Outside Influences

In a unique partnership, Duke cancer and environmental scientists are reaching outside their own spheres to study how environmental factors may give rise to cancer — and what we can do to protect ourselves.

published in DukeMed magazine, Fall 2009

She was standing at the kitchen sink, washing dishes, just as she had dozens of times in my childhood when I had walked in with a question about something I didn’t understand.

But the question we were discussing was not one between a young mother and a curious kindergartner; it was between a 50-year-old woman whose breast cancer had been in remission for a year and her college-aged daughter who wondered what sort of fortunes might await her own body, yet to be told.

My mother was convinced that stress — losing her father, moving to a new state — had caused her disease, for there was no history of it in our family. I was thinking about the other tapestries of her life: the coal mining she grew up around; the chemical plants that billowed clouds of smoke and dotted the landscape of the region where we made our home for the first 16 years of my life.

Could any or all of these factors have caused her cancer? Would they one day haunt me or my children?

For most of us — even for many researchers — the relationships between nature and nurture remain murky.

But scientists at the Duke Comprehensive Cancer Center and the Nicholas School of the Environment believe that such questions are answerable, that our lifestyles, our environments, even the possible effects of what’s stored underneath that kitchen sink, can be shrunk from imposing questions to understandable relationships, from theory to therapy, from perhaps to prevention.

The partnership is one-of-a-kind: No other institution in the country boasts such a level of collaboration between environmental and cancer researchers.

The effort began in 2005, seeded with a series of joint projects funded by Fred and Alice Stanback of Salisbury, North Carolina (who have since contributed an additional $6 million to the cause).

Over the years the initiative has grown and given rise to new research in both domains, with scientists coming together to explore questions that once ended where another discipline’s research lab began.

Researchers are visiting their neighboring schools, borrowing the proverbial cup of sugar, and getting personal — just like the disease itself.

“You can find the big answers if you have the culture and the willingness to work together,” says William Chameides, PhD, dean of the Nicholas School. “You have to be willing to say, ‘Yeah, I’m going to stretch a little bit, and I’m going to get a little bit out of my element, because I see the big payoff.'”

In pinpointing our environmental enemies more precisely, the eventual payoff could indeed be huge — and more than a little alarming.

“I have three kids: an eight-year-old, a six-year-old, and a four-year-old,” says H. Kim Lyerly, MD, director of the Duke Comprehensive Cancer Center. “So there’s stuff in the backseat of the car. There are plastic drinking cups, toys, balls, and other man-made things.”

To contemplate the spectrum of dyes, paints, and coatings on the endless odds and ends that we dig out from between the car seats and behind the sofa cushions, all the materials that end up on our skin or — more likely — in our children’s mouths, it’s easy to spin into paranoia or a sense of futility.

But the goal, says Lyerly, is not to “panic about the things we find; it’s to discover what kind of impact they have. If something is harmful, we want to know why. We want to link actual biology with detection in the environment.

“Let’s say we find a new type of molecule that causes cells to duplicate themselves uncontrollably,” he explains.

“That’s a new insight that might help us understand cancer and therapies for the disease. But it’s also an insight we can give to the Nicholas School and say, ‘Do you find this molecule in populations that are at greater risk based on your screening?'”

Mapping Cancer Risks

New tools such as geospatial mapping are making these collaborations efficient for both sides. Researcher Marie Lynn Miranda, PhD, who leads the Nicholas School’s Children’s Environmental Health Initiative, has helped advance this mapping technique — which uses a range of spatial data layers — in North Carolina and nationally through her work on environmental contributors to maternal and child health.

Now, geospatial mapping is being expanded to other fields as well, including cancer.

The mapping tools herald an age of “personalized environmental health,” paving the road to a better grasp on where cancers occur and why, says Amy Abernethy, MD, associate director for IT and informatics at the Cancer Center, who often works with Miranda.

Using a database of Duke cancer patients, Abernethy says, researchers are compiling where patients with different kinds of tumors live and then correlating their information with geographic maps of known heavy metals or other kinds of exposures considered potential carcinogens — arsenic, radon, and even the sun itself.

As more and more information is gathered and other databases are folded in, those maps will be not only heavy-duty tools for research, says Abernethy, but eventually clinical tools to help drive home the importance of proper screening. Like the old picture of lungs blackened from smoking, physicians can pull out a map during an office visit that details their patients’ risk based on geography.

“It allows people to see that, ‘Wow, I live in Johnston County and these are the things that I need to worry about, and this is based on real-life data,'” Abernethy says. “It becomes much more meaningful.

