Study the Clones First

Twin research is finally beginning to reveal what really makes us tick.

By Jeff Wheelwright, Chris Buck|Monday, August 02, 2004
RELATED TAGS: GENETICS
twins-opener
twins-opener

Casey (left) and Kayla Heim, age 9, inhabit a world of twins. Their best friends are twins, and they even have custom-made twin dolls. The sisters are participating in a twin study of family dynamics, cooperation, and other behavioral traits.

All roads lead to me,” says Nancy Segal, as the car turns down a residential street just south of Los Angeles. On her way to visit a favorite set of identical twins, she is not bragging about her status. If you are a scientist or a journalist pursuing the characteristics of twins, sooner or later you will come across Nancy Segal, the doyenne of didymology in America.

The 53-year-old psychology professor is the author of an everything-you-wanted-to-know book called Entwined Lives: Twins and What They Tell Us About Human Behavior. She writes a bimonthly news column about notable twins in academia, the arts, and sports for the journal Twin Research, and she directs her own behavioral studies of twins from the helm of the Twin Studies Center at California State University at Fullerton.

Part of Segal’s authority comes from being a twin herself. Her sister, a lawyer, lives on the other coast, in New York City. The two are fraternal twins and not much alike.

“Ah, this must be the right house,” she says, nodding at a minivan parked in a driveway. “Mothers of twins always have vans.”

Inside the house are 9-year-old Casey and Kayla Heim and their beaming parents. The two girls, who are genetically identical, are dressed alike for the occasion. Monozygotic twins can easily confuse a stranger, but sometimes a clue lies in their mirror-image features, such as hair that whorls in opposite directions or birthmarks on opposite sides of faces. Kayla has a mole on her left cheek, and Casey has the same mole on the right side of her neck. When addressed, the twins speak almost simultaneously, as if there is an echo in the room.

“When’s your birthday?” they are asked.

“November 11th,” they answer. Even the month and day are twins.

Professionals and the parents of twins often remark on the special bond between identical pairs—how as children they act and communicate on the same invisible wavelength. They may even speak to one another in a private idiom. Sitting across the dining room table from the Heim twins, Segal and an assistant are testing the sisters’ cooperation through games called Island Survival and Prisoner’s Dilemma.

In the first game a barrier is placed between them, and each girl, stranded on her “island,” selects three cards from a deck. The cards depict items, like food or matches, that they think they will need for survival. The twins don’t pick the same three items. But in the second part of the game, the negotiation, which is a test to see who dominates whom, Casey and Kayla quickly agree on the three choices.

An extraordinary result occurs in the next game. At Segal’s direction the girls sit with their backs to each other. For each round of the game, they are asked to hold up either a red or a blue flag. The goal is to win the most points. If both display the same color flag, each receives the same number of points. Two red flags are worth one point to each contestant; two blues merit three points each. But a red flag matched against a blue garners the red twin five points while her blue sibling gets none. Thus the game permits either competition, if a red twin pulls the rug out from under a blue, or bland cooperation.

Time after time Casey and Kayla put up red flags. (As they acknowledged in the review session afterward, they intended to tie each other or to let the other twin win.) But suddenly, having raised a dozen red flags in a row, each girl throws up a blue. Jaws drop around the room. How did they do that? When the game ends after 25 rounds, their scores are exactly tied.

Segal doesn’t try to explain such spookily synchronized outcomes, but her studies suggest that the harmony between identical twins stems in large part from shared genetic identity. That is, their cooperation is inherited as much as it’s learned. Other students of twins have found strong genetic components of behavior, personality, and intelligence. Twins also shed light on the heritabilities of more objective conditions like heart disease and the physical capacity for exercise. In short, virtually any human trait, when brought into focus through the dual lenses of twins, can be traced to the hardwiring of genes.

“They are a beautiful experiment in nature,” says Richard Fabsitz of the National Heart, Lung, and Blood Institute. Fabsitz has followed the risks of heart attack, stroke, and now Alzheimer’s disease in a group of twins who served in World War II. “They’re born on the same day,” he says, “and they’re reared in the same family. When you study twins, you’re getting rid of the extraneous factors.”

