The DNA Files:
Unraveling the Mysteries of Genetics
As heard on National Public Radio
Rewriting Heredity: Environment and the Genome
Hosted by John Hockenberry
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JOHN HOCKENBERRY: This is The DNA Files. I'm John Hockenberry. In the next hour, a collision with the American diet leaves an indigenous people reeling from runaway obesity.
PETER BENNETT: They had an extremely high prevalence of diabetes that was estimated to be eight to ten times higher than in any other population in that particular time. In truth, we had really no idea what the underlying causes were.
JOHN HOCKENBERRY: Meanwhile, in the Court of Long Beach, an asthma epidemic, but the sufferers tend to be related.
KARENA HAMILTON: My mom takes daily medicine for it, an inhaler, and my sister does as well and her daughter.
JOHN HOCKENBERRY: And scientists are learning that our genes and the environment are entangled in an embrace that may alter our legacy to our children and our children's children. Join us for "Rewriting Heredity: Environment and the Genome" after the news.
JOHN HOCKENBERRY: This is The DNA Files. I'm John Hockenberry.
Welcome to New York City, eight million sharp elbowed homo sapiens, crowded together, breathing, eating, jostling.
JOHN HOCKENBERRY: Hi, how are you doing?
JOHN HOCKENBERRY: Each one a little different, but all immersed in the same complex environment. Truck exhaust. [laughs] There's somebody smoking over there. That means I'm smoking.
JOHN HOCKENBERRY: Sorry. It's okay. It's fine. I don't want to cause a fight.
JOHN HOCKENBERRY: Like pedestrians in a crowded city, the chemistry of the human body is constantly being bumped and elbowed by the environment -- pollution, pathogens, stress --
JOHN HOCKENBERRY: Whoa. Hey. What are you trying to do, kill me? Hey, you almost ran over me, what's going on?
JOHN HOCKENBERRY: Even what you eat and drink affects the chemistry inside your body where the crucial genetic machinery does its work. From the gene's point of view, your diet is part of the environment, but each one of us responds to this environment a little differently. Hang on a second.
JOHN HOCKENBERRY: Hot dog? Hot dog?
VENDOR: Hot dog? How many?
JOHN HOCKENBERRY: Yeah, with everything. One.
JOHN HOCKENBERRY: With everything.
JOHN HOCKENBERRY: I mean, everything.
JOHN HOCKENBERRY: Take this New York delicacy, for example.
JOHN HOCKENBERRY: Oh, yeah.
VENDOR: 2, 3, 4, 5. Thank you very much.
JOHN HOCKENBERRY: Change.
VENDOR: Have a nice day.
JOHN HOCKENBERRY: All right. Thanks so much
JOHN HOCKENBERRY: A hot dog wolfed down on the street isn't on anybody's celebrity diet plan, but some people can eat anything, and never gain a pound, while others diet constantly, and just can't seem to lose weight. Well, no mystery there. It's genetic, right? Some people are just naturally slim. So, then why is America suddenly in the midst of an obesity epidemic? Are we all changing genetically?
For nearly a century, geneticists have searched for the code that makes one person fat, another thin, one sickly, the other robust. The quest has drawn them into a labyrinth of genetic pathways and environmental turning points, the plan of which is still unknown. In the American Southwest, one historically isolated population has been devastated by unprecedented rates of obesity and diabetes. For more than 40 years, scientists have been asking why. Producer Vicki Monks reports from Arizona.
VICKI MONKS: An hour before sunrise, 15 Tohono O'odham runners leave their encampment on the sacred mountain southwest of Tucson, Arizona, descending the mountain, moving across the desert floor. The runners are lean, athletic, conditioned to the Sonoran desert heat that's pushing over 100 degrees before 10 AM.
Runs similar to this one have been part of sacred ceremonies going back longer than memory. Not so many years ago, nearly all the Tohono were as fit and healthy as these runners, but now, too many people are overweight, in wheelchairs. Some have amputated feet or legs from diabetes. Tohono are Pima Indians who have inhabited what is now the American Southwest for millennia. Their cousins, a bit to the north, occupy reservations on the Salt and Gila Rivers bordering the Phoenix metropolis.
Epidemiologist Peter Bennett visited the Pimas at Gila River in the 1960s to study rheumatoid arthritis, hoping to find arthritis free populations in this hot, dry climate. The study was a disappointment. There was plenty of rheumatoid arthritis among the Pima, but he noticed something else.
PETER BENNETT: They had an extremely high prevalence of diabetes that was estimated to be eight to ten times higher than any other population in that particular time. Of course, we didn't know why it was so frequent. One hypothesis was simply that the Pimas might have been a genetic isolate, and for some unknown reason, those few people with diabetes genes had multiplied and formed the Pima tribe. That was one hypothesis.
VICKI MONKS: Another hypothesis was that some environmental agent was responsible.
PETER BENNETT: Another pretty wild idea, but nevertheless one that we examined at least to some extent was that perhaps the toxins provided by scorpion bites would precipitate diabetes, because there was some fractional evidence that the toxins in scorpion bites would actually cause hypoglycemia in I believe it was mice, if I recall correctly. So, that was one possibility, and of course, that fell flat on its face, too. We could find no evidence that there was an excess of scorpion bites among those who had diabetes as compared to those that did not. In truth, we had really no idea what the underlying causes were.
