endeavors Winter 2008
Research and Creative Activity • The University of North Carolina at Chapel Hill
A Nobel for Oliver page 10
Dan Sears
Oliver Smithies at the bench.
One evening last year, Oliver Smithies
stood in front of a crowd of retirees, students, and various other admirers who had gathered to hear him speak. He did not boot up a PowerPoint presentation. He did not lecture. He did not attempt to wow us with his wizardry. Instead he told us a story. Occasionally, to illustrate a point, he stepped to the whiteboard and scratched out a diagram with colored markers, but he is so color-blind that the colors were meaningless to him. He had brought along a stack of his laboratory notebooks—worn, rumpled journals packed full of his script. Modestly, he led us back in time, confessed his wrong turns and misguided assumptions, and then he read aloud the record of each moment when a mountain of hard work cracked open and revealed to him the jewel of an idea. These were the ideas that would eventually earn him a Nobel Prize. But on that evening last year, they were nuggets of spine-tingling drama in a rich and fascinating tale. And even though he was speaking about
some of the most sophisticated problems in genetics, his audience understood every word. He charmed us, he enlightened us, and no one who heard him that evening will ever forget his story or the joy he had found in his work. When Mark Derewicz was writing the cover story for this issue, he contacted some of the former students and postdoctoral fellows who had worked in Smithies’ lab and asked them what they’d learned there. Josh Knowles, now a fellow at Stanford, sent Mark a list of lessons from his mentor. They included: 1. Find something you love to do enough that you are willing to sacrifice perfectly good Saturdays for it once in a while. 2. When giving a talk or writing a paper, tell a story. 3. When telling a story, work as hard as possible to explain complicated things in a simple way. Noted, Dr. Smithies. —The Editor
endeavors Winter 2008 • Volume XXIV, Number 2 Endeavors engages its readers in the intellectual life of the University of North Carolina at Chapel Hill by conveying the excitement of creativity, discovery, and the rigors and risks of the quest for new knowledge. Endeavors (ISSN 1933-4338) is published three times a year by the Office of the Vice Chancellor for Research and Economic Development at the University of North Carolina at Chapel Hill.
Send comments, requests for permission to reprint material, and requests for extra copies to: Endeavors Office of Information and Communications CB 4106, 307 Bynum Hall University of North Carolina at Chapel Hill Chapel Hill, NC 27599-4106 phone: (919) 962-6136 e-mail: endeavors@unc.edu
James Moeser, Chancellor Bernadette Gray-Little, Provost and Executive Vice Chancellor Tony Waldrop, Vice Chancellor, Research and Economic Development
contents winter 2008
2 overview
A mysterious allergy afflicts the South, blocking HIV in the womb, bingeing for two, mites among the machines, and sex and the spadefoot toad.
cover story 10 A Life at the Bench
In the 1930s, Oliver Smithies was tinkering with telescopes and radio-controlled boats. Last October, the Nobel committee called. by Mark Derewicz
features 16 The Mouse Mess
Have we bred some of the medical value out of lab mice? by Sarah Whitmarsh
18 The Bug Zappers
26 Why Be Happy?
How positive emotions do us good. by Mary Russell Roberson
30 The Tangled Roots of OCD
Can science sort out obsessive-compulsive disorder? by Prashant Nair
33 Where the Trail Has Led
Carolina’s stories of American Indians. by Mark Derewicz
38 In Hot Water
Coral reefs lose their cool. by Mark Derewicz
40 The Magic Man
Busting bacteria’s resistance to drugs. by Danielle Jacobs
Daniel Wallace became a big-time novelist one sentence at a time. by Mark Derewicz
20 Tiny Steps on a Tightrope
43 The Reasons for Rebellion
22 Meet the Bucket Brigade
47 in print
24 Guatemala City’s Dirtiest Secret
49 endview
Mapping the structure of an ancient protein. by Prashant Nair
The J-school rescues a paper in peril. by Kelly Chi
A volunteer steers scavengers’ kids out of the dump. by Margarite Nathe
The real causes of unrest in Iran. by Mark Derewicz
Transcendental optimism, auction fever, and the change to strange.
A circle of friends.
Editor: Neil Caudle, Associate Vice Chancellor, Research and Economic Development Associate Editor: Jason Smith Writers: Neil Caudle, Kelly Chi, Danielle Del Sol, Mark Derewicz, Danielle Jacobs, Prashant Nair, Margarite Nathe, Sheila Read, and Sarah Whitmarsh
On the cover: Oliver Smithies in his early twenties, sitting on a motorcycle that he continually tinkered with. At the time of this photo, he was a university student at Oxford. Photo courtesy of Oliver Smithies.
Design: Neil Caudle and Jason Smith Print production, online design: Jason Smith
http://research.unc.edu/endeavors/
©2008 by the University of North Carolina at Chapel Hill in the United States. All rights reserved. No part of this publication may be reproduced without the consent of the University of North Carolina at Chapel Hill. Use of trade names implies no endorsement by UNC-Chapel Hill.
overview
“It was obvious there was something strange going on that had nothing to do with the way we were doing things,” O’Neil says. O’Neil’s team created guidelines for dealing with potential reactions. Rule number one was that an advanced care practitioner always had to be present when an Erbitux infusion began, so the team could immediately administer epinephrine and steroids if the patient had an allergic reaction. The story got stranger as O’Neil talked to more oncologists. He heard that a colleague in Nashville, Tennessee, was finding the same problem. But when O’Neil spoke to oncologists from other areas of the country, they didn’t know what he was talking about. A prominent colorectal oncologist in New York “thought we were lying or crazy,” O’Neil recalls.
WHEN BERT O’NEIL began giving Erbitux to
colon-cancer patients in clinical trials, he had no reason to be wary. After all, the drug had already been tested and was FDA-approved for use in colon cancer. But at Carolina’s Lineberger Comprehensive Cancer Center, the first three patients who received the drug had potentially life-threatening allergic reactions. They collapsed to the floor, O’Neil says. “They had lost their blood pressure; they had become hypotensive.” He didn’t realize it at the time, but these patients’ reactions were O’Neil’s first clue to a baffling regional pattern of hypersensitivity to Erbitux. The medical team quickly gave the patients epinephrine and high doses of steroids to help their blood pressure return to normal. The patients had to stay in the hospital’s intensive care unit for a day, just in case they had another reaction. What had happened to the patients was an anaphylactic reaction, similar to what happens when a bee stings someone who’s allergic to bee venom. Anaphylaxis, which is sometimes fatal, is a type of allergic reaction. Symptoms may include itching, hives, swelling throat, shortness of breath, or a drop in blood pressure. O’Neil, a medical oncologist who runs clinical trials for the gastrointestinal cancers group at Lineberger, was surprised. In large studies both in the United States and in Europe, the rate of serious allergic reactions to Erbitux was quoted at two to three percent, he says. At first, O’Neil and his team thought they had gotten a bad batch of Erbitux. But when Bristol-Myers Squibb sent staff to investigate, they found that the doses had come from different batches. “At that point,” O’Neil says, “we decided to carefully move forward and hope it was just a fluke that we had these three patients in a row.” For a while, the team didn’t see any more anaphylactic reactions in patients. Then the reactions began again. 2 endeavors
E
rbitux, also known by its generic name cetuximab, is used in conjunction with chemotherapy and is useful in shrinking tumors, O’Neil says. Erbitux is a genetically engineered version of an antibody that combines mouse and human components. The Erbitux antibody works by sticking to the outside of a molecule called the epidermal growth factor receptor, and blocking it from functioning. This causes some cancer cells to die because the growth factor receptor can no longer transmit signals from outside the cancer cell telling the cell to grow. Eventually O’Neil and his colleagues decided to pursue a study to confirm his suspicion: that patients in North Carolina and Tennessee were experiencing abnormal hypersensitivity to Erbitux. Carolina researchers pooled data from patients treated here with Erbitux with data from patients in clinical trials at Vanderbilt’s Ingram Comprehensive Cancer Center and the Sarah Cannon Cancer Research Institute, both in Tennessee. The findings showed an “alarming frequency” of hypersensitivity to Erbitux at the three sites, according to a study published in the September 2007 issue of the Journal of Clinical Oncology. Of the 88 patients treated as part of trials in North Carolina and Tennessee, 22 percent experienced a serious hypersensitive reaction. In a
European clinical trial, only 1.2 percent of 329 patients experienced a serious hypersensitive reaction to Erbitux. The mystery remains as to why patients are more prone to allergic reactions to Erbitux in the middle South. (O’Neil says he’s heard of hypersensitive reactions to Erbitux in Arkansas.) Among the speculations are that the reaction is caused by an antibody that people in the region have developed after exposure to a certain kind of mouse, plant, or tree pollen. “The idea is that, by coincidence, they’re allergic to something, and the antibody that’s created as part of that allergic reaction happens to also stick to Erbitux,” O’Neil says. “Antibodies are very specific in what they stick to, so that’s a fairly unusual kind of problem.” The study also showed that a history of allergies can partially predict whether a person might have a reaction to Erbitux. “The chance of having an allergic reaction was about three times as high in the people who already had some other kind of allergies,” O’Neil says. Although the allergic reactions can usually be countered with drugs, they can still be fatal. One patient died of a reaction at Sarah Cannon Cancer Research Institute. Later, Sarah Cannon discontinued all clinical trials of Erbitux.
L
ineberger, though, is pressing forward with studies of Erbitux. Carolina had committed to clinical trials of the drug to determine if it’s effective in treating other types of cancer, including breast cancer and lung cancer. Despite the high incidence of serious reactions to Erbitux in the region, O’Neil believes the drug has a place in cancer treatment. “We’re treating people here who have terminal colon cancer, and most of them have no other treatment option,” he says. “That’s the thing you have to weigh. Yes, there’s that risk, but on the other hand, most of these patients getting this drug are in a bad situation.” Meanwhile, researchers have moved one step closer to solving the mystery. Thomas Platts-Mills, an allergist at the University of Virginia, collected serum samples from healthy volunteers in Tennessee and found the antibody that appears to cause the reaction to Erbitux, O’Neil says. Platts-Mills
Jason Smith
discovered that the antibody was almost always present in people who reacted to Erbitux and was not present in those who did not react to the drug. Next, researchers will attempt to develop a clinical test to screen for people who have the antibody. Scientists at Carolina plan to collaborate with Platts-Mills and colleagues in Tennessee to determine whether such testing is accurate enough to be used in the clinic. Such a test could eventually be used in the middle South to guide treatment decisions, O’Neil says. Still, the main puzzle remains—just what is the allergen to which people are developing antibodies? —Sheila Read Sheila Read is a master’s student in medical journalism at Carolina.
An HIV-positive mother with her children in Lesotho, southern Africa. Photo: Kim Haughton/Alamy
Can a mutant gene save children from AIDS? More than half a million children worldwide are infected with HIV every year. Most live in sub-Saharan Africa and get the virus from their mothers while still in the uterus, during delivery, or through breastfeeding. But less than a third of infected mothers pass on the virus to their babies. Steven Meshnick and his team of researchers at Carolina’s School of Public Health uncovered a genetic mutation that might protect babies from picking up the virus from their mothers before or during birth. 4 endeavors
The team studied a group of 552 HIVpositive Malawian women and their infants and found that differences in the gene for a human protein that binds HIV accounted for the difference in mother-to-child transmission of HIV. The protein CCR5 sits on the surface of immune cells and latches onto chemical messengers that help the body fight infection. HIV subverts CCR5, among other proteins, by latching onto it and gaining entry into human cells. Meshnick’s team found differences in the CCR5 gene in babies that were infected and in those that were not. A single nucleotidebase change in CCR5 made the uninfected babies’ white blood cells resistant to infection by HIV. The mutation probably decreased the amount of CCR5 on the surface of the white blood cells. But these babies were only protected if the amount of virus in the
mother was below a certain threshold. Above it, the babies were infected regardless of the CCR5 mutation. “Mother-to-child transmission is a big problem in Africa, but not here,” Meshnick says. During the middle of pregnancy, infected mothers in the United States get antiretroviral drugs that prevent further infection and curb disease progression. They also get cesarean sections, which greatly reduce the chances of infection for the baby, Meshnick says. But fewer than 10 percent of eligible women have access to antiretroviral drugs in sub-Saharan Africa. The findings suggest that drugs that block or reduce the amount of CCR5 on white blood cells without harming the mother could protect against HIV in high-risk populations. But the study is only meant to serve as a jumping-off point for a more exhaustive analysis of other genes that could be involved. “We’ve only scratched the surface with CCR5,” Meshnick says. “We’re now planning a genome-wide hunt for genes that may be protective.” Understanding the genetic basis of mother-to-child transmission is crucial to uncovering exactly how HIV gets transmitted, he says. “This could help us develop drugs and possibly a vaccine to prevent AIDS.” Joseph Eron, a scientist at Carolina’s Center for Infectious Diseases, says the study clearly demonstrates that the human genetic makeup influences the likelihood of passing on HIV from mother to child. “These results raise the possibility that newly developed HIV medications that inhibit HIV replication by blocking the CCR5 receptor might be useful in interrupting mother-to-child transmission of HIV,” Eron says. In August 2007, the FDA approved Maraviroc, the first CCR5 inhibitor drug that can be taken orally. Though Maraviroc didn’t cause serious side effects in clinical trials, the drug hasn’t been studied long enough to rule out less common side effects. —Prashant Nair Prashant Nair is a master’s student in medical journalism at Carolina. Steven Meshnick is a professor of epidemiology in the School of Public Health. His study appeared in the September 5, 2007 issue of the journal PLoS One. The study’s lead author was Bonnie Pedersen, also of the School of Public Health. The study was funded by the National Institutes of Health and Carolina’s Center for AIDS Research.
W
hen you’re pregnant, simple cravings and extra snacks are par for the course, Cynthia Bulik says. It’s when your eating gets out of control that you need to worry. In a study of 41,000 pregnant women, Bulik and her colleagues at Carolina and the Norwegian Institute of Public Health found that many women who had never had an eating disorder developed one—in this case, binge eating disorder—after they became pregnant. Doctors already knew that women who’ve been living with an eating disorder sometimes find that it goes into remission during their pregnancy. But Bulik and her colleagues found that women who already had binge eating disorder were more likely to continue bingeing than they were to go into remission. The main difference between binge eating disorder and plain old overeating, Bulik says, is that people with the disorder tend to lose control, quickly consuming huge portions on a regular basis, even when they’re not hungry. They eat until they’re past the point of being full and, unlike people with bulimia nervosa, binge eaters don’t purge what they’ve eaten. Health care professionals should be on the lookout for unhealthy changes in eating habits in pregnant women, Bulik says, especially those women with lower levels of education and income. “It’s possible,” she says, “that pregnancy is even more stressful for women with poorer social support and resources.” —Margarite Nathe Cynthia Bulik is a professor of eating disorders in the School of Medicine and in the department of nutrition in the School of Public Health. Other UNC authors of the study, which was published in the August 2007 issue of Psychological Medicine, include biostatistician Ann Von Holle, professor of psychiatry Robert Hamer, associate professor of nutrition and epidemiology Anna Maria Siega-Riz, and professor of psychiatry and genetics Patrick F. Sullivan.
Bingeing with baby For some women, pregnancy triggers out-of-control overeating. Steve Exum
endeavors 5
MITES among the MACHINES Day and night, children toiled in North Carolina textile mills. IF YOUR FAMILY HAS BEEN AROUND North Carolina’s Piedmont for a century or so, chances are some of them earned their living in a textile mill. And they may have started pretty young. Twelve-year-old kids (and many even younger) were on the payroll at textile mills all over North Carolina. If an eight-year-old girl claimed in a job interview to be fourteen, she was ready to start earning fifty cents a day—as long as her parents stood nodding behind her. In the early 1900s, the National Child Labor Committee set out to show the government that the United States needed stricter child labor laws, and that employers all over the country were ignoring the laws already in place. That’s when they hired a photographer named Lewis Hine. Hine’s most famous shots are of construction workers 6 endeavors
swinging out over the New York City skyline on beams and ropes, piecing together the city’s skyscrapers. But in 1908, Hine was making his way from Maine to Texas, taking photos of children who worked as coal miners, shrimp sorters, oyster shuckers, cigar rollers, newsies, and factory workers. In 2007, historian Robert Allen was scrolling through images at the Library of Congress. It was an accident, really, when he happened on the Hine photographs. But when he did, he saw hundreds of North Carolina children toiling away during all hours of the day and night. Hine had stopped and set up his camera at mills all across the state, including the Loray Mill in Gastonia, where Allen’s own grandparents lived and worked. In the 1900 census, Allen found the occupation of his grandmother listed as “a spinner in a cotton mill”; she was eleven years old. (continued on page 8)
One hundred years ago, Lewis Hine toted his camera across the country. He found the worst conditions and most serious violations of child labor laws in the North Carolina textile mills. Facing page: Twelve-year-old Giles Newsom had been working three months in the Southern Cotton Mill in Bessemer City when he fell into the open gears of a spinning machine. It tore out two of his fingers. His aunt said, “He’s jest got to where he could…help his ma, an’ then this happens and he can’t never work no more like he oughter.” Above: Hine took this photo in Hickory and labeled it: “Some doffers and sweepers, plenty of them.” Below left: Women and girls were cheaper to employ than adult men. This little girl was a spinner in Gastonia. Below right: A young doffer in Lincolnton. Hine suspected many children lied about their age. “Many boys and girls much younger,” Hine wrote. “Boss carefully avoided them, and when I tried to get a photo which would include a mite of a boy working at a machine, he was quickly swept out of range.” Photos courtesy of the Library of Congress.
endeavors 7
The textile industry needed those child workers, Allen says, and their families needed the income. Wealthy mill owners decided where to build their factories based on where they could find cheap land and a reliable source of water power. The owners often set up shop in unpopulated places, building up the machines before they had anyone to work them. Then they sent messengers into the mountains and the countryside to lure workers with promises of paid work. Times were lean for North Carolina farmers, and hundreds of hungry families were carted to the factories. But to be allowed to rent a home in the mill town, each household had to provide a certain number of workers. There was a shortage of adult white male workers; North Carolina’s rural population was already sparse, and the population was still lopsided from all the deaths during the Civil War. Mill owners wouldn’t hire black workers to work alongside white workers, Allen says. That’s how women and children ended up on the payroll— they were cheaper to employ, and their low wages helped keep rates low for white male employees as well. At the time, a seventh-grade education was thought to be plenty for many kids in North Carolina, and those who finished or dropped out of school were expected to
earn their keep. Some mill jobs, Allen says, were better suited to tiny, nimble fingers. Adults couldn’t work as fast or as easily with whirring spools and tightly bunched spinning gears, and so doffing and spinning were left to the young. Accidents were common. During a class Allen teaches on the history of the family, he pulled up the 1910 census enumeration which included his grandfather. Allen realized then that his grandfather had lived only a few doors down from some of Hine’s subjects. That’s when the grim history of Southern mill culture slowly entered his work. He planned to hunt for the descendents of Hine’s subjects using online genealogical research sites such as ancestry.com and Heritage Quest, only in reverse—past-topresent, he says, rather than present-topast. But his project took on unexpected speed when a story about his work came out in the Charlotte Observer. That’s when those children’s descendents began to contact him.
