AS WE LEARN MORE ABOUT THE GENES THAT INFLUENCE SUSCEPTIBILITY TO DISEASE, MILLIONS OF PEOPLE COULD BE OFFERED THE CHANCE TO SEE THEIR MEDICAL FUTURE. BUT DO WE REALLY WANT TO KNOW?
The call came when Monica Bradlee was at home in Tewksbury last April, her family anxiously gathered around her, waiting for the phone to ring. Two weeks earlier, Bradlee had given a blood sample for DNA testing that would reveal whether her life would be likely to end, like her father's, in a slow dance with death from Huntington's disease. Whatever story the DNA told, it would ripple out to encompass all those near her -- and some not yet born.
At 44, Bradlee had no symptoms of the disease that began to attack her father at the same age, but she had lived in its shadow for more than 20 years. That shadow extended to her children, 17-year-old Scott and 26-year-old Kelley, and to the children Kelley hoped to have after her approaching marriage. If their mother had inherited the Huntington's gene, Scott and Kelley would be at risk, too.
The gene test would end the uncertainty, and Bradlee was not one to shy away from such knowledge. Unlike her brother and sister, who shared the same 50-50 chance of having inherited the gene but preferred not to learn their fate, Bradlee had a motto: "The devil you know is far better than the one you don't know."
The phone rang. "Monica," began Dr. Daniel Sax, a neurologist at Boston University Medical Center, "I'm calling to tell you that you do" -- here someone in the room gave an immense, involuntary sigh, blotting out the rest of his words.
"Do what? Do what?" cried Bradlee in alarm.
"Do not have the gene," repeated Sax. "You do not have the gene."
"Spell it!" demanded Bradlee, taking no chance that at this crucial moment she had misunderstood her doctor.
After Sax had reassured her, she leaped into the air and hugged her husband, her son and daughter, and her daughter's fiance. Elated, the family drove to a nearby liquor store, purchased a bottle of champagne and some plastic glasses, and headed to the house in Somerville where Bradlee's mother lives alone. Bursting through the door, Bradlee blurted out: "I found out what I'm not going to die of."
Her euphoria was short-lived, however. Six months after the gene test had removed the shadow of Huntington's disease from her future, Monica Bradlee found herself oddly confused, unsettled, and not, as one might have imagined, at peace. Why, she wondered, wasn't she happier?
After a landmark genetic discovery in 1983, experimental testing of individuals at risk for Huntington's disease began cautiously in 1986. But only since the gene itself was isolated, in 1993, has testing become widespread.
Huntington's disease is rare, affecting one person in 10,000. About 150,000 relatives of HD patients in the United States are at risk; only time or a predictive test can determine whether they have inherited the mutant gene.
Beyond Huntington's lie a large and unknown number of other, more common, diseases that are influenced by the genes we are born with. As technology has begun to unravel the genetic mystery, scientists have isolated a growing list of genes involved in colon, breast, and other forms of cancer; cystic fibrosis and muscular dystrophy; and some types of high blood pressure and heart disease. Some researchers believe genes also play an important role in certain mental disorders. In the future, genetic testing may well become standard medicine.
Not only those with Huntington's will confront the issues of genetic foreknowledge, predicts Monica Bradlee: "It will be all of us."
As we learn more about the genes that influence susceptibility to diseases or traits considered "abnormal," millions of people could be offered the chance for "genetic clairvoyance," as one psychologist calls it. Whether they will choose to look into this crystal ball is another question.
Because more people have undergone predictive testing for Huntington's than for any other genetic condition that appears in adulthood, HD is setting the standards. There are no reliable figures, but, by now, probably several hundred people have been tested in the United States, and more than 500 have been tested in Canada.
One of the lessons patients and counselors have learned from this experience is that knowing one's genetic fate is not for everyone -- especially when, as is the case with Huntington's, knowing what's ahead doesn't help one to avoid it. Before the HD test became available, people who were at risk showed strong interest in a predictive test. But when the test appeared, fewer people than expected actually stepped forward.
Some fear a bad test result, but others are justifiably worried that health or life insurers or employers will discriminate against them if the information leaks out.
Another, more surprising, lesson is that people who receive good news from a genetic test can be as seriously troubled as those who discover the worst. ''We've learned that the psychological issues for people who find they don't have the gene are often as dramatic, or more dramatic, than for those who carry the gene," says Barbara Bowles Biesecker, a genetic counselor with the federal Center for Human Genome Research. And, counselors say, no one can predict an individual's reaction.
From the beginning, people who have requested DNA testing for Huntington's have been required to go through counseling before they undergo the test. The patient almost always receives the results in person and is urged to have someone come along. Afterward, the individual must return for at least one follow-up session and extra counseling if needed. Monica Bradlee's case was unusual in that she received her results by phone, which Sax, her neurologist, said he felt was appropriate because he was providing good news.
