The DNA Files: Unraveling the Mysteries of Genetics
“Predictive Genetic Tests: Do You Really Want to Know Your Future?”
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“Predictive Genetic Testing: Do You Really Want to Know Your Future?”
JOHN HOCKENBERRY: This is The DNA Files. I’m John Hockenberry. Imagine a test that could tell you how sick you might become at 50 or 60. Would you take the test or wait and see what fate has in store?
NANCY WEXLER: The impact of knowing your future is infinitely more than people bargained for. And even people themselves will say no amount of conversation or planning before the event really prepared them for what knowing their future would be. You need to practice what it feels like to have both outcomes. What it would really, really mean in terms of your own personal life.
JOHN HOCKENBERRY: As our ability to predict disease increases, so does our anxiety about genetic testing. Will we be able to get the tests we want? And will those results be used to help us or harm us? In the next hour we’ll look at “Predictive Genetic Testing: Do You Really Want to Know Your Future?”
Bad genes. Where do they come from? And, more puzzling still, why don’t they go away? Genetic diseases like sickle cell and cystic fibrosis can kill in early infancy. Evolutionary theory says the genes for these diseases shouldn’t get passed on. Now an unlikely pair of scientists – one a university biologist, the other a free lance physicist – have an explanation. They’ve developed a powerful new evolutionary analysis of human disease, as John Rieger reports.
JOHN RIEGER: Genetic mutations occur all the time. They create the genetic variation that makes evolution possible. Some of these mutations inevitably cause birth defects or disease. So in one sense it’s perfectly obvious what causes genetic disease. But in another sense, it’s not. Take the case of sickle cell disease. In parts of Africa, as much as 20 per cent of the population carries the gene for this fatal disorder. Sickle cell reduces a population’s evolutionary “fitness”— that is, fewer offspring live to reproduce. So by the law of natural selection, the sickle cell gene should disappear. Paul Ewald is a professor of biology at Amherst College.
PAUL EWALD: It’s only when you say, “Well, how do those bad genes maintain through time?” that it becomes apparent that you have an evolutionary problem here. Something else has to be going on, something that allows those bad genes to be maintained through time.
JOHN RIEGER: That something else is malaria, a deadly disease caused by a blood parasite. Malaria may be as old as homo sapiens, and over millenia of evolutionary time, it’s put relentless pressure on the human species to evolve a defense. Sickle cell is that defense. The malaria parasite is finely tuned to attack the human body. But the sickle cell gene throws a wrench in the works. In effect, it breaks the machine to defeat the parasite. Greg Cochran is Paul Ewald’s research partner.
GREG COCHRAN: Paul and I have been calling it “self-destructive defenses.” You’re sort of dealing with a wily and complex foe. Infectious diseases can be finely adapted to take advantage of particular features of certain cells in your body. And if you change them, then the infectious organism is not as good at colonizing. It may not be able to at all. So just breaking things can change things in a way that protects you.
JOHN RIEGER: But why would evolution favor a defense against malaria that itself causes a fatal disease? People with just one copy of the sickle cell gene are resistant to malaria, and that evolutionary advantage has caused the gene to survive and spread in malarial areas. But having two copies is fatal, so the gene never spreads to more than about 20 per cent of the population. Ironically, that’s one of the reasons the sickle cell gene continues to be effective against malaria. If everybody had the gene, the malaria parasite would be forced to evolve around it. Greg Cochran.
GREG COCHRAN: If we had a gene that gave really good protection against malaria, and had almost no side effects, probably it would be spread rapidly, become common, and then stop working, kind of like penicillin.
JOHN RIEGER: So the sickle cell gene retains its effectiveness, and survives in the genome, because it’s harmfulness makes it self-limiting. Sickle cell does kill people but malaria kills more. Paul Ewald says the human genome is “littered” with these kinds of self-destructive defenses.