A
llen immediately heard from several different families, he says, none of whom had ever seen the Hine photographs of their kin. Most of the people who contacted him still lived in North Carolina, but some families had since migrated as far as California. Library of Congress
When Alan Hogan, 54, of Richmond County, N.C. saw the photos in the Charlotte Observer, he told the newspaper, “My reaction was, ‘Dear God, that’s my grandfather a hundred years ago.’” Nita Bell Groves, 87, still lives in Gastonia where Hine photographed her father, Eugene Bell. “I’d never seen a childhood picture of my father,” she said. North Carolina novelist Flora Ann Scearce saw the newspaper piece as well. Her mother worked in the Rosemary Mill in Roanoke Rapids at the age of twelve, and passed on to Flora Ann her diaries, letters, photographs, and a rare time-book kept by the mill overseer. Time-books held records of all the workers’ hours, wages, and deductions for rent, and overseers guarded them carefully to keep secret how much—or how little—they paid their workers. In October 2007, Scearce donated the time-book to Carolina’s Southern Historical Collection. The rush of public interest spurred Allen’s work. He set up a web site for the descendents to connect with one another, and he hopes to hear from even more families in the coming year. “The people who were a part of that history are dying out,” Allen says. The memory of North Carolina’s old mill culture is evaporating. The Loray Mill still stands in Gastonia, although it’s just been sold. Soon, he says, it will house condominiums. —Margarite Nathe Robert Allen is James Logan Godfrey Professor of American Studies, History, and Communication Studies in the College of Arts and Sciences. He’s working with the Gaston Public Library and the Gaston County Museum of Art and History to arrange a centennial commemoration of Hine’s photographs in Gaston County in November 2008. Lewis Hine’s photos are in the National Child Labor Committee Collections online at http://lcweb2.loc.gov/pp/nclcquery.html. If you think one of the subjects may be related to you, contact Allen at 919-962-5165, or email robert_allen@unc.edu. For more on child labor in the North Carolina textile industry, read Like a Family: The Making of a Southern Cotton Mill World by Jacqueline Hall and Jim Leloudis.
“Been at it right smart two years,” is what this boy said when Hine asked about his job in the Loray Mill in Gastonia. The mill village is behind him.
8 endeavors
Viva la difference! Puddles, procreation, and the not-so-picky spadefoot toad
M
ating outside the species? For animals large and small, that’s generally a big no-no. But UNC researcher Karin Pfennig has discovered that some spadefoot toads will jump the species barrier—if their offspring can benefit. Pfennig observed that female spadefoot toads, S. bombifrons, will mate with S. multiplicata—a different but closely related species—if it seems to ensure better survival for their offspring. The hybridization doesn’t create any sort of super-toad. But it does allow the trait of fast development that is present in S. multiplicata to transfer to S. bombifrons’ offspring. And in an environment where the ponds or puddles where toads lay their eggs can quickly dry up, that can mean the difference between life and death. Cross-species breeding helps S. bombifrons females ensure their offspring will develop out of the tadpole stage in time to survive. This doesn’t mean that the female spadefoot toads always hybridize; only certain conditions encourage this behavior. Hybrid males are potentially sterile, and hybrid females produce fewer eggs than pure species spadefoots. If a pond lasts long enough, females mate with their own species rather than risk producing infertile offspring. But if a pond is drying so fast that pure S. bombifrons tadpoles can’t escape it, S. bombifrons females do better to hybridize.
So while hybridization only happens in certain circumstances, Pfennig says, “it can dramatically affect the outcome of sexual selection and, ultimately, speciation.”
—Danielle Del Sol
Danielle Del Sol is an Information and Communications Specialist in UNC’s Institute for the Environment. Karin Pfennig performed her research at UNC and in Arizona over the course of seven years. She is an assistant professor in the Department of Biology, the Institute for the Environment, and the Curriculum in Ecology. Her findings were published in the November 9, 2007 issue of the journal Science. Photos by David Pfennig
endeavors 9
Dan Sears
a Life at the
Bench Early in the morning on October 8, Oliver Smithies got the call. Carolina’s first Nobel Prize winner had spent half a century doing the science he loves. By Mark Derewicz In 1936, when Oliver Smithies was eleven years old, his uncle lent him a telescope with a broken lens. Oliver wanted to fix it, so he read stacks of Scientific American magazines at the local library. “I remember getting quite a long way with making an eight-inch lens,” Smithies says. “But at one stage I had to heat it up and unfortunately I didn’t understand something properly and it cracked.” 10 endeavors
Days of work down the drain. But Smithies shook it off and tried to make a smaller lens with the remnants of the first. He sprinkled grinding powder on a thick slab of mirrored glass and used a metal soup can attached to a drill press to cut the glass down to size. He wasn’t sure the edge of the soup can was sharp enough to cut the mirror, but he tried anyway. For hours, Smithies withstood the piercing screech of metal boring into glass, turning that drill handle and watching the soup can rotate slowly until it finally cut through. “And I did make that lens,” he says. “But I could never get that telescope to work.” Smithies, though, realized that he loved the process more than anything. He loved making things. And he did eventually make a telescope, along with a bunch of other cool stuff. As an adult, he was still tinkering and inventing. By age sixty, in 1985, Smithies had garnered several awards for various discoveries and inventions, and was still working at his lab bench every day. But at that time, Smithies was in the throes of a complex series of experiments, well beyond telescopes and pulverized glass and so tediously long that graduate students left to pursue other goals. Many scientists doubted his hypothesis. Could Smithies actually insert a segment of DNA into the gene of a mammalian cell, and prove that the DNA segment took up residency at the proper location in the cell’s genetic material? Smithies thought he would have quite an invention on his hands—a way to target specific genes so that, potentially, mutated genes could be replaced or repaired. The method took years. It was cumbersome and unwieldy, but he got it to work. He successfully targeted a specific gene. Around the same time and independently of Smithies, geneticist Mario Capecchi also figured out gene targeting. And in England, Martin Evans had successfully isolated the embryonic stem cells in a mouse, altered the genes of those cells, and reintroduced the cells into a foster mouse to create genetically modified offspring. Biomedical research has never been the same. Using the discoveries of these three scientists, researchers around the world, including Smithies, created hundreds of mouse strains that genetically model human diseases. They also made thousands of mouse models that have altered genetic material so
scientists can figure out what specific genes are responsible for doing. “There is no doubt that this work will lead to new therapies in virtually every disease that has a genetic basis,” says Etta Pisano, vice dean of UNC’s School of Medicine and professor of radiology and biomedical engineering. Mouse models have opened up countless avenues of research, created a vast amount of scientific knowledge, and led to the creation of drugs for cancer and other diseases. For this, Smithies, Capecchi, and Evans won the 2007 Nobel Prize for Physiology or Medicine. Smithies, 82, says the award capped a long career. “But,” he adds, “I don’t think I’m finished yet.” From comic books to Oxford The son of an English teacher and an insurance salesman, Smithies grew up in Copley, a small industrial village two hundred miles north of London. It was a happy childhood spent with his fraternal twin brother and younger sister. But in 1932 Smithies contracted rheumatic fever, which can cause damage to the heart. He was bedridden for ten weeks and wasn’t allowed to play sports until he was fourteen. “It was sad not being able to play games outside as a boy, but I enjoyed reading,” he recalls. “And I’m naturally optimistic, so having rheumatic fever didn’t make me unhappy or anything. It was a fact of life.” While Smithies was reading, a character in a comic book—an inventor—caught his eye. Already fond of tinkering in his father’s garage, Smithies announced to his family that he would become an inventor. As luck or fate would have it, his best friend’s dad managed a clock-making company. “He had a lathe, a drill press, things like that,” Smithies says. “At first we got motorcycles to run and made radio-controlled boats. Oh, we had a grand time.” Smithies made radios and telescopes, and tried to make a remote speaker system out of a pig’s bladder, learning the scientist’s credo early in life: “If you need something that’s not available, you make it.” In his lab is equipment he made twenty years ago. He nods toward a polymerase chain reaction machine, which isolates different parts of the DNA sequence from genetic material. “When it was invented, you couldn’t buy one right away, so I made one,” he says.
In 1943 Smithies earned a scholarship to Oxford instead of getting drafted into the army. “I never really understood what happened there,” he says, “but they had some sort of board that directed students what to do. I was directed to go on with my studies; I haven’t the faintest idea why. They must have decided that some people would make a greater contribution to the war effort by doing research or whatever, instead of, unfortunately, the horrible jobs that soldiers had to do.” At Oxford Smithies considered becoming a physicist, but then thought he’d be able to help more people in a direct way if he studied medicine. After two years of medical school he was given a choice between clinical work and extra schooling for an honors degree. He chose the latter and studied animal physiology. “And that’s when I realized I wanted to do research,” he says. “It’s not that I didn’t think medicine was interesting; I just couldn’t not do research, as it were.” During that honors year, his favorite teacher was Sandy Ogston, a molecular biologist at a time when molecular biology didn’t exist as a formal topic. Under Ogston’s tutelage, Smithies figured out a way to detect interactions between proteins by measuring osmotic pressures. The experiments took more than two years, and although they were ultimately successful, nobody ever used his method. He would later say that his discovery was useless, but he considered the work good training. And he felt satisfied. Smithies earned his doctorate, and then Ogston advised him to work abroad, maybe in the United States. “I wasn’t very keen on that idea,” Smithies remembers. “I didn’t particularly like America, but I didn’t know anything about the country.” Ogston told Smithies, “All the more reason you should go.” Remembering the jelly Smithies did his post-doctoral work at the University of Wisconsin before heading to Connaught Medical Research Laboratory in Toronto, where he worked from 1952 to 1960. Scientists there had two main duties: make compounds not readily available in Canada and do research. Smithies worked with insulin; he suspected that there was a precursor to the hormone. To find out, he had to separate proteins in blood, and for that he chose a method called electrophoresis. endeavors 11
Courtesy of Oliver Smithies
Above: Oliver Smithies, left, as a teenager in England with his younger sister Nancy and fraternal twin brother Roger. Right: Smithies at the University of Wisconsin, where he delved into genetics research from 1960 to 1987 before coming to Carolina. It was at Wisconsin that he developed the initial method for gene targeting that led to mice that model hundreds of human diseases.
On weekends, he soars in his glider or works in the lab. “I don’t think I’m finished yet,” he says.
12 endeavors
Courtesy of Oliver Smithies
Mark Derewicz
Tiny flags on a map outside Smithies’ office show where some of his former graduate students work.
The experiment went like this: you put a spot of protein mixture in one place on a wet piece of filter paper and then pass an electric current through the paper. Proteins that were negatively charged would move toward the positive end of the paper. Viceversa for positively charged proteins. This way, the proteins would separate. “But I noticed that insulin stuck to the paper,” Smithies says. “It didn’t really move; it just unrolled like a carpet, and then it stopped.” He couldn’t figure out anything about insulin this way. Smithies turned to starch electrophoresis, a similar sort of experiment. “It was like having a tray full of wet sand,” he says. “You might call it a wet starch pie, a sand pie. When you’d pass an electric current through the starch, the proteins would migrate through the starch grains; they wouldn’t stick. But the only way of finding the proteins was to cut that starch pie into slices and do a protein determination for each slice.” That meant doing fifty protein determinations for one experiment.
“I couldn’t afford to do that experiment,” Smithies says. “But I knew starch would work. I was thinking about this one day when I remembered my childhood. I used to help my mother do the laundry; she’d starch my father’s shirts, and in those days you cooked the starch. When finished, the starch turned into a jelly. So I thought, okay, all I had to do was cook the starch, make a jelly instead of a loose slurry, and then I could stain the proteins with dye because I knew that the dye wouldn’t stick to the starch. I could avoid this business of cutting that pie.” It worked. The proteins separated, the dye stained them, and Smithies studied them. Before this, scientists thought that a molecule of blood contained five different proteins. Smithies found twenty-five, and also determined that all of us have very different mixtures of proteins in our blood. Scientists everywhere began looking for genetic differences in blood and finding them, opening up a whole new realm of biological understanding and leading to the use of blood proteins in forensic science.
Scientists eventually found several hundred different proteins in blood. His invention, gel electrophoresis, turned out to be a much more powerful method for separating proteins than typical starch electrophoresis. Gel electrophoresis is the father of acrylamide gel electrophoresis, which labs everywhere still use today. For this work, Smithies won the Gairdner Foundation International Award, considered a precursor for the Nobel. More importantly, his experiments piqued his interest in genetic differences. Around the same time, Francis Crick and James Watson discovered the structure of DNA. Smithies became a geneticist. The eureka moment In 1960 Smithies returned to the University of Wisconsin, where he discovered that some people have duplicates of parts of certain genes: they have two copies of a given gene instead of just one. He also found that these partially duplicated genes can match up on the chromosome in two endeavors 13
different ways, in some cases leading to the creation of a gene that is three times the normal length. As genetic science advanced through the 1970s, Smithies began studying individual hemoglobin genes. Up until that point, scientists worked with hemoglobin proteins. Vernon Ingram, for instance, discovered the particular amino acid that causes sickle cell anemia. Then scientists discovered the lone gene implicated in the disease. Meanwhile, Smithies was one of the first scientists to physically separate a gene from the rest of the DNA of the human genome, a process referred to as isolating a gene. His lab then isolated the normal DNA that corresponds to the hemoglobin gene that is mutated in sickle cell patients. “So I thought surely it should be possible to use the normal DNA to correct the abnormal DNA,” Smithies says. He thought this could lead to cures for diseases in which one gene is implicated. Then in 1982 Smithies read a paper about a complex method for finding one piece of DNA among hundreds of thousands of
pieces. He wondered if he could use a similar procedure to find out if a foreign piece of DNA that he inserted into a cell could find the corresponding spot in that cell’s genome, and then replace that gene. If this could work—this gene targeting—then theoretically scientists could correct faulty genes. “So I thought about that paper and taught about it—I was teaching a graduate class at the time—and then ten days later I realized how to do the experiment,” he says. It took three years, but toward the end he found some evidence that DNA injected into cell culture did find the right spot in the cells’ DNA through a process called homologous recombination. But he still needed definite proof of success or failure. Smithies was trying to show that beta-globin genes and hemoglobin genes with eleven thousand base pairs were altered. If so, they’d have only seven thousand bases. “We had about thirty bottles of cells lined up and we thought that one of them ought to have worked,” Smithies says. “We should be able to find a piece of DNA that was seven thousand bases long. So we isolated
In 1988 Nobuyo Maeda and Oliver Smithies left Wisconsin and settled into their lab in UNC’s Brinkhous-Bullitt building, where Maeda created the first mouse models of atherosclerosis and Smithies tackled the complex genetic causes of high blood pressure. They also married. Dan Sears
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the DNA from each of these thirty bottles, used an enzyme that cuts the DNA, and put it into a gel electrophoresis so that the bands of DNA would separate according to their sizes. And we looked to see if there was a band that was seven thousand bases long. One collection of cells had been altered. We knew it had worked.” Smithies says that his eureka moment felt like coming out of the clouds while flying a plane, a hobby he picked up in the 1970s. “Instruments indirectly tell you where the runway is so that when you come out of the clouds the runway should be right in front of you,” he says. “If not, there are procedures you can do to try again without crashing.” Smithies had landed, but the ride was a little rocky. His method was complicated. “It took three years and it did work,” he says. “But it was a poor method in the end; the success rate was extremely low. It’s not a method anybody would ever dream of using anymore. I don’t use it. But it showed the principle.” Until then, gene targeting had only been achieved in yeast. Many researchers were skeptical of targeting human genes because human genes and cells are much more complex than yeast. Smithies forged ahead along with a few other optimists, including Mario Capecchi, who Smithies says devised a more efficient method for gene targeting that allowed scientists to see what certain genes are responsible for. “Mario realized that it was important to knock out a gene in a mouse to see what that gene does,” Smithies says, “whereas I was interested in correcting a mistake—a mutated gene.” Then Smithies attended a conference in Scotland where Martin Evans showed how he had removed embryonic stem cells from a mouse, altered the genes, and inserted the stem cells into a different mouse. That mouse’s offspring had the same genetic alteration, and the implications were enormous. Smithies wanted those embryonic stem cells. He spoke with Evans, who later delivered some to Smithies in a vial in his shirt pocket. Smithies and Capecchi, still working independently but now in closer contact, grew the stem cells in their labs, studied how they evolve, and later created mouse models that show precisely how genes function and how gene mutations can cause human diseases. They won the Gairdner Award
for their work in gene targeting; it was the second time Smithies won. In 2001, Smithies, Capecchi, and Evans won the Lasker Award, considered the American version of the Nobel Prize. Nearly 50 percent of Lasker winners go on to win the Nobel, and Carolina was abuzz with the possibility that Smithies would soon fall in that category. “Gene targeting was a revolution twentyfive years ago, and now it’s absolutely fundamental,” says UNC geneticist Fernando Pardo-Manuel de Villena, who is researching gene diversity in lab mice (see “The Mouse Mess,” page 16). “I remember when I started graduate work, people were talking about Oliver’s discovery, and we all thought it was too good to be true. It was truly remarkable. And it’s remarkable to me that it took so long for him to win the Nobel Prize. To me, it should have happened at least ten years ago. Without Oliver, biomedical research would not be where it is today.” Gene targeting 101 Smithies says that the science behind gene targeting is difficult to explain. So he likes to use a pair of analogies. Imagine a book with one thousand pages, each page containing one thousand words. Now imagine three thousand of these books. All those words represent all the genetic information in a human body. Gene targeting allows scientists to pinpoint one word on page ninety-one in volume 1,349. The procedure allows scientists to knock out that word or replace it. “So now imagine a car,” Smithies says, putting us in the seat beside him. He points up to the dome light and says, “If you knock out that light bulb, nothing really changes other than the fact that you can’t read a newspaper at night. But knock out that wheel or the drive shaft. That’s pretty bad.” That’s how genes work. Some don’t do much, if anything. Others are responsible for quite a lot. Sometimes, if just one gene is mutated, you can get a disease such as cystic fibrosis, sickle-cell anemia, or Lesch-Nyhan Syndrome, a rare disease that causes sufferers to severely mutilate themselves. In Smithies’ lab, geneticist Nobuyo Maeda managed to correct that Lesch-Nyhan gene in cell culture. Two years later at UNC, Smithies and geneticist Beverly Koller created the first mouse model of Lesch-Nyhan Syndrome. And in 1992, Smithies and Koller made the first mouse model of cystic fibrosis.