Alike and different in ways that scientists can dissect, twins provide grist for the long-running debate about nature and nurture. The idea to use them germinated 130 years ago in England, when Sir Francis Galton, a cousin of Darwin’s, wrote, “their history affords means of distinguishing between the effects of tendencies received at birth, and of those that were imposed by the circumstances of their after lives; in other words, between the effects of nature and nurture.”

“Twins tell us what might be genetically controlled and what might not be,” explains Fabsitz. “Before we had tools of molecular biology, twins were the early genetic studies.” However, as a body of work it has a horrible skeleton in its closet. In the 1930s and ’40s the Nazis perverted the science of twins to further their racist agenda. For years geneticists have struggled to overcome the stigma of those grotesque experiments.

Today in the United States there are at least a dozen twin registries that researchers draw upon for both biomedical and behavioral studies. The world’s largest collection is in Sweden, with 140,000 pairs on file, counting both dead and living twins. The Danish national twin registry, which is celebrating its 50th anniversary this summer, includes health records of pairs born as long ago as 1870. In Australia, another leader in twin studies, researchers have surveyed 30,000 pairs, looking at everything from their drinking habits to male-pattern baldness to the incidence of melanoma. Sri Lanka, Italy, Korea, and China are just getting twin registries started.

twins-barrett-rotating
twins-barrett-rotating

Jason (left) and Danny Barrett are 11-year-old identical twins with autism. Both are participating in a study of the disorder.

The 21st-century studies of twins have gotten a shot in the arm from new molecular technologies. By merging national samples into an international database of DNA, twin researchers hope to pinpoint not only the genetic bases of mankind’s common diseases but eventually to locate the sources of traits like the Heims’ unique form of cooperation.

Identical twins are called monozygotic because they spring from a single zygote, the technical name for a fertilized egg. After combining the genes of the mother’s egg with those of the father’s sperm, a zygote starts to develop into an embryo. At some point during the two weeks following conception, a zygote may split into genetically identical halves. These continue growing as twins. Any further splitting leads to monozygotic triplets, quadruplets, and so on.

In fraternal twinning two zygotes occur simultaneously, because a double ovulation has taken place and separate sperm have fertilized the two eggs. Genetically speaking, the relationship between a pair of fraternal twins is the same as between ordinary brothers and sisters. The only difference is that dizygotic (two zygote) twins start life at the same time. Fraternal twins may be of opposite sexes; monozygotic twins are of the opposite sex only in the rarest circumstances.

For nature-nurture researchers, the distinction that matters is that fraternal twins share on average only half the DNA that identical twins do. This permits a simple exercise, known as the classical twin method, in which scientists compare sets of identical twins with sets of fraternal twins. Assuming that the two types of twins display different responses to the same test, a ratio can be calculated between genetic and environmental influences for the trait under study.

The first published demonstration of the method was a study of skin moles. In 1924 Hermann Werner Siemens, a German, theorized that any condition that could be inherited should be more concordant in identical twins than in fraternal twins. Concordance is a measure of the similarity between two individuals. If genes dictated the formation of skin moles, siblings with the same set of genes ought to be more concordant in moles than siblings of different genetic mixtures. Indeed, in Siemens’s survey of twins, the monozygotic pairs—regardless of the number of moles each displayed—were closer in count than the dizygotic pairs. The difference was held to be proof of moles’ heritability.

It is because the environment intervenes that identical twins don’t have precisely the same number of moles. In the broad sense, “environment” is a way of saying that identical twins lead nonidentical lives. Subtle and unequal pressures, starting even in the womb, will cause them to differ.

Since the method for comparing identical and fraternal twins was popularized, both biologists and psychologists have had a field day estimating the relative contributions of genes and environment to the formation of human traits. Because the two forces in the nature-nurture paradigm can be added together to account for the whole, if you determine the one, you can figure the other at the same time. What follows is an arbitrary catalog of results from the literature. It’s important to remember that all numbers are derived from dozens or hundreds of sets of twins and do not describe any one individual.