PAUL EWALD: So for example, in Africa, we see sickle cell anemia. In northern Europe, we see cystic fibrosis as a defense against typhoid fever. In southern Europe, we see glucose six phosphate dehydrogenase deficiencies, thalassemias, which are imbalances in the relative frequencies of the building blocks of the hemoglobin molecules.
JOHN RIEGER: Ewald and Cochran have taken their evolutionary analysis one big step further. They believe that only infection can trigger serious widespread genetic diseases. And so they argue that virtually any disease or condition like sickle cell that reduces a population’s fitness, and yet has endured over many generations, must have some connection to infection.
GRED COCHRAN: If there is a disease that reduces fitness, that reduces your number of kids, and it’s been... you know, at least moderately common - perhaps at least one in 100, or one in 300 people, or more - over a long time, it’s hard to see how you keep that going, unless it is somehow connected to... infectious disease. It may simply be an infectious disease... okay? Or in some cases, it might be an expensive defense.
JOHN RIEGER: While the scientific community has yet to digest this argument, it points the way to some astonishing inferences. Cochran and Ewald suggest that heart disease, or severe depression, rheumatoid arthrititis, schizophrenia-any condition that reduces the population’s ability to reproduce, and has existed for a long time, may very well exist because of an infectious disease. Think about it.
I’m John Rieger, for the DNA Files.
JOHN HOCKENBERRY: This is The DNA Files. I'm John Hockenberry.
[Sounds from tour of Myriad; collage of voices]
ROBERT WEINBERG: My laboratory has focused over the last quarter century in trying to find the genetic and molecular roots of human cancer. Trying to find the genes and the proteins which cause normal cells to grow uncontrollably into cancer cells.
NANCY WEXLER: If you think about what's actually required, you're plowing through 6 billion rungs of DNA, looking for one rung, which for all you know, looks exactly the same as any other run. The other problem was that there was no way really of knowing what you were looking for.
[lab voice continues: “This is a process that is about to happen to the blood that we saw….”]
JOHN HOCKENBERRY: Do you really want to know your future? Would you want to know that you, for sure, will eventually die of Huntington's disease or that you're much more likely to develop colon cancer, or breast cancer?
MARK SKOLNICK: We began the company specifically to search for the predisposing gene for breast cancer, BRCA1 AND BRCA2, and have since expanded the company to look for genes in cardiovascular disease, asthma, osteoporosis, obesity, depression, stroke and pulmonary disease.
JOHN HOCKENBERRY: Genes and disease. Genes that increase our chance of getting
cancer, or developing heart problems, or dementia. Do our genes determine our fate in life?
ROBERT WEINBERG: Only in a small percentage of human diseases are the genes absolute rulers, dictators over whether or not we get sick.
JOHN HOCKENBERRY: Biologist Robert Weinberg is a member of the Whitehead Institute of Biomedical Research at M.I.T. in Cambridge, Massachusetts.
ROBERT WEINBERG: In the vast majority of cases, there's an interplay between the genes we inherit and our lifestyle, and our diet, and our smoking habits and our environment. A complex interplay. Only in a very small number of cases can we actually explain away disease by saying, that individual got a gene at birth, and was preordained from that moment of birth to come down with the disease. This research on genes has already and will lead to enormous benefit for the public. But it’s also thrown up a lot of quandaries.
JOHN HOCKENBERRY: The ability to test a person's DNA for genetic variations is a relatively new scientific development within the past ten years. But evidence of some problem mutations were obvious decades ago.
[Sound of music from the early ‘70's]
MICHAEL KABACK: Now if you go back to the early 70's, there were efforts to do screening in the black communities of America for sickle trait.
JOHN HOCKENBERRY: Dr. Michael Kaback is a professor of pediatrics and reproductive medicine at the University of California in San Diego.
MICHAEL KABACK: They were not very successful, there was not sufficient organization of the education and counseling components.
JOHN HOCKENBERRY: Actually, the sickle cell testing debacle of the early 1970's is
seen by many as an object lesson for today, an example of how misinformation about genetically linked disease can lead to all sorts of unintended consequences.
JAMES BOWMAN: The early testing began with the commercial manufacture of a test which would detect sickling in the blood vessels.