VICKI MONKS: Diabetes and obesity are closely linked. Obesity is the greatest risk factor for adult onset diabetes that usually develops after age 35. Bennett began to look for high rates of diabetes or obesity in other populations. By that time, he had been joined by other researchers with their work funded through the National Institutes of Health. The team discovered another desert tribe with extraordinarily high rates of both diseases -- the Tohono O'odham, closely related by language and culture, to the Pimas at Gila River. That discovery reinforced the plausibility of a genetic explanation, but what was it, and how might it work? Eric Ravussin, a young specialist in obesity joined the team in Phoenix to investigate how the Pima might be examples of the thrifty gene hypothesis, first postulated in 1962 by pioneering human geneticist, James Neel.
ERIC RAVUSSIN: And he postulated the hypothesis that diabetes has to be associated with a survival advantage. He didn't know what it was.
VICKI MONKS: According to Neel's scenario, the ability to store fat conveyed an evolutionary advantage.
ERIC RAVUSSIN: Larger weight was a good thing in the history of mankind. It's only over the past 70 years that it's becoming a bad thing. Our genome, which has been modified over thousands of years have been adapted to scarcity of food and not abundance.
VICKI MONKS: Eric Ravussin and other NIH researchers embarked on a more than 40 year quest to find evidence of a thrifty gene operating in the Pima Indians. Along the way though they discovered several things about how and why people gain weight, and why it's so difficult to lose it. But to understand, we need to back up and follow the path the Pimas took into the modern world.
WOMAN: Squash, cheese, uh shredded beef, green chile, corned beef, red chile burro, and bean and cheese, and soda.
VICKI MONKS: In Sells, Arizona, on the Tohono O'odham reservation, everyone drives cars these days. So, it's the parking lots where vendors do their best lunchtime business. You can buy pork tamales, pizzas, sodas -- high fat, high calorie quick food.
TERROL DEW JOHNSON: You know, I used to drink at least a 12-pack of soda a day. Two, three in the morning, two, three for lunch, two and three or four for dinner.
VICKI MONKS: At 6 feet tall and 300 pounds, Terroll Dew Johnson seems an unlikely figure to be the leading health advocate on the reservation, but over the past 12 years, his organization, Tohono O'oodham Community Action or TOCA has been fighting some of the more destructive effects of modern life by helping people reclaim traditional diets.
TERROL DEW JOHNSON: This is the food the Creator gave us. This is what kept the people in a desert, where there's hardly any rainfall, alive for thousands of years.
DANIEL LOPEZ: Sometimes we just walked out in the desert to look for mesquite bean when they were in season. That was our sweet. The mesquite sap called usabi
VICKI MONKS: Daniel Lopez was born in 1936 when most Pimas still held to traditional ways, relying on desert plants for food. Cholla buds, mesquite beans, wild spinach, the sweet red fruit of the saguaro cactus, and there was plenty of physical activity.
DANIEL LOPEZ: Well, we didn't have TV. We didn't have Game Boys, but our playground was the desert, and the girls were over there by this clearing near the ceremony house, and they're playing the woman's game called Toka. I mean, you're running back and forth -- that's a very active, strenuous game, the same thing with the kickball that the boys played. We ran all the way up there, barefooted, you know. But we did it back then.
VICKI MONKS: But changes were coming fast.
DANIEL LOPEZ: Maybe around the 1940s, the cotton field era came in, and the farmers would come out and recruit O'odham families to go and pick cotton. That's when I say the traditional farming began to decline, because so many people were gone, because to go to the cotton field, chop cotton, starting May, then pick cotton, starting about September, and yet you plant in the summer time. That's when you plant it traditionally with corn, beans, and squash, but now the farmer take it to the store, and you can purchase your canned goods, your bread, your soda, your candy, probably the things that we shouldn't have been eating, but this was things available, you know. We had no choice. That's the only thing we could eat, you know.
VICKI MONKS: Then came World War II.
TERROL DEW JOHNSON: My grandfather was in the Navy. He was taken from his farm and put on a boat where he learned how to cook doughnuts.
VICKI MONKS: When the war ended, Terrol Johnson's grandfather couldn't find a job on the reservation. So he improvised.
TERROL DEW JOHNSON: He made doughnuts in the village and would sell them to people to make maybe one cents or two cents. People loved it, because it was something different.
VICKI MONKS: By the 1950s, the pressures to abandon traditional lifestyles intensified and the disruptions that began with the cotton fields and the war accelerated. As Arizona cities grew, so did demands for water. So the federal government stepped in with money to dam the rivers. That brought traditional farming to an end, and pushed Pimas into the cash economy, earning the lowest wages. Healthy eating can be expensive, and there was the pressure to fit in.
DANIEL LOPEZ: We could eat like you guys, you know -- eggs and ham and all that. The thing is mindset, you know. But we wanted to be like the dominant culture -- dress like them and talk like them, eat like them.
VICKI MONKS: Of course, Pimas value modern innovations as much as anyone else. The Internet's an important tool on the reservation, and without cars to travel vast expanses of desert, it could be nearly impossible today for the Tohono O'odham to hold jobs or carry on business. But changes over the past 60 years have been disastrous for Pima health. College professor Tony Chana recalls his own diagnosis with diabetes in 2002, when he was 63 years old.
