To Know or Not To Know
Genetic screening can answer life or death questions once known only to the gods. Such knowledge can be transformative. It can also be toxic.
By Bruce Grierson published May 3, 2011 - last reviewed on December 20, 2020
Paula Wishart, a career counselor from Ann Arbor, Michigan, learned in her 40s a sinister family secret: Lynch syndrome runs through their genes.
Lynch syndrome is caused by a collection of genetic mutations that vastly predispose a person to an early and aggressive form of colon cancer. (In women it's linked, too, with uterine or endometrial cancer.) The mutations were discovered in the early 1990s. That was too late for a whole string of Wishart's ancestors—including her great-grandfather and her grandfather. Their mysterious deaths fostered the mythology that there was, as Wishart puts it, "bad blood in the family."
Lynch syndrome is like an assassin hiding in the attic with a dozen different ways to kill you. It's a specter so dire that, when Wishart's aunt learned a decade ago that there were now tests for diseases like Lynch, "she wanted no part of it," Wishart recalls. "The feeling was, 'Why would I want to know that?'" That aunt died of colon cancer. Shortly thereafter, her daughter—Wishart's beloved first cousin—succumbed to cancer in her 40s. "If my aunt had been screened, then my cousin would have been screened earlier," Wishart says. "It could have prevented their deaths."
Wishart's aunt's choice to remain in the dark was by no means unusual. Genetic screening for a potentially fatal illness is so fraught and frightening that most candidates for such a disease don't get tested.
Wishart, too, had been scared to know. But she was more scared not to know. When her mother's tissue sample tested positive for Lynch syndrome, she and her four siblings were tested. Her three older siblings came out clear. Wishart and her twin brother weren't so lucky.
She had a mutation in one of the Lynch genes. Initially, the recommended course was that she just keep close watch, via regular internal exams with a scope. Then one of those exams revealed a small polyp. Within a year, it had swelled into a growth that completely encircled a portion of her colon. This wasn't cancer—but cancer is certainly what it would become, doctors insisted, unless decisive measures were taken. That meant radical preventative measures to remove not only the growth but places cancer might appear in the future. Like her colon. And her uterus. And potentially her ovaries.
Now the full calculus of life and death and risk and pain and prevention came into play. Her cancer-stricken cousin had left small children behind. Paula could not bear to think of her own kids growing up without a mother. She dutifully reported for the full program of excisions. She was 44 years old.
Not long ago, fatal vulnerabilities were known—so it was said—only to the gods. Mortality was fated. Then doctors replaced gods and that information passed into their hands for safekeeping. Now the so-called genomics revolution has changed the game again. It has passed that information on to us. This has complicated matters, for better and worse.
Genetic tests vary wildly in their predictive value— from absolutely definitive to so speculative as to be worth not much more than a horoscope. (This latter is the realm of direct-to-consumer outfits that cater mostly to healthy, curious tire-kickers—with no known hereditary risk of serious disease.) Fatal diseases are very rarely linked to a single gene—usually they are the product of an interplay of genes beyond the current understanding of scientists. So discovering you have a glitch in a snippet of DNA thought to be linked to a disease may be quite significant or not very significant at all. "Probability rather than certainty is the rule," says Edward McCabe, a Denver pediatrician and former president of the
American Society of Human Genetics. Usually, when someone's a candidate for a heritable disease, at least one piece of the puzzle—a reliable test or an effective treatment—is missing.
And so the era of widely available genetic testing has created a kind of laboratory for studying uncertainty: How well do we handle it?How clearly can we see our way through it?
"I think a lot of patients fall into the category of, 'If it doesn't tell me for sure then it's not that helpful,'" says Elizabeth Kearney, president of the National Society of Genetic Counselors.
Indeed, some of the most devastating diseases with a heritable component—from Alzheimer's to ALS—raise the specter of so-called "toxic knowledge." That's information that clouds rather than clarifies matters, ultimately doing more harm than good when testing positive isn't useful in any practical way because no cure exists for the disease. Proposed tests for these afflictions—like PET scans that could detect Alzheimer's years before a patient even starts showing symptoms—are tantalizing but as yet so murky that their chief virtue may be to present the "worried well" something more to worry about.