Height is said to be 90 percent heritable, which means that the environment, such as childhood nutrition, has only a 10 percent effect on whether you’re going to be shorter or taller. General intelligence is about 50 percent heritable, as are various categories of personality. The risk of developing asthma is somewhat genetic, which may surprise those who look for culprits in the environment. The risk of developing autism, according to one study, is more than 90 percent heritable because the concordance for autism is high in monozygotic twins and low in dizygotic twins. The heritable component of cancer is quite low, notwithstanding the discovery of genes for particular tumors. The risk of developing post-traumatic stress disorder after enduring a terrible event has 30 percent to do with your genetic makeup.

Even such subjective traits as job satisfaction are influenced by genes. Whether or not you are happy at work is 70 percent due to the nature of your job and to the aptitudes and attitudes about work that you have acquired since birth. But your DNA may influence as much as 30 percent of your outlook about your job.

To weigh the influence of the environmental half of the nature-nurture equation, twin researchers use a second technique: the co-twin control method. These studies assume that if the genes of identical twins are the same and yet the individuals are somehow different, the environment has to be the decisive factor. Something like a disease or a critical experience has happened in the life of one sibling that didn’t happen in the other’s.

In their decadelong study of chronic fatigue syndrome, an illness of exhaustion and pain affecting mainly women, University of Washington researchers Dedra Buchwald and Jack Goldberg have brought two dozen identical pairs of twins to Seattle for examination. The team previously established through a classical twin study that chronic fatigue has a genetic component. (The identical pairs were more concordant in contracting the illness.) Yet in this particular set of monozygotic twins, one sister had the symptoms and the other did not. Why?

Tami Spangler and Pam Judy, whose maiden name is Nyborg, arrived for testing last February. Forty-two years old, Tami and Pam still live in the same Idaho town where they were raised and see or talk to each other nearly every day. They might have been the Heim girls grown up. On any given topic each woman appears to know what the other is about to say, and currents of emotion, mainly laughter but also tears, break mysteriously through the surface of their conversation. Like other identical pairs, they have a favorite twin story to relate: When Pam went into labor with her first child, Tami, miles away and unaware of her sister’s condition, felt pains in her stomach.

twins-asarnow
twins-asarnow

Seymour (left) and Martin Asarnow, 78-year-old identical twins, are part of a twin registry of U.S. World War II veterans, which contains data on 26,894 veteran twins—11,832 identical and 15,062 fraternal.

Although the Nyborg twins did not go separate ways—far from it—life stepped between them. Pam dated more, married sooner, quit college, had kids first, paid more attention to her looks and clothes. Tami stayed in college, was a bit more serious, a bit less social, and she got better jobs. Both were dynamos, to hear them tell it, mothers who took on a million things at once. Both had gathered weight in the hips, Pam more than Tami. Both were cheerful in spite of setbacks. Pam was the twin who developed chronic fatigue syndrome.

Over a week the twins were subjected to medical tests and psychological interviews. They rode stationary bicycles wearing lung monitors, they slept with electrodes on their skulls, and they plunged their arms into a cooler of ice water and (each twin out of hearing of the other) reported on the level of the pain. Pam appeared to be more sensitive to pain.

The beauty of the co-twin method is that the healthy twin serves as the control for the sick twin. Control in this context means to remove genes from the equation, in the way that two equal quantities cancel each other out. Also, differences in the twins’ childhood environment are removed, because it’s assumed that both women were reared in the same way and ate the same food. Buchwald, the lead investigator, explains: “It’s been very unclear what group is the best control for chronic fatigue syndrome. Everyone’s struggled with it. Other researchers have used healthy people, depressed patients, even multiple sclerosis patients. No one knew what group to use for comparison. And none of those groups were controlled for environment or for genetics.”

The ultimate goal is to grasp the underpinnings of the disorder. If chronic fatigue syndrome has a signal—a distinct biological or psychological feature—Buchwald and Goldberg hope that the co-twin experiments will detect the signal amid the noise of human variation. The note that is most revealing so far is the capacity to consume oxygen during exercise. The researchers learned that the ill twin of the pair couldn’t pedal the bike as long as the other. Of course, individual fitness has a role, yet a person’s maximum oxygen capacity is largely inherited, according to—what else?—studies of twins.

