The Human Epigenome Project
There are maps, and then there are maps. We're embarking on a kind of mapmaking that will usher in new ways of understanding ourselves-a map that can explain why identical twins are not truly identical, so that one succumbs to schizophrenia while the other remains cognitively intact; why what your mom ate can save or sabotage your health (as well as that of your children and your children's children); and how our genetic fates can be tuned by such simple universals as love or vitamins.
It's The Human Epigenome Project (HEP). It's the next step after the Human Genome Project, which in itself was as audacious as the Apollo space program or the Manhattan Project, mapping 25,000 genes and the 3 billion pairs of bases in our DNA. And yet, what The Human Genome Project mapped is like land without borders, roads without names, a map without movement. Genes are silent unless activated. To have them is not necessarily to be under their influence.
"Land lies in water, it is shadowed green," begins Elizabeth Bishop's classic early poem, "The Map." The double helix lies in the epigenome like land lies in water. The epigenome is a flute playing a tune that charms the snake-coiled snake that is the code of life-and the snake spirals upward in response. A long bundle of biochemical markers all along the genome, the epigenome responds to environmental signals and then switches genes off or on, upregulates or downregulates their activity. And in that change lies a great part of our destiny.
In 2003, in a widely discussed experiment, scientist Randy Jirtle of Duke University Medical Center in Durham, North Carolina, showed that he could change the activity of a mouse's genes by giving supplements to its mom prior to, or during, very early pregnancy. A mouse with yellow fur, whose offspring would normally also be yellow, will give birth to brown-furred babies if fed a diet supplemented with vitamin B12, folic acid, betaine and choline. Even the offspring of the mom's offspring will be born with brown fur. The genes themselves have not changed at all, but their expression has, and that lasts for at least two generations. And a fungicide used on fruits led to sperm abnormalities in rats-abnormalities passed down at least four generations. This gives us insight into nature's ways: apparently she figures any change in the food supply will last a while, and isn't just a seasonal fling.
Then, in 2004, Moshe Szyf, Michael Meaney and their colleagues at McGill University in Montreal, Canada, showed that love can work in a similar way. If mothers don't lick, groom and nurse their babies enough, a molecular tag known as a methyl group-a tiny molecule made of three hydrogen atoms bound to a single carbon atom-is added to a gene that helps regulate an animal's response to stress. In pups that aren't nurtured properly, the methyl group downregulates the genes' activity for life. The pups have higher levels of stress hormones and are more afraid to explore new environments. What is nature saying? If a mom didn't attend to her newborn much, it's probably because the environment was hostile and stressful. Better to be vigilant and cautious, even afraid. Later, Meany and his colleagues showed that a common food supplement could do exactly the same thing to the genes of well-licked and nurtured rats. Once the pups were three months old, researchers injected a common amino acid, L-methionine, into their brains. This methylated the same gene, downregulated it, and turned the rats into anxious wallflowers.
Last June, the European Human Epigenome Project published its first findings on the methylation profiles, or epigenetics, of three chromosomes. The push to map the epigenome is on. In the last few weeks alone I've seen very different epigenetic stories coming across the science wires. From the University of Texas Medical Branch at Galveston came the news that breastfeeding protects children who are genetically susceptible to repeated ear infections because of common variants in their genes. The tendency toward ear infections runs in families, and researchers found the culprit in two gene variants that increase inflammatory signaling molecules in the immune system. Remarkably, breast milk seemed to permanently quiet the genes, so that even later in childhood, long after the children had stopped breastfeeding, they were protected from recurrent infections.
In research from the Universidad Nacional Autonoma de Mexico and the Instituto Nacional de Cancerologia, Mexico, epigenetic drugs are now being studied in breast, ovarian and cervical cancer. These drugs affect genes that, when reactivated, help regulate cell proliferation, cell death, cell differentiation, and drug resistance. They're cheaper than designer-name cancer drugs, and might help increase survival rates.
Even water fleas are joining the epigenetic act. In a December study from the University of California at Berkeley expression of genes in water fleas changed in response to common contaminants. Water fleas are regularly used to monitor freshwater toxicity, usually with a "kill 'em and count 'em" approach. Researchers found that copper, cadmium and zinc decreased expression of genes involved in digestion and infection. Screening like this might help industry assess and avoid particularly toxic contaminants.
Epigenetics offers us a different kind of map. One where we can zoom in and zoom out. A map of many colors, with street signs so we can navigate, routes that we can choose, destinations that we can change. Maybe the gene isn't selfish. Maybe it's actually sensitive. "More delicate than the historian's are the mapmaker's colors." So concludes Elizabeth Bishop's poem, and the epigenome may prove to be one of the more beautiful, delicate, subtle maps of all time.