Gary Reiswig, a 71-year-old retired innkeeper and writer from East Hampton, New York, has thought longer than most about what constitutes toxic knowledge. Reiswig's family carries a rare and devastating gene mutation known as PS2 that causes early-onset Alzheimer's. Reiswig had a 50/50 chance of inheriting it, and he was terrified. (He documented his family's travails in his memoir, The Thousand Mile Stare.) But he ran between the raindrops: He is PS2-free.
What Reiswig did inherit was the ApoE4 gene mutation, which has been linked to Alzheimer's of the more common, later-onset variety. The two gene mutations—PS2 and ApoE4—are potentially quite different in their psychological blowback. PS2 is a relatively imminent death sentence. ApoE4 bequeaths a slightly elevated probability of eventually developing a disease you can't do much about anyway.
Reiswig was tortured by the possibility he might have PS2. But ApoE4 is so much less vivid a threat that he wouldn't even have bothered to be tested for it were he not already being screened for PS2. "I have one copy of ApoE4, making the odds I have Alzheimer's by age 80, one decade from now, about 50/50." He doesn't lose any sleep over it.
You could say that Reiswig's PS2 score was toxic knowledge to him, and his ApoE4 score isn't. Toxic knowledge is knowledge that because it's not definitive or not actionable or both, is simply not worth knowing. It poisons relationships and emotional well-being. When the odds of getting useful data fall below some subjective threshold—when the grain of salt the test results come with becomes too large—genetic counselors will usually advise against testing. But individuals respond differently to threatening information. One person's neurotic fixation can be another's catalyst to growth.
The Truth Shall Set You Free
Bonnie Beaver, a Minnesota-based office manager, has a family history of breast and ovarian cancer. In the early 1990s, two gene mutations—BRCA1 and BRCA2—were found that link tightly with the two diseases. So when Bonnie was diagnosed five years ago with a breast tumor, she opted to peer into her genome. Therein was BRCA1. She was 35 years old.
Beaver had opted for the genetic test to help her decide whether to get a lumpectomy to attack what already was, or a full mastectomy to prevent what might be. She needed to attach a probability to that "might be"—and then answer the nagging question, "If it's positive, then what?"
When Beaver discovered BRCA1, she considered her next step a no-brainer.
"I didn't question whether I needed to have a mastectomy—I knew I needed to have one," she says. Without it, odds were she would get cancer again, and "why would I even want to have that risk?"
For Bonnie, the cancer diagnosis had opened the door to potentially eliminating that longstanding uncertainty. Was she afflicted with the mutation or not? Getting the test would quell some of that ambiguity. (Not all, for the mutation does not condemn one to cancer, even when there's a strong family history.) Following through on the mastectomy would further resolve matters. To Beaver, it was the possibility of "absolute peace of mind" that made the decision easy. "It's just such a relief to know this gene can't get me," she says. "I have defeated it."
Her decision, she reckons, saved not only her own life but the life of her niece—who, though cancer-free, was moved to get tested, and learned she has the gene. After a more complicated cost-benefit analysis than Bonnie's (she was only 24), she opted for a double mastectomy.
It's hard to overstate the human hunger for certainty. Our pattern-making brains have a search-and-destroy relationship with ambiguity. While uncertainty can sometimes be a pleasurable state when we expect a positive outcome ("Will this date who sent me flowers be The One?"), it's distinctly unpleasurable for most of us when we fear the worst. In such circumstances we're intensely motivated to resolve the not-knowing, come what may. Most people prefer bad news to no news.
A recent Harvard medical school study confirms just how corrosive waiting in limbo really is. A total of 214 women awaiting three kinds of medical procedures were asked to report their stress levels. The most anxious were women awaiting the results of breast biopsies to determine whether they in fact had cancer. This group's stress was markedly higher even than a group of women who had already been diagnosed with liver cancer and were awaiting treatment.
"Why would we prefer to know the worst than to suspect it?" psychologist Daniel Gilbert framed the issue in a 2009 New York Times essay. "Because when we get bad news we weep for a while, and then get busy making the best of it. We raise our consciousness and lower our standards. We find our bootstraps and tug. But we can't come to terms with circumstances whose terms we don't yet know. An uncertain future leaves us stranded in an unhappy present with nothing to do but wait."