TONY CHANA: My blood sugar was over 500. They put me on IV and said that I was critical. And when I was lying there, taking the IV, I thought about all the kinds of things that people who have diabetes seem to go through -- many of my friends who have diabetes where they've lost their toes, some of them who eventually died from failure of heart or something like that -- diabetes related, I'm sure. Now I see it in people younger than myself, and it's tragic, even kids who have diabetes.
VICKI MONKS: More than three-quarters of older Pima adults have diabetes, and this adult onset disease is now showing up in Pima children as young as 7. Obesity among children is the culprit.
JOHN HOCKENBERRY: When The DNA Files returns, measuring a metabolism. This is "Rewriting Heredity: Environment and the Genome." I'm John Hockenberry. We'll be back in a minute.
JOHN HOCKENBERRY: Welcome back. This is The DNA Files. I'm John Hockenberry. It was a promising hypothesis -- a tribe living where food was scarce might harbor a thrifty gene that promoted fat storage. One way such a gene might work is by lowering the rate of metabolism. Perhaps the Pima was fat, because they conserve more calories. Investigator Eric Ravussin's team began the painstaking work of measuring the metabolic rate of the Pimas, one individual at a time. And in Phoenix, they built a special sealed room called a metabolic chamber to do the measuring, a facility much like this one, back on the streets of Manhattan, at Columbia's New York Obesity Research Center.
DR. ALLAN GELIEBTER: A metabolic chamber is used to measure the amount of energy that an organism consumes by measuring the amount of oxygen consumed and carbon dioxide produced.
JOHN HOCKENBERRY: Dr. Allan Geliebter is a senior research scientist to Columbia University. In metabolism, you'll remember, the body consumes oxygen, and produces carbon dioxide. Got it? So a person in a sealed room gradually changes the composition of the air. You may have noticed this. The faster their metabolism, the faster the change. So as the air in the room is gradually refreshed, scientists can measure the gases in this outgoing air.
JOHN HOCKENBERRY: It looks like a regular hospital room, sort of, but uh we've got the vacuum door there.
JOHN HOCKENBERRY:There's a sink and other necessities for a 23 hour visit. Tasty meals arrive periodically through an airlock.
DR. ALLAN GELIEBTER: No, we'd rather people in here are not bored. We do have some nice videos.
JOHN HOCKENBERRY: The Abyss, Special Edition, Fargo.
DR. ALLAN GELIEBTER: It's one of my favorites, Fargo. There's a window they can look out.
JOHN HOCKENBERRY: And if you put up a little "Help Me" sign, you can just put it up to the window there.
JOHN HOCKENBERRY: In Phoenix, more than a thousand people spend up to a week in Eric Ravussin's metabolic chamber, but the researchers found no evidence that the Pima had a thrifty metabolism. Then the investigation took an unexpected turn with the discovery of another native population in a remote part of Mexico. They were also Pima, and they were thin. Vicki Monks picks up the tale.
VICKI MONKS: The village of Maycoba nestles beneath dramatic cliffs in Mexico's Sierra Madre Mountains. Traveling there can be risky. Livestock or fallen rocks often block the narrow highway. In the mid-90's, when scientists first came here, the road had just opened. Before that, if you wanted to get to Maycoba, you could drive down a steep gorge and through the river or take your chances on a rickety footbridge.
In a highland meadow near Maycoba, Pima elder Jose Angel Galaviz is constructing a wooden plow for planting corn. It's built on the same design used by his ancestors who inhabited this region for at least 500 years, when it's believed they drifted apart from their Pima cousins in Arizona. Wiry, thin, and muscular, like most of the Pimas here, Angel is fit by default. Survival for Maycoba Pimas depends upon constant work.
JOSE ANGEL GALAVIZ: (speaks Pima)
INTERPRETER: One person turns the ground with burros or with oxen, and the other goes to plant, and then the corn is born. When the cobs are there, then you start to pick -- to pick the corn. So from there, we can feed all of the indigenous companions for the whole rest of the year.
VICKI MONKS: Scientists working with the National Institutes of Health who had been studying the Arizona Pimas wondered if the Maycoba Pimas could help prove the thrifty gene theory. They reasoned that even though intense physical labor and a limited food supply kept the Maycoba group thin, the Pimas there might still be genetically susceptible to obesity. In 1995, the scientists hauled a trailer into the mountains to set up a makeshift research station. It's been shuttered now for several years, and locks were rusty when Julian Esparza and Leslie Schulz opened it again last spring, their first visit in more than a decade.
LESLIE SCHULZ: Yeah, it was pretty fancy at the time. [laughs] Now it doesn't look quite so fancy any more.
JULIAN ESPARZA: You see?
LESLIE SCHULZ: Yeah.
VICKI MONKS: Esparza and Schulz are both specialists in the nutritional aspects of diabetes and obesity. Collaborating with other scientists under a grant from NIH, the team ran the same battery of tests here in 1995 that they’d used earlier in Arizona. If the Maycoba Pimas had thrifty genes, the resting metabolic rate should be lower than that of non-Pimas. Eric Ravussin was part of the team.