Meanwhile, hundreds of other scientists began using this new gene-targeting tool. Jeremy Berg, director of the National Institute of General Medical Sciences (NIGMS), says, “Gene targeting has had such an incredible impact on the study of human diseases that it’s hard to imagine biomedical research without it.” Before gene targeting, Berg says that it was difficult to prove which mutated genes caused certain diseases. But then along came the knockout mouse. “For instance, there’s a gene associated with atherosclerosis,” Berg says. “The inheritance link in this disease was somewhat surprising, but the knockout mouse model was made, and sure enough, it confirmed the link. The animal model for the human disease could then be studied in detail.” NIGMS has granted nearly twenty million dollars to Capecchi and Smithies since 1968 and 1973, respectively. And their work, Berg says, has dramatically increased our knowledge of biology, genetics, and human diseases. It’s inspired new lines of basic research and has led to the creation of drugs, such as the cancer drug Imatinib. Tens of thousands of jobs—many of them in North Carolina—have been created as part of the multi-billion-dollar biotech industry that’s built on basic research such as the original work of Smithies and Capecchi. Not the end In 1987 Smithies finished his twenty-seventh year at the University of Wisconsin. He was sixty-two, and he and Nobuyo Maeda fell in love. The next year, Wisconsin failed to offer a job to Maeda. UNC hired her and Smithies followed her to Chapel Hill; a $900,000 grant from the North Carolina Biotechnology Center helped bring them both here, along with five other promising scientists. Smithies and Maeda were soon married, and moved into a house not far from campus. They also moved their labs into the seventh floor of UNC’s Brinkhous-Bullitt building, where they still work today. Inspired by his wife’s research on the genetic causes of atherosclerosis (she created the first mouse model of the complex disease), Smithies began studying the equally complex genetics of hypertension. By the year 2000, forty-some graduate students had worked in the Smithies-Maeda lab. Josh Knowles was one of them.
“Oliver is obviously brilliant, but I also can’t imagine another scientist with such generosity of spirit,” Knowles says. “Oliver and Nobuyo don’t just want you to crank out data; they want genuine relationships. He spent hours helping me improve some of my manuscripts. And he didn’t just criticize; he taught me how to be a better writer.” Knowles, now a research fellow at Stanford, was in Chapel Hill for a wedding last October when the announcement came that Smithies had won the Nobel Prize. “My first thought was that I won’t get to visit with him because he’ll be too busy,” Knowles says. “My second thought was that it’s about time.” Knowles remembers Smithies saying that young scientists should try to find something they love so much that they’d sacrifice a weekend for it. Smithies still follows this advice, often working seven days a week. And still, at 82, he conducts experiments himself, an uncommon thing for an accomplished scientist of any age. Smithies is also fond of saying that scientists should have three things in life: their work, a hobby, and a family. His family is Nobuyo. His hobby is flying. And his work continues. He is currently researching how kidneys separate large and small molecules. “I suspect it has to do with a gel,” he says. “And I like gels, you see.” One sunny Sunday last October, Smithies spent several hours in his lab—not at the bench, but at the desk. He was working on a grant proposal. “I was doing something most scientists will recognize,” he says. “I was writing a reply to a committee that turned down my request for funding.” Later that day, he and Maeda enjoyed lunch together. And then he took his plane for spin above Chapel Hill. It was a really good day, he says. At five o’clock the next morning, his phone rang. It was the Nobel Foundation. A peaceful feeling came over him. “I hope that this isn’t the end of my time here,” Smithies says. “I hope to enjoy this a while yet. But if I die somewhere—which I’m sure will happen—it might as well be at the bench, because that’s where I’m happiest.” e Oliver Smithies is Excellence Professor in the Department of Lab Medicine in the School of Medicine. He received funding for his work on gene targeting from the National Institute for General Medical Science. endeavors 15
Andrei Tchernov, Emilia Stasiak
the mouse mess by Sarah Whitmarsh When one Carolina researcher looks at a lab mouse, he sees what most researchers see: a crucial player in the battle against human diseases. But he also sees a major problem. For Fernando Pardo-Manuel de Villena, the problem lies within the lab mouse’s DNA. Pardo-Manuel de Villena and a team of researchers at Carolina and the Jackson Laboratory in Bar Harbor, Maine, took a closer look at the genes of mice studied in labs. And their findings were surprising. Turns out that the most common types of lab mice studied today represent only a fraction of the genetic diversity found in mouse populations. So what’s wrong with that? The most common diseases, such as heart disease and obesity, are also the most complex, affecting multiple genes at different locations in our DNA. Understanding the genetics of these diseases requires the ability to study an organism exhibiting variation in DNA sequences between different strains, or families, of lab mice, Pardo-Manuel de Villena says. Different strains of the commonly used lab mice simply don’t have this kind of genetic diversity, or genetic variation. 16 endeavors
Mice and men The genetic history of lab mice is intertwined with a social history of humans. Mice were first domesticated as pets in China about two thousand years ago. When Chinese mice were brought to Europe in the nineteenth century, a pet mouse craze exploded. “Almost all wealthy Western European women would have mice as pets—more than cats or dogs,” Pardo-Manuel de Villena says. Breeders in Asia and Europe bred mice to produce attractive pets called fancy mice. Breeders could produce offspring with a range of sizes and coat colors, including blue and albino, and with characteristics that were more attractive to buyers and less useful for the mouse as a species. A popular type of “waltzing” mouse, which looked like it danced in circles, actually suffered from a kind of seizure, Pardo-Manuel de Villena says. Pet mice became bigger, fatter, and more docile than their wild cousins. Fancy mice spread from Europe to the United States and, in the early twentieth century, into the hands of Harvard scientists. To them, fancy mice seemed ready-made for research. Thousands of generations of selection for specific characteristics had resulted in mice that were nearly identical. Researchers, whose work relies on carefully controlled laboratory conditions and experimental replication, could produce genetically identical mice by mating brothers and sisters from these fancy mice over several generations. Like the Europeans who selected their pet mice by color, scientists choose to study certain mice based on their susceptibility to cancer and other diseases. Like breeders, geneticists manipulate mouse DNA, albeit more directly, using techniques to inactivate one or more genes (see “A Life at the Bench,” page 10). But scientists conduct experiments almost exclusively on a few fancy-mouse strains, Pardo-Manuel de Villena says. The centuries of inbreeding almost certainly resulted in strains of lab mice with little genetic diversity. But how little?
because his team analyzed the DNA data in a different way, he says, sequencing multiple mouse strains at many locations in their DNA. The competing study used an old model that is disproved by the more recent and comprehensive data, he says. But of the forty million variations found, most were not present in the strains of mice that are commonly used in labs. Wild-derived mice contained ten times more genetic variation than classic lab mice, Pardo-Manuel de Villena says, and the genetic disparity between strains implies that existing genetic research involving lab mice has limited applicability. Not all research on lab mice is problematic, though. Classic lab mice are still useful for studying diseases that affect one gene at a time, such as cystic fibrosis. But the findings point out the need for “a new population of mice that has more diversity,” Pardo-Manuel de Villena says.
The “model” model Pardo-Manuel de Villena and scientists at several other universities are working to fill that need, creating new strains of lab mice specialized for complex disease research—strains that maximize the amount of diversity. The group, called the Complex Trait Consortium, mixed classical and wild mouse strains together and bred a new model called the Collaborative Cross. Each progeny has a “checkerboard of variation,” says David Threadgill, a Carolina researcher involved with the Collaborative Cross. He says the group plans to produce a thousand highly diverse, highly randomized mouse strains. In two years they will have about half of the strains developed, he says, but some strains are already under evaluation in cancer-related studies. In time Threadgill hopes the new mouse strains become a genetic reference population, so they can be used as a common denominator to support data integration from all types of biomediMapping mouse genes cal research. The Complex Trait Consortium has a long way to To measure the genetic variation in go—95 percent of all mouse research has populations of lab mice, the team cominvolved descendants of the European pared the DNA strains (called classical fancy mice. Centuries of inbreeding inbred strains) to more natural mouse But Pardo-Manuel de Villena says strains (called wild-derived strains). that scientists are starting to warm up to almost certainly resulted in Using data from the National Instithe idea of a new type of mouse model lab mice with little genetic tute of Environmental Health Sciences, for research. diversity. But how little? the researchers looked for differences “People have come to realize the among four wild-derived and eleven severe limitations of classical mouse classical inbred strains at the smallest strains for genetic studies,” he says. “And subunit of DNA—the base-pair. If you they’re beginning to see the very, very think of DNA as a large spiral staircase, large pool of genetic variation in the the base-pair would be a single step. The number of variations mouse that can be tapped by using wild-derived strains.” e among the types of steps indicates how different each mouse strain Sarah Whitmarsh is a master’s student in medical journalism at is from another. Carolina. The team found a surprisingly high level of variation—about Fernando Pardo-Manuel de Villena is an associate professor in the forty million among the fifteen strains. In other words, the genetic Department of Genetics. His study was published in the online version variation among the three sub-species of mice may be analogous of Nature Genetics in July 2007. The National Institute of General to the genetic variation between humans and chimpanzees. “To Medical Sciences, part of the National Institutes of Health, funded his us, mice don’t look that different,” Pardo-Manuel de Villena says. research. “But they are different.” David Threadgill is an associate professor in the Department of Pardo-Manuel de Villena’s team found almost five times more Genetics. The Collaborative Cross receives funding from the Ellison Medivariation than a competing studying using the same data. That’s cal Foundation and from the National Institutes of Health. endeavors 17
Scott Lujan
If a bacterium has resistance to antibiotics, it can donate that resistance to other bacteria by copying DNA strands that contain the resistance genes. UNC scientists have discovered that drugs called bisphosphonates (inset top left), already approved to treat bone loss, can stop the transfer of antibiotic resistance genes. They can even selectively kill bacterial cells that harbor resistance.
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the bug zappers
by danielle jacobs
Bacteria are getting it on. Unfortunately, some of them are also passing on antibiotic resistance. But Matt Redinbo and Steve Matson say they can put an end to that.
B
acteria are pretty simple. They have no secret compartments. They’re just tiny bags of stuff, mostly chromosomal DNA and plasmids. Chromosomal DNA is necessary for bacteria to live. Plasmids are not. They’re simply long, circular coils of DNA that broke free from the chromosome at some point in the bacteria’s evolution. But plasmids carry genes that can encode for such traits as antibiotic resistance. They can also replicate and donate themselves—and their resistance—to other bacteria. Plasmids are copied and carried to other cells by a mechanism called conjugation. (Imagine sharing a stick of braided licorice: grab a strand, tear it apart from the rest, and give it to a friend.) DNA has two doublehelix strands—one called Watson, the other Crick (they’re named for the scientists who first described them). To conjugate, the E. coli bacterium uses three enzymes. First a relaxase grabs onto Watson and breaks it. Next, while the relaxase is still holding on, a helicase unravels Watson from Crick. A replisome bursts in while the strand is unwinding; it shadows and copies Watson, replacing it with an entirely new one. After the helicase has gone around one complete circle of the plasmid’s coil, the relaxase lets go of Watson, setting it free into another bacterial cell. Once there, Watson is replicated and reunited with his old friend Crick once again. And if Watson had antibiotic resistance, now the new cell has it, too.
Matson has been studying bacterial conjugation in E. coli since the early 1980s, when Redinbo was still in high school. Matson decided to study TraI, which scientists had identified as a helicase—the enzyme responsible for unraveling the plasmid. But in 1991 Matson and his lab found that TraI was a lot more talented than anyone thought. It carries both the helicase and the relaxase— something that had never been seen before. TraI has all the tools to grab, unwind, and release a strand into a new cell. Matson now had even more questions to answer, but he wasn’t intimidated. He wanted to learn more about the relaxase. But even after he isolated and purified the relaxase portion of TraI, he couldn’t see how it worked. He sought out Matt Redinbo, now a biochemist with a track record for crystallizing complex proteins (essentially taking a still photo on an atomic level). But getting a good picture of the relaxase wasn’t easy. It took Redinbo’s team three years to get the shot. And just a few months before they got it, a group in Baltimore got it first—a glamour shot of the enzyme all alone, primped for its moment in the spotlight. But while getting a snapshot of an enzyme by itself is good, catching it in the act is even better. Scott Lujan, a graduate student in Redinbo’s lab, crystallized the relaxase doing its business with DNA, which finally allowed the chemists to understand how TraI grabs and releases a single strand of plasmid DNA.
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fter decades of learning how TraI works, Matson and Redinbo wanted to figure out how to stop it. Knowing that conjugation in E. coli is dependent on a well-functioning relaxase, the biochemists believed they could inhibit conjugation—and thus the transfer of antibiotic resistance—by making the relaxase bind with something that merely resembled the plasmid. DNA’s strands—Watson and Crick—are made up of sugars and phosphates. Bisphosphonates are molecules that are made up of two phosphates. Lujan used the simplest bisphosphonate he could find, hoping to confuse TraI so that it couldn’t interact correctly with the plasmid. And it worked. It worked so well that the E. coli donor cells died before they could even attempt to share their goods with anyone else. The results were so surprising, Lujan says, that he “actually did that first experiment eight times.” But when they brought in other bisphosphonates, including two simple drugs already on the market for osteoporosis, they saw similar effects. “We finally convinced ourselves that it was real,” Lujan says. Redinbo and Lujan think that the cells die after the relaxase tears apart the two strands and the helicase starts to unwind them. The bisphosphonate prevents the relaxase from letting go of the unwound strand. Instead, Lujan says, “it just keeps unwinding and unwinding around and around, until it uses up all of the cell’s resources.” The cell dies, leaving behind only pieces of Watson and Crick.
B
ut Matson and Redinbo only studied this relaxase inhibition in E. coli bacteria—which despite their reputation, are relatively benign: right now, there are billions of them in your lower intestine. The E. coli F plasmid,
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Lujan says, “was the first one ever discovered, so it’s been the most intensely studied and made a good model system.” Now Redinbo’s lab is certified to bring in nastier, meaner bugs to test: harmful bacteria such as Pseudomonas and Staphylococcus, which often have plasmids that encode for antibiotic resistance. As of now the team’s bisphosphonates don’t appear to be picky about the plasmids they work with—and when it comes to killing antibiotic-resistant bacteria, that’s a good thing.
tiny steps on a tightrope
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ulti-drug resistant infections such as MRSA—a kind of staph bacteria that’s resistant to the antibiotic methicillin—are, ironically, most often picked up at the hospital. Redinbo foresees his team’s inexpensive bisphosphonates being a first line of defense against these infections. “If you’re going in for standard surgery,” he says, “and somebody on the ward has a resistant infection, you could give this as a preventive medication, especially for the elderly or young.” And for patients who are already sick, Lujan says, the worst thing you can do is loosely dispense more antibiotics. Instead he envisions bisphosphonates used in hospitals to treat resistant infections prior to antibiotics. “One thing to understand is that none of the bisphosphonates are particularly good antibiotics,” Lujan says. “A good antibiotic will wipe out 99.999 percent of the bacterial population. The best we’ve been able to do is 99 percent.” So instead of trying to kill all of the bacteria in one fell swoop with an antibiotic, inevitably leaving resistant stragglers behind, Lujan suggests fighting bacteria with a one-two punch: hospitals could first administer bisphosphonates to an infected patient, wiping out the cells containing antibiotic-resistant plasmids. Once those cells are all dead—the team has seen this in as little time as an hour and a half—doctors could then hit the patient with a standard antibiotic, which should effectively kill off the rest of the bacteria. But even if it doesn’t, at least the few left won’t have any resistance to give away. e
“If you’re going in for standard surgery, and somebody on the ward has a resistant infection, you could give this as a preventive medication, especially for the elderly or young.”
