When I talk to Kathy on the phone, in July 2008, she has survived eleven years, despite being initially told she would die in three. “Telling my sister the diagnosis was devastating,” Kathy recalls. “I think when you grow up as a twin, you believe the twin will always be there for you. I had to explain that I wouldn’t be. I had already researched the disease; everything about it was ‘incurable,’ ‘fatal,’ ‘only going to live two to three years.’ By the time I made that phone call to Karen, I knew I was going to die. I said to her, ‘You know I’m usually a fighter, but there’s no hope with this disease.’ She refused to accept that. She was like a pit bull, calling everyone she knew, doctors, sending articles, helping me figure out what my next step should be.”
Karen not only used her contacts at Time Inc. to mount the first of many successful fund-raisers but she didn’t hesitate to give Kathy her bone marrow for a transplant. They had to confirm they were identical—”We’d never known for sure,” Kathy says—in order to make sure they were a match. “That moment was a turning point for me,” Kathy tells me. “I thought, Okay, this is the most horrible thing that could have happened, but maybe there’s hope.”
Hope was an understatement. The transplant put her into “complete response,” which means doctors can’t find the cancer cells anymore. That doesn’t mean the cancer is gone. “I can relapse anytime,” Kathy explains. But for the time being, she’s alive, feeling stronger, and thrilled to be able to watch her daughter’s cheerleading squad and her son’s all-star games. “With an incurable cancer, you always live your life on the edge,” she explains. “I know that whatever I’m seeing could be the last time I ever see it. So I’m just happy watching any moment that’s important to my family. Do I think my son will get into another all-star league? Yes. Do I think it will happen again in my lifetime? No.”
Kathy Giusti has no resentment that she was the twin who got sick, but she is curious about the biological or genetic reasons for it. “There are times when I say to myself, Something else must have happened to me,” she says. “I do believe there are viruses—like mononucleosis—that happen to you along the way. Or I could have a weaker immune system. I tended to get sick more than Karen when we were kids.”
When Kathy was first trying to entice researchers to study her cancer, she leveraged her twinship, knowing that scientists hunger for cases where identical twins are discordant for a chronic disease. But some doctors, according to Kathy, were initially reluctant about exploiting the information Karen carries inside her. “The last thing anyone wants is to take a healthy twin and make her sick,” Kathy explains. She said that she and Karen had to convince researchers that they were not only willing to accept the risks but eager to do so. “It’s one thing to create a foundation to fund the research,” Kathy says. “But we wanted to be the research. I think twins care so much about each other, they’re willing to do anything.”
In 1997, Kathy moved to southern Connecticut to live near her sister, in large part because she wanted Karen close enough to help raise her two children, Nicole, then four, and David, then a year old. “If anything were to happen to me,” she says, “I knew she would be there to help my husband, Paul. Karen and Paul are the two rocks in my life. I’ve needed to be strong for my children and for the foundation, but the people I can fall apart with are my sister and my husband. My sister is a great mom, and she has three phenomenal children, all incredibly close to my children.” She adds a thought that chokes me up: In thinking about her inevitable absence, she was comforted by the assurance that her kids, Nicole and David, would continue to know her through Karen. “Because she’s so similar to me,” Kathy explains. “My kids see that Karen and I are different. But I always felt that if they wanted to know what their mom was like, they would know me by knowing her.”
Dr. Thomas Mack’s life’s work has been centered around these kinds of cases—where one twin is chronically sick and the other isn’t. He says identical twins tell a story others can’t because they start the same genetically and when one diverges, the cause can often be traced. A towering, burly lumberjack of a seventy-two-year-old, Mack is dressed in suspenders when I meet him in Los Angeles. He graduated from Columbia Medical School, worked in Pakistan for the Centers for Disease Control, became a professor of epidemiology at Harvard’s School of Public Health, and now teaches preventive medicine at the Keck School and USC/Norris Comprehensive Cancer Center.
Mack gives the example of Hodgkin’s disease, which he and his wife, Dr. Wendy Cozen, have studied for years. “Someone years ago suggested the hygiene hypothesis,” he tells me over a soda water in a loud Los Angeles restaurant, “which means the cleaner you are, the more you are at risk for certain diseases, including asthma and Hodgkin’s.” So Cozen suggested they ask twins which of them put more dirt in their mouths. “And we also asked about every other difference like that, which we could pick up between them. And it turns out that those are, in fact, pretty substantial determinants.”
How can twins know who put more dirt in their mouths over a lifetime?
“Well, the nice thing about twins—are you a twin?”
I say yes.
“So if I asked you, ‘Who put her thumb in their mouth more often when you were kids, you or your sister?’ you’d know.”
Robin did.
“See? We find that both identical twins agree as to which one did. So we tested that, decided it was a reliable determinant, and then looked at the one who did it more often.”
The one exposed to fewer germs was more likely to get Hodgkin’s.
So the dirtier you’ve been, the better off you are?
“Right. Now we haven’t published that yet, but the evidence was fairly strong.”