The surprising finding is that, on average, the monozygotic twins in the University of Washington study, both those with chronic fatigue and those without, fall below normal in exercise capacity. The stationary bike tests have produced a biological clue, but it still doesn’t explain why only one twin in each pair got sick.

The research by Buchwald and Goldberg is hands-on experimentation, entailing the physical manipulation of twins, as opposed to simply observing their behavior or questioning them about their health. The researchers are well aware of twin experimentation’s ugly past.

Before World War II, twin studies were conducted in the Soviet Union, England, and the United States, but Germany was the site of the most advanced work. The world’s leading twin scientist was Otmar von Verschuer. He wrote a book on tubercular twins, arguing that susceptibility to the disease had a genetic foundation. Von Verschuer compiled a large file of twins in the Berlin area, in effect the first twin registry, and he compared the children for features like lung capacity and intelligence.

In the 1930s Von Verschuer headed the Institute for Hereditary Biology and Racial Hygiene in Frankfurt, where his favorite graduate student was Josef Mengele. The German scientists believed in eugenics. Adolf Hitler’s rabid program of eugenics required the improvement of the so-called Aryan race and the elimination of other “races” that were deemed inferior, especially Jews. Thus Von Verschuer, Mengele, and their colleagues were commissioned to find measurable ways of telling the races apart.

Twin studies conducted at the Auschwitz concentration camp in 1943 and 1944 became a central part of this effort. Mengele personally picked pairs from the crowds of incoming prisoners and performed grisly experiments on them. He would subject one twin to X-rays, blood transfusions, or bacterial injections and not the other, and then look for differences in their organs. He listed the eye colors and other features of twins of several nationalities, trying to tell which traits were genetically fixed and which might be malleable. Geneticists now know this was a scientifically doomed project, since the genetic variation within any ethnic group far exceeds the variation between different groups.

Mengele’s notes and findings were lost. Good riddance, say those who work with twins today, most of whom cannot bear to talk about Mengele. In the aftermath of World War II, scientists shied away from a biological or inherited framework for people’s differences. The nature-nurture pendulum swung toward environmental causes of disease—industrial pollution for cancer, for example. Autism was believed to be caused by bad parenting—a failure of the home environment, not an innate deficit. Learning and conditioning were held to be the font of all behavior, not genes. Statisticians reexamined the body of work on heritability in general and declared the sample sizes too small to support the nature-nurture statistics. Worse, fraud appeared to sully a celebrated British study of twins’ intelligence.

Twin studies did not get back on their feet until 1979. Psychologist Thomas Bouchard of the University of Minnesota, fending off comparisons with Mengele, founded the Minnesota Study of Twins Reared Apart. Bouchard helped introduce a new study approach by systematically finding and following adult twins who had been separated since their early childhoods. The first pair to be scrutinized were the famous “Jim” twins, two identical brothers who reunited in 1979. Not only were both named Jim (a coincidence of their adoptions) but they also shared a taste for woodworking, bit their fingernails to the nub, had identically named sons, smoked the same brand of cigarettes, drove the same cars, and held the same kind of job. Growing up, these twins had no experiences in common, yet they had turned out intriguingly the same.

twins-sanchez
twins-sanchez

Virginia and Elizabeth Sanchez, 22-year-old identical twins, are participating in a study of behavioral traits among twins. Virginia says she and her sister are very similar.

The Minnesota studies of the inheritance of IQ and other traits were “hugely important in changing people’s minds about the roles of genes and the environment,” says Nick Martin, an Australian who edits the journal Twin Research. “These studies had great cumulative weight.” Nancy Segal, who trained with Bouchard, points out that the study comprises 134 sets of twins at present, 80 of whom are identical. Objections sometimes are raised that twins from the same household are not innately similar but merely copy each other or learn similar behaviors from their parents or peers. The Minnesota design takes copying and learning off the table.

In her recent work at California State University at Fullerton, Segal has gone Bouchard one better. She has assembled a group of what she calls “virtual twins.” These are unrelated children of the same age—most often both are adopted—who are being brought up together. “Virtual twins share environments but not genes,” she says, “and that makes them the inverse of monozygotic twins reared apart.” Both kinds of twins—fraternal as well as identical twins such as the Heim girls—are compared with sets of virtual twins.