“I think ultimately we’ll become more and more sophisticated in our risk-modeling.
We’ll be saying: ‘This is a 33-year-old woman living in Johnston County, near Highway 242, who has lived in Wake and Durham counties at prior points in her life, and her risk of having this type of cancer by the time she turns 70 is x.’ And it may influence the screening we recommend.”

What’s in the Water

Cancer is an intimate foe; when you have it, and even when you no longer do, reminders of its presence pockmark your body and your psyche.

And many of the environmental insults that are linked with oncogenesis, as Nicholas School professor Avner Vengosh, PhD, knows, also pockmark the landscape that surrounds us.

Vengosh is a geochemist who is known internationally for his expertise on the chemical and isotopic composition of water contaminants, developing tracers for contaminants in water supplies from the Middle East to the mountains of western North Carolina, where harmful radon in groundwater was exposed.

He has collected samples of the coal-ash waste that spilled from the Tennessee Valley Authority’s Kingston coal-burning plant on December 22, 2008, covering 300 acres of land and water with sludge and damming a tributary of the Emory River there.

Coal ash has relatively high levels of toxic elements such as radium and arsenic; long-term exposure to either has been deemed a cancer risk by the Environmental Protection Agency.

“The massive coal-ash spill contaminated associated surface water — specifically with arsenic—but the good news is, we detected only trace amounts of arsenic in waters beyond the dammed tributary,” Vengosh says.

“The data suggest that river flow has diluted the arsenic content. The river is relatively clean, but the water from areas like the dammed tributary, where the coal ash accumulated, still contains high arsenic levels.”

The Tennessee coal-ash spill is a wake-up call, as about 70 million tons of coal ash are stored around the United States.

Avner and fellow Nicholas School investigators worked with Julia Kravchenko, MD, PhD, of the Cancer Center on a paper (published in May in Environmental Science & Technology) that examines the link between environmental contaminants found in the Kingston coal ash, contaminated water, and health risks — the first of several planned studies of the biomedical implications of environmental disasters.

Chameides is particularly interested to see what the Vengosh team finds as its research into these links unfolds during the coming year; hundreds of coal-ash retention ponds exist in the United States, he says, and if high levels of carcinogens are found in Tennessee, those data could ultimately unlock clues about cancer incidence in other areas of the country.

“If you try to understand in general the impact of environmental pollution on human health,” Chameides says, “it’s sometimes useful to look at places where you see a really high impact, a larger signal such as the coal-ash spill, and then work backward from that to see what’s happening in a more subtle way in other places.”

The Hopeful Science

In 2003, Duke epigenetics expert Randy Jirtle, PhD, proved that while our genome is fixed when we’re born, our epigenome — the collection of chemical switches that tell the genes what to do — is not.

If the genome is the hardware of our bodies, the epigenome is the reprogrammable software capable of yielding to outside influences, says Jirtle.

In his study, baby mice suffered from a flawed gene that led to increased susceptibility to obesity, diabetes, and cancer — except among those whose mother had been fed a prenatal diet including folic acid.

In that group, the extra nutrients acted at the molecular level to latch onto the troubled gene, resulting in its appropriate regulation. Those mice were born healthy.

Jirtle reported a similar finding last year on folic acid countering the negative effects of BPA, a chemical found in many plastics.

What’s more, says Jirtle, once this good-guy methylating gang does its work in the embryo, the genomes of those mice’s offspring are permanently mended, carrying the good alteration throughout the individual’s life. It is, he says, a hopeful new way of looking at life, and at medicine.

Of course, it also means that, as more is learned about the epigenomic switches, clinicians will have to ask their patients to sidle up to the responsibility trough and get smart about their lifestyle and environment choices based on the findings.

“What you eat, what you drink, and so on can affect not only yourself, but generation upon generation after you,” Jirtle says.

That is why, although researchers continue to study the effects of nutrition and lifestyle on cancer incidence, Jirtle believes doctors should urge their pregnant patients — and women thinking of starting a family — to start limiting their exposure to BPA now by avoiding food from cans coated in plastic and water from plastic containers made from BPA, which may mimic estrogen(s) in the body.

Along with oncologist Victoria Seewaldt, MD, Jirtle also is working with a subset of our genome called “imprinted genes” to learn more about the influence of environment on breast cancer.

Unlike other genes we’re born with, in imprinted genes, only one of the two copies inherited from the mother and the father works. This nonworking gene is epigenetically switched off, or methylated, in a normal gene. But, if either both copies or no copies are working, susceptibility to disease increases.

Jirtle estimates that only about 200 of the 25,000 genes in our makeup are imprinted, but these are the ones Jirtle believes will unlock the mysteries behind many diseases, especially cancer.

