Temple researchers explore how the body's bookmarks might prevent disease.
Story by Elisa Ludwig, CLA ´99
Illustration by Neil Webb
We know that smoking is bad for us and that we should watch our calories and get exercise. But what if we understood the ways in which unhealthful behavior could affect not only our own lives, but also the biochemical legacy we leave to our grandchildren? Could the toxins to which mothers are exposed before pregnancy make their children more susceptible to developing adult-onset diseases? And might the reverse also be true, that diseases could be prevented by eating well or taking supplements before or during pregnancy?
Researchers in the field of epigenetics are investigating exactly how human DNA is altered over time, both now and transgenerationally. In the School of Medicine´s Fels Institute for Cancer Research and Molecular Biology Director Jean‐Pierre Issa is working on several research projects that explore how our lifestyles affect epigenetics and how epigenetics affects our wellness.
In essence, epigenetics is the normal and natural process by which cells that contain the same DNA are differentiated. “Our body is made of one genetic code, one sequence of DNA,” Issa says. “But within that code are epigenetic marks—a series of tags that can differentiate what type of tissue that DNA will form. If you consider DNA the book of life, you can think of those tags as bookmarks.” The body has more than 200 tissue types, and an epigenetic tag helps the body compartmentalize the DNA and specifies “hair,” “eyes” or “skin.”
Unlike genetics, which involves changes in the DNA sequence, epigenetics is the change related to how genes are expressed. Issa says that some of those tags change DNA through a process called methylation. But they also can act on histones—proteins wrapped in DNA.
“[Epigenetic tags] can hide genes, serving as gatekeepers for the DNA, saying, ‘This one is good and you can use it to make RNA,’ or ‘Move along and don´t look here,’” Issa explains.
Together, those tags are known as the epigenome, and scientists have been mapping it, in the same way they have mapped the human genome, to create a comprehensive framework for epigenetics research. In addition to programming cells for various functions, epigenetic tags are responsible for certain diseases by turning a gene´s “switch” on or off. Their organization can be inherited or accumulated over time, either through simple aging or environmental exposures.
“Biochemical tags need to be reset constantly,” Issa says. “Every time a cell divides, and as it evolves and ages, the tags can potentially be affected.”
Some studies have shown that the food pregnant mice eat can lead to marked epigenetic changes in their offspring. And studies of mothers in Africa show that children born during times of the year when food availability ebbs or flows will have a corresponding epigenetic makeups.
Though we cannot change our DNA sequences, we might be able to control how our bodies turn “on” genes that promote health and turn “off” disease‐promoting genes. Issa says it takes more than casual behavior changes in either direction to make a difference. “Does that mean that eating a hamburger during pregnancy will negatively affect your child´s tags? No,” he says. “But it might if you´ve been eating one every day for years. We already know that exposures to certain substances such as arsenic, tobacco and BPA [a chemical used in making plastics] can alter DNA.”
AGING AND DNA
In the Fels Center, Issa is looking at DNA methylation across a number of studies. In one study, animals subjected to caloric restriction had far less methylation, and their tissues appeared more youthful than those with nonregulated caloric intakes.
Issa and his colleagues also examine chronic inflammation on an epigenetic level. They hypothesize that the regular use of aspirin could slow aging and prevent the onset of inflammatory bowel disease or chronic viral hepatitis because of the drug's effects on the epigenes.
Though his research is in progress, Issa theorizes that our lifestyles might not affect our epigenetic makeup directly but rather the rate of epigenetic change as we age. “I personally believe that exposures and diets and lifestyle choices can change the rate of accumulation of these events, and what could be considered a healthful lifestyle would slow down the process of tag degeneration,” he says.
Though the term itself was first coined in 1942, epigenetics became a serious field of inquiry in the 1970s, when researchers Arthur Riggs and Robin Holliday proposed that chemical modifications of DNA could influence gene expression. In the 1990s, epigenetics gained momentum as scientists began to better understand the mechanisms at work. Today, epigenetics is a dynamic discipline that has advanced genetics, genomics—the study of the genome, or the complete set of DNA within an organism´s cell—and molecular biology, extending beyond medicine to our understanding of human evolution.
Issa first became interested in the field about 25 years ago, when he was at Johns Hopkins University in Baltimore, and the field was fledgling. As a cancer physician and researcher, Issa was struck by the early hypotheses of scientists who found cancer patients´ tags abnormal compared to those in healthy patients.
“At the time, the general dogma was that cancer was caused by genetic damage to the DNA,” he says. “The researchers [at Johns Hopkins] were positing that it wasn't just genetic, but a reshuffling of the tags that was causing cancer cells to grow. That idea was very attractive to me as a new way to understand the disease, and I started working in a laboratory with an investigator who was promoting it.”
All tags degenerate with age, and those researchers came to the conclusion that since cancers such as myeloid leukemia (that of the bone marrow) are more prevalent among older patients, there was an epigenetic cause. (Prostate and cervical cancers are other examples of cancerous growths that can be incited epigenetically.)
Perhaps most importantly, Issa´s work has shown that epigenetic cancers can be reversed with specific therapies: A decade's worth of clinical study has contributed to the development of nontoxic alternatives to chemotherapy and radiation. Those drugs do not kill the cancer cells; they “replenish or rearrange” the epigenetic tags instead. They have served not only to help sick patients, but also as proof of concept that epigenetics is indeed at play in their diseases. Now Issa is working to develop new compounds that might have a similar effect, and he plans to do more clinical research around other epigenetically caused diseases, such as lung cancer.
In years to come, the study of epigenetics might affect the wider population, as research findings could empower individuals to make better decisions about their health and wellness. “There are no absolutes, but there are things we can do to prevent disease, and we're trying to learn more,” Issa says. “With the right lifestyle, people who are genetically predisposed to cancer, for example, might be able to avoid it or get a much milder form of it than they might have gotten otherwise.”
With many epigenetic studies in their earliest stages, Issa is careful not to overhype such connections. “There are still many question marks around our lifestyle choices, whether its diet or exercise,” he says. “It should be emphasized that, thus far, our ideas are speculative. However, we do know that ultimately these discoveries could have great implications for our health.”