He found the same counterintuitive result with sun exposure and multiple sclerosis (MS): the more sun, the less chance of disease.
“If we’re right that sunlight does, in fact, protect,” Mack says, “and I don’t know if we are right, because we don’t know the mechanism by which it would happen, but if we’re right, then because we know that MS is, in fact, a strongly familial disease—in other words if you have it, your kid has a four or five times increased risk of having it—then I’m going to tell you, ‘Get your kid out in the sun.’ Now I don’t want to tell you to do that too much because I don’t want you getting melanoma. But we know that the sun has both negative and positive aspects and you should get a little of the positive as well as the negative. Keeping that kid in the dark all the time is not a good idea.”
I would have assumed that the identical twins in his MS study would have had similar sun exposure in childhood and thus would not have been helpful to test the hypothesis that more ultraviolet light means less chance of having MS. “Obviously, we wouldn’t have learned what we did if there hadn’t been some twins who were in the sun differently,” Mack explains. “We only can use the twins when we’re very sure there is a difference; one of them wanted to be on the beach all the time and the other one didn’t want to. One of the other questions about MS when we started that study was, ‘Could it be caused by a virus coming from dogs?’ So we asked twins who slept with the dog the most. And we got very clear answers about that.”
Mack has also studied lupus, childhood diabetes, breast cancer, and melanoma. He said the hardest part of his research is recruiting enough twins. He built his twin roster one twin pair at a time. “Years ago, I put an ad in the Los Angeles Times, asking for twins with chronic disease, and eighty pairs responded. I put an ad in the Seattle Post-Intelligencer and the Des Moines Register and I got exactly the same response. I received several grants and began putting ads in papers all over America. Over the long term—over the course of ten years, I got seventeen thousand pairs with chronic disease. If we could just get enough twins with a given disease, we could characterize their genome, and then look within pairs to see what the environmental exposures are by controlling the genome.” In other words, look at two people who have the same genetic code and do detective work to
track where their environments or exposures varied. That variance may tell you what caused the disease in one but not the other.
“But that’s hard,” Mack admits, “because it takes a lot of twins.”
So is Mack saying that environment, not DNA, is ultimately the determinant of whether one gets sick?
“It’s both,” Mack states. “It’s always both. And twins are the best single example of why that is necessarily true. There are going to be diseases—like some of the metabolic diseases—that are due to one single gene abnormality. For example, Tay-Sachs—the Ashkenazi gene: You will find twins who are concordant when that gene is present. But for almost all important diseases, twins are not concordant. For example, in Hodgkin’s disease, twins are fifteen times as likely to be concordant—both affected—if they’re identical. But that meant that most twins weren’t—just ten pairs out of 350 twins were affected. So something else has to be responsible for all that other difference. And that’s always the case.”
The new frontier for understanding the mechanism behind discordance in twins is called epigenetics. The field is considered groundbreaking because its premise defies the conventional wisdom that genes dictate our destiny. Epigenetics tells us genes can actually be changed by environmental factors over the course of a lifetime. They can be turned on or off—expressed or repressed—based on our behaviors or exposures. Epigenetics literally means “on top of genetics”: It’s now widely believed that there is some force “above the genes”—chemical modifiers or “methyl groups” of hydrogen and carbon—that attaches to a chromosome and renders it dormant. Methylation can be instigated by environmental exposures, some of which include tobacco smoke, diesel exhaust, radioactivity, pesticides, bacteria, basic nutrients, and certain viruses.
“What it means,” Mack explains, “is that the methyl group gets in the way of the function of the gene; it’s like putting a cap on the gene. Tissues develop in different ways because some genes are turned off.”
And environment is one force that can turn them off?
“It must be,” Mack replies. “Because we know that differences between identical twins become greater as they get older.” In other words, the longer Robin and I live, and the more our habits, vices, behaviors, or environments diverge, the greater the differential impact on our genes. Mack makes sure I understand how the term environment is used by scientists: “When we say, ‘environment,’ we mean ‘everything but genetics.’”
Identical mice have been the involuntary pioneers for this science. In one 2006 experiment led by Eric J. Nestler at the University of Texas Southwestern Medical Center in Dallas, researchers put small, genetically identical mice in a confined space alongside larger, aggressive, mean mice—bullies—and watched how the smaller mice reacted. (The model is actually—hilariously, I think—called “social defeat.”) While some of the identical small mice became cowering, anxious, and depressed, interestingly, some of the small mice stood their ground. To oversimplify: For those mice who became depressed, the intimidation had a chemical effect, deactivating the genes that normally make a mouse resilient. So theoretically, if one could prevent that chemical change, or counter it once it has occurred, those “defeated” mice would not have been so flustered by the bullies. That is what conventional antidepressants are supposed to do: counter dejection. Though drugs may not prevent it—”social defeat” still takes root—scientists can counteract it, emboldening the mouse.