JOHN HOCKENBERRY: In the early 1970's, Dr. James Bowman was a professor of
pathology and medicine at the University of Chicago. He was a distinct minority, a black man teaching at an elite, mostly white educational institution.
JAMES BOWMAN: There are many community groups that formed free standing health clinics throughout the city because they felt that the major medical centers were ignoring poor people.
JOHN HOCKENBERRY: There was a lot of misinformation about sickle cell disease. One day, recalls Dr. Bowman, a contingent from the Black Panther Party visited his office. They informed him that they'd already tested 5,000 black Chicago school children for sickle cell disease.
JAMES BOWMAN: And I was rather surprised and shocked. I'd heard about it but I didn't believe it. And they told the mothers that their child would be dead before the age of 20 and the reason why is because it was being ignored and that this is a racist society and there was evidence of genocide. And then I was asked to comment and I said, that's absolute nonsense.
JOHN HOCKENBERRY: Dr. Bowman told the Black Panther leaders that while sickle cell disease can be passed on by two parents who carry the trait, there's only a small probability that each of their children would inherit the disease. James Bowman says that his explanation fell on deaf ears.
[Sound of Black Panther Party press conference circa 1972]
JOHN HOCKENBERRY: Sickle cell disease was lumped in with sickle cell trait, and community activists and some civil rights groups supported mass screening programs. Says Dr. Bowman, it led to faulty classification of people.
JAMES BOWMAN: And not delineating the trait from the disease. Now even publications of the National Institutes of Health confused the trait with the disease.
JOHN HOCKENBERRY: Now, remember, this was an era in which black Americans were just starting to see the end of certain segregationist policies. The misinformation about people who carried sickle cell trait rapidly eroded some of that progress. Suddenly, black Americans found themselves facing added discrimination, not just because of the color of their skin, but also because of a "perceived" genetic disability. Activist efforts to empower communities had the opposite effect. Armed with misinformation about sickle cell trait, employers and others had a nice, supposedly scientific rationale for racially discriminatory policies.
JAMES BOWMAN: All of the airlines started testing flight attendants, and they discharged them. And the Air Force started testing all of the pilots and banned anyone who had sickle cell trait from flying. Even in schools they started testing and kids who had...were positive, they said, well, you can't participate in sports. And so, as a result there was mass community screening. Insurance companies began to hear of this and said, ah ha, about ten percent of the population have this horrible thing. And they raised insurance rates on African Americans, and began testing for that.
JOHN HOCKENBERRY: And, says Dr. Bowman, it wasn't as if this was a failure of
science. The techniques were available to tell the difference between a person with the trait, who could have no symptoms, and sickle cell disease, which can cause organ damage and in some cases an early death. The misinformation and high emotion from the sickle cell controversy back in the early 70's did convince the medical genetics community that screening without counseling and education could do far more harm than good.
JOHN HOCKENBERRY: Do you really want to know your future? And how much of that guide to the future can be found in our genes, anyway?
MARY CLAIRE KING: The genetics of each of us is the consequence of our genetic ancestry.
JOHN HOCKENBERRY: Dr. Mary Claire King is a professor of medicine and genetics at the University of Washington in Seattle.
MARY CLAIRE KING: And the genetics of us as a species is the consequence of a combination of mutations that have occurred largely by chance, in populations going back thousands and thousands of years.
JOHN HOCKENBERRY: Each cell in our body, and there are trillions of them in there, contains a copy of our body's genetic information.
NANCY WEXLER: If you unroll that genetic information and then you stand it end to end, it's going to be about the length of a six feet tall man.
JOHN HOCKENBERRY: Professor Nancy Wexler of Columbia University in New York is an expert on genetic disease. She says, imagine that all your genetic information is as tall as say, the actor, Mel Gibson.
NANCY WEXLER: If you have Mel Gibson rolled up in every cell and you unroll Mel Gibson, and then you stretch a trillion Mel Gibsons end to end, that's just the amount of DNA one person has in...in one person’s body.