Steven Matson is a professor in and chair of the Department of Biology. Matthew Redinbo is a professor in the Departments of Chemistry, Biochemistry, and Biophysics, and a member of UNC’s Lineberger Comprehensive Cancer Center. Scott Lujan is a post-doctoral fellow studying biochemistry in the School of Medicine. 20 endeavors
Scott Lujan
Tracking down how proteins have evolved is something of a detective game.
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istorically, scientists have worked backward in time using educated guesswork and knowledge of protein chemistry to figure out the probable evolutionary routes that proteins took to their modern form. Until recently, that is. Matt Redinbo and his colleagues decided to start near the beginning. Redinbo and Joseph Thornton at the University of Oregon used crystallography to create the first map of the exact structure of an ancient protein. Then they virtually strolled down the evolutionary path taken by the protein more than four hundred million years ago. Organisms typically get more complex as their proteins evolve new functions. To do that, proteins must undergo mutations that change their structure. Some of these mutations are clunky and break the protein, but others are vital and endow the protein with new traits. To identify which historical mutations were vital, Redinbo’s team compared proteins to their precursors through evolutionary time. They reconstructed the ancestor of two hormone receptors, which function like locks in a lock-and-key mechanism. When a hormone binds a receptor, the receptor switches on a cascade of signals that allows the cell to perform a specific function. Redinbo’s ancestral protein ultimately evolved into the stress hormone receptor, or the glucocorticoid receptor (GR), and the mineralocorticoid receptor, which controls kidney functions. Humans and bony fish have both receptors; sharks, which took a different evolutionary path, have only the latter.
Eric Ortlund
Along the path to becoming our modern glucocorticoid receptor, this 470-million year old receptor (blue) evolved into key intermediate states (green and orange). At each state, the protein could have followed other evolutionary roads (heading off to the right). And between states, the protein could have taken several paths (represented by grooves in the road). But the protein followed only a single evolutionary road between states. “Silent” or “permissive” mutations—those that seemed to have no function beyond slightly tweaking the fold of the protein—were crucial to the protein, and drove its evolution.
“This wasn’t like Jurassic Park where there was a sample drawn out of a fossil,” Redinbo says. “We statistically determined the sequence of the hormone receptor’s ancestor from an organism that lived over four hundred million years ago in the deep oceans. You can think of this creature as the last common precursor of a sea bass and a human.” Once the team had determined the sequence of the ancient receptor, they engineered bacterial cells to produce the ancestral receptor by injecting the gene corresponding to its sequence into the bacteria. The reconstructed receptor was stable and functioned normally, which confirmed that their statistical predictions were correct. What they did next gave them unique insight into how the protein evolved. Using a biophysical technique called X-ray crystallography, they pinpointed the precise location in three-dimensional space of every single atom in the reconstructed receptor. Redinbo’s team bombarded the crystals of the ancient receptor with X rays, which bounced off the crystals. The X rays were then exposed to a film, where they formed a blueprint of all the atoms in the receptor. The team then compared the ancestral receptor to the modern GR found in humans, and looked for mutations that changed the former into the latter. Five specific mutations stood out. These seemed to be responsible for the new function that
the ancient receptor had evolved: specificity to the stress hormone cortisol. Next the team engineered those five mutations into the ancient receptor in hopes of creating the modern GR. To their surprise, the new protein fell apart. They were either completely on the wrong track, or they were missing a vital link.
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n closer examination, the team found two other mutations that happened by chance earlier in the evolutionary timescale. These two mutations didn’t seem to have any function other than slightly tweaking the fold of the protein. The new fold, though, turned out to be pivotal in strengthening the structure that the five later mutations dictated. “It’s like cutting a window in your house and having your whole house fall down,” Redinbo says. “But if you were to alter the floor of the house just a little bit, then that new window would work out and change the way the house functions.” And that’s what they discovered: without the two silent mutations, the five specific mutations made the protein unstable. It’s as if the ancestor were walking an evolutionary tightrope toward its new function, Redinbo says. “As random mutations kept happening, those that destabilized the ancestor would cause it to fall off and were therefore thrown out, but those that added zero value to it were not always eliminated. The two mutations that survived turned out
to be essential for the five later ones that gave the ancestor a completely new function. We think that such permissive mutations may underlie the new functions taken on by most proteins in their evolutionary history.” Evolutionary forces are intimately tied to cancer and other diseases, as well as resistance to antibiotics, says Eric Ortlund, first author of the study and a former postdoc in Redinbo’s lab. “One could certainly accelerate evolution in the lab to understand how proteins may circumvent inactivation by drugs while preserving their function,” he says. “This wonderful piece of structural biology fills a big gap in the great conceptual puzzle of how proteins adapt to new functions,” says Ichiro Matsumura, an evolutionary biologist at Emory University. “I expect it will take time for Redinbo’s ideas to percolate through the scientific community. But that is the price one pays for thinking ahead of the curve.” e —Prashant Nair Prashant Nair is a master’s student in medical journalism at Carolina. Matthew Redinbo is a professor in the Departments of Chemistry, Biochemistry, and Biophysics, and a member of UNC’s Lineberger Comprehensive Cancer Center. His team was funded by the National Institutes of Health, the National Science Foundation, and by a Lineberger Comprehensive Cancer Center Postdoctoral Fellowship. endeavors 21
Vickie Ripley
Veteran editor-publisher Ken Ripley (seated, center) of the Spring Hope Enterprise is surrounded by community-journalism students. From left, Laura Davenport, Gregg Found, Kate Newnam, Sam Giffin, Kendal Walters, Marianna King, Elyse Archer, Emily Burns, Cody Braun, and Cameron Weaver. Not pictured: Jon Sullivan. Instructor Jock Lauterer is at lower right.
Meet the Bucket Brigade With its editor out of action, Spring Hope needed its news. Carolina’s J-school hit the road. by Kelly Chi 22 endeavors
A cooler full of soft drinks and his photographer’s vest in
the trunk, Jock Lauterer begins every other Friday dispensing wisdom to his students during a one-hour car ride east to Spring Hope, N.C., where they have become reporter-photographers on a rescue mission. “Let me tell you something about teachers,” he begins. Or, “In my day…” During this particular Friday in early October 2007, as Lauterer pulls onto the main strip of the tiny town of Spring Hope—a place he calls “real North Carolina”—he has more specific advice for the students in his community journalism class. Carolina senior Kendal Walters will cover a pumpkin-recipe contest, part of the two-day pumpkin festival during which the town’s population of twelve hundred will swell to twenty thousand. Lauterer says, “Make sure to get tons of names of local people and find out where they’re from.” He’s sending sophomore Sam Giffin to a soap-making demonstration at Doug’s Antique Store. “Emphasize the people, not the process,” Lauterer says. “I still want to know how they make soap,” Walters says. “We’ll slip it in there,” Lauterer assures him. This fall, Lauterer has turned his class into a bucket brigade. They’re responding to a small-town newspaper in crisis—the veteran editor-publisher of the town’s weekly paper, the Enterprise, has been in and out of the hospital for several months getting both his hips replaced. Despite his condition, Ken Ripley has been putting the paper together from his hospital bed and home while the staff of four sells ads and reports local news. Adding Lauterer’s eager undergraduates into the mix, the newspaper’s staff has grown to ten. The students take photos and write feature stories.
The welfare of one of the state’s 192 small newspapers matters, says Lauterer, who calls all-local newspapers like the Enterprise “the heartbeat of American journalism.” In May 2007, Lauterer saw a news report on the devastating Greensburg, Kansas, tornado. A former publisher and editor of a small newspaper himself, Lauterer watched as the editor of the Kiowa County Signal described the tornado’s effects. “He was almost in tears, and he said, ‘I don’t know how I’m gonna do it, but I’m going to put out a paper next week’,” Lauterer says. He realized how natural disasters or other emergencies could prevent community news from getting out. That got Lauterer thinking about how he could form an emergency response team of community journalists for North Carolina. But he needed a more predictable disaster than a tornado. It just so happened that Ripley, a Carolina alum and regular guest lecturer in Lauterer’s class, needed his help. The idea that outsiders can parachute in and become community journalists seems like a contradiction, Lauterer admits. But before dropping into town, his students prepared for several weeks, learning the names and latest news in Spring Hope. Even after all the studying, it’s been a steep learning curve, he says. When the students first showed up in the tiny newsroom, Ken Ripley had left them a short list of story ideas. Each idea was only a few words: “agriculture education at Southern Nash High School,” “Momeyer Ruritan chicken barbecue,” and “Grand Marshals of Pumpkin Parade,” to name a few. “We were kind of confused and bewildered,” Giffin remembers.
Lottie Lou gives him her age—eightytwo—and then laughs and says to him, “Why, you’re still a teenager.” Lauterer, sixty-two, loves it. As Lauterer totes his camera back to the newsroom, he tells Lottie Lou’s age to a reporter. Then, for the first time in months, Ripley arrives at the newsroom; he is equipped with one new hip. A cane in each hand, he gingerly steps out of his blue Chevy and walks painstakingly into his newsroom. “Hurry up, Ripley!” Lauterer jokes. When Ripley gets his second hip and makes a gradual transition back to the newsroom, Lauterer will have to find another community paper in crisis. Lauterer says that at least thirty community papers are within a one-hour radius of Chapel Hill, and he knows newspapers all over the state. He just received a two-year grant from the Carolina Center for Public Service to help fund future bucket brigades. Meanwhile, the students learn some new lessons that go beyond journalism. Giffin says that people in Spring Hope are focused
on the little joys in life. While Giffin covered soap-making, two women showed him how to make soap and told him about their families and ties with the town. “Understanding that I was an outsider, they were patient with me about learning some of the traditions of Spring Hope,” he says. “I learned that there’s so much more to small towns than I gave them credit for.” Until Ripley gets his second hip—which he expects to happen in early December 2007—he runs the paper from home. He’s glad Lauterer’s students have helped. “I couldn’t have done it without them,” he says. “And you can quote me on that.” e Jock Lauterer teaches community journalism, photojournalism, and newswriting classes in the School of Journalism and Mass Communication. He is the founding director of the Carolina Community Media Project and writes occasional columns for the Carrboro Citizen. The third edition of his textbook, Community Journalism: Relentlessly Local, was published in January 2006 by the University of North Carolina Press.
Emily Burns, a junior majoring in journalism, tries out the editor’s seat. News topics? Chicken barbecue, ag education, and the Pumpkin Parade. Rob Matteson
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his early October Friday is no exception. As Kendal Walters arrives at the pumpkin-recipe contest and looks at the goods, she wonders what a “pumpkin jack” is. Turns out it’s just like a turnover, she says. But one of the contestants pokes a bit of fun at her—“You’re not from around here, are you?” Walters makes her way around the room, taking names and getting comments from the contestants about their pumpkin dishes, while Lauterer snaps a few photos and gets ideas for captions. Then he does a daring thing: he asks Lottie Lou—the lady in charge of fussing over the entries—her age, so he can include it in a caption. endeavors 23
Brandon Kearns
The Guatemala City garbage dump is the biggest landfill in Central America. Over a third of the country’s total trash ends up there. The scavengers who recycle the dump’s trash reduce Guatemala’s waste by a million pounds a day, but they have to breathe toxic fumes and sift through biohazardous materials to do it.
Guatemala City’s dirtiest secret
Courtesy of Brandon Kearns
by Margarite Nathe
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hey say in Guatemala that if you’re born poor, you die poor. And if you’ve ever been to the garbage dump on the edge of the capital city, you can see why. The Guatemala City basurero covers forty acres of land with the city’s trash. Yellow trucks line up every day to tip their loads onto the heap, and residents of the slums outside the dump crowd around the trucks before they even come to a stop. Scavengers with the most seniority rush to touch the trucks’ sides—a flat palm against the cargo hold marks their scavenging space for when the trucks pull away, unleashing crumbling waves of garbage. There are stories about people charging in too quickly and getting crushed under the trucks’ tires. Along with the tons of trash are recyclables, and the lucky hangers-on get dibs on glass, aluminum, old furniture, and any other hot commodities that come pouring out. Regulars at the dump know which trucks carry trash from supermarkets and restaurants, so every morning is a race to grab up anything edible, or that can be sold. 24 endeavors
Brandon Kearns, a sophomore at Carolina, sits with one of his students. Kearns is a volunteer at Safe Passage, a free program for children of families who scavenge in the dump.
The piles are so tall and dense that there are occasional avalanches; if someone is caught underneath, the scavengers say, their bodies are almost never found. Until 2005, when the cloud of methane gas that hovers over the dump ignited and caused a massive fire, entire families worked, lived, and slept in the basurero, scavenging at all hours of the day and night. After the fire, though, the city built a wall around the dump and stationed armed guards to keep people out between dusk and dawn. Children were no longer allowed inside. The basurero was closed temporarily after the fire. “And believe it or not,” Brandon Kearns says, “that took away a lot of people’s livelihoods.” Kearns, a sophomore majoring in health policy and administration at Carolina, rode a noisy, standing-room-only school bus past the dump every day over the summer of 2007. Kearns was riding with a few other volunteers to Safe Passage, a half-day program for the children of the families working in the dump. Safe Passage began in 1999 when a young woman named Hanley Denning, who worked with Head Start in North Carolina, opened the doors of an unused church to teach a handful of young Guatemalans. The project now includes over five hundred children. “Public schools in Guatemala are half-day,” Kearns says, “and Safe Passage is a place for the kids during the other half. Otherwise, they would… Well, I don’t know what they would do.” On his first day at the school, the kids ate fried chicken feet in the cafeteria and eyed the new volunteers. Before long, though, even the most hesitant kids—such as those who had never seen a black person before, Kearns says—had warmed up to them. Kearns and the others taught English, reading, and math to the kids, and played soccer with them at recess. They heard gunshots only occasionally.
“If you don’t make your payment, they pull the coffins out or dig them up, and push them down the hill into the dump,” Hoffman says. “When we went down last time, a number of them had just been pulled.” There are no restrictions on what citizens can throw away, says Hoffman, now a master’s student of environmental management at Duke. The ravine likely contains a water source for the city, and biohazardous materials are shoveled into it every day. The conditions are ripe for a public health nightmare. Lice epidemics are common among the kids who come to Safe Passage, and outbreaks of tuberculosis are not unheard of. Kearns and Hoffman say that the dump is fertile ground for Carolina researchers who want to get their hands dirty, including anyone studying aspects of public health, elementary education, or environmental science. And Safe Passage is always looking for dedicated volunteers, they say. For the families who work in the basurero, Kearns says, “it’s dogeat-dog, more or less.” So their children at Safe Passage live day to day, and the volunteers can never be sure who’ll be in class from one session to the next. But the kids are rambunctious and happy.
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t’s hard to tell where the basurero ends and the workers’ homes begin, says Cassie Hoffman, who’s been involved with Safe Passage since she graduated from Carolina in 2005. She now leads groups of volunteers, and it was through a flyer she had posted that Kearns found out about the program. The shacks outside the dump are piled with old mattresses where families and their animals sleep eight or ten to a bed. Recyclables spill out of the windows and garbage lines the streets. The neighborhood is built on top of land that was reclaimed from the basurero years before, Hoffman says, meaning that beneath a few thin layers of sand are mounds of old, rotting garbage. While the kids either walk or take a bus to school (a Safe Passage volunteer passes out bus tokens to the kids every day), their parents don ID tags—another innovation since the 2005 fire—and head over to the dump to get an early start. As the scavengers pull out anything they can sell, bulldozers continually push the remaining garbage into a ravine, where they compress it and cover it with layers of sand. City officials estimate that the gorge will be full in a year or two. After that, Hoffman says, they’ll keep stacking more on top. But it’s not just trash that ends up in the ravine. Guatemalan citizens who can afford to purchase grave plots have to pay for them annually, and payments have to keep coming even after the purchaser has died. In Guatemala City’s main cemetery—which happens to be on the edge of the dump—huge above-ground walls hold up to a hundred coffins pegged in like drawers.
The poor who scavenge in the dump can’t afford grave plots in the cemetery. Instead, they construct makeshift graves and mark them with wreaths of tires and colorful trash.
A few days before the end of Kearns’ stay, a little boy named Julio wanted to know when Kearns was leaving. “Cuando te vas?” he asked. “On Friday,” Kearns answered. “This Friday?” Julio said, his face falling. “That’s my guy,” Kearns says affectionately. “These kids. They’ve got spirit.” e To learn more about the Guatemala City garbage dump, watch the documentary film “Recycled Life,” available at www.recycledlifedoc.com. Learn more about Safe Passage at www.safepassage.org, or contact Cassie Hoffman at cassie.hoffman@gmail.com. endeavors 25
Jason Smith
Why be happy? Barbara Fredrickson is trying to find out if positive emotions do us any good. by Mary Russell Roberson 26 endeavors
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ere I am sitting down to write an article. If I allow myself to worry about whether the editors will like my work, I’m likely to do a worse job than if I concentrate on how fascinated I am by the subject matter. That’s because people experiencing a positive emotion are more open-minded and creative, at least in the moment, than people experiencing a negative emotion or no emotion. Losing myself in fascination can benefit me in the long run as well, according to Barbara Fredrickson. For twenty years, Fredrickson has been asking the question, “What good are positive emotions?” Her work is illuminating the pathways by which positive emotions lead to a wide range of life outcomes such as health and satisfaction. When Fredrickson first began her research, other psychologists were already studying negative emotions, which offer clear advantages to survival. Negative emotions narrow attention and rev up the body to meet an immediate threat. For example, fear causes the urge to flee; anger causes the urge to attack. They also produce measurable physiological changes, such as increases in heart rate and blood pressure, which ready the body for action. Positive emotions, on the other hand, don’t produce such clear physical changes, nor do they invoke urges to perform specific behaviors. This piqued Fredrickson’s interest, as did the fact that no other scientists had begun looking for the evolutionary advantages of positive emotions. “What appealed to me was the uncharted territory,” she says. “I wanted to study something that no one had ever studied.” Robert Levenson, Fredrickson’s mentor at Berkeley, had proposed that positive emotions might undo the cardiovascular effects of negative emotions. Fredrickson decided to test the idea. She measured heart rate and blood pressure of volunteers, then told them they would have to give a speech that would be videotaped and evaluated. As expected, the heart rate and blood pressure of the volunteers went up. After a few minutes, she told them they didn’t have to give a speech after all. All the subjects immediately watched a short film. Those who watched films designed to elicit amusement or contentment returned more quickly to their baseline physiological measures than those who watched a neutral film. Those who watched a sad film recovered slowest of all.