ERIC RAVUSSIN: And in the same environment, there are people calling themselves "blancos" or "mestizos" who are not Pimas, and they are different genetically, but they live in the same environment. And we're hoping to find a difference between Pima in this environment versus non-Pimas.
VICKI MONKS: But as it turned out, there was no difference. The Maycoba Pimas didn't have thrifty metabolisms. The research team in Mexico now expanded the investigation to include environmental factor, such as diet and physical activity Leslie Schulz turned to doubly labeled water, a technique for measuring energy burned as people carry on their daily lives A research subject drinks a short glass of special water containing heavy isotopes of hydrogen and oxygen that can be tracked as they're gradually eliminated from the body.
LESLIE SCHULZ: It's perfectly safe. It sounds terrible when you say you're giving people this water that has isotopes in it, but they're both stable, and they're perfectly safe to consume.
VICKI MONKS: A few hours after someone drinks the water, researchers collect a urine sample, then wait one week, and collect another. By comparing the ratios of hydrogen to oxygen in the samples, they can calculate precisely how many calories that person burned during the week. The test is expensive, about $500 a glass, and the team found that follow-up in these mountains could be problematic.
LESLIE SCHULZ: It's very important that they are available for that seven day follow-up to give another urine sample. Some time life gets in the way. [laughs] And so if somebody has work to do out in the field, they don't have time to come into the clinic in order to give their urine sample. That's not their biggest priority in the day.
VICKI MONKS: More than once, the researchers climbed through the mountains to do their follow-ups. Esparza lived among the Maycoba Pimas for two years during the study. His rapport with the community set this study apart from other research involving Native Americans. It's a common complaint that scientists focus so much on the science, they ignore the people themselves.
JULIAN ESPARZA: I grew up in the kind of community like that, so that was like my home. So I think it was one of the key to have good relations with this community. If we have this good relations with the people, I think we have the best real information.
VICKI MONKS: The doubly labeled water study provided critical data on energy expenditure. Leslie Schulz said the Arizona Pimas burn just as many calories each day as those in Mexico.
LESLIE SCHULZ: The heavier a person is, the more energy it takes to do everything, because you're moving more mass through distance. When we look at the total energy expenditure, if you just look at the total levels, they're not that different, because the Arizona Pimas are considerably heavier. However, if you make that adjustment for their body weight, you find that the total energy expenditure in Mexico is much greater than it is in the Arizona Pimas, and it's definitely an indication of the lifestyle.
VICKI MONKS: So the intense physical activity in Mexico seems to protect Pimas there from developing obesity, and there's one other crucial difference.
CLIFTON BOGARDUS: The difference between people who weigh a lot and people who don't weigh a lot is the people who weigh a lot eat a lot.
VICKI MONKS: Clifton Bogardus is chief of the NIH clinical research branch in Phoenix. He believes that genetic signals are involved in the desire for food.
CLIFTON BOGARDUS: So it's not because they're slovenly, gluttonous individuals. They just have a genetic drive to eat more. The question is, "Why? Why do they eat more?" And I don't think we have a good answer for very many people. I mean, there's a few genetic mutations that cause overeating and obesity in humans, but they account for 5% of the overweight people in the world and no more than that.
VICKI MONKS: The researchers began looking at hormones that control appetite. The hormone leptin, for example, suppresses appetite in animal studies. So in theory, a person with high leptin levels would be satisfied with less food. A person with low leptin levels would eat more. If Pima Indians did have thrifty genes to help them put on fat quickly, they'd most likely have lower leptin concentrations than non-Pimas.
ERIC RAVUSSIN: Once again, we could not say that leptin was the problem.
VICKI MONKS: Eric Ravussin.
ERIC RAVUSSIN: We found that the leptin concentration in Pimas in Maycoba was totally normal compared to the non-Pimas. And, you know, this is frustrating, because we have been trying to find these signals, which confer so much susceptibility.
VICKI MONKS: In the 40 some odd years that they've been studying the Pima, scientists haven't found quite what they're looking for. Pimas don't have genetically slower metabolisms, and they don't have genetically lower hormone levels. Given the sum of these results, is it possible to identify any thrifty genes? Do thrifty genes even exist? Clifton Bogardus.
CLIFTON BOGARDUS: No and no. So it's a very nice theory, but I don't think anyone has found such a thing in a human as yet.
VICKI MONKS: So the thrifty gene was out, but the leptin studies uncovered something else. After adjusting their results for body weight, the researchers discovered that the Maycoba Pimas were actually producing more leptin than genetically similar Arizona Pimas. The finding was a revelation. Somehow something in the Maycoba environment appears to ratchet up leptin production or something in the Arizona environment ratchets it down. Whatever the case, the Maycoba Pima seem to be getting signals earlier to stop eating.
LESLIE SCHULZ: Then when can we learn from that, that's in their environment that's making that difference, that could then potentially cause people to be leaner?
VICKI MONKS: Corn is the staple in Maycoba, along with beans, squash, potatoes, greens, and peaches. The diet contains lots of fiber and healthy nutrients. The leptin studies point to the possibility that this diet or physical activity or both may be influencing gene expression in ways that aren't yet understood.
When we find Maria Luisa Lao Rodriguez, she's washing clothes at a mountain stream, rubbing them with a coarse soap, slapping them on a flat rock.