The researchers are looking at people with a high risk of breast cancer to see if there are epigenetic changes in the KCNK9 imprinted gene, a potassium channel that has been shown in previous studies to result in breast cancer when overexpressed. Jirtle says they have already seen some evidence of a relationship at the epigenetic level.

Jirtle’s studies even investigate how the environment within the body may affect the epigenome — specifically, he’s researching the link between neurological disorders and cancer, because patients with schizophrenia are known to have low incidence of cancer.

He believes that one day, when these ties are better understood, therapies might be introduced to turn off disease-causing genes and turn on protective mechanisms at the cellular level.

“With epigenetics,” he says, “for the very first time, the word prevention comes into cancer. To get to the answers, though, you have to bring together groups of people that possibly have never been brought together before; and in fact, that’s what’s happening right now between the Nicholas School and the Cancer Center.”

Disrupting the Status Quo

BPA is one of several known endocrine disruptors — though it has received by far the most attention, causing certain plastic water bottles, baby bottles, and other goods to be shunned almost overnight.

But Jirtle’s colleague, Duke molecular cancer biologist Donald McDonnell, PhD, discovered startling information regarding endocrine disruptors and pharmaceuticals that should give pause to doctors prescribing medications with hormonal components.

McDonnell’s team showed why a common solvent used in industrial cleanrooms and one of the most popularly prescribed drugs in the country could lead to increased risk of cancer in some individuals.

His team tested a cleaning agent known as ethylene glycol methyl ether (EGME) that’s used in varnishes, paints, dyes, fuel additives, and the semiconductor industry; and valproic acid (Depakote), a drug with a similar chemical makeup that is prescribed for migraines, seizures, and attention deficit and bipolar disorders.

They discovered that EGME, when metabolized, and valproic acid both act as hormone sensitizers—they enhance progesterone and estrogen activity inside cells.

When that hormonal activity is accelerated in a person who is already ingesting a drug that contains synthetic progestin and estrogen (such oral contraceptives or hormone replacement therapy), the extended, double exposure of hormones in the body is likely to increase cancer risk.

McDonnell says the results are a break from more traditional thinking on the work of endocrine disruptors, where the focus has been on agents that mimic estrogen in the body rather than those that change the way cells see estrogen.

That mimicking also has been the main focus of drug testing for such disruptors, and until testing strategies take this new mechanism into account, he says, physicians need to act cautiously before prescribing any drug in combination with hormone-containing pharmaceuticals.

“This adds fuel to the debate as to the effectiveness of the currently used tests for endocrine disrupters,” says McDonnell. “The drug-testing programs are outdated and do not adequately incorporate our current understanding of hormone action.”

McDonnell suggests taking particular caution with tamoxifen, which is widely used in the treatment and prevention of breast cancer but is chemically altered from an antagonist to an agonist in the presence of EGME and valproic acid.

And while he has received some feedback from oncologists who do check with their patients about valproic acid use, for the most part, he says, “the message hasn’t yet hit home” in the medical community.

McDonnell adds that there’s no doubt in his mind that the environment contributes in a very significant manner to cancer susceptibility.

“Endocrine disruptors have received a lot of attention of late but there are likely to be hundred of other types of agents in the environment that impact cancer risk.”

Ready for Its Close-up

Environmental effects on cancer are taking center stage in the medical research community and likely will become a greater topic of conversation around dinner tables, too.

It’s precisely that growing curiosity among the public about what’s safe around us and what isn’t that is fueling the partnership between the Nicholas School and the Cancer Center.

Patients want answers; researchers want to give doctors the right tools to provide those answers.

In the coming months, Lyerly and Chameides will see the connections they’re making at Duke unfold nationally. The President’s Cancer Panel, a group Chameides spoke to last fall which is tasked with appraising the National Cancer Program, will focus its annual report to President Barack Obama on the links between the environment and cancer.

Lyerly and Chameides also are co-chairs of a state cancer-plan task force on the same topic, and the foundation Susan G. Komen for the Cure also will be putting a brighter spotlight this year on environmental links to breast cancer.

“When I first called Bill to get directions to his office, he told me, ‘Just follow the
Birkenstocks to the Levine Center,'” Lyerly says.

Now that trail has becoming a well-beaten path — and a road that the two hope others may follow.

“The more we work with the School of the Environment, the more we understand that there are few people at the Cancer Center who couldn’t find ways to interact with their expertise,” says Lyerly. “We’re hoping this will be a model for other places, for balancing individual research accomplishments with the collective good.

“We can find the answers if we work together.”

This article was first published in the Fall 2009 edition of DukeMed Magazine.