Too much time spent with a racing heart students in her previous lab at the University and elevated blood pressure can contribute of Michigan in Ann Arbor, she found that to heart disease, so as a recovery tool posi- positive emotions increase what she calls a tive emotions may contribute to health. But person’s thought-action repertoire, which Fredrickson wasn’t satisfied that she had is essentially the answer to the question, “What do you feel like doing right now?” or uncovered the full story. “Is this the evolved purpose of positive “What actions are an appropriate response emotions—that they are a reset button?” to this situation?” In one study, she showed she asks. “That would suggest that most of different short films to volunteers to elicit our positive emotions would occur in the amusement (penguins hopping, sliding, and context of negative emotions.” Obviously, swimming), contentment (sunny mountain though, people experience positive emotions scenery), anger or disgust (people taunting in many situations, not just those involving others), anxiety (a cliff-hanger), or no emonegative emotions. So Fredrickson kept tion (a video of colored sticks). Then when she asked them to write down all the differlooking. Some research shows that people feeling ent things they felt like doing, those who positive emotions perform better on tests had seen the clip invoking positive emotions designed to measure creativity, flexibility, compiled longer lists than the others. They and open-mindedness, although these bene- were also more likely than the others to see fits are just as transitory as the emotions that the big picture in a visual test designed to produce them. But Fredrickson suspected measure global thinking. that these transitory states must produce long-term survival advantages—otherwise, why would positive emotions have evolved in the She suspected that the benefits from first place? And why would positive emotions must produce longthey have remained such a central part of the human term survival advantages—otherwise, experience?
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why would positive emotions have evolved in the first place?
o answer her own questions, Fredrickson describes a chain reaction that she calls “broaden and build.” Step one: Positive emotions cause people to think more broadly in the moment. Step two: Broadened thinking leads to the development of long-lasting personal resources, including physical health, social support networks, psychological resilience, and problem-solving skills. Step three: These personal resources allow people to thrive and flourish over time. While anger spurs people to attack, joy may spur people to learn something new, make new friends, or go for a walk outside. When the joy wanes, the resources remain. The effects of positive emotions grow over time, Fredrickson says. As personal resources accumulate, she says, “they change you as a person, equipping you to better handle threats to life and limb.” Nice idea. But how do you prove it? Fredrickson started with the “broaden” part of her theory. Working with graduate
In another of Fredrickson’s studies, invoking positive emotions temporarily did away with the “own-race bias,” which is the fact that most people aren’t very good at recognizing individual faces of other races. Scientists speculate that we perceive faces holistically, unless the face is of another race, in which case we see it as a collection of attributes. In Fredrickson’s study, white people who had just experienced positive emotions were able to differentiate between black people’s faces just as well as they differentiated white people’s faces. Volunteers feeling neutral or negative emotions exhibited the own-race bias. She believes positive emotions helped people think more holistically during the face-recognition experiment. The way Fredrickson sees it, broadened thinking—that is, seeing the big picture— endeavors 27
encourages people to learn, explore, play, connect with others, and try new things. These actions build knowledge, health, confidence, and social support. This part of her theory is tricky to prove. She needs to be able to increase the intensity of positive emotions experienced by an experimental group of volunteers and then compare them to a control group for an extended period of time. “We need to create ways to change the emotional fabric of people’s days over months,” Fredrickson says. “It’s not so easy; changing people’s emotional habits is like moving a river.” First she tried asking volunteers to write down the positive meaning in both positive and negative events every day for a month. “It worked well for some people but not others,” Fredrickson says. “People get bored; they think it’s hokey.” Next she turned to meditation. Researchers who had conducted MRI studies found that people who meditate regularly had more activity in the left sides of their brains than those who don’t. Previous studies had shown that increased activity on the left side correlates strongly to positive emotion. Other studies clearly showed that meditation helped people avoid relapse into depression. While still at the University of Michigan,
Fredrickson teamed up with colleagues to carry out a large meditation study at a computer software corporation. People in the experimental group participated in weekly meditation classes and daily practice for seven weeks. Those in the control group were placed on a waitlist for the meditation class. Each day all one hundred forty-one participants kept track of their most intense positive and negative emotions. Before and after the study, everyone completed a battery of tests designed to measure eighteen different personal resources, including symptoms of illness, pathway thinking (ability to think of multiple solutions to a problem), environmental mastery (feeling competent to meet life’s challenges), and social support (both given and received), and then filled out questionnaires designed to assess life satisfaction and depressive symptoms.
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fter the data were collected, Fredrickson accepted a position at UNC and moved her lab to Chapel Hill in January 2006. “One of the great things about moving here is that there’s a quantitative psychology doctoral program at UNC,” Fredrickson says. Students in that program worked with Fredrickson to perform statistical analyses on the meditation data. They found that
Jason Smith
“Positive emotions build resources that allow you to meet the challenges of life. It’s not that life satisfaction and positive emotions are the same thing.”
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the meditators did experience a significant increase in positive emotions over the nineweek study. “In fact,” Fredrickson says, “the number of minutes they meditate is the best predictor of positive emotions.” This finding allowed the team to compare self-reported changes in personal resources between the experimental and control groups. The bottom line, as summed up by Kimberly Coffey, fifth-year graduate student in Fredrickson’s lab and chief data-cruncher on the project: “Increases in positive emotions were associated with increases in resources, and increases in these were associated with increases in life satisfaction and decreases in depression.” “We argue that the reason high positive emotions and life satisfaction go together is because positive emotions build resources that allow you to meet the challenges of life,” Fredrickson says. “It’s not that life satisfaction and positive emotions are the same thing.” To reach this conclusion, the team tested a dizzying array of possible causal pathways to untangle the relationships between baseline positive emotions, increase in those positive emotions, change in resources (eighteen of them), and change in life satisfaction. The data showed that positive emotions improved life satisfaction only to the extent that they increased personal resources. “By analogy, think of it this way,” Coffey says. “When UNC has a big athletic event on a weekend, I’m in a bad mood. However, the reason is not that UNC athletic events affect my mood one way or another by themselves. They affect my mood to the extent that they influence parking on campus—it gets vastly worse—and parking influences my mood.” Could the increase in positive emotions have been caused by the placebo effect? “There’s a lot of research on placebo effect that shows they are very fast to occur and they dissipate readily,” Fredrickson says. “Our changes were very slow to appear and stayed on. But that doesn’t rule it out.” And the clear dose-response relationship (more minutes spent meditating equaled more intense positive emotions) argued against a placebo effect. In an ideal world, she’d like to conduct a double-blind study, but she hasn’t yet figured out how to give a control group something that looks like a meditation class but isn’t. Fredrickson thinks that we should look for ways to increase positive emotion in our
lives. “But you don’t have to be happy all the time,” she says. “That presumes that negative emotions are always dysfunctional and that’s just not true.” In fact, the participants in the meditation group had about the same number and intensity of negative emotions as the control group did. Positive emotions aren’t the only way to build personal resources, Fredrickson says—they’re just the most efficient. Sure, an angry person can trudge to the gym, and a frightened person can use techniques from a self-help book to meet new people. But the joyful person who starts a pick-up basketball game and the amused person who shares a funny observation with a stranger achieve similar results with a lot less work. In the years since Fredrickson first developed her broaden-and-build theory, other researchers have demonstrated in a number of ways that happy people live longer, achieve more professionally, and have more stable marriages than unhappy people. “These fleeting states add up to a huge impact on life outcomes,” she says.
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n the fall of 2007 Fredrickson and her students replicated and expanded the meditation study using UNC faculty members and staff as subjects. The Michigan study relied solely on self reports, but Fredrickson’s new study incorporated physiological measurements and cognitive tests as well. She and her students are analyzing the data and hope to publish the results soon. Meanwhile, Fredrickson is pursuing a new goal of reaching out to the public. She’s writing a book for a popular audience, to be published by Crown in 2009. “Positive emotions aren’t trivial; they’re an essential state that you diminish or ignore at your own peril,” she says. “I didn’t go into psychology to be in the helping profession. I was drawn to the puzzles of science. That’s not my sole motivation anymore. “This is really about something that could help people and change the world. This is the contribution I want to make.” e Barbara Fredrickson is Kenan Distinguished Professor of Psychology and principal investigator of the Positive Emotions and Psychophysiology Laboratory at UNC. Other authors were graduate students Kimberly A. Coffey and Jolynn Pek of UNC, meditation instructor Sandra Finkel, and graduate student Michael A. Cohn of the University of Michigan.
Upping your daily dose of positive emotions Eat more ice cream? Unfortunately, no. For most people, that generates pleasure, not positive emotion. Pleasure and positive emotion often come wrapped together—eating ice cream as part of a social gathering, or enjoying sexual pleasure as part of a loving relationship—but it’s important to distinguish between the two. “Pleasures are more triggered by physical sensations,” Barbara Fredrickson says. “Positive emotions are more triggered by finding positive meaning in a given circumstance.” She suspects that pleasure actually narrows thinking, because of the intense focus on the physical sensation. “I don’t think pleasures are bad,” she says. “They just don’t necessarily buy you as much meaning-based positive emotion.” Change the way you think Positive emotions can’t be forced, but changes in thinking patterns can. “Just saying ‘I’m going to be happy,’ doesn’t do it,” Fredrickson says. “But if you frame things you encounter as gifts to be treasured, that unlocks emotions of gratitude. If you can view your circumstances as going your way, even better than you expected, joy pops up.” Lose yourself When you become so involved in an activity that the whole world goes away, you are experiencing a positive emotional state that psychologists call “flow.” Practicing a skill, craft, or sport also generates a sense of accomplishment and well-earned pride. Go for a walk—outside One of Fredrickson’s colleagues in Michigan showed that people who spent more time outside in beautiful weather (high pressure or warm—not hot—temperatures) experienced more positive emotions. Stop and smell the roses “Most moments in life are at least mildly positive,” Fredrickson says. “But negative things just jump out and scream at you.” Give positive moments their due—train yourself to look for them and appreciate them. Get off the treadmill A new gadget may make you happy, but usually not for long. The urge to regain that happiness by purchasing a bigger, better gadget puts you on the “hedonic treadmill.” Positive actions can also lose their luster through repetition. For those who tire of the daily gratitude journal, Fredrickson suggests varying the content and the timing of the entries. “Increase the variety in how you approach things,” she says. “Keep things fresh.” Meditate Research has shown loving-kindness meditation to be a remarkably reliable way to produce positive emotions. (The research specifically applies to loving-kindness meditation, but this doesn’t mean that other types of meditation don’t produce similar results.) “Meditation works because every day it’s a new challenge,” Fredrickson says. She’s a daily meditator herself.
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www.jonbeinart.com
Rootbound System by Jon Beinart. Felt-tip pen on paper, 2004.
The tangled roots of OCD by Prashant Nair
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itch is one of a large group of people with obsessive-compulsive disorder, or OCD. People with OCD have obsessive thoughts, which are often accompanied by repetitive behavior. In the United States alone, about one in fifty adults has OCD, according to the Obsessive Compulsive Foundation. Traditional treatments rely on antidepressants such as Paxil and Prozac, which are known to have side effects. Jonathan Abramowitz, a clinical psychologist at UNC’s Anxiety and Stress Disorders Clinic, uses a different approach. Abramowitz teaches OCD patients to overcome their fears. “Wondering if you left the iron on at home might be a normal thought most of us have,” Abramowitz says. “But people with OCD worry if the speed bump they just ran over was a human body.” Some patients can’t even go to work because their compulsive behavior takes too much time or because they’re worried they’ll catch germs. Others have recurrent senseless thoughts, which they constantly struggle to suppress. Because of embarrassment and fear of unwanted thoughts, OCD patients tend to have constant low self-esteem. “It doesn’t go away on its own,” Abramowitz says. People who don’t seek treatment are constantly fighting a losing battle. For those who do seek treatment, Abramowitz uses cognitive behavioral therapy, or CBT, which clinical trials have shown to be more effective than talk therapy or medication. “In CBT, we teach people lifelong skills to control the anxiety associated with obsessive thoughts,” Abramowitz says. He puts OCD patients in simulated situations that resemble real life as closely as possible, and trains them to manage their anxiety when it comes time to face their thoughts. He also teaches them to repeat certain statements and actions to overcome their fears. “If someone’s afraid of door handles because they may contain germs, we help them to touch a bunch of door handles so they can see that realistically it’s safe,” Abramowitz says. And he’s found that the patients in his program who don’t take medication do just as well as those who do. But CBT doesn’t work as well for patients who have no insight into their condition. “For those who don’t even realize that their actions and thoughts are irrational, CBT might not be the best answer,” Abramowitz says. “Probably because they’re too fearful to follow through the course of the treatment.” Many partners of OCD patients play along with the patients’ fears and obsessive behavior in order to make life easier, Abramowitz says. Couples therapy aims at educating partners . and helping patients deal with OCD as a team. “That’s not only a bonding experience for the patient but also an effective way to communicate in an anxious situation,” Abramowitz says. e still don’t know what causes OCD. It may arise from a combination of factors, and no one gene or protein has been identified as the cause in humans. “Anxiety is a helpful thing; it protects us from harm,” Abramowitz says. “But people who tend to be more anxious than others are more apt to develop OCD.” An effective test to identify patients susceptible to the disorder, though, is unlikely. “Psychological problems demand a psychological answer,” he says. “We can’t simply reduce it to biology.” But neuroscientists are looking for biological explanations, and Guoping Feng at Duke decided to look for them in mice. Feng teamed up with Richard Weinberg at UNC’s Neuroscience Center and other researchers to uncover an instance of OCD-like behavior in mice. The
When he was sixteen, a young man we’ll call Mitch couldn’t sleep. He worried about nuclear war. He was convinced it would happen soon and dreaded the day. He spoke of it all the time to friends and family, who shrugged him off as silly. And then the thoughts began to obsess him. His grades dropped, and he couldn’t concentrate on school work anymore. As the years passed, Mitch got more nervous and anxious. He worried about crossing narrow bridges and intersections, and cringed at traffic lights. He stopped driving altogether. Eventually he stopped working. His psychiatrist helped him file for mental disability. He lived on social security for three and a half years
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scientists suspected the answer lay in nerve impulse transmission, and wondered if rejiggering the junctions of nerve impulse relays could lead to OCD-like symptoms. Feng had long been fascinated by synapses, the structures that relay nerve impulses across nerve cells. The signal-receiving end of the synapse, called the postsynaptic complex, houses receptors that transmit impulses. The complex is less than a micrometer across and has hundreds of proteins enmeshed by molecular scaffolds and buttresses, most of whose functions are still unknown. Feng unhinged the complex by removing a protein called SAPAP3. He expected these mutant mice to be different but he had no clue how they would behave.
returned working versions of the lost SAPAP3 gene into the mutant mice by injecting a virus bearing it into the mice’s brains to see if their lost function could be restored. Six months later, five of the eight mice recovered. They had no lesions, were less anxious, and their synapses transmitted impulses normally. Feng’s team is now trying to identify mutations in human SAPAP3 in families with a history of OCD. Christopher Pettinger, director of the Yale OCD Research Clinic, says, “This is the best characterized and most convincing mouse model of OCD that has been described to date. It would be exciting if we learned that SAPAP3 is one of the mutated genes in OCD patients, but we’re not there yet.”
“The mutant mice would spend more than a third of their time scratching themselves sore and self-inflicting lesions while the normal mice slept. The mutants would compulsively groom themselves.”
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cientists are also nowhere close to doing the kind of therapeutic gene-jockeying in humans that they did with the mice, Weinberg says. “Right now that stuff is pie in the sky. Do we really want to inject a virus bearing SAPAP3 into a person’s brain? How long do we have to study the person before we know that we don’t hurt the neurons? Maybe some day in the far future, but I’d be surprised if it happens in the next twenty years,” he says. But drug companies could identify chemicals that interact with SAPAP3 and correct its function by testing them in mice. Feng has already started collaborations with drug manufacturers who will use the mice to screen libraries of such chemical compounds. “That would be a more science-based therapy with an understanding of what goes wrong in OCD,” Weinberg says. Current therapies are based on trial and error. Abramowitz, though, is not convinced. Most of the repetitive behaviors seen in OCD patients happen in response to obsessive thoughts. But not all OCD patients have rituals. A driver who clutches a steering wheel harder because he fears he may turn the car into oncoming traffic could have OCD, Abramowitz says. But the important thing is that the action happens in response to an obsessive thought. “We don’t know if mice have obsessive thoughts,” he says. e Jonathan Abramowitz is an associate professor in the Department of Clinical Psychology. Richard Weinberg is a professor in the Department of Cell and Developmental Biology in the School of Medicine. Guoping Feng is an assistant professor of neurobiology at Duke University.
y the time Feng’s mice were six months old, lesions and patches of hairless skin appeared under their eyes and snouts, then spread. Feng’s team videotaped the mice and observed a remarkable thing: “The mutant mice would spend more than a third of their time scratching themselves sore and self-inflicting these lesions while the normal mice slept on,” Feng says. “The mutants would compulsively groom themselves.” The OCD mice were also more anxious. They skulked in dark areas and along the walls of the experimental chambers while the other mice scuttled around open spaces. Seeking shelter in the chambers is a sign of anxiety in the mice, Feng says. “When we gave these mice Prozac, they recovered and the lesions disappeared,” Feng says. But the researchers needed to know what losing SAPAP3 did to the mice’s brains, and Weinberg had the answer. “When you remove one protein from a region in the brain,” Weinberg says, “you may not always see an effect, because other proteins do the same job, or because the protein Guoping Feng you removed didn’t do much. With SAPAP3, it was different: it was the only one of its kind present in a region of the brain called the striatum.” The striatum is involved in addiction and in situations that require resisting temptation or overcoming a strong habit. Not only did the mutant mice have altered synapses that were less able to transmit signals, but Weinberg’s team found subtle defects in the structure of the postsynaptic complexes in the striatum. “My guess is that other proteins may be missing in the synapses of these mutant mice since the scaffolding protein was removed, but that hasn’t been identified yet,” he says. Feng wanted clinching evidence that SAPAP3 A sagittal section of a mouse’s brain. Arrows indicate the circuitry involved in OCD-like behavior. was indeed involved in these behaviors. So his team 32 endeavors
Brett Riggs
The Trail of Tears has left a deep scar on the landscape of North Carolina.