VICKI MONKS: Trabajo, mucho trabajo. It's a lot of work. Duro. Your work is hard.
MARIA LUISA LAO RODRIQUEZ: Pues, ni modo. Tengo que trabajar duro.Well, whatever, I have to work hard.
VICKI MONKS: Maria's neighbor, 75-year-old Egriselda Coronado Galviz, is hauling water from the spring up the hillside to her home. It's a twice daily chore.
EGRISELDA CORONADO GALAVIZ: Descánsate, pues,esta muy pesado It's really heavy. Let's take a rest.
VICKI MONKS: Whether it's the diet or the grueling work, something in Maycoba seems to play a role in preventing obesity and diabetes. Scientists don't know what it is or how it works, but they suspect that these environmental influences exert their most profound effects in the very earliest stages of life. Twenty years ago on the Pima reservations in Arizona, scientists observed that babies of diabetic mothers were far more likely than other children to become obese. In fact, other studies confirmed that these children are 10 times as likely to be overweight by the time they're 7 years old, and at much greater risk of developing diabetes later on. Eric Ravussin says it's not a matter of simple genetic inheritance.
ERIC RAVISSUN: It's been very well shown by the studies in Pima Indians that if you have diabetes during pregnancy, the impact on the fetus is to provide some excess susceptibility to diabetes, totally independent of your coding DNA
VICKI MONKS: The search to discover why this happens may just unlock some of the mysteries behind the escalating worldwide epidemics of diabetes and obesity.
JOHN HOCKENBERRY: What happened to the Arizona Pima? Obesity rates now exceed 70% among the Pima, and more than three-quarters of older Pima adults have diabetes, and the rest of us may be following in their footsteps. From the science section to the late night infomercials, the drumbeat is relentless. Americans are getting fat, fat, fat. Something is changing our relationship to food at a fundamental level, but the change is happening too fast to be in our genes. So what is it?
RANDY JIRTLE: It's not subtle. One is blond, and the other animal it’s brown.
JOHN HOCKENBERRY: In 2000, Duke University researcher Randy Jirtle performed a landmark experiment with a special little mouse called the Viable Yellow Agouti, abbreviated AVY or “Avy.” Avy mice have been inbred for generations until they are as alike genetically as clones or identical twins. [laughs] Yet some are brown and some are yellow.
RANDY JIRTLE: Now, why this is so very important is that these yellow mice, as they grow, they become obese, they get diabetes, and they get cancer.
JOHN HOCKENBERRY: But when Jirtle fed these yellow mice a special diet during pregnancy, their offspring grew up svelte, brown, and healthy, instead of obese, yellow, and diabetic. The change to brown, Jirtle showed, was caused by a chemical process called "methylation," in which a quartet of carbon and hydrogen atoms called a "methyl group" attaches itself to a spot on the mouse's DNA and blocks the gene for yellow coat color, the Agouti gene. The gene can turn on only in the right place at the right time, making a protein that adds a touch of yellow to the hair. But without that methyl group, the Agouti gene turns wildly overactive, and the mice turn really yellow.
RANDY JIRTLE: Animals that are yellow produce that Agouti protein continuously throughout the body. That's what gives rise to the yellow coat color, but it also is produced inappropriately in the brain, and it blocks a receptor in the brain that's involved with the mouse's ability to determine whether or not it's full. And as a consequence, these animals don't perceive that they're ever full, and they eat themselves into obesity. They're always hungry.
JOHN HOCKENBERRY: But a diet rich in methyl donors shuts down the overactive gene. Here's how it works. Methylation occurs throughout the genomes of multicellular organisms. Think of it as tiny methyl groups clinging to the DNA like charms on a charm bracelet. It's one of a family of so-called epigenetic mechanisms, most of them still poorly understood, that actually tell the genome when, where, and how to work. They're kind of like programs on a computer. They're an intrinsic part of the genetic machinery of the cell.
RANDY JIRTLE: Because you've got to remember, every cell in our body has exactly the same genetic information, but yet we have skin cells, liver cells, eye cells. So how does this happen? It's done through programming differences. There are genes that are turned on and other ones that are turned off, and as a consequence, that repertoire of expressed genes varies from cell to cell. That is done through epigenetic changes.
JOHN HOCKENBERRY: Jirtle had shown that an environmental factor, maternal diet, can reprogram this epigenetic machinery in Avy mice, and there may be a bigger revolution in store. Dr. David Martin is a senior research scientist at Children's Hospital in Oakland, California.
DR. DAVID MARTIN: We were working with what we call "transgenic mice," which are mice that have had exogenous pieces of DNA -- pieces of DNA that have been constructed in the lab, inserted into their genomes in a sort of random fashion.
JOHN HOCKENBERRY: Martin's transgenic mice produced unusual red blood cells. You could spot the difference in a microscope. But over several generations, the transgene that produced this effect stopped working in some of the mice, although they were genetically identical. When they mated these mice with mice from a different strain, the gene turned back on. It had been there, silent all along.
DR. DAVID MARTIN: What that study demonstrated was that a piece of the genome could undergo epigenetic silencing in the germ cells, and that that silencing could be stable for generations, but then be reversed.
JOHN HOCKENBERRY: So an epigenetic state, an acquired trait could be inherited. Scientists searching the genome for the keys to disease susceptibility are now recognizing the power of the environment to alter the epigenome. Some common diseases may have their roots in epigenetic changes caused by the environment in the womb. Randy Jirtle.