Most people adapt surprisingly quickly to one big hit of terrible news. But deferring that news or replacing it with a stream of smaller disappointments fails to trigger what Gilbert calls the "psychic immune system." Instead of adapting, we get chronically stressed out, in a way that can do permanent damage to the hippocampus. Note that bad news is antithetical to "toxic knowledge" in that ambiguous news muddies questions, rather than resolves them.
Paula Wishart now thinks her decision to get tested was a way of imposing order on chaos. "For years it felt like our family was in this shooting gallery of cancer," she says. "But now I feel like we've got a plan. We can do something about it."
Whether to court toxic knowledge may be a question for terror management theory. This relatively new branch of psychology concerns itself with how we brace against awful potential outcomes. One phenomenon, routinely observed by psychologists, is that in the face of a death scare we grow more conservative. We risk less. Suspended in that limbo of scary uncertainty, we seek the security of the familiar, and double down on our existing beliefs. And when people are really frightened, they miscalculate the odds of the worst occurring.
These days some astute doctors and genetic counselors have almost as many books in their offices on probability as they have books on medicine. Sound thinking requires calibrating one's certainty to the level of the evidence—but that is a rare skill (and one that, it turns out, eludes a lot of conventionally smart people). Where health risks are concerned, thinking errors abound.
Such errors have fancy names like "denominator neglect"—that is, we focus on the number of people who died from an illness, forgetting about the vast numbers of healthy folk in the huge subject pool. The dead scream louder than the living in the echo chamber of the id. In one recent Swedish study, 120 men with prostate cancer in the family were asked what they thought their risk of getting the disease was. "As many as 40 percent of the study subjects perceived their lifetime risk of prostate cancer as 67 percent or more," state the researchers. "That's around twice as high as the actual risk." Such miscalculation matters because those who overestimated their risk were more prone to rumination and depression.
It's the emotional freight of the C-word that knocks sound judgment out, making us overestimate the chance of it happening to us. "I think that people often don't want to hear about the results of these tests because they view their genes in more deterministic ways than they should," says University of British Columbia psychologist Steven Heine. "Knowing that you might have a tiny increased genetic risk gets misunderstood to mean that one possesses bad genes."
So when we hear that we have some genes that may, possibly, mildly, predispose us to a form of cancer, we hear "cancer gene" and get scared—more scared than the facts actually warrant, too scared, perhaps, to face a test.
Genetic counselors, in particular, help patients clear the fog of cognitive biases. Paula Wishart believes her counselor helped flip the switch. She was leaning toward doing nothing: no tests, no surgery, leave the outcome to fate. But "that intervention changed the trajectory for me from not knowing to eagerly wanting to know." Without it, she says, "I probably would not be here today."
Staring Into The Abyss
We tend to prefer certainty, prefer even bad news to no news. But there are some cases where ignorance is bliss. Huntington's disease is an inherited, incurable neurological affliction that strikes its victims between age 30 and 50, progressively robbing them of muscle and brain function until it kills them. The responsible gene is identifiable and 100 percent fatal, and you either have it or you don't. Odds of inheriting it: 50/50. A Huntington's candidate faces the decision, as one researcher icily puts it, of whether or not "to maintain the current state of ignorance." There is no uncertainty here—unless the patient chooses not to know.
And that's exactly the choice most Huntington's candidates make. Approximately half of this group says they're interested in theory in knowing. But only about 15 percent go through with the test. For most people a Huntington's diagnosis is toxic knowledge—a piece of news that clouds rather than clarifies. Ignorance, in this case, is a kind of manufactured certainty. Knowledge of the disease, on the other hand, shades every day on earth thereafter with new problems and impossible decisions, and absolutely nothing can be done about the underlying condition.
Hebrew University psychologist Ilan Yaniv coined the term "protective ignorance" to explain the reluctance of people he questioned to want to know if they're doomed to an illness like Huntington's—one that is both "threatening and uncontrollable at the same time."
Even superrational types who live by the dictum "knowledge is power" often balk at the prospect of a Huntington's test. (Both Harvard psychologist Steven Pinker and DNA dicoverer James Watson, for example, have said that if the mutation ran in their families, they wouldn't want to know whether they had it.)
So why would anyone want to know? What explains that other 15 percent? And how, for that matter, do we determine when knowledge becomes a burden— when it is toxic—or when it is a positive thing, spurring change and constructive behavior?