JOHN HOCKENBERRY: Mel is now wrapped around the world, end to end. Scientists looking for a disease causing genetic mutation must hunt down the equivalent of perhaps half an inch to find it. Again Nancy Wexler.
NANCY WEXLER: A little tiny hole, a little tiny mistake, a little piece of the DNA that turned around or backwards or is missing -- so, it is a minuscule mistake, just minuscule.
JOHN HOCKENBERRY: Our genes serve as minuscule directors -- telling our cells what to do. We all have tiny mistakes in our genetic make up. They're called mutations. Mostly these mistakes never manifest into anything but that's not always the case. We each inherit our individual genetic blueprint from our parents. And, as biologist Robert Weinberg explains, the ongoing effort to map out the entire human genome has helped researchers find genes with those tiny mistakes. And some of these mistakes have more of an influence on our health than others. They can make people more susceptible to disease.
ROBERT WEINBERG: In the case of cancers, one now realizes that by being able to diagnose a mutant gene in somebody’s DNA, which gene they may have inherited from one or another parent, one may be able to predict long before a tumor appears that this person has a susceptibility or a risk for
getting a certain kind of cancer.
JOHN HOCKENBERRY: But being susceptible or at risk for a certain kind of cancer, still doesn't mean that a person will in fact get the disease. And scientists say there are a multitude of other factors at work here ranging from our personal lifestyle choices, to exposure to toxins and pollutants that can help break down the proper functioning of a cell.. In some cases, the existence of one copy of a mutated gene can cause a disease. And if you test positive for that specific causative gene, you know absolutely that you will get sick someday. You just don't know when it will happen. Producer Kathy McAnally brings us the story of one family that has lived for decades in the shadow of Huntington's disease.
KATHY MCANALLY: Milton Wexler and Leonore Sabin met in the mid 1930's. Milton started his professional career as a lawyer, found he hated it, and decided to train as a psychoanalyst instead. Leonore had a strong interest in science, especially genetics. She worked as a teacher. The couple married, and produced two daughters, Nancy and Alice.
ALICE WEXLER: Huntingon’s Disease was a big secret in the family. My sister and I never
knew anything about this.
KATHY MCANALLY: Alice Wexler, the eldest daughter, grew up to become a writer and historian. She teaches women's studies at UCLA. Alice has shadowy childhood memories of uncles who behaved oddly. Alice Wexler never met her mother's father.
ALICE WEXLER: My grandfather, who had the disease, had died when my mother was very young. She had never told us what he died of, and may not have even told my father when they got married. It was very stigmatized, very secret, very shameful.
KATHY MCANALLY: The wall of secrecy was maintained even as Leonore's brother’s symptoms grew worse. By then, father Milton knew that the strange affliction, so prevalent in his wife's family, was Huntington's disease. It's a neurological disorder that begins with symptoms like clumsiness and minor personality changes. Huntington's matures into dementia, and inability to control bodily movements. Death from Huntington's disease comes slowly, its victims usually suffer terrible symptoms for many years. In 1968, Alice's mother, Leonore, was diagnosed with Huntington's.
ALICE WEXLER: And at that point, my sister and I found out about it. And learned that we were at 50% risk.
KATHY MCANALLY: Dr. Milton Wexler.
MILTON WEXLER: When I suddenly discovered that my wife was diagnosed with Huntington's and my two lovely daughters were now at 50/50 risk, I felt there was nothing else to do except to go after the cure.
KATHY MCANALLY: Now, Dr. Wexler's experience was in exploring the mysteries of patient's unconscious minds. Not misfirings in their genetic code. But Milton Wexler was not without resources. His practice in Beverly Hills had brought him into contact with artists and actors. People he could call upon to support a major research initiative on Huntington's disease. But how to look for it, and how would the scientific community respond to a research initiative spawned by an outsider, an anxious father wearing his heart on his sleeve? At first Milton Wexler worked with younger scientists, believing they'd be more open to new ideas, more daring in searching out the genetic link to Huntington's disease. He began organizing workshops, brainstorming sessions. As it turned out, the researchers loved being liberated from the isolation of their own labs for a weekend to work in a truly cooperative environment.