RANDY JIRTLE: Many of our chronic diseases -- for example, diabetes, cardiovascular disease, cancer, obesity, etc. develop not really in adulthood, but the susceptibility to getting these problems were established at the very earliest stages of development. But, see, nobody really knew what was the link, the memory that would allow something that occurred very early in development to result in these amazingly devastating chronic diseases in adulthood. What we showed is that link is epigenetic changes.
JOHN HOCKENBERRY: Researchers have now reported that diet, pollution, and even maternal nurturing can cause epigenetic changes in mice. But mice and humans may have very different epigenetic programs, says Randy Jirtle, and David Martin counsels caution.
DR. DAVID MARTIN: We do have evidence that epigenetic states can be passed on from one generation to the next, but that evidence is very sketchy, and I think it's very important when dealing with an issue like this to make sure that one does have the evidence.
JOHN HOCKENBERRY: Coming up next on The DNA Files, genes, the environment, and the frightening incidence of asthma. I'm John Hockenberry. We'll be back in a minute.
JOHN HOCKENBERRY: Welcome back. I'm John Hockenberry. A century ago, asthma was a rarity. Today, it's a scourge for 300 million people around the world, most of whom live in western countries, where asthma has become the most common chronic disease of childhood. The obvious suspect is our man-made environment, but asthma is a heritable disorder, involving dozens of genes, some connected to the lungs, some connected to the immune system, and that all vary from person to person. Scientists need a map of that underlying genetic variation to have any hope of pinning down the scope and action of the environmental causes of asthma In 1992, scientists began a massive study in about a dozen Southern California communities, examining the effects of air pollution and other environmental exposures on the respiratory health of children. But more recently, they have been trying to understand how genetic makeup and environmental factors interact, as producer John Kalish reports.
JOHN KALISH: Seth and Karena Hamilton live with their two kids in a middle class section of Long Beach, known as Belmont Heights. Mom, Dad, and their son all have asthma.
RICHARD HAMILTON: My name is Richard Hamilton.
JOHN KALISH: And how old are you?
RICHARD HAMILTON: Five.
JOHN KALISH: You got any animals in your house?
RICHARD HAMILTON: My doggie.
JOHN KALISH: Named?
RICHARD HAMILTON: Bell.
KARENA HAMILTON: Why can't we have a kitty?
RICHARD HAMILTON: Because we don't want a kitty.
SETH HAMILTON: Are you allergies to kitties?
RICHARD HAMILTON: Yes.
SETH HAMILTON: And do those make your asthma worse?
RICHARD HAMILTON: Yes.
JOHN KALISH: Asthma began at different times in the Hamilton family. Karena, the mom, has had it her whole life, as did her mother. Karena's sister and niece also suffer from asthma, and son, Ricky has had it most of his young life. Her husband, Seth, however, didn't develop asthma until the family moved to Long Beach.
SETH HAMILTON: The doctor said, "You've got it really bad, and it isn't going away, and you're going to be stuck with this now."
KARENA HAMILTON: For him, it was kind of annoying to be having to take these medicines.
SETH HAMILTON: Yeah.
KARENA HAMILTON: To me, it's just old hat. I've been taking them all my life, at least some form of them, and I've just said, "Welcome to the club, honey."
SETH HAMILTON: Yeah.
KARENA HAMILTON: Now you know what the kids and I feel like.
JOHN KALISH: With so many cases of asthma in their family, the Hamiltons are inclined to believe that heredity plays a role, but they also realize that air pollution in Southern California may have caused Seth's asthma, and may be making asthma worse for Karena and Ricky.
KARENA HAMILTON: I've often thought, "Should we be here?"
SETH HAMILTON: Is there somewhere better that we can live or are we just in L.A., and L.A.'s got polluted air, because there's too many cars and too much industry, and where would we go? I don't know.
DR. FRANK GILLILAND: There's been a number of studies trying to identify genes involved that might explain this inheritance in families.
JOHN KALISH: Dr. Frank Gilliland is a professor of preventive medicine at the University of Southern California.
DR. FRANK GILLILAND: But we know that you can't just focus on the genes. You have to think about the combinations of the genes and the environmental exposures together. If we just think of the environment and we just think of the genes, then we're not going to make very much progress.
JOHN KALISH: Gilliland and his colleagues at USC and UCLA are a part of the Southern California Environmental Health Sciences Center. Since 1992, Gilliland has been studying the respiratory health of thousands of Southern California school children. This children's health study has focused on how air pollution affects kids. Not only does Southern California have some of the most polluted air in the nation, but the City of Long Beach has some of the worst pollution in the region. Scientists and public officials say the asthma rate in Long Beach is double that of the rest of California.
The source of most of the pollution is the Port of Long Beach, the second largest port in America. Art Wong with the Long Beach Harbor Department stands on a pier, watching a 15 story high crane pluck containers from a giant ship, and place them on the beds of waiting tractor trucks.
ART WONG: Each year, about 100 billion dollars worth of products are shipped through here, and that's clothing, toys, furniture, TVs, everything you can think of in a shopping mall or a Home Depot has probably come through here.
