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Epigenetics research takes aim at cancer, Alzheimer’s, autism and other illnesses
DURHAM, N.C.—In the classic movie "It's a Wonderful Life," George Bailey wonders what life would be like if he'd never been born. As we all know, his guardian angel Clarence Odbody shows him the kind of mark he's really made on Bedford Falls.
What George Bailey didn't know was the mark we all make in our lives from birth—the impact made by our DNA and its role in our traits.
There exists a mediator between nature and nurture known as epigenetics. A group of molecules that sit atop our DNA, the epigenome (which means "above the genome") tells genes when to turn on and off.
"Epigenetics research refers to the study of heritable changes in gene function that occur without a change in the sequence of the DNA, but rather involve alterations in DNA methylation and the histone code," notes Duke University's Randy Jirtle. "Thus, if you think of the genome as being comparable to the hardware of a computer, the epigenome is the software that tells the computer when, where, and how to work."
Jirtle points out that in the past only genetic mutations were thought to cause diseases and neurological disorders. Thus, much time, money and effort has gone into defining mutations involved in human diseases.
"This approach has been quite successful since gene inactivating mutations have been found that result in a number of human diseases like sickle cell anemia, cystic fibrosis and breast cancer," he says.
Epigenetic changes can cause inappropriate gene function by resulting in either over or under expression.
"A number of developmental disorders are caused by epigenetic changes such as Beckwith-Wiedemann, Angelman, Prader-Willi, and Silver-Russell syndromes. Type I and Type II diabetes have been associated with imprinted genes—a subset of genes in which one parental copy of the gene is normally silenced epigenetically," notes Jirtle. "Autism has also been recently associated with epigenetic deregulation of the oxytocin receptor gene (OXTR). Epigenetic dysregulation of genes is also intimately involved in cancer formation."
It has just been demonstrated that histone methylation plays a crucial role in the long-term actions of cocaine on neuronal morphology and behavior that may underlie cocaine addiction.
"Although both genetic mutations and epigenetic changes result in human diseases, I think that it will ultimately become clear that epigenetic changes give rise to human diseases more frequently that genetic mutations," Jirtle adds.
Jirtle points out that epigenetic deregulation of gene expression causes myriad human diseases and neurological disorders.
"Consequently, we finally appreciate that there are novel targets for which drugs can be designed that focus on the epigenome rather than the genome," he says. "This is comparable to finding a completely new mine to extract gold."
Having made its impact, epigenetic therapy has a bright future.
"Epigenetic therapy is already being used to treat Myelodysplastic Syndrome (MDS). Valproic acid is used to treat epilepsy and bipolar disorder," Jirtle says. "Interestingly, it is a histone deacetylase (HDAC) inhibitor. Thus, it is possible that its efficacy in treating neurological problems may result, in part, on its ability to alter the epigenome."
The focus of medicine in the past as been on therapy, and Jirtle says there is a bright future for drugs that target the epigenome.
"I also believe, however, that there will be a substantial market for chemical agents and nutritional factors that prevent inappropriate epigenetic events from occurring during our life. For example, we demonstrated that these nutritional supplements (e.g. methyl donors or genistein can counteract the reduction in DNA methylation caused by the endocrine disruptor, bisphenol A, used in manufacturing hard clear plastic and sealants," he says. "To paraphrase what Hippocrates stated over two millennium ago, food is medicine."
Part of Jirtle's work includes research with mice. In one project one mouse weighs 20 grams and has brown fur. The other is a hefty 60 grams with yellow fur and is prone to diabetes and cancer. They are identical twins, with identical DNA.
So what accounts for the differences?
Jirtle made one of the mice brown and one yellow by altering their epigenetics in utero through diet. The mother of the brown, thin mouse was given a dietary supplement of folic acid, vitamin B12 and other nutrients while pregnant, and the mother of the obese mouse was not. (Though the mice had different mothers, they're genetically identical as a result of inbreeding.) The supplement "turned off" the agouti gene, which gives mice yellow coats and insatiable appetites.