MILTON WEXLER: But the idea that I could get together and pull together top level scientists to come to my workshop, and they would come for a whole weekend and speculate, and talk, develop ideas, thoughts, hypothesis, and that a Nobel prize winner would work for me for nothing, blew my mind.
KATHY MCANALLY: Nancy Wexler was in graduate school when her mother was diagnosed with Huntington's. Her Ph.D. dissertation explored the cognitive and emotional consequences of being at risk for Huntington's disease. Leonore Wexler died in 1978. By then, Nancy had become a nationally known leader in the search for the Huntington's genetic marker. Dr. Nancy Wexler.
NANCY WEXLER: In the beginning we had a discussion about whether or not we should wait until the entire human genome was mapped and then look for Huntington’s Disease. In which case, we'd still not have our gene.
KATHY MCANALLY: The scientists working on the search for the genetic marker for Huntington's wanted to study families with the disease. Basically, the idea was to try to look at blood and tissue samples of people with the disease to find some unique sequences of DNA, a marker.
NANCY WEXLER: So every time you find a new marker, you can use it both to map the genome, but also use it to see whether or not that marker is close to the Huntington’s Disease Gene.
KATHY MCANALLY: It was in 1872 that a Dr. George Huntington wrote about a disease that was confined to certain, and fortunately a few, families. "It has been transmitted to them,” he wrote, “an heirloom from generations a way back in the dim past."
[Music: Venzuealan guitar folk tune]
KATHY MCANALLY: In 1952, Dr. Americo Negrette began practicing medicine in a
remote Venezuelan community near Lake Maracaibo. He saw residents stumbling and weaving and falling down, and concluded that they were drunk. But the local residents explained that no, it was a sickness they had, called el mal. Americo Negrette became an advocate for his patients, writing and lecturing about their plight in Venezuela. But his work there remained unknown to the international community of Huntington's researchers until it was presented at a conference in the United States in 1972. The existence of such a huge concentration of Huntington's fascinated Nancy Wexler.
KATHY MCANALLY: In 1979, Nancy Wexler led a team of doctors and researchers to the area.. At first, the villagers were very suspicious. Nancy Wexler explained to them that her own mother had just died of the sickness. That the shadow of el mal hung over her life, as well.
NANCY WEXLER: And they said, this can't be true because the United States is so rich and so smart and how can you have a disease like Huntington's, why don't you get rid of it?
KATHY MCANALLY: They were trying to get rid of it, explained Wexler. But first the researchers had to figure out what caused Huntington's disease. Wexler asked the villagers to share their family stories about the sickness with the researchers. She also asked them to donate samples of their blood and skin. The villagers weren't sure they wanted to do that. A Spanish speaking nurse working with the team pointed out to the skeptical villagers that Nancy had a scar on her own arm where a skin sample been removed.
NANCY WEXLER: And she took me by the arm and she just walked me around and everybody was going, oh my gosh, you know, she has the mark. And then they really believed that nobody would mutilate themselves for no particular reason. So, then they actually did believe that I did have this in my family.
KATHY MCANALLY: Along with blood and skin samples, the researchers collected family histories. Research through local death records, coordinated by historian Alice Wexler, led the team to a woman named Maria Concepcion, who appeared to be the "common ancestor" of the local families with Huntington's disease. They suspected that she'd been fathered by a European sailor in the early 1800's. He'd passed the deadly genetic mutation on to his daughter, and her descendants, who now numbered in the thousands.
KATHY MCANALLY: The samples collected in Venezuela became part of the search for the Huntington's disease marker. In 1993, Dr. James Gusella of Massachusetts General Hospital isolated the gene that caused Huntington's disease. Before long, a simple blood test was available that could tell people at risk for Huntington's whether or not they will someday get the disease. Milton, Nancy and Alice Wexler talked it over, and decided that they didn't want to know. Both women are now in their 50's, past the age when symptoms usually appear, although people as old as 60 have developed the disease. Alice Wexler is now writing a book on the history of Huntington's disease.