"I think our experience has reinforced our feeling that people need extensive opportunities to withdraw," even after their initial requests for testing, says Biesecker. She and other genetic counselors worry that as the tests become easier to administer and demand increases, these safety nets may fall away and leave people vulnerable to psychic disaster. A recent suicide in Minnesota in the aftermath of a patient's hearing test results over the phone is widely seen as a case in point.
Monica Bradlee's feelings of unease aren't uncommon among those who beat the odds on Huntington's. Like lottery winners, people who receive the gift of unexpected genetic health face the quandary of what to do with it. Such a profound change in one family member's fortunes -- whether the news is good or bad -- can weigh heavily on others in the family. Sometimes one person's reprieve is interpreted, wrongly, as another's doom.
"It's funny how you react," says Bradlee, formerly a dental hygienist and now a marketing specialist for Digital Equipment Corp. "It's taken a long time for me to be able to feel the good news."
The relief she experiences is genuine, and she is grateful for it, but it also has created an identity crisis. "I don't know who I am or what my goals are," she says. "The whole world is open to me now. Before, I lived a year at a time; I always had short-range goals. I got my associate's degree, then my bachelor's, then a master's, and I switched careers so I would be working for an employer where I would have good benefits and be protected by federal laws. Now, I don't know what I want to do -- I just know that I'm restless."
Bradlee has long been active in the Boston chapter of the Huntington's Disease Society, which was involved in recommending the procedures for testing and counseling at Massachusetts General Hospital and Boston University. At a conference in St. Louis last summer, Bradlee spent some time with 15 other people who had received gene-test results, both positive and negative. "It was amazing," she recalls, "to see how much better the people were doing who had found out they had the gene than those who had found out they did not.
"A long time ago, I had said to many of the people in Boston that they had better prepare for the people who found out they were OK. At the time, I didn't know how right I was."
It has been no surprise that negative test results sometimes prompt "survivor guilt" -- a reaction that is common after situations in which some escape while others perish, for no obvious reasons. Bradlee is keenly aware that her siblings are also at risk, and though they could also be free of the lethal gene, she wonders, "Why was I the lucky one?" The feeling that she must somehow pay a price for her good fortune jolts her at unexpected times: During her trip to St. Louis, she experienced a sudden fear of flying. ''Oh, please, God," she remembers praying, "Just because you gave me this gift, don't make me die in a plane crash!"
Genetic counselors say the majority of those found free of the Huntington's gene don't develop serious emotional problems. And, in fact, those who have been told that they will develop the disease seem to be doing relatively well. But because the studies are of limited duration, they are not definitive.
Columbia University psychologist Nancy Wexler, who was a driving force behind the effort to find the gene for Huntington's disease, is somewhat skeptical that those who've gotten bad news are doing that well. "A lot of times, people have a vested interest in saying they're feeling great," she says. "Nobody wants to say they're sorry they got the information." Despite early fears that people would kill themselves after hearing bad news (doctors have long known that Huntington's patients have an increased rate of suicide), there has been only one reported fatality after a test result.
There's no doubt of the wrenching force of even a good-news verdict. "It's a real shock for people to find out they don't carry the gene," says Wexler, who heads a federal panel on the ethical, social, and legal implications of genetic research. Her mother died of Huntington's, leaving Wexler and her sister at risk. The psychologist has declined to say whether she, herself, has been tested. "All the emotional problems they blamed on Huntington's they now have to accept as their own, and all the special allowances their family and friends made for them no longer are there."
Moreover, people who undergo testing usually have lived with their at-risk status for many years. "Many people have already made irreversible decisions in regard to their future, like marriage or job or reproductive choices," says Dr. Michael Hayden, director of a large Canadian study of predictive testing. "When they find out that the reality is going to be different, it significantly disturbs their conscious and unconscious views of the future." People at risk for HD may have decided against buying a home, or marrying, or venturing on a particular career path, and now they find it's too late. Many have decided not to inflict the risk on offspring and now find themselves mourning a child they might have had.
Living mainly in the present has been inescapable for some, but one young man took it to extremes. The son of a physician who had Huntington's, the man simply assumed that, despite the 50-50 odds of not having inherited the gene, he was doomed.
"He had a vasectomy," says Hayden, who is a professor of medical genetics at the University of British Columbia. "He had a series of short-term relationships. He lived dangerously, getting involved in bungee jumping and mountain climbing and hang gliding and every kind of sport where he could have gotten killed. And he lived life recklessly in financial terms, too. He gambled and incurred tens of thousands of dollars of debt, figuring that his insurance policies would take care of it after he died."