It turns out that tolerance for ambiguity is quite a personal thing. Certain personality types seem to tolerate it better than others.
"Some people are so terrified by the diagnosis that they can't deal with the next question, which is whether to be tested," says genetic counselor Joy Haidle. "And some people take the opposite tack." They need total data now, so they can, if needed, go right into the O.R. and get the goddamn thing out of their life. Patients can be shocked into paralysis or, conversely, shocked into action.
Genetic counselors must go on intuition to assess whether their client is ready or willing to get tested. But there have been attempts at a more rigorous metric to determine who can handle the full facts.
In the spring of 2003, the personality psychologist Lew Goldberg slipped a provocative question onto a questionnaire he gave to Oregon residents: If there existed right now a genetic test that would tell you, with accuracy, when you were going to die, would you want to take it?
Goldberg is a father of the Big Five theory of personality traits—the idea that there are five core dimensions to the human personality. And so he was naturally interested in which personality types would prefer to have such medical certainty in their life. (Goldberg asked a second question: When would you want to know—ranging from "as soon as possible" to not until you were over 50.)
Goldberg found that most people don't want to know their expiration date even if they could. Only a third of his subjects were open to that knowledge. Who were these people? Two personality dimensions that came into play were intelligence and openness to experience—a measure of curiosity and hunger for novelty. "More intellectual and open, and more highly educated persons are more likely to want to be informed," Goldberg says. Another personality trait—agreeableness, linked to a general satisfaction with life—correlated strongly with wanting to know, but maybe not in the way you'd expect. Happy people didn't want to know; grumpy, unsatisfied ones did. Combining Goldberg's research with other data on personality, it appears that young, slightly prickly and restive intellectual folks tend to say: Gimme the news, Doc, and the sooner the better.
Therese Marteau, a professor of health psychology at King's College in London and a leading expert in psychological responses to genetic testing, maintains there is enough data to suggest that "those who do [opt for testing] are more psychologically robust than those who do not."
Indeed, personality might ultimately explain the story of Gary Reiswig.
After his father died in 1965, when Reiswig was just 25, it became clear that a kind of curse ran through the family: the lethal genetic mutation we now call PS2. At the time there was no individual genetic testing for PS2. Reiswig participated in medical research to help determine the cause of his father's death, but he couldn't know if he had it, even if he wanted to. He would have to wait three decades for definitive news. When the word finally did come, it came by accident, the day he read a scientific article lent to him by a friend, and recognized himself in the lineage of a family extensively afflicted by the gene mutation PS2. He didn't have the mutation. He was 55 years old.
During that time in psychological limbo, Reiswig cooked up a kind of thought experiment to deal with the data void. His gambit—and like much defensive pessimism, it may not even have been entirely voluntary—was to pretend he had tested positive. "To expect to get the disease, and then get it, is one level of disappointment," he explains. "To expect not to get it, then get it, would be a much higher level of disappointment, so I did not allow myself to think positively."
Where there was chaos, Reiswig would impose order. Early on, he realized that there is one way to gain some control over a death sentence: You can still decide when. He made suicide plans.
Then the boom swung 180. Instead of trying to stop life, he would gorge on it, in whatever time he had left. "I became imbued with some sense that life had speeded up," he says. Feeling the acute need, now "to try to do everything in anticipation that my life could be cut short." But how?
Contradictory thoughts duked it out involving care of the body, care of the mind.
Take vitamins. Explore macrobiotic diets competed with pleasure-principle thoughts of the eat-dessert-first variety. Remember, knowledge is the only thing of value, he reasoned. So pursue that Ph.D. But at the same time: Education is a waste. You'll forget everything. Live more.
Reiswig decided, in the end, that neither life nor education nor anything else, really, was a waste. The clock was whirring. Having already quit the ministry (his first job), he plowed ahead on a Ph.D. in education at the University of Pittsburgh. (It would allow him to be a little more wealthy, he reckoned, "which would open the door to life's opportunities a little wider.")
He held a variety of jobs, including giving instruction in a speed-reading technique invented by a local optometrist. (This last detail now strikes Reiswig as a short-story-perfect overreach, symbolic of "my wish to speed things up, get as much living in as possible.")