Where the trail has led Scholars are piecing together a surprising new picture of American Indians. By Mark Derewicz
I Gun parts and a pipe found by archaeologists Brett Riggs and Stephen Davis.
n 1783 the Treaty of Paris set the official boundaries of the United States from the Atlantic Ocean to the Mississippi River, and from the Great Lakes to Spanish Florida. American Indians were not part of that treaty. As the United States grew westward, Indians were usually forced from the land of their ancestors. In the stories that follow, researchers shed light on the decline and unlikely resurgence of American Indians, and a Carolina med student inspires volunteers to learn from and help North Carolina’s first people. Right below: Clara Sue Kidwell at age two with her grandmother. Above: Kidwell’s grandparents, Susie Ellen Thompson and Hardin Milam Kidwell.
endeavors 33
Dug from the past
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rett Riggs and Stephen Davis trudged up a hill near Fort Mill, South Carolina, before coming to a level clearing. They started digging, and just below the grass they found clusters of pipe and pottery shards, fragments of wine bottles, and pieces of metal tools—remnants, they thought, of a small group of eighteenth century Catawba Indian homes. But when they tried to find the edge of that cluster, they found a much larger group of artifacts in the nearby forest. Riggs and Davis looked at each other, checked their maps, and realized that they had likely discovered Nassaw, the central town of eighteenthcentury Catawba society. Before that, Nassaw existed only on a very old, hand-drawn map. Riggs and Davis, archaeologists at UNC, measured the bore-holes of clay pipe stems found at the site to determine when they were made. Sure enough, the pipes dated back to the 1750s. Then Riggs and Davis
Metal gun parts found by archaeologists Brett Riggs and Stephen Davis.
34 endeavors
found knives, handmade nails, lead shot, brass kettle fragments, and various parts of flintlock muskets. They uncovered darkened circles of soil where wood posts had held up houses. And they found thousands upon thousands of tiny glass beads scattered everywhere—beads that they knew Catawbas had used for jewelry and embroidery. “It looks like there must have been a brief occupation of this town,” Davis says. “Maybe ten years. We didn’t find the intensity of post holes and other things that you find if people had lived there a while.” “But there was a lot of debris—pottery, beads, and such,” Riggs says, “which means there must have been a lot of people there for that much trash to accumulate in such a short time.” These facts fit the storyline. The Catawbas periodically moved this village to bluffs above rivers and streams. The main Catawba town was always named Nassaw no matter where they moved. In 1759 a smallpox epidemic killed half the Catawba population, forcing survivors to abandon the town that Riggs and Davis unearthed and then to resettle sixty miles downriver. Last summer Riggs, Davis, and UNC students excavated the site; local Catawba children helped sift through hundreds of gallons of dirt to find things that their ancestors had used. Before Riggs and Davis excavated the site, which is just south of Charlotte, Kanawha Development had planned to build a mixeduse neighborhood on a four-hundred-acre tract that includes the archaeological site. An elementary school was planned for the exact location where Nassaw was unearthed. Not any more. The developers changed their plans so that the village site will be preserved as a park. And adjacent to the new neighborhood, York County Culture and Heritage
Museums will build a new museum that will feature installations Riggs and Davis will help create. The artifacts, curated by the Research Laboratories of Archaeology in Chapel Hill, will see the light of day again. Riggs and Davis have excavated three other old Catawba towns, hoping to piece together Catawba history. The tribe had a vibrant economic presence, modeling their pottery after European styles to create a market for their goods in South Carolina. Catawbas leased land to white settlers for profit, and they lived in cabins that were very similar to homes in the back country of the Carolinas. The Catawbas were skilled hunters, fishers, and farmers; they were selfsufficient. But the Catawba population, which numbered about five thousand in the early eighteenth century, steadily decreased throughout Colonial times. They were at constant war with rival tribes to the north. In fact, Catawba Nation was made up of various tribes that had thrived in North Carolina before Seneca Indians continually raided the Piedmont, forcing them southward.
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uring the Revolutionary War, the Catawba tribe joined colonists against the British, fighting under the command of UNC founder William Davie. And for this decision, many Catawba men died, and British soldiers burned down Catawba villages. Riggs says that only about a couple hundred Catawbas were left in South Carolina in the early 1800s. And this, he says, might be why the federal government didn’t force the Catawbas completely off their land during the forced Indian removals of the 1830s. “White settlers assumed that the Catawbas would be extinct within a couple decades,” Riggs says. By the mid-1800s, the Catawbas were living in the cracks of Southern society, contributing economically, politically, and socially. Unlike the major tribes of the South, the Catawbas did not form a government, create a constitution, or otherwise threaten the white establishment.Today some Catawbas live on a reservation that is a small fraction of the land they once called their own. Stephen Davis is the associate director of UNC’s Research Laboratories of Archaeology,
and Brett Riggs is a research archaeologist in the Research Laboratories of Archaeology, both in the College of Arts and Sciences.
Trail of Tears C
hickasaws, Seminoles, Creeks, Choctaws, and Cherokees were all large sovereign nations in the South before the United States was formed. But after the Revolutionary War, state politicians wanted land that Indians occupied. The United States, a very new and vulnerable nation, had little money or will for a protracted war against Indians. So politicians tried something else.
west of the Mississippi River. In today’s vernacular, Green says, this removal policy would be called ethnic cleansing. Cherokees opposed this policy in several ways. They sent delegations to Washington D.C. and presented memorials to Congress. They made their case in the columns of The Cherokee Phoenix, a bilingual newspaper. At the time, Perdue says, “most Americans found it remarkable or unbelievable that an Indian tribe published a newspaper. It generated a great deal of public interest and sympathy for the Cherokee cause.” The Georgia legislature countered by making Indians subject to state law. The Cherokee Nation took one case—against a Cherokee accused of breaking state law—all the way to the U.S. Supreme Court, but the Court ruled that the Nation had no standing. But a second case in which a white missionary to the Cherokees was convicted for violating Georgia law brought momentary
George Washington and Secretary of War Henry Knox wanted U.S. citizens to respect Indian sovereignty. States such as Georgia, where many Cherokees lived, disagreed. What transpired between 1790 and 1840 is a sad and sordid story that Theda Perdue and Michael D. Green tell in their new book, Cherokee Nation and the Trail of Tears. Perdue and Green say that Knox Brett Riggs decided on a policy of “civilizing” the Indians because he thought it could appease tribal leaders and, eventually, Southern states. “For Knox,” Green says, “civilization meant that Indians would give up hunting and warring and become peaceful farmers willing to sell surplus land to white neighbors.” Knox wanted them to learn English, become Christians, adopt republican governments, and live on individual homesteads. The U.S. government agreed to provide livestock in the hope that Indians would slowly sell their vast hunting grounds and use the proceeds victory. Chief Justice John Marshall wrote, “The Cherokee Nation is a distinct comto improve the land left to them. Many American Indians, Perdue says, munity, occupying its own territory, with were not opposed to certain European cus- boundaries accurately described, in which toms. Some Indians embraced Christianity. the laws of Georgia can have no force.” But Georgia authorities refused to impleThey wore Western clothing and learned English. They built toll roads and ferries, ment the decision, and President Jackson did and opened inns for travelers. They engaged not enforce it. “Jackson did not consider tribes soverin commercial farming and bought livestock and farming equipment. Essentially, Indians eign,” Green says. “He considered Indians took what they found useful from Anglo- subjects.” Georgia citizens continued to encroach American culture and passed over whatever they did not. They never agreed to give up on Cherokee land, building new houses their national sovereignty, or most of the and seizing Cherokee homes. At one point, Cherokee Chief John Ross returned from land that the tribe held in common. The “civilization” policy stalled in the late Washington to find a Georgia family sit1820s, so President Andrew Jackson took ting at his dinner table. The family had won a more direct approach: move the Indians Ross’s land in a state-sponsored lottery.
“He rented a room that night,” Perdue says, “and the next morning he found his wife and children in a two-room cabin across the state line in Tennessee.” No Cherokee wanted to leave the East, but a few prominent Cherokees decided to cut their losses. They met with a federal delegation at the Cherokee capital in what is now north Georgia to sign a treaty without their tribal council’s approval: $5 million for millions of acres of Cherokee land. When the tribal council and Ross found out, they deemed the treaty fraudulent and the Cherokee signers traitors. Ross, though, could not convince the federal government to overturn the agreement. By the time the deadline came for all Cherokees to leave their homes on May 23, 1838, only two thousand had done so. At least thirteen thousand remained. U.S. Army soldiers began taking Indians from their homes and putting them in newly built forts. Corn was left unharvested and sometimes dinner was left on the table. Parents returning home from work found empty houses; soldiers had taken their children and the grandparents. Many Cherokees spent months at these forts before they marched to Indian Territory—modern day Oklahoma—along several paths that came to be known collectively as the Trail of Tears. On the eve of his departure, Cherokee William Shorey Coodey said, “At this very moment, a low sound of distant thunder fell on my ear. In almost an exact western direction, a dark spiral cloud was rising above the horizon and sent forth a murmur I almost fancied as a voice of divine indignation for the wrongs of my poor and unhappy countrymen, driven by brutal power from all they loved and cherished in the land of their fathers, to gratify the cravings of avarice.” Thousands died of cholera, measles, whooping cough, dysentery, and respiratory infections. Wealthier Cherokees were not immune. Chief Ross’s wife died outside Little Rock, Arkansas. The Cherokee Nation survived, but its sovereignty had been put to the test, along with the sovereignty of the four other nations of the South. Theda Perdue is a professor of history, and Michael D. Green is a professor of American studies, both in the College of Arts and Sciences. endeavors 35
The end of history W
ith the United States pushing westward during the early 1800s, Choctaw Indians of southern Mississippi had a choice between the lesser of two evils: they could stay on the land of their ancestors, own small individual farms, and dissolve their tribal government, or they could move to Oklahoma—a Choctaw word meaning land of the red people—and keep their tribal government intact. Most headed to Indian country. And for those who didn’t, their land was usually taken from them anyway, says Clara Sue Kidwell, director of Carolina’s new American Indian Center. Kidwell, who is part Choctaw and Chippewa, says that her ancestors from Mississippi were not forced into prison camps as the Cherokees were, but they were forced to move to Oklahoma in large communities with whatever possessions they could carry with them. And they had to leave behind their livestock. Still, she says, they acclimated fairly well to eastern Oklahoma. “Most importantly, the Choctaws had their written constitution; they had their sovereignty,” she says. For a little while, that is. In her new book, The Choctaws in Oklahoma, Kidwell shows how this sovereignty was whittled away. Throughout the 1800s, whites trickled west until the intercontinental railroad led to mass westward migration. Coal was discovered, and towns formed near the mines. Whites pressured Congress to loosen Indian control in eastern Oklahoma, Kidwell says, and Congress responded in the late nineteenth and early twentieth centuries by breaking up the Five Nations into small allotments that were granted to individual Indians and whites. All leftover land was bought up, usually by whites. Kidwell says that tribal leaders accepted this allotment policy at the turn of the twentieth century because the nations might have been left with nothing had they not negotiated with Congress. Also, culture and society were changing for everyone. Many Indians became more interested in per capita payments for their land than in the integrity of the land for its own sake. “I won’t say that all Choctaw people changed,” Kidwell says. “But the leadership changed. Sometimes there were very bitter disputes about allotment. Nevertheless, the Choctaw tribe was converting into a semi-industrialized, moneydriven economy, where self-interests began overriding communal interests.” Kidwell’s grandmother was allotted three hundred acres in south-central Oklahoma, where she wound up marrying a white cattle rancher from Texas in 1910. Years later Kidwell’s father told stories about how her grandfather married her grandmother for the land. True or not, that allotment was prime grazing land. And Kidwell’s grandfather, who earned and lost lots of money in the cattle business, eventually sold bits and pieces of the allotment. The family moved to a small town called Ringling, a long way from communal life. Intermarriage certainly changed the way land was used and sold, Kidwell says, but the really disastrous thing about allotment came in 1908, when the federal government used blood quantum to determine which Indians were competent to manage their land—the more Indian blood you had, the less competent you were deemed. Kidwell says that guardians—often white lawyers, bankers, and upstanding members of society—were put in charge of land that had been allotted to full-blood Indian children. “But these guardians often didn’t have the children’s best interest at heart,” she says. Many children never saw their entrusted allotments. “It was a national scandal.” Clara Sue Kidwell is the director of the American Indian Center at UNC. 36 endeavors
Wendell Long
Choctaw pride W
endell Long was one sevenyear-old Choctaw who did receive a piece of land after the United States broke up Oklahoma’s Five Nations into allotments. He went on to study medicine at Harvard and to marry a Norwegian woman. When he died, his wife sold off the allotment, but the family still owns several other plots. One day some of that land will be passed down to Long’s granddaughter, Valerie Lambert, an anthropologist at Carolina. Lambert was an avid reader growing up in Oklahoma City in the 1970s, and she wondered why her tribe did not resemble the powerful Indian nation of the 1800s. “It was confusing,” she says. “A lot of people acted as if there was no tribe.” As she got older, she saw the tribe get stronger, both economically and politically. It was common knowledge that Hollis Roberts, Choctaw Chief from 1978 to 1997, led the Choctaw resurgence. But Lambert found that this resurgence would not have been possible if not for a young Choctaw named Charles Brown, who led a movement in 1970 to save her tribe from complete collapse. Lambert recounts this effort in Choctaw Nation: A Story of American Indian Resurgence. For much of the twentieth century, many
people, including some Indians, began to think tribes were a thing of the past. They wanted Indian nations officially terminated—that is, to be no longer federally recognized. Tribes could no longer negotiate with the federal government, nor would they receive federal money for educational programs, social services, law enforcement, health services, or resource protection. During the 1950s Choctaw Chief Harry Belvin wanted to dissolve the tribe, sell off tribal assets, and give the proceeds to individual Indians. So he and others worked with the federal government to schedule termination, which after several postponements was set for August 25, 1970. In the fall of 1969 Lambert says Charles Brown found out about the termination legislation and set out to overturn it. He called everyone he knew and formed a youth movement that went door to door in Oklahoma City to inform Choctaws about Belvin’s plan. Brown lobbied Congress and the Bureau of Indian Affairs, and gained hundreds of supporters who made it clear to the
rest of the tribe and the federal government that they did not support tribal termination. Brown cranked out a newsletter and sent it to Choctaws around the country. He gave speeches: he said that defeating termination legislation would mark the rebirth of the Choctaw tribe, that Choctaws were destined for great things. Belvin saw public sentiment tilt Brown’s way, Lambert says, and so Belvin began opposing the termination act, too. One day before termination was to take place, the legislation was repealed. Brown’s vision was realized throughout the next thirty years as Choctaw chiefs, including Roberts, used economic development plans to rejuvenate Choctaw Nation. Casinos, grocery stores, manufacturing plants, truck-service plazas, department stores, and independent businesses all took root in southeastern Oklahoma, bringing in revenue and creating jobs for Choctaws. Tribal assets totaled $14.5 million in 1981 and $144 million in 2002. As a result, roads have been paved, loans granted, and firms
Earning a welcome I
n 2004 two UNC doctors, Ziya Gizlice and Sara Huston, found that Indian adults in North Carolina have significantly higher rates of chronic conditions and risk factors—such as diabetes, asthma, high blood pressure, and obesity—than whites. Indians have less access to health care and a lower quality of life. And in North Carolina—which has the largest Indian population of any state east of the Mississippi but only one federally recognized tribe—Indian tribes are centered in the most rural counties, where there’s less access to health services. That same year, medical student Anthony Fleg started Native Health Initiative (NHI), an organization he codirects with his wife Shannon. NHI sends student volunteers to Indian communities to learn about tribes and partner with Indians on health and education issues. The Flegs had six volunteers their first year. Now they have more than thirty from across the country. But creating NHI wasn’t easy. “Tribes have grown leery of people just coming in for a short time, gathering information for a dissertation, and then leaving,” Anthony says. But he didn’t want to collect data; he wanted to learn and build a partnership. Before Anthony founded NHI, he tried for three years to find an internship with a tribe anywhere in the country. Then in 2002, Navajo Nation in Arizona took him in and he helped doctors study iron deficiency in infants. He also met Shannon, a Navajo. A year
created, including the Choctaw Manufacturing and Development Corporation, which has contracts with the U.S. military. “We were a formidable political and economic presence before the United States was a country,” Lambert says. “It’s almost as if our capabilities and talents had been beaten down for so long that only recently have we been able to reemerge and resume what we believe to be our rightful place on this continent.” Casinos bring in the most money for federally recognized tribes and allow tribes to accomplish what some other communities can’t—such as building a hospital, as Choctaw Chief Greg Pyle did in 2000. When Lambert did field work in Oklahoma, a long-time Choctaw doctor from Oklahoma City told her: “In all my years of medicine, I have never seen a more efficient, more professional, and more outstanding health-care delivery system than the one that Chief Pyle and Gary Batton have built.” Valerie Lambert is assistant professor of anthropology in the College of Arts and Sciences.
later, he saw a listserv posting from a med student in Norway who wanted to volunteer with an Indian tribe. “That was the moment I knew I had to do something about the fact that there aren’t any volunteer programs for students,” Anthony says. He set up a meeting with North Carolina’s Commission on Indian Affairs, which led Anthony to meet Lumbee tribal leaders, who agreed to let volunteers—including that Norwegian student— work with doctors in Pembroke. NHI immediately partnered with tribal leaders to create cooking classes to combat obesity. NHI volunteers shadowed doctors to learn about Lumbee health needs. And Anthony teamed up with pastors, including Bruce Swett, to start diabetes screenings at local churches. “UNC students brought their talents and gifts to the community,” Swett says, “and we knew that if they came here also to learn, then our community would love them back. And that’s what happened.” NHI volunteers helped put together a lacrosse team to increase physical activity for Indian youth. In 2006 volunteers helped screen homebound Indians for diabetes and other chronic conditions. And last summer, twenty-six NHI volunteers helped with eight different health and education projects for five tribes: the Occaneechis, Tuscaroras, Waccamaw-Siouans, Lumbees, and the Eastern Band of Cherokees. Anthony and Shannon Fleg are codirectors of NHI. Anthony is a fourth-year medical student in the School of Medicine; he earned his master’s degree from the School of Public Health in December 2007. Shannon is a social research associate for the Center for Health Promotion and Disease Prevention. endeavors 37
“Half of the world’s reefbuilding corals have already died,” says John Bruno. Even where humans try their best to tread lightly.