Soon afterward, he underwent DNA testing and was shocked to find that his life was not to be cut short by Huntington's. And he simply couldn't deal with it.
One day, a check came across his desk that was not clearly written; he changed the name of the payee and committed a clumsy fraud to pay back the gambling debts that now loomed.
"He panicked," says Hayden. "It was a crisis, realizing that he had a future. He faced a life that looked less exciting -- he was going to be like everybody else." In addition, he had fallen in love with a woman -- but refused to admit it to himself or to her. Hayden says that a year of counseling enabled this man, "who was quite near disaster, to recognize that he could fashion a future filled with promise and joy." With a lot of help from his family, he pulled himself together and proposed to and married the woman he loved. And, basing his legal defense in part on the stress of his genetic quandary, he received a suspended sentence on the embezzlement charges.
In a less dramatic case, but one that reveals what Hayden calls the "unconscious contracts" that often underlie relationships, a woman learned she was free of the Huntington's gene, and her husband, upon realizing that she would not need his lifelong support, went into a depression. "The fear," says Hayden, "was that now she would leave him, because she didn't need him anymore."
Another predictive-testing specialist, Kimberly Quaid, of Indiana University, recalls a woman at risk for HD "who had married someone who also had a genetic condition. When she found out she was at very low risk of Huntington's, she divorced the guy in the blink of an eye. She felt that she now deserved to have someone who is fine genetically."
Regardless of the verdict, coping with a sudden change in one's future puts added stresses on families already damaged by the illness, deterioration, and death of a family member. Andrea Zankow, a genetic counselor at the University of California, San Francisco, studied 49 families of individuals who underwent gene testing for HD. "We found a high proportion of children that came from disorganized homes. These are kids growing up in a home with a parent who becomes increasingly inappropriate and ineffectual. The other parent often was overwhelmed, or absent, or alcoholic, and so the kids were really raising themselves, and they didn't have the role models for daily skills or coping mechanisms."
Monica Bradlee's father, Harold (Lefty) Bruning, grew up in Somerville, served in the Marines, and married young, supporting his family with his earnings as a welder. His wife, Monica, gave birth to three children: Monica, Deborah, and Harry. Bruning's official Marine portrait shows a grinning, square-jawed youth. Those who knew him recall a good-natured guy who was fond of his beer. Thus, even his family did not immediately take notice of the clumsiness that Bruning began to exhibit in his mid-40s. Like folk singer Woody Guthrie, the most famous person to die of Huntington's disease, Bruning was considered to be displaying the signs of a frequent drinker.
"He was a nice guy," recalls Harry's wife, Lisa, who knew Bruning when she was a child. "He was a good, old-time guy. He was funny, he was a hard worker. He did drink and hang out down at the store and smoke cigarettes. I remember as a child thinking he was drunk."
It was his daughter, Monica, who first raised the concern that more than alcohol was at work. Monica Bruning, Lefty's widow, recalls her daughter's saying, "There's something wrong with Dad," and arranging for him to see a doctor.
Lefty Bruning received a diagnosis of Huntington's in 1973, when his daughter Monica was 23. Known as an adult-onset disease, Huntington's usually doesn't appear until the 30s, 40s, or later (though symptoms can appear earlier). As vital parts of the brain atrophy, the person progressively loses control of body movements, causing characteristic dancelike writhing and grimaces. Personality changes and depression are common and complicate the diagnosis. As years go by -- usually 15 or 20 -- the disability and dementia worsen, destroying memory and speech. The HD patient often dies of a respiratory infection such as pneumonia -- as Lefty Bruning did -- or from other infections.
Bruning was one of 13 children, and several of his brothers died of Huntington's in the days when diagnosis was often missed or inaccurate. As HD cases go, Bruning's own ordeal was relatively merciful. Lisa Bruning and other family members recall going to see him in Middlesex County Hospital, holding to his lips the cigarettes he still enjoyed but could no longer grasp. During the year before he died, his family held a 60th-birthday party for him. A photograph shows Lefty, gaunt and twisted, sitting in a chair, surrounded by relatives and his many friends. He could no longer speak, but his widow says he retained his dignity for a long time.
People who are at risk for inheriting the Huntington's gene often have witnessed a parent's deterioration. It is a sobering experience, but some genetic counselors point out that diagnosis, social tolerance, and drugs that help relieve symptoms have improved from one generation to the next, even if the disease isn't curable.
Even so, the specter of having children who might be stricken was overwhelming for Monica Bradlee's 26-year-old daughter, Kelley, who married Jim Rodolakis last October. If Monica Bradlee did harbor the Huntington's gene, then Kelley knew that her risk of developing the disease was 50 percent, and Kelley's children would have a 25 percent risk. "I don't think I could have lived with myself if I had had children and found out they had it," Kelley says.