Epigenomes vary greatly among species, Jirtle explains, so it cannot be assumed that obesity in humans is preventable with prenatal vitamins. But his experiment is part of a growing body of research that has some scientists rethinking humans' genetic destinies. Is our hereditary fate—bipolar disorder or cancer at age 70, for example—sealed upon the formation of our double helices, or are there things we can do to change it? Are we recipients of our DNA, or caretakers of it?
Last year, the National Institutes of Health announced that it would invest $190 million to accelerate epigenetic research. The list of illnesses to be studied in the resulting grants reveals the scope of the emerging field: cancer, Alzheimer 's disease, autism, bipolar disorder, schizophrenia, asthma, kidney disease, glaucoma, muscular dystrophy and more.
Epigenetics have been a focal point for Jirtle for more than a decade. When he held is first epigenetics conference in 1998 in Raleigh, N.C., epigenetics was such a small field that he worried nobody would come. About 160 people attended. Jirtle hosted another conference in 2005; it attracted 470.
"It's the flavor of the month," Michael Meaney, a brain researcher at McGill University in Montreal, tells the Washington Post.
When a gene is turned off epigenetically, the DNA has usually been methylated. Biologists have known for decades that methylation is involved in cell differentiation in utero, making one cell a skin cell, another cell a liver cell, and so on. Cell differentiation is also what happens when scientists prompt an embryonic stem cell to grow into a specific type of cell. But five years ago, when Meaney submitted a paper suggesting that DNA methylation happens throughout life in response to environmental changes, he was told, "This just can't happen."
"When a methyl group binds to cytosine in DNA, it can project into the major grove of the double helix molecule, blocking the ability of some transcription factors from binding to the promoter region of a gene," Jirtle says. "DNA methylation coupled with molecular changes in the histones (e.g. acetylation), which DNA is wrapped around, can result in chromatin condensation, and gene inactivation because the transcription factors required for gene expression cannot access the DNA."
Epigenetic events are permanent, but reversible.
"Thus, even though epigenetic changes may be difficult to alter once established, it is possible to reverse them otherwise epigenetic therapy would not be effective in the treatment of some cancers," Jirtle adds.
Duke Department of Medicine researcher Simon Gregory described the link between DNA methylation and autism in a paper published in October in the journal BMC Medicine.
Most genetic studies of autism focus on variations in the DNA sequence itself, especially on genes that are missing. Gregory and his colleagues looked at an oxytocin receptor gene, called OXTR, and found that about 70 percent of the 119 autistic people in his study had a methylated OXTR; in a control group of people without autism, the rate was about 40 percent. Oxytocin is a hormone that affects social interaction; difficulty relating to others is common for those with autism spectrum disorders.
Because this was only a pilot study, more research is necessary. But Gregory tells the Washington Post that methylation-modifying drugs may be a new avenue for treatments. He also hopes that his findings will provide a new tool for doctors to diagnose autism.
"Methylation has been very hot in the cancer field for a number of years," Gregory tells the Washington Post. "To find something like this associated with autism is very exciting."
Epigenetic therapy is still very inexact—"a pretty broad brush," adds Jirtle. But oncologists have seen some success in using it against leukemia. Azacitidine, sold as Vidaza and used to treat bone-marrow cancer and blood disorders, became the first FDA-approved epigenetic drug in 2004. When tumor-suppressing genes aren't doing their job, due to a genetic mutation or hypermethylation, cancer cells can replicate uncontrollably. But by manipulating the epigenetic marks, doctors can get tumor-suppressing genes to work again. Toxicologists also have a big stake in epigenetics.
The potential human implications— do the chemicals we ingest today affect our great-grandchildren?—are tremendous. In addition to pesticides, toxicologists are studying chemicals in plastics, such as phthalates and bisphenol A, to see if they could enhance our risk of disease by altering the epigenome.
As a result of epigenomic research, we know the mark we make our own lives starts at birth and extends beyond the impact George Bailey had on Bedford Falls.