What Reiswig's thought experiment did, perhaps above all, was force him to seek greater autonomy in life. He quit a high-level job in the City of Pittsburgh planning department and he and his wife moved to East Hampton to run the venerable old inn they had purchased. ("If I began to lose my mind, I wanted to work as long as possible, just as Dad had kept working on the farm with Mother's help," Reiswig wrote in his memoir.) Together they ran the establishment while his wife subtly watched Reiswig "for the dreaded forgetfulness."
"The disease has finally given me a direction and purpose for the rest of my life," Reiswig says—"writing about it and helping my family and others who are facing the same thing."
There is another reason one might choose to test for a bomb like Huntington's or PS2, and it has to do with plain practicality. Very bad news, so long as it's definitive, is useful in that it helps you plan.
In the 2003 film My Life Without Me, a young mother of two young children, played by Sarah Polley, learns she has inoperable cancer. She goes to feverish, quiet work recording tapes for her children, and sealing each in an envelope to be opened on their birthday, year by year, 18 years into a future she will never live to see.
Genetic counselors often see the same soberly heartbreaking planning at play in their Huntington's patients. Liz Kearney remembers one young man she worked with, whose career options lay before him.
"He was in his early 20s and was thinking about medical school," she says. "A lot of people in his family were physicians. But he was also thinking, 'If I'm going to develop Huntington's, I don't want to spend the next 10 years doing med school and then a residency. Because by the time I got out of school I'd be starting to watch for symptoms. I'd be limited in terms of how long I'd be able to practice.' He thought: 'This knowledge is empowering. Whether I have the gene or I don't will determine my path.' So he proceeded with testing. He was positive. He decided not to go to med school and he opened a sporting goods shop. You can't treat Huntington's, so having that knowledge didn't make a difference in terms of his medical treatment. But in terms of his life decisions, it was critical."
There is another reason one might want to be tested. There may be no cure now, but you are in a position to help get one found.
A few years ago, Google's Sergey Brin took a genomic test that revealed a vulnerability to Parkinson's—another of those devastating, progressive diseases for which there is as yet no treatment. Brin has since pumped millions into Parkinson's research. It is enough money, perhaps, to "move the needle." If he becomes symptomatic, years down the road, there might be a cure.
Similarly, one reason Alzheimer's research has been a bust is that drug treatments have been tested on symptomatic patients—and once the plaques have developed, it's now thought, it's too late for a cure. Real progress may yet depend on subjects who are as yet nonsymptomatic—because drug treatment may yet be effective for them.
At some point in her decision process to be tested for the breast-cancer gene, Bonnie Beaver realized the decision wasn't just about her. What her test revealed could potentially influence other family members with their own choices.
And it did.
Surfing Your Own Genome
"For the cost of a cheap suit," says Canadian health-policy expert Tim Caulfield, anyone can spit in a vial, pop it in the mail, and have their genome read by a direct-to-consumer testing outfit like 23andme or Navigenex. In this model, a few hundred thousand genetic markers potentially linked to diseases and traits are read. They're called SNPs (pronounced "snips")—single nucleotide polymorphisms.
But when it comes to uncovering genetic vulnerability that is worthwhile, let alone actionable, direct-to-consumer testing is a very different tool than is testing for particular afflictions. The ease and range of these mail-order tests come at the expense of accuracy. In one study, the U.S. Government Accountability Office (GAO) hired donors to take tests offered by 10 different consumer-genetics-testing companies. Those donors, according to the GAO, "often received disease risk predictions that varied across the four companies, indicating that identical DNA samples yield contradictory results."
As far as whole-genome glimpses go, a more promising strategy may be a technique called copy-number variation genomic micro-arrays. The procedure scans the entire genome, and when it discovers abnormalities it flags spots that may be significant. All the flags sit atop potentially high-value targets. "Basically, you're covering a three billion base pair genome with two million probes," says Edward McCabe. The technique has been used at hospitals such as UCLA since 2006.
Scientists predict that the cost of whole-genome sequencing may drop to less than a thousand bucks. This price point, one that many think will "democratize" genetic testing—may be less than five years away. But while it'll be vastly more useful than current direct-to-consumer testing, don't expect miracles of accuracy even then.
"If we're learning to live with uncertainty with the micro-array data, there'll be even more uncertainty with full sequencing," McCabe says. "The equipment is touted at 99.99 percent accurate. In a genome of six billion base pairs, that means 3 million errors."