For the same reason, it was important to Kelley that Monica receive her results before she and Rodolakis married last fall. "I wanted Jim to know what he was getting into," Kelley says. "After seeing what it was like . . . it would have affected his life so greatly. I would want him to know, so he could have changed his mind."
At this, Jim protests quietly. "I don't think I would have. I don't know for sure . . . but I don't think so. I would have taken my chances if Monica had had it. If Monica hadn't been tested and didn't know, I definitely would not have changed my mind. If she knew that she carried the gene" -- he pauses -- "I probably wouldn't have changed my mind. It would have caused me to step back and think about it, I guess."
"Does it feel awful to hear that?" Monica asks her daughter.
"No, that's what I would have wanted him to do," Kelley replies.
It was in a laboratory headed by James Gusella, a molecular geneticist at Massachusetts General Hospital, that the first clue to the Huntington's disease gene was discovered in 1983. It was the discovery of a genetic marker -- a sort of biological signpost on chromosome 4 indicating the region where the gene must lie -- that enabled some families to undergo predictive testing.
Some specialists take exception to the term "predictive." Sax, the Boston University neurologist who treated Lefty Bruning and gave Monica Bradlee the results of her gene test, argues that even a positive HD test doesn't predict when the disease will appear. And for other kinds of genetic testing -- predisposition to cancer, for example -- some people who carry the gene may never develop the disease, so the test yields only a probability, not a specific prediction. Nevertheless, the term has gone into wide use, and no one has suggested an alternative that has caught on.
Although HD testing based on the genetic marker began in 1986 at a number of centers around the country and in Canada, it was expensive and required blood samples from several family members. For many people, including Monica Bradlee, the pattern in which the genetic marker was inherited through their family made it impossible for a test to yield an unambiguous result. Not until 1993, when Gusella's team at MGH and a large number of collaborating scientists identified the Huntington's gene itself, could Monica Bradlee begin the process of informational and psychological counseling and neurological examination that led to DNA testing.
When she called her brother, Harry, and told him the results, Bradlee sensed what many others in her situation have: that it was received with mixed feelings. "He was happy for me, but he was scared for himself, and you could hear it in his voice," she recalls. Harry, who says that he has no plans to take the test for fear that he could not handle bad news, may have unconsciously felt that if his sister got a lucky roll of the dice, it raised the odds of an unlucky roll for him. That's an understandable reaction, say genetic counselors, but the odds for any child of a parent who has Huntington's are independent of the odds for other children.
Harry Bruning, who is 28, says he was only happy to hear of his sister's good fortune. He says he believes Monica was inherently more driven to seek testing because of her personality -- "She needs to know where her life is going and be in control of it as much as possible" -- and her age. She is the same age as Lefty was when when he developed symptoms.
Harry's wife, who is a nurse, shares his views: "My whole attitude on life is that I don't want to know my destiny." While she tries not to think about the possibility that her husband might develop the disease, she admits to moments of fear. "We'll be lying in bed, and he'll twitch -- you know how you jump before you fall asleep sometimes? I think, 'Oh, my God, is he twitching because it's the beginning of Huntington's, or is he doing what everybody else does?' "
Given the stresses that weigh on the offspring of an HD patient, it's no wonder that a relative's test result, whether good or bad, strains family dynamics. "If you're siblings who are at risk, you're all in the same boat," says Quaid, the predictive-testing expert at Indiana University. "You all have this shared thing, but once one person in the family gets tested, then that person is on the island or in the water with the sharks, but they're not in the boat anymore. I've seen cases where someone got good news and called up the people they loved, and had a sibling hang up on them. Later, they apologized but said they immediately felt that as a result of the other person's getting a clean bill of health they were going to get it." In another case, a woman whose gene test brought her great relief avoided telling her family for several months, fearing that a sister who had previously tested positive would be resentful.
If the ability to learn one's number in the genetic lottery surrounds us with dizzying dilemmas, does that mean we have signed a Faustian bargain that society may come to regret? In their darkest hours, some critics take that view. On balance, though, those who have given the genetic news and those who have received it say that the DNA crystal ball is a positive thing -- if the medical community and society can use it with appropriate caution. "We need wise people with a conscience involved in this," says Zankow, the genetic counselor in San Francisco.
"Many times," Zankow says, "I have asked my families, 'Is this a good thing we are doing?' What they've told me is that when they get their information, they feel so thankful that it is available. Many of them have lived with this risk for so many years, that to now have that control, to have some input into their own future -- at least it allows them to put the uncertainty to rest and, hopefully, to move forward. I've asked people, 'Are you glad now that you did this?' and I have not yet found anyone who said they weren't."
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Last updated: Nov. 13, 2010