AIMS Long Term Monitoring Program
IN HOT WATER
A one-of-a-kind study exposes the sharp decline of coral reefs around the world. By Mark Derewicz 38 endeavors
Bruno, a marine ecologist at Carolina, and graduate student Elizabeth Selig came to this conclusion after two years of compiling and analyzing 6,001 scientific surveys of 2,667 coral reefs in the Pacific Ocean from Indonesia to Hawaii. They found that nearly six hundred square miles of these ecologically diverse underwater forests have disappeared every year since the mid-1980s. That’s about 1 to 2 percent of the world’s coral reefs dying each year, nearly twice the rate of tropical rainforest loss. The Indo-Pacific is home to 75 percent of the world’s coral reefs, which are composed of tiny marine animals. The reefs support thousands of fish species and other aquatic life, and coastal communities depend on healthy coral reefs for fisheries, tourism, and protection from storm surges. “These reefs are incredible buffers,” Bruno says. “You can literally have fifty-foot waves break on a reef during a cyclone, and the waves on the beach are one or two feet high.” When corals die, they leave skeletons that erode quickly. Fish go away; fisheries suffer. And sea walls disappear. “And the next time there’s a hurricane,” Bruno says, “those fiftyfoot waves will slam on the shore.” Bruno and Selig tracked the decline of coral cover—the measure of how much live coral covers the ocean floor in a given area. Coral cover is a key indicator of reef health in the same way that canopy cover is indicative of tropical rainforest health. In places where coral grows, it has historically tended to cover about 50 percent of the ocean floor. But Bruno and Selig found that coral cover throughout the Indo-Pacific declined from 40 percent in the early 1980s to 20 percent by 2003. Today, only 2 percent of Indo-Pacific reefs come close to the 50 percent baseline. This same rate of decline exists in Hawaii, Indonesia, Australia, and all points in between. And Bruno and Selig say that such a region-wide decline is the most surprising result of their research because not all coral reefs face the same dangers. Some coral live in tight quarters, which means that viruses
can more easily infect and kill nearby coral. Some reefs are over-fished and face more pollution and sediment runoff from coastal development and agriculture. Other reefs are isolated and pristine. The Great Barrier Reef off Australia’s northwest coast, for instance, is a protected area. Scientists had assumed that coral cover would be better there. They were wrong. “Coral cover on the Great Barrier Reef was not significantly greater than reefs in the Philippines, where reefs are often thought to be highly threatened and poorly managed,” Bruno says. Coral cover in Hawaii is just as good—or bad—as coral cover in Australia, despite the particular protection policies of the two areas and the fact that the Great Barrier Reef is much more ecologically diverse. “The Great Barrier Reef is in the coral triangle,” Bruno says. “So it’s the center of biodiversity for the whole ocean. It’s where most of the fish species are, and where most of the different types of invertebrates such as crabs and lobsters live.” There are hundreds of different species of coral off Australia’s coast. There are about fifty in Hawaii. “Ecologists had thought that the IndoPacific reefs were dying at a slower rate
than say, Caribbean Sea reefs, which don’t support as many species and face at least as many threats,” he says. “We assumed that the Indo-Pacific was better off. But it’s just not, at least in terms of coral cover.” All this leads to a troubling conclusion: coral decline is likely due to large-scale stressors. In a separate study, Bruno and Selig demonstrated that warmer ocean water can cause coral bleaching and exacerbate coral disease outbreaks.
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ther researchers had studied single reefs over the course of a year and found that warmer ocean temperatures created a breeding ground for coral disease. “But we looked at forty-eight reefs over six years,” Selig says. “That hadn’t been done before.” And they documented just what warmer water can do to a coral. Bruno says, “If you raise the temperature of the ocean just one degree Celsius in the summer, coral can bleach, turn stark white. And if the water remains too warm for too long, the coral will die; you’ll have mass coral die-off.” This is what scientists found in 2005 when the Caribbean Sea stayed warmer than usual
all summer. There was also massive coral bleaching in 1998 when there was a strong El Niño weather pattern. And all over the world, as Bruno and Selig are proving with every piece of evidence they keep in their databases, coral are bleaching and dying faster than previously thought. Pollution from fossil fuel is not only warming the atmosphere and the oceans but increasing the acidity of the oceans, Bruno says, making it harder for corals to secrete their calcium carbonate skeletons, which they must constantly do to keep pace with erosion. “So the implication is that local reef management doesn’t have that much to do with coral cover,” Bruno says. “Local management does affect other things—if you stop fishing, you get lots of big fish on your reef. But it doesn’t seem to affect the measure of the health of the reef. And the reason is probably that managers just can’t manage the big impacts, such as climate change. We need to deal with that at a national and global scale.” e John Bruno is an associate professor of marine sciences in the College of Arts and Sciences. Elizabeth Selig is a fifth-year doctoral candidate in Bruno’s lab. AIMS Long Term Monitoring Program
Death by warming Right: This photo of the Great Barrier Reef shows a portion of a coral reefscape that is still very healthy. Less than 5 percent of the world’s coral reefs are as healthy as this one. Facing page: A coral colony on the Great Barrier Reef that is infected with white syndrome, a disease that is increasingly responsible for the declining health of dense coral reefs like the one pictured to the right.
endeavors 39
Jason Smith
by Mark Derewicz 40 endeavors
Daniel Wallace never thought he’d be a novelist. The prospect seemed so unlikely that he left college to work for his dad. Years later, in 2002, he was brunching with movie director Tim Burton, who was basing a film on Wallace’s novel, Big Fish, the quirky but poignant story of a son trying to know his dying father. The book— a series of myths, mostly— became a best-seller.
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oday Wallace teaches creative writing full-time at UNC and is the author of four novels. His latest, Mr. Sebastian and the Negro Magician, is a story of perception—or misperception—that’s narrated by the most bizarre but lovable circus freaks one magician could ever hope to know. There’s Jenny the Ossified Girl who can’t move any part of her body except her mouth. There’s Rudy the Strongman who isn’t really that strong without the whisky. There’s J.J. the Barker, ringleader of Jeremiah Musgrove’s Chinese Circus, which isn’t actually a Chinese circus. They all tell the story of one Henry Walker, who might be the worst magician ever, or the best. He might have sold his soul to the devil. He might be able to raise the dead. It’s tough to know anything for sure. Wallace’s tale gets more perplexing as the point of Henry Walker’s tragic life comes to light. By the end, you’re left wondering how the heck Wallace pulled off such a trick.
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espite his kooky imagination, Wallace’s decision to leave UNC in 1982 was based on his logical perception of reality. An English and philosophy major, his creative writing potential didn’t overwhelm his professors. None of them pulled him aside to say he could or should be a writer. His talent, it seemed to him, was marginal. And his dedication was suspect. He assumed he’d wind up working some sort of job in the business world. So he cut to the chase and left Carolina to join his father’s import/export business in Japan. He stayed there for two years, making good money, until his father gave him an ultimatum: fully commit to the company with an eye toward taking it over one day, or leave. “I quit,” Wallace says. “Or I was fired, depending on who you talk to.” He came back to Chapel Hill to give writing a shot. “As far as being called to write, or chosen, or feeling as though I had something to say,” Wallace says, “there’s nothing like that. It’s all very selfish. I just like to write.” But it didn’t come easy. Still in his twenties, he read novels and how-to books and wrote all day long. After a year he still hadn’t found any takers for his short stories. But then he read an article in Esquire about Gordon Lish, senior editor at Alfred A. Knopf, who had published Raymond Carver, Barry Hannah, Richard Ford, and many others before anyone had heard of them. “I really needed to figure out where I stood as a writer,” Wallace says, “and Lish seemed like a guy who would tell me the truth and maybe give me some direction.” Wallace wrote Lish a letter, asking to join his summer seminar at Columbia University. Lish wrote back, telling Wallace that working hard is more important than having talent. Promise to work hard, Lish said, or stay home. Wallace packed for New York. “Lish’s idea was that he knew how to write; we didn’t,” Wallace says. There was no writing workshop where students took criticism from peers. Instead students read their stories aloud, and Lish stopped them when he got wind of a troublesome sentence. At that point, the story was dead, never to be read to the end. Then they’d talk for an hour about why that sentence stunk. No one made it past the first sentence on their first try, and lots of students dropped the class. Wallace loved it. endeavors 41
“The main thing that class showed me is that in order to write anything—a story, a novel, a trilogy—it has to happen sentence by sentence,” Wallace says. “Each one has to pass your own personal test of goodness. And if you’re not present for every sentence, then sooner or later everything is going to fall apart. “I looked back at older stuff I had written and could see a sort of nonchalance. A lot of sentences just didn’t mean anything, didn’t push the story forward, or weren’t thought through. There wasn’t anything interesting about them. So I started looking at stories not as whole pieces but as collections of sentences. And that changed everything.” Wallace eventually conquered Lish; he made it to the end of two stories. And Lish pulled Wallace aside to tell him to keep at it; his hard work was paying off. Wallace published three short stories from that class, and several more in subsequent years. An agent named Lisa Bankoff took notice and told Wallace that if he ever wrote a novel, she’d love to read it. He wrote one, and Bankoff loved it. But she couldn’t find a buyer. He wrote two more books that Bankoff didn’t like and a fourth that she really didn’t like. He wrote five in all but remained unpublished as his thirty-eighth birthday approached. Fortunately he and his wife at the time had a successful business— they sold Wallace’s drawings, usually for refrigerator magnets. So they didn’t depend on income from his writing. “The first book did come close to being published, but if it had, I think it would’ve been pretty bad for whatever career I was going to have,” Wallace says. “It wasn’t a good book. It was disjointed. If you were to read it, you’d say, this is somebody’s first book. And I think one of the reasons why Big Fish works, and still works for me, is that it’s not a first book; it’s a sixth book.” So Big Fish was a product of years of practice. But at first, it wasn’t supposed to be a novel at all.
that when I had a son, so I didn’t want to set myself up for failure. I was buying time, just writing, kind of like working out for a sports event that may or may not happen.” But after mythologizing different periods of this man’s life, Wallace began to see that his stories composed an arc: stories from childhood, stories of a married man. “That’s when I got the idea that if I wrote more of these stories and filled in the missing pieces of this guy’s life, it could be a book.” At the center of Big Fish is Edward Bloom, a dying father who told so many stories that his own life became a collection of tall tales. Edward once saved his hometown from a cave-dwelling giant that ate livestock and pets and possibly people. Edward was a businessman, so successful that he purchased a whole town but didn’t change one bit of it because he liked it just the way it was. Everyone loved Edward, and so did his son, William. But every time William tried to get to know his father, Edward told jokes and hid behind stories.
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allace finished Big Fish around the time his dad, a charmer in his own right, went to the hospital for a quadruple bypass. He never came out. All he knew of Wallace’s life as a writer were those five unpublished novels. He never thought his son would find success as a novelist. Although he had been close to Daniel, he had always wished his son had taken over the family business. Holly Wallace
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ack in 1997, Wallace was taking care of his one-year-old son Henry. When Henry napped, Wallace wrote. And, fascinated with Greek mythology, he started spinning myths about one character. “I knew what it took to write a book, the amount of concentration and time, and the way a storyline has to stay in your head for a long time,” he says. “I knew I couldn’t do 42 endeavors
Wallace and his father, E.D. Wallace, in the early 1980s.
“I think he’d be happy now,” Wallace says. “He probably would’ve gotten more press during Big Fish than I did because he would’ve claimed kinship with the father.” Big Fish found an audience, he says, probably because lots of people have an Edward Bloom in their lives. But Wallace also says that he finally stopped trying to write a book that he thought others would want to read and concentrated instead on telling a story he’d want to read. His voice came through more clearly. His style took shape. Screenwriter John August liked Big Fish so much that he told Sony he wanted to write an adaptation. Sony executives read the book, but didn’t see a plot that would translate to the big screen. They hesitated. But August, who had already piled up ideas for his script, kept prodding Sony, which finally relented. This process was kind of backwards for Hollywood, Wallace says. Typically, production companies buy the rights to a book they think can be adapted to the big screen relatively easily. Then they find a screenwriter. Without August pushing Sony so hard, Big Fish would probably never have been made into a movie. Nor would it have been made if August and the producers couldn’t find an A-list director. At the top of their list was Tim Burton, the director of several fantastical films. Burton loved the screenplay. So did Wallace, who wound up with a cameo as an economics professor. The theatrical success of Big Fish in 2003 didn’t change much for Wallace, except that he could afford to buy a house in Chapel Hill, where he still lives with his wife Laura and their son Henry. Today his writing supports him only if he keeps getting published, which, he says, is not a foregone conclusion. All he knows for sure is that he’s worked hard to get to this point in his life, and that he likes how he feels when he writes. So that’s what he does. Now, he’s working on another novel. “There’s no father or magician. It’s about two sisters. One is blind and the other’s not. But I have no idea where the story is going. This morning I wrote seven hundred words, which is great for me. It justifies the rest of my day. Actually, I think I stopped in the middle of a sentence.” e Daniel Wallace is the J. Ross MacDonald Distinguished Professor of English in the College of Arts and Sciences.