JOHN KALISH: Fueled by increasing global trade, the volume of ship traffic here is expected to triple in the next 15 to 20 years. For the people who live in this busy port city, that will mean a lot more exhaust in the air from the ships. Many of these giant vessels burn bunker fuel -- a low grade form of diesel. Just one of these ships emits the same amount of air pollution as 12,000 cars. Diesel burning trucks and freight trains then haul the containers on to local freeways or nearby rail yards, passing through residential areas of Long Beach.
The Hudson School on the west side of Long Beach serves grades K through 8. It's on a suburban street lined with beautiful violet Jacaranda trees, but the rear of the school faces the terminal freeway, where some 3,000 trucks a day, most heading to or from the local piers, drive by spewing diesel exhaust. Researchers say data indicates that truck exhaust pushes the asthma rate up in Long Beach.
In early 2007, local parents used air monitoring equipment, provided by the Southern California Environmental Heath Sciences Center and found high levels of particulate matter, both inside and outside the school. Particulates are tiny, solid, or liquid particles of diesel exhaust that can get stuck in the lungs, triggering asthma attacks. Suzanne Arnold is a nurse at the Hudson School.
SUZANNE ARNOLD: Trucks are literally 20 feet from the chain link fence at the back of the playground where the children are playing. There have been a number of occasions when I've had to go out to the field with my wheelchair, and bring a child back to the office, or take an inhaler to them, and wheel them back into the office. That usually happens when the weather is warmer, and when they've been running. That's usually when I have that kind of a problem.
JOHN KALISH: Nurse Arnold says that protecting the health of kids in her school made it necessary for her to speak out against a proposed rail facility across the freeway from the school. That rail yard would bring even more trucks and trains into the area. But there's no simple relationship between asthma and air pollution. Even at the Hudson School, not every child will develop asthma. Yes, pollutants can bring on an asthma attack, but so can emotional stress, mold, and cold air. Professor Gilliland and USC biostatistican Jim Gauderman have been studying a number of genes and genetic variations that are thought to make people either susceptible or resistant to pollutants. For example, one gene called GSTM1 helps the body rid itself of toxins that enter through the lungs. Jim Gauderman.
JIM GAUDERMAN: GSTM1 is what I think of as a garbage truck gene. It goes around and tries to clean up the garbage, meaning things like external environmental toxins, and people that have the null genotype don't have that garbage truck to go around and pick up those kinds of toxins.
JOHN KALISH: 40 to 50% of the people in the world are this null genotype, meaning they don't have a working GSTM1 gene. A study led by Dr. Frank Gilliland found that kids who don't have the GSTM1 gene are at greatest risk for developing asthma, if they're exposed to certain environmental toxins, even in the womb.
DR. FRANK GILLILAND: If you're missing this gene, then if you're exposed to, say, an allergen you're allergic to and an environmental exposure like diesel exhaust, your responses are 20 fold higher than if you had this gene. We don't really understand all the different mechanistic basis for why this gene is so important, and we're frankly surprised by it, but there's lots of work being done on trying to understand that better.
JOHN KALISH: That work is complicated by the fact that GSTM1 is just one of roughly 20 known genes that seem to work together and have strong ties to asthma in multiple populations. Many more genes, perhaps 30 to 50, seem to chime in for different people at different times.
DONATA VERCELLI: Is there anything such as an asthma gene? The gene that is going to explain asthma? The answer is no, I think. That leaves us with a constellation of genes.
JOHN KALISH: Donata Vercelli is assistant director of the Arizona Respiratory Center at the University of Arizona. Not only is asthma genetically complex, says Vercelli, it clearly shows evidence of the epigenetic effects -- genes that work differently based on the environment.
DONATA VERCELLI: What we see is that a certain gene can be associated with less asthma in a certain environment, with more asthma in another environment, and with no effect in yet another environment I think that it is only epigenetics that make it possible for the same gene to do the opposite thing.
JOHN KALISH: It is exactly this astonishing ability of the environment to change the way our DNA works, says Vercelli, that makes it essential to identify the responsible environmental factors.
DONATA VERCELLI: Because we can't change the genes, but we can act on the environment.
JOHN KALISH: Dr. Gilliland says genetic and environmental science will have an important role to play in the development of public policies to curb the kind of air pollution that affects kids at the Hudson School.
DR. FRANK GILLILAND: Right now, there really are no regulations that are directed towards being exposed to proximity to busy roadways or freeways. You can imagine -- it's a whole other level of regulatory approach that would be needed in terms of long term land use planning and school site-ing and other things that need to be considered to be able to address this potential threat to children and asthma in particular.
JOHN KALISH: In the meantime, work continues at the Southern California Environmental Health Sciences Center to develop a better understanding of how the genetic and environmental underpinnings of asthma work. Using genetic samples from thousands of Southern California school children, Gilliland and Gauderman hope to identify what they suspect are tens or maybe even hundreds of genetic variations that play a role in asthma. For The DNA Files, I'm John Kalish.
JOHN HOCKENBERRY: Once upon a time, scientists racing to sequence the human genome believed they would soon have the map to disease susceptibility. [laughs] Now we know that a complex regulatory system of epigenetic mechanisms, the egigenome, can alter and even reverse gene function in different environments. Scientists suddenly find themselves, like eager cave explorers, back facing a baffling network of dark passages, uncertain of which way to proceed.