ALICE WEXLER: It’s not gone away and the best therapy has been to work like hell. Really, my sister, of course, it's her whole life, as a researcher and as an activist. And I think that psychologically, you know, that it's incredibly helpful. It makes you feel like you're really doing something. You're not just sitting there waiting for it to happen.
KATHY MCANALLY: Nancy Wexler is one of the most outspoken advocates for caution in the face of tests that can tell you about your health future. Especially in cases where there is no good treatment or cure.
NANCY WEXLER: The impact of knowing your future is infinitely more than people bargained for. And even people themselves will say no amount of conversation or planning before the event really prepared them for what knowing their future would be. You need to practice what it feels like to have both outcomes. What it would really, really mean in terms of your own personal life.
JOHN HOCKENBERRY: So, we’re back to our original question: Do you really want to know your future? In the case of Huntington's disease, some people do. Because the pre symptomatic test can tell a person whether or not they'll get the disease, some people want to be able to use that information to plan their future. You can't do anything to change your health future but you can decide how you'd like to spend your time while you’re still healthy. But not all genetic tests can provide such clear-cut medical answers. Kathy McAnally returns with the story of one family's history with Alzheimer's disease.
KATHY MCANALLY: A stumble while walking down the street. Losing your car keys or your temper. For people who have family histories of late onset neurological disease, such minor incidents are pretty frightening. There's that inner voice saying: Is this an early symptom of something really bad?
JANE NEILSON: What happened that we started noticing is that she would do strange things like she would want to set the table but she could no longer figure out how to do it.
KATHY MCANALLY: Jane Neilson is talking about her mother -- a sweet, loving homemaker who was in her 80's when the strange behavior began.
JANE NEILSON: She went through a battery of tests and we had a family consultation about the results, and they concluded that she probably did have Alzheimer's. That did help my father accept it. And it did help him start on a path of doing something for her.
KATHY MCANALLY: Jane had an older sister, Dorothy Ann.
JANE NEILSON: She lived in New York City. She did public relations work. She was like the bigger sister who had this profile in my mind of somebody very glamorous.
KATHY MCANALLY: At age 54, Dorothy Ann started having trouble holding on to jobs. She said it was age discrimination. On a Christmas visit, Dorothy Ann was behaving strangely.
JANE NEILSON: But she was dressing well and she was talking well and a social worker who visited my parents knew something was wrong, but never guessed Alzheimer's because she was so young.
KATHY MCANALLY: Back home in New York, Dorothy Ann's decline was apparent to
friends. She'd drop in on them at work, then sit around, cutting up little pieces of paper. She mailed her child like handiwork to former employers, along with demands for payment. Alarmed, her New York friends called Dorothy Ann's family in California. Jane traveled east to help her sister.
JANE NEILSON: She refused to go to a doctor. And you can't force someone to go to a doctor. I think she refused to go to a doctor because she realized something was wrong with her, and that if she did, she’d lose control of her life.
KATHY MCANALLY: Jane Neilson worked with social service agencies to have her sister qualified as having a disability. Dorothy Ann's adult son made sure that she had food. Eventually though, Dorothy Ann wasn't able to live independently.
JANE NEILSON: My sister was placed in a nursing home within five months of my mother being placed in a nursing home.
KATHY MCANALLY: The diagnosis was probable Alzheimer's disease. Doctors can't be positive in a diagnosis, because it can only be confirmed by studying the brain during an autopsy. The presence of plaque proves Alzheimer's. Jane was listening to a radio talk show, when she heard about a genetic link to Alzheimer's disease. That it was possible to have a genetic test to see if she was at increased risk for the disease that had incapacitated her mother and sister.
JANE NEILSON: Do I really want to go through this? And what if I found out I was susceptible?
WILLIAM JAGUST: There are three types of Alzheimer's disease as far as the genetics.