In her study, Segal has found that the virtual pairs are most dissimilar in IQ and temperament, especially in contrast to the biologically identical sets. “Genes versus environment—people say it’s been asked a zillion times,” Segal says, “but the question hasn’t been looked at in quite this way before.”

In the new century the gene once again is riding high. If twin researchers are going to nail down the heritability of human traits, they must uncover specific genes: the pieces of the DNA molecule that are important to, say, altruism and cooperation or that set our blood pressures and baldness patterns. Finnish geneticist Leena Peltonen says: “Twin researchers are a species of their own, and they haven’t been integrated with the molecular geneticists as much as they should. They’ve been making their bread on monozygotic versus dizygotic differences. It’s a bit trivial.”

Nancy Segal and Nick Martin acknowledge that progress in finding genes through twin studies has been next to nil. Therefore they look to the Human Genome Project and to scientists like Peltonen who manipulate DNA. Their traditionally low-budget science, which needs only pencil and paper to tally shared traits in the classical twin studies, has entered the high-tech world of genetic epidemiology, which traces the power of genes to influence the health of populations. “Our work will become less inferential,” says Segal, “but it’s going to take some time.”

A good example of the evolution can be seen in approaches to cigarette smoking. Twin researchers in Sweden and the United States started to study smoking behavior in the 1950s, and in due course they demonstrated that identical twins were more likely than fraternal twins to have in common either smoking or nonsmoking tendencies. Here was simple evidence of behavioral genes at work. As they continued to follow the twins in the databases, researchers showed that a twin who smoked was likely to die earlier than a twin who didn’t. Whether the twins were identical or fraternal didn’t have an effect; smoking usually hastened death no matter what amount of genes were shared. Here was evidence that the environment, in the form of cigarettes, could prevail over any genes for longevity.

At SRI International in Menlo Park, California, twin researchers have delved into the physiology of smoking, acting on the theory that certain people can metabolize nicotine faster than others. The idea is that the fast metabolizers may become addicted more readily. About 70 percent of this trait has been determined to be heritable, at least according to the different responses of the pairs in the SRI study.

And some relevant DNA has been uncovered. A team at Virginia Commonwealth University in Richmond recently found that three genetic polymorphisms—variants in the “spelling” of a certain gene—are connected to nicotine addiction. For their raw material the team analyzed the DNA of 688 twins from the Mid-Atlantic Twin Registry, one of the venerable collections in the United States.

The gene that the Virginia team identified is not the whole story behind nicotine addiction, because all such conditions and the majority of common diseases involve multiple genes and multiple interactions with the environment. Yet as a small, discrete piece of the biology of smoking, the DNA finding moves twin work far past such survey questions as, Does your father smoke? Your mother?

Fraternal twins are the best choices for molecular analysis. Say that a pair of dizygotic twins is discordant for smoking. Biologists will focus the gene hunt on the stretches of DNA where the two siblings differ. Of course, the approach won’t work with monozygotic twins, whose genes are identical. But if a promising gene shakes out of the fraternal study, it’s simple enough to look for the same gene in the identical pairings.

That is the strategy behind the world’s largest twin scan just under way in Europe: GenomEUtwin, it’s proudly called, the middle letters standing for the European Union. Directed by Peltonen, the study represents a collation of national twin registries from Denmark, Finland, Italy, the Netherlands, Norway, and Sweden. Recent entries from Great Britain and Australia make for a grand total of 800,000 twins. The siblings in the twins’ families will extend the health database even further. The first run-through of GenomEUtwin will search for genes that control height, a trait everyone can relate to, but the genes for humanity’s common diseases are the real prizes. By 2010 the scientists hope to have some of them.

A universal truth about twins is that they seem to like the attention of scientists. No country requires them to enroll in studies or make available their DNA and family histories, but over the years most twins have been eager to help. Twin Research editor Martin says: “Twins are sufficiently rare as to feel themselves special and pleased that researchers take an interest in them but not so rare as to be freaky. So their cooperation is often surprisingly good.” Then again, cooperation is in their genes.

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