But the Pima Indians don't have the luxury to wait around. For health reasons, they need to act. And while the epigenetics of complex diseases like asthma and obesity remain obscure, some of the environmental components are coming into clearer view. As Vicki Monks tells us, this is the challenge for the Pima. What to do right now?
VICKI MONKS: In the cool of a light spring desert evening, Rose Martin and Terrol Dew Johnson are picking buds from the cholla cactus. The buds are unopened cactus flowers, one of the desert plants that Pima Indians relied on for centuries. Scientists now understand that cholla buds and other desert foods actually slow down the release of sugars into the bloodstream. They're the perfect foods for preventing diabetes.
Karen Blaine is sauteing cholla buds with olive oil, onions, and garlic, a cooking demonstration.
KAREN BLAINE: We use it in salads. A really great thing about cholla is that it's very high in calcium. One tablespoon is equal to an eight ounce glass of milk.
VICKI MONKS: It's one of the strategies TOCA -- Tohono O'odman Community Action -- is using to promote dietary changes. Cooking lessons will only go so far though, if the foods aren't available. So, TOCA's taking on that mission, too. TOCA's co-director, Tristan Reader, is checking the old irrigation pumps watering farmland on a remote stretch of the reservation where TOCA's growing traditional crops -- corn, squash, watermelon, and tepary beans.
TRISTAN READER: If you tell someone, "You need to eat these foods," but they can't go to the grocery store and buy them. They no longer farm, they're not available anywhere, then all the choices in the world make no sense.
VICKI MONKS: So TOCA's raising traditional food crops on a commercial scale. The effort could go a long way in improving health here, but projects like this don't get much government support. Pima Indians in Arizona have cooperated with government scientists for decades, and all the while diabetes and obesity rates were escalating. Reader believes that the Pimas would be better off if just a fraction of the millions spent on genetic research could have gone to helping people lead healthier lives.
TRISTAN READER: There's a real sense that research has made Native peoples the subjects of the research, but never the beneficiaries, that they've never really been partners. It says, "There's something wrong with you fundamentally, genetically, and it's hopeless, unless the scientists find an answer." What we're saying is, "No, you do have the capacity to choose what you eat, to engage in traditional games and traditional dancing and other forms of physical fitness. You do have that power within yourself, within your family, within your village, within your community to really make changes.
ERIC RAVUSSIN: I think that if I was Pima, I would be very disappointed, too.
VICKI MONKS: Eric Ravussin.
ERIC RAVUSSIN: Because these people have provided help to the scientific community for almost 40 years now, and they have more obesity, they have more Type 2 diabetes. But the thing that we don't know, without these studies, without the careful checking of the population, it would be even worse.
VICKI MONKS: Pima Indians are faced with trying to reverse the effects from 75 years of escalating health problems, brought on by abrupt drastic changes in lifestyle. They can't roll back history and return to completely traditional ways. They live in the modern world. Going back to a subsistence lifestyle plowing with mules isn't the answer. But reestablishing healthy food choices and other traditions could help. From what we know now about epigenetics, intervention is most crucial during key points of development, such as during pregnancy as the fetus develops. And that's the part of this epigenetic research that holds promise for the Pimas. Knowing this much, it's possible to do something, even before all of the science is fully understood. From the Tohono O'odham reservation, I'm Vicki Monks.
JOHN HOCKENBERRY: So we return to the question with which we began. Why do some people get sick while others remain healthy in the same environment? Could it be that large parts of our modern lives -- the food we eat, the air we breathe, the uncounted details of life in our all enveloping manmade world have become an accidental epigenetic experiment. Are we rewriting heredity by inadvertently tinkering with the software that controls our genes or our children's genes? As scientists grope their way towards a new paradigm of gene /environment interaction, we must all take another look at how we choose to live, for what we eat, drink, breathe, how we work and play may exact a personal toll, not only on us, but on our children and their children to come. I'm John Hockenberry. Thanks for listening to The DNA Files.
To find out more about genes and environment, visit our website at dnafiles.org where you can download a podcast of this program. This series, The DNA Files, was produced by SoundVision Productions with funding by the National Science Foundation, U.S. Department of Energy, National Institutes of Health, and the Alfred P. Sloan Foundation. This program, "Rewriting Heredity: Environment and the Genome" was produced by John Rieger, Jon Kalish, and Vicki Monks. The DNA Files is managing editor, Loretta Williams, editor, Deborah George, science content editor, Sally Lehrman. Research director is Adi Gevins. Production support by Noah Miller, Julie Caine, and Liza Graffeo. Office support provided by Steve Nuñez and Beverly Fitzgerald. Our web director is Ginna Allison. Technical engineer and music director is Robin Wise. Our host is John Hockenberry. Our theme music was composed and performed by Steve White. Additional music by Steve White, Conrad Praetzel and Robert Powell. Marketing of The DNA Files is by Schardt Media. Legal services by Cooper, White and Cooper and Spencer Weisbroth. Special thanks to Murray Street Productions. Send your responses and letters to firstname.lastname@example.org. For CDs and transcripts, call 888-303-0022. That's 888-303-0022. The executive producer is Bari Scott. This has been a SoundVision production, distributed by NPR, National Public Radio.