Even more intriguing is that the effects of the intimidation on the relevant genes—even if the behavior is mitigated successfully by a drug—may still be passed on to the next generation. The genes may have been altered in such a way that the behavioral traits get inherited. A monthly journal on how the environment affects human health, Environmental Health Perspectives, called a similar 2005 report “startling” because it suggested “that epigenetic changes may endure in at least four subsequent generations of organisms.”
Psychiatrist Peter Kramer, who wrote Listening to Prozac and writes a regular blog on Psychology Today’s Web site, said the bully mouse study shows “how adversity might reach inside the brain and scar the gene within the nerve cell. The research also points toward a medically exciting, if ethically complex, future in which traumatized people might be restored to the neurobiological state of their resilient twins.”
One rat study in 2004 demonstrated that it’s not just chemicals or foods that influence a gene’s expression; affection, or the lack of it, may also have an impact. The experiment, conducted at McGill University, in Montreal, found that rats who were not licked and groomed by their mother as often as their siblings went on to exhibit more stress. Dr. Moshe Szyf and his colleagues discovered that the mom’s neglect had the effect of turning off the rats’ stress-mitigation response, thus spiking their anxiety levels. Rats that weren’t licked as babies ended up with methylation on a particular gene that normally produces a coping brain receptor. “The offspring of the high-licking moms exhibited better response to fear,” explains Dr. Szyf, who headed the research.
The trauma from maternal disregard was not irreversible: Drugs could bump off the methyl group, change the gene’s activity, and reduce a rat’s stress. In an e-mail to me, Szyf explained that derailing the methylation—which had muzzled the gene in the first place—allowed the rat to get a grip and cope.
In the summer of 2005, a research group led by Manel Esteller at the Spanish National Cancer Center in Madrid, found that out of eighty sets of identical twins, 35 percent of the pairs differed from each other epigenetically, and the older the twins were, the less identical. Those who had spent the most years living in different places with different lifestyles showed the greatest DNA differences, more proof that epigenetic differences can account for why one identical twin gets a disease and the other doesn’t. For example, both twins may start with the same genes that normally battle tumors, but one twin’s tumor-fighting DNA is rendered impotent by an epigenetic change, and that twin ultimately gets cancer.
I asked Dr. Mack how he would counsel my sister, for instance, if I were diagnosed with breast cancer. “I can actually reassure her,” Mack replies. “I would tell you that it would be more likely than not that she would never get breast cancer, but she would have a substantially higher risk than an ordinary person. It still would be less than fifty percent. Fifty percent refers to lifetime risk. But if most women have a twelve percent chance, she might have as high as a forty percent chance. So it’s substantially higher than the average person but still less than fifty percent.”
Mack urges me to put in perspective the studies that say identical twins prove certain diseases are inheritable just because they’re found to be more alike for disease than fraternal twins. “Almost always conveniently, these studies omit the fact that identical twins tend to consciously adopt similar behavior,” Mack cautions, “and therefore have the same exposures not because of specific parts of the genome but because commonality of the entire genome makes them identify with and therefore copy each other.”
I tell Mack that the following day I’m scheduled to meet his compatriot, biologist Dr. Eric Vilain, a professor of human genetics based at UCLA’s David Geffen School of Medicine, who is applying epigenetics to the question of homosexuality—what makes one identical twin gay and the other straight? He and Mack are on similar quests, except where Mack is deconstructing predictions of disease, Vilain is trying to crack sexual orientation. “To me, he’s trying too many possibilities,” Mack says bluntly. “I think it’s a long shot. If it really works, in the sense that I mean it, it’s going to be a revolution—because we will know the biologic basis for homosexuality, or one of them. And if it’s epigenetic, well, we know we can influence epigenetics, so in theory, we could influence homosexuality. For example, if you eat a lot of broccoli when you’re little, and you get a lot of folic acid, you may have different epigenetic patterns than if you don’t. Well, so in theory, if you think a kid is susceptible to homosexuality, you might change eating
habits to impact the genes. Now that’s pie in the sky. It’s predicated on Eric being right—substantially right—and everything falling into order, so I don’t think that will really happen. But let’s give it a shot. Because I think a lot of gay people really want to know why.”
Dr. Vilain is a youthful forty-one-year-old Parisian with wide-set eyes and the pale skin of a scientist who doesn’t leave the laboratory much. We talk in his sunny, cramped office, sitting side by side next to his blondwood desk and built-in bookshelf; glancing at the wall behind him, I notice indecipherable equations scrawled on a dry-erase board. He has a thick French accent and speaks in a hurry. “I only became interested in sexual orientation a few years ago. I’m not a twins researcher. We’ve just started using twins recently because we think it’s a great hypothesis to test the idea that epigenetic/environmental influences are important in behavior. … We’re asking the question, ‘Do we see a difference in genes being turned on or off between co-twins who have opposite sexual orientation?’” In other words, is something activating or deactivating certain genes that results in homosexuality?
“People will say, ‘Are you studying the gay gene?’” Vilain asks the question for me. “No. We’re studying the gene that makes people attracted to either males or females. So in many respects, we’re studying the straight gene; we’re just using gay individuals as a model.”
One and the Same Page 21