ABBAS/Magnum Photos
Outside the U.S. Embassy in Tehran, 1980. Inside, Americans were being kept hostage.
reasons for rebellion
the
Thirty years ago, Iran toppled a dictator. Today it is ruled by a theocracy that’s nearly as unpopular as the regime in 1978. Could history repeat itself? by Mark Derewicz
IRAN, 1978—Millions took to the streets to protest Shah Mohammed Reza Pahlavi, Iran’s dictator. Liberals, communists, moderates, feminists, students, Kurds, Christians, Muslim radicals, and even Iranian Jews all had grievances against the shah. Business owners and oil workers went on strike, crippling the economy. Demonstrations grew so large that the shah’s military and secret police could not quash the rebellion. Some soldiers even joined the protestors. The shah’s grip on power deteriorated so rapidly that he fled Iran on January 16, 1979. A provisional government took over. And Ayatollah Ruhollah Khomeini, Iran’s most famous religious and political dissident, returned from exile. Iranians hoped that human rights would finally be upheld and democracy allowed to flourish. Instead Khomeini’s followers crushed all opposition and installed a strict Islamic government, the only such regime in the Islamic world to seize power through popular revolution. Women were ordered to wear traditional garb and lost several legal rights. Independent journalists were tormented, even killed, and so were outspoken students and scholars. Thousands of people—mostly those deemed loyal to the shah—fled the country. Thousands of others were jailed or killed. In November 1979, after President Jimmy Carter allowed the shah to enter the United States for medical treatment, Khomeini’s most virulent supporters captured sixty-six hostages from the U.S. embassy. New Prime Minister Mehdi Bazargan, whom Khomeini appointed, tried to get the hostages released, but Khomeini refused. Bazargan resigned. And U.S. citizens instantly threw their hate toward Khomeini. endeavors 43
Stateside, Charles Kurzman
was a teenager back in 1979 when he gathered with classmates outside a Washington D.C. mosque. They waved signs: Honk if you hate the Ayatollah. “Lots of drivers honked,” remembers Kurzman, now a sociologist at UNC. But the D.C. mosque was not Iranian or even Shi‘i, the main branch of Islam in Iran. The mosque was Saudi-affiliated, a Sunni house of worship. So protesting outside that particular mosque was like protesting outside a Baptist church because of something the Pope did. “I was embarrassed when a teacher pointed this out to me,” Kurzman says. He then learned that Khomeini wasn’t even an ayatollah, the title for high-ranking Shi‘i clergy. A year earlier, Khomeini had been promoted by his followers to the title of Imam, which set him apart from other leaders. “To religious Iranians, continued reference to the ayatollah was a sign of ignorance or hostility.” As a Harvard undergraduate, Kurzman wrote his thesis on the Iranian Revolution, and continued his work as a Cal-Berkeley graduate student. He found plenty of reasons why Iranians would protest and strike in 1978. Pahlavi was a tyrant who suppressed political dissent and abolished Iran’s multiparty system. He actually said his people weren’t mature enough for democracy. He hoarded vast oil wealth while the lower class suffered. The reasons are endless. But protests, Kurzman knew, don’t usually lead to full-blown revolution. In 1978, as the protests were in full swing, the shah’s regime remained strong. The United States fully backed it. His military was intact, his secret police still brutal. How exactly could protests and strikes lead to the shah’s ouster? Today, anti-government rallies are popping up again in Iran. Could Iran undergo another revolution? Sidling up to Iranians In 1989 Kurzman applied for a visa to Iran to interview participants in the revolution, but his request was denied. Instead he went to Istanbul, where a large business district caters to Iranian importers and tourists. With a notepad and bulky tape recorder, Kurzman approached Iranians and gave his spiel in Persian: “Hello, I’m an American 44 endeavors
student writing a dissertation. Can I interKurzman says that Khomeini called for view you about your experiences during the widespread rebellion in 1977 but the people revolution?” did not respond, much to Khomeini’s chaKurzman conducted over one hundred grin. An entire year passed before demoninterviews and compiled evidence that strations and strikes attracted huge numbers debunked some of the typical explanations of people. And this happened when Iranians for why the revolution had happened. began thinking that the movement could One historical explanation was that actually overthrow the regime. “Only then Khomeini called for protests and people did a lot of people begin to consider the flooded the streets in the name of Islam. monarchy illegitimate,” Kurzman says. Kurzman talked to one man who said that “Only then did they testify to the power he didn’t attend a demonstration against of Islam.” the shah because he had previously planned Today in Iran, demonstrations are relaa family picnic. “I was religious,” he told tively small—but so were the ones in 1977 Kurzman, “but not blindly religious.” before the revolution was in full swing. Another explanation for revolution was Kurzman wrote his dissertation but didn’t that international pressure forced the shah publish a book on his theory until he caught to uphold human rights, which opened the a huge break. In 1999, as an assistant profesdoor for people to organize and publicly sor of sociology at UNC, Kurzman went to protest the government. But Kurzman spoke to people who said they still feared retribution from the shah’s secret police despite international For decades Iranians thought pressure. that supplanting the shah Also, some sociologists assumed that revowas unthinkable. lutionaries met covertly Even Khomeini was doubtful, in mosques to copy and distribute Khomeini’s according to his letters. pronouncements and to concoct plans for demonstrations. But one man told Kurzman that he and others could not gather in mosques because most senior clerics were opposed to such blatant activism. A lot of a conference in Iran. In a bookstore across clerics didn’t even agree that the shah should the street from Tehran University he found be overthrown. an entire shelf of declassified documents, Kurzman found that a lot of people partic- including detailed notes from the shah’s ipated in the revolution because the crowds secret police about opposition meetings and of demonstrators were already so large. One memoirs from religious leaders, moderates, person told him: “I hadn’t planned on taking and liberal oppositionists. It was the mother part in the demonstration; I just wanted to lode, released to the public under Iran’s see what was going on. But when I came and reformist president Mohammed Khatami. saw so many people, I suddenly decided to Kurzman mailed the boxes of books to join in.” Chapel Hill, where he pored over the colOther researchers found similar accounts, lection with a skeptic’s eye for two years. which helped Kurzman conclude that mas- And with help from other scholarly works sive numbers of Iranians joined the move- that had popped up since his dissertation, ment only when they decided there was he published The Unthinkable Revolution enough safety in numbers and only when in Iran, a book that punches holes—lots of they began believing that daily protests and them—in the accepted explanations for the strikes could actually topple the regime. shah’s ouster.
The usual suspects The sociologists were right. At first, international pressure caused the shah to loosen his stranglehold on political dissent. As a result, liberal activists published pro-democracy pamphlets and organized meetings. But Kurzman found that President Jimmy Carter did not push the matter when he met the shah in the autumn of 1977, after which moderate opposition leader Mehdi Bazargan said, “Repression again seemed the order of the day.” Sure enough, U.S. diplomats confirmed that the shah’s secret police “clamped down rather severely in late November 1977.” Liberals retreated back into silence. “There was no political opportunity here,” Kurzman says. Only after the shah’s secret police clamped down did radical Muslims begin to organize. But senior clerics wouldn’t allow them to use the mosques at first. Other sociologists determined that revolution erupted because of Iran’s unique cultural and religious traditions. Kurzman says the opposite: revolutionaries subverted these traditions. For instance, radicals marched during Ramadan and women joined demonstrations. Both were traditional no-nos. Mourning ceremonies for martyrs had always been reserved for prominent figures, such as Khomeini’s son Mostafa, who died in 1977. But radicals began organizing such ceremonies for ordinary people. That was not traditional at all. Neither was setting up microphones for anti-government speeches during such religious processions. Kurzman says that for decades, being religiously devout meant certain things, including supporting the shah. That changed during the revolution. All of a sudden being religiously devout meant that you were opposed to the shah. Some sociologists say that Shi‘i Muslims were more willing than Sunni Muslims to die a martyr’s death. “But self-described ‘fanatics’ who had pledged to give their lives for the cause told me they turned and ran when security forces arrived,” Kurzman says. Most incredibly, extremists forsook centuries of religious tradition when they ordained Khomeini as divinely inspired and the leader of Iran. Revolutionaries wanted one religious authority to rule Iran. That was a new thought—Khomeini’s, actually.
The anti-explanation It would be easy to assume that Iran’s set of novel circumstances—including a sluggish economy—formed a perfect storm for the shah’s ouster. But if so, why couldn’t the U.S. government see it coming? In October 1978, during the heat of protest, a then-secret CIA analysis determined that the shah would remain in power: “The political situation is unlikely to be clarified at least until late next year when the shah, cabinet, and the new parliament…begin to interact on the political scene.” The United States Defense Intelligence
the ground. In October 1978, Stempel said that common Iranians were giving “serious coffee-house thought to other possibilities” besides the monarchy for the first time in twenty years. Washington ignored his warnings. For years, Kurzman says, Iranians had been asking themselves if the opposition movement had a chance of ousting the shah. The answer was usually no. He says that Iranians who lived through the protests and strikes could not afford to sit on the sidelines; they had to predict who to support and how to carry on.
Bruno Barbey/Magnum Photos
Imam Ruhollah Khomeini in exile in France, 1978.
Agency (DIA) agreed: “The shah is expected to remain actively in power over the next ten years.” One hundred days later, the shah was tossed out. Khomeini—a seventy-nine-yearold religious cleric who had been in exile for fifteen years—took over. The CIA and DIA were not alone. For decades Iranians thought that supplanting the shah was unthinkable. Even Khomeini was doubtful, according to his letters. But Kurzman uncovered a telling statement from U.S. diplomat John Stempel that sheds light on what was happening on
For instance, many shop owners and workers went to work even though they knew Khomeini had ordered a nationwide strike. Many people decided to stay at work or return home based on what their neighbors did. Iranians started making decisions on the fly, not necessarily because of politics, culture, or religion. Shopkeepers put photos of Khomeini in their windows not because they loved him, but because they thought revolutionary youths would shatter store fronts that had no photo of Khomeini. And the more people that joined the endeavors 45
strikes and protests, the better Khomeini looked. A lot of people supported Khomeini even though they didn’t like him. Kurzman found this statement from a banker in 1978: “Right now, Khomeini is the best hope to get rid of the current leeches of society. For now, I support him.” Another protester said, “I hate Khomeini… but I hate the shah even more.” Opposition leader Mehdi Bazargan said, “I don’t believe that religious scholars can run a government.” A month later he changed his mind. Kurzman says that people from all walks of life began to see Khomeini as a viable alternative to the shah. And when they began believing that protests and strikes could actually dethrone the shah, the movement attracted more and more people who had been sitting on the sidelines. Then the rebellion reached a critical mass. Millions of Iranians brought their country to a screeching halt. The shah was forced to flee. But why did so many Iranians support Khomeini? “On the one hand, Khomeini downplayed his vision of an Islamic government during the protests and strikes,” Kurzman says. “He restrained himself in public pronouncements and said other things instead, things about democracy and anti-imperialism that people wanted to hear.” Khomeini even said that he would retire or play a small advisory role after the revolution. “On the other hand,” Kurzman says, “the other groups—communists, liberals, moderates—felt that they could take advantage of this widespread movement, which they thought presented the best opportunity to overthrow the shah. Then they’d take
advantage of Khomeini, whose rule they thought would be a short-lived transition to something else. And all these groups had a different vision of what that something else would be.” They were united in their hate for the shah, but not in their view of governance, and not organizationally. Khomeini’s supporters crushed them. The hereafter Today Iran is arguably the best example of a democracy in the Middle East outside Turkey and Israel; Iranians elect their Parliament and president. Even so, Iran is still ruled by a theocracy headed by Grand Ayatollah Ali Khamenei. And no matter what President Mahmoud Ahmadinejad says— and he has said many outlandish things—he does not call the shots when it comes to foreign policy. Khamenei does. The United States now has Iran in its crosshairs because of Iran’s alleged uranium enrichment program and military support of Shi‘a militia inside Iraq. But Kurzman doubts that the United States will attack Iran because he doesn’t think U.S. military and mid-level civil servants will go along with politicians who want all-out war with Iran. And Kurzman doesn’t think the odds for another revolution are very good, either. There are signs, though, that Iranian society is evolving, he says. In 2003 Kurzman created a survey to study Iranian attitudes toward gender equality and hired a private research group in Iran to implement it. The results show that a majority of Iranians say they are feminists. “Even a majority of men say they’re feminists,” Kurzman says. “Even a major-
ity of older, uneducated men say they are. Something has changed over the past quarter-century.” In 2007 a women’s rights campaign called Change for Equality sent women door-todoor seeking one million signatures for a petition demanding an end to discriminatory laws. Iran also has a vibrant democracy movement that speaks for the millions of disillusioned Iranians who weren’t happy with the changes brought by the revolution. There have been pro-democracy and women’s rights rallies at Iranian universities. And there is a strong reform movement, though political reformists in Parliament have been marginalized. Iran may be at a crossroads. Sixty percent of Iranians were born after the 1979 revolution, and most students are not passionate supporters of their government. In one recent display of antagonism, Iranian students burned a photo of Ahmadinejad when he gave a talk at a school. But students do not burn pictures of the Supreme Leader. For that, they could be jailed or killed. Kurzman is quick to point out that these examples don’t mean that a revolution is inevitable any more than massive U.S. peace protests will end the war in Iraq. “Could any country have a revolution at any moment? Yeah,” Kurzman says. “There’s plenty of latent sentiment that can be used against a lot of governments. But revolutions are rare and they don’t usually happen when you want them or expect them.” They’re unpredictable, and as Iran shows, so are their outcomes. e Charles Kurzman is an associate professor of sociology in the College of Arts and Sciences. Jason Smith
Kurzman: Something in Iran has changed over the past quarter-century.
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in print American Transcendentalism: A History. By Philip F. Gura. Hill and Wang, 365 pages, $27.50.
Earnest and fiercely optimistic. Transcendentalists, who included in their number such poetically polemical firebrands as Ralph Waldo Emerson and Henry David Thoreau, pursued with a passion the most fascinating ‑ism in American culture.
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ranscendentalists weren’t keen on conforming to doctrine, and they didn’t all sing out of the same hymnbook, but they did generally hold a few notions in common. A human being, they believed, possessed in his or her experience and nature the aptitude for truth and spiritual enlightenment. Even in the rough-hewn heart of a brandnew nation, an individual could rise above brute appetite and the cruel machinations of industry and government, attaining the spiritual altitude required to reform society and do right by one’s fellows. For its era, this was a profoundly compelling idea, and it sent a jolt of energy into American religion, literature, politics, and thought. It also moved people to action. Transcendentalists opposed slavery, argued for women’s rights, stood up for oppressed laborers, and agitated for all kinds of reforms in religion, education, politics, and law.
Transcendentalism was a big tent, and it attracted a motley crew of kooks and crackpots along with some of the nation’s leading lights. Emerson, describing a confab of religious reformers, wrote, “If the assembly was disorderly, it was picturesque. Madmen, madwomen, men with beards, Dunkers, Muggletonians, Come-outers, Groaners, Agrarians, Seventh-day-Baptists, Quakers, Abolitionists, Calvinists, Unitarians, and Philosophers—all came successfully to the top, and seized their moment, if not their hour, wherein to chide, or pray, or preach, or protest.” As an ambitious movement to unify and reform society, transcendentalism failed, and its influence waned during the latter half of the nineteenth century. After all, it’s hard to codify social conduct if an individual has the sole authority to decide what’s right and wrong. But if the ism itself is now mostly a
Figure derived from William B. Greene’s Transcendentalism (1849).
matter for historians, its ideas and ideals still exert a powerful influence on American culture. Today’s campaigners for social justice, environmentalism, human rights, individual liberties, and liberal education fortify their arguments with values transcendentalism put on the front burner almost two centuries ago. If there’s one quality that unites past and present in this enduring tradition, it may well be optimism, Philip Gura concludes. And sure enough, the fundamentally optimistic belief that people can rise above their plight and make the world better shines as a bright, warm sun on every chapter of this truly American story. —Neil Caudle Philip Gura is the William S. Newman Distinguished Professor of American Literature and Culture. endeavors 47
Auction fever Everyday eBay: Culture, Collecting, and Desire. By Ken Hillis, Michael Petit, and Nathan Scott Epley. Routledge, 328 pages, $24.95.
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wo Christmases ago I gave my mom a few stretched-out Coke bottles with long twisty necks. She loved them. Last year I plunked an original G.I. Joe Cobra Commander inside a scotch tumbler for my brother—these days he’s flying jets over foreign countries, and it was only when he opened that box that he forgave me for snapping in half his original original Cobra Commander when I was eight. This year, it’s a 1979 issue of National Geographic for my dad—he accidentally threw his out. You can find all this stuff in one place: eBay. The online auction site has evolved into a global economic and cultural phenomenon, according to Ken Hillis and his colleagues.
In their book, Everyday eBay, they talk about eBay’s place in the global economy, as well as what makes it so darn irresistible (besides the vintage Pez dispensers). It’s the experience that makes eBay stand out, Hillis says. It’s not just about buying something, whether car or kitschy bauble. People will always pay for those things, but they’ll pay a premium for an exciting buying experience. And some eBay auctions can be as intense as a rugby game. Anybody can sell through eBay—you could even run a business that way. Each of a seller’s listings are like mini-web-sites that fall under eBay’s umbrella, and that fosters brand loyalty, Hillis says. So no matter what you’ve found or who sold it to you, as long as you had a good time buying it, it’s eBay you’ll come back to. —Margarite Nathe Ken Hillis is an associate professor and assistant chair in the Department of Communication Studies in the College of Arts and Sciences. Skeletor action figure, circa 1981. Find one just like it on eBay—prices range from 99 cents to $3,892.53.
Normal: the enemy of great
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he mechanics at the General Electric airplane engine factory in Durham, N.C. are strange. They’re obsessed with being the best. They devise new ways to assemble engines so they can limit defects and save time. They create teams that are in charge of their own budgets. They rearrange their schedules to meet delivery goals. They report directly to the plant manager—no middle managers. They meet for an hour every single morning, and they themselves hire new mechanics, spending twelve hours on a single candidate. They also rotate into leadership roles so that every one of them attends GE business meetings. These are bizarre traits for a group of mechanics, says UNC business professor Daniel Cable. In his new book, Change to Strange, Cable shows how to create a strange band of workers that will make something valuable and difficult to imitate. 48 endeavors
Change to Strange: Create a Great Organization by Building a Strange Workforce. By Daniel Cable. Wharton School Publishing, 174 pages, $25.99.
During a five-year stretch, those GE mechanics reduced the cost of producing a CF6 engine by 10 percent every year. They reduced the average number of defects by 75 percent—from four per engine to one. “They did not miss one on-time shipment in thirty-eight months and five hundred engines,” Cable says. “Do you think that Boeing, their largest customer, noticed 75 percent fewer defects and immaculate ontime delivery?” You bet. During the airline slump between 2001 and 2003, the Durham Engine Facility did not lay off one mechanic and remained profitable when other factories slumped. Cable’s book has dozens of strange examples that all have one thing in common: they show that creating and keeping a strange world-class workforce isn’t easy. Otherwise, everyone would do it. —Mark Derewicz Daniel Cable is Townsend Distinguished Professor of Management and Behavior/Strategy at the Kenan-Flagler Business School.
endview Dan Sears
The Guest of Honor Several hours after geneticist Oliver Smithies received a call from Stockholm informing him he and two other scientists had won the Nobel Prize in medicine or physiology for their work in gene targeting, colleagues and admirers gathered to honor Smithies with an impromptu celebration at the Lineberger Comprehensive Cancer Center. Smithies said he was happy to have made so many other people so happy. In this photo, he is just below the center of the frame, speaking to a gentleman wearing a suit.
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Office of Information & Communications Research & Economic Development CB 4106, 307 Bynum Hall Chapel Hill, NC 27599-4106
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endeavors
Page 26: What good does it do us to be happy?
Page 6: Your ancestors may have worked in a
Page 40: Big Fish author Daniel Wallace says he
Barbara Fredrickson may have figured out why people evolved positive emotions. Photo by Jason Smith.
North Carolina textile mill—and may have started at a younger age than you’d guess. Photo by Lewis Hine, courtesy of the Library of Congress.
never felt like he was chosen to become a writer. He just likes to write, one sentence at a time. Photo by Jason Smith.
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