggs daily nearly satisfies the dietary requirement of 450 milligrams in pregnancy (550 milligrams when nursing). Did Einstein’s mom love eggs?
The natural temptation is to gorge on supplements that contain choline, folic acid, soy, and other methyl-bearing chemicals. We shouldn’t. Getting these nutrients in the foods we eat is beneficial; excessive pill popping is not (although folic acid supplements are often prescribed by doctors because of the widespread deficiencies in B vitamins).
Here’s the reason why. Throughout fetal development, genes methylate and demethylate all by themselves, turning off and on, higher and lower. This is why heart cells behave differently from brain cells even though both have the same DNA. Timing is everything to the fetus. At an early phase of development, it might be helpful for the baby to suppress or overexpress a certain gene, but the same tweaks could be harmful later. Add extra sugar at the beginning of the recipe and the cake tastes better; add it later and the texture goes to hell. Quantity counts too. Some of us may have underlying genes that are supersensitive to small quantities of certain supplements— just as in some recipes, even a pinch of chili pepper goes too far. We can expose the fetus or ourselves to too much of a good thing.
For instance, studies on folic acid found that a minimum of 4 milligrams daily dramatically reduces the risk of neural tube defects—disorders in which the neural tube fails to close, resulting in spina bifida (an opening in the spine that may cause paralysis) or anencephaly (an opening near the head resulting in an absence of much of the brain and skull), among other conditions. Fortified bread and cereal are a great public health coup because they help prevent these birth defects. They exist for the same reason that doctors often prescribe folic acid pills—because some of us don’t eat enough leafy green vegetables, beans, egg yolk, and liver. But the big picture is more complicated. There is evidence that excessive, overexuberant supplementation of folic acid and other B vitamins during pregnancy is linked to higher rates of asthma (in human babies) and tumor development (in mice).
Some experts fear that excess parental multivitamin consumption, acting through epigenetic factors, may predispose children to the curses of obesity, heart disease, and type 2 diabetes later in life. When pregnant rats on an otherwise normal diet were overfed multivitamins, their babies grew up hungrier and with little ability to control their food intake. Expectant moms exposed to a glut of vitamin E in supplements gave birth to babies with a five- to ninefold increase in risk of congenital heart disease. Consider the epidemics of obesity, heart disease, and other medical problems in the United States, and the news is especially thought provoking. The health-obsessed (and the nutritionally lax) take two to seven times the recommended dietary allowance of ten vitamins, not to mention fortified cereals, energy bars, and vitamin-enriched water.
Not even soy is above suspicion. Researchers suspect there are phases in fetal development when exposure to a lot of genistein in soy is protective against cancer and times when it is not. One study found that fetal exposure to soy must be followed up after birth and into adolescence for true cancer protective benefits. But it’s not clear-cut. Some researchers warn that too much soy too early in life, as when newborns drink soy-based infant formula, may increase cancer risk because it interferes with other developmental processes, or because it’s consumed with folic acid, which may cause conflicting epigenetic effects.
These studies on soy, choline, B12, and folate give us just a taste of the chemicals in foods that alter gene expression. Targets of future study include epigallocatechin (in green tea), baicalein (in a Chinese herb) and curcumin (in curry), ibuprofen, lycopene (in tomatoes), pomegranate extracts, quercetin (in plants), selenium (in plants and seafood), alpha- and gamma-tocopherols (antioxidants), valproic acid, and zinc.
Vitamin D (in eggs, yogurt, wild salmon, liver, and sunlight) is thought to be an epigenetic gold mine. A prenatal vitamin D deficiency is associated with a higher risk of asthma and wheezing in childhood. Omega-3 (in fish and flaxseed) affects genes involved in brain development. Alcohol and a high-fat diet may increase the risk of disease by turning down or switching off vital genes, while a healthy diet may do the reverse of these undesirable effects. Some foods may interfere with another’s health benefits; for example, green tea reduces the absorption of folic acid.
How simple it was for scientists to once think our and our babies’ genes were closed systems, separate and removed from drinking water, hen’s eggs, chocolate-covered candies, and all else they may encounter! Now we know, in a very real sense, that genetic behavior depends on our eating habits.
Epigenetics may be cutting-edge, but the prenatal diet is not. It’s essentially the one we were taught as schoolchildren: eat leafy greens, eggs, fruit, fish, nuts, beans, whole grains, soy, and some fat and dairy. Because excess pesticide exposure can also harm a fetus’s development, we should scrub our fruits and vegetables and try to eat organic varieties of those that are the most contaminated: peaches, apples, sweet bell peppers, celery, strawberries, cherries, pears, grapes, spinach, lettuce, and potatoes. Everything low-toxin, nutritionally balanced, and in moderation. Some cake is okay, not too much (but how could you eat too much cake?).
This is all the practical wisdom that science can offer—at least until diet can be tweaked for each mother’s and baby’s genome. There isn’t a perfect recipe, not yet anyway, for the bun in the oven.