KATHY MCANALLY: Dr. William Jagust, a neurologist, directs the Alzheimer's Disease Center at the University of California at Davis.
WILLIAM JAGUST: Some of it is very, very strongly genetic. It's what we call autosomal dominant, and that means in a family with autosomal dominant Alzheimer's disease, the second generation, each individual in the second generation, has a 50% chance of inheriting the gene and getting the disease.
KATHY MCANALLY: This kind of Alzheimer's has been linked to three separate genes. But, cautions Dr. Jagust, the autosomal dominant type is quite rare, and accounts for just a small percentage of Alzheimer's cases.
WILLIAM JAGUST: The second kind of Alzheimer's disease where one has familial risks, is not very well understood, but one of the strongest risk factors is clearly genetics, and it's been associated with a risk factor gene called apo lipo protein e or APOE for short.
KATHY MCANALLY: Now, we all have APOE in some form and the one called type four is seen as a sign of increased risk for developing Alzheimer's. Two copies of type four ups your chances even more. Conversely, you can have two copies of the APOE 4 gene and never develop Alzheimer's. It's a risk factor, in the same way high cholesterol is for heart disease.
JANE NEILSON: Each year I visited her, she became more vacant looking and more...showing more...more signs of Alzheimer’s -- confused look and not standing up straight.
KATHY MCANALLY: Jane Neilson went back and forth in her mind as to whether she wanted to know what her future held. Was it better to know, or not know? Should she just be tested and not tell anyone the results?
JANE NEILSON: I would want to know if my cognitive life was going to be shortened so that I could make the best of what I have. But I was also thinking, if I knew, would I want my husband to know? Why burden him with that same knowledge? That would be two depressed people.
KATHY MCANALLY: Jane finally decided that she couldn't keep something that important from her husband, but that she did want to be tested. But, after talking with counselors about her family's disease history, Jane Neilson was told that she was not an appropriate candidate for genetic testing, that there wasn't enough Alzheimer's in her family tree to suggest the presence of the autosomal dominant gene.
JANE NEILSON: I was stunned. I was almost angry because I'd gone through all the introspection and didn't get the goods. But on another level I was also relieved because I didn't have to face it.
KATHY MCANALLY: According to Dr. William Jagust, the genetic test for APOE 4 is used primarily as a diagnostic tool once a person has begun to show symptoms of Alzheimer's disease. And that's because its predictive value, on it's own, isn't all that good. Dr. Jagust also says that many people who develop Alzheimer's have no known genetic risk for the disease at all.
WILLIAM JAGUST: We can do tests for every gene that we now know, and even if they are all negative, we can't tell you you won't get Alzheimer's disease because there are undoubtedly genes that we have not yet discovered that may be very important. And so, the only thing you can get
from these tests is bad news.
KATHY MCANALLY: Jane Neilson's mom and sister both died in nursing homes. She doesn't know for sure what she would do if a more highly predictive test for Alzheimer's became available.
JANE NEILSON: I'm not sure what I would do in the future. I'm glad I faced the question and decided to pursue it because it made me face things that one would tend to avoid facing, and I came to a peace about it. I learned a lot by going through the process. And, I learned the importance of living in the moment. It’s the only moment you have anyway to be happy.
JOHN HOCKENBERRY: The scientific search for genetic mutations that are associated with disease are part of the quest for treatments and cures. The tests that have been developed are part of this scientific journey. When will there be therapies for Huntington's disease, or Alzheimer's, or other now incurable conditions? Will that be in five years, or in fifty?
JOHN HOCKENBERRY: Later in the program – What about cases in which a predictive genetic test can lead to life saving treatment?
JOHN HOCKENBERRY: This is The DNA Files.
JOHN HOCKENBERRY: This is The DNA Files. I’m John Hockenberry. Do you really want to know your future? Do our genes determine our fate? In some cases, yes they do. With Huntington’s disease and rare forms of Alzheimer’s disease, genetic tests can tell you that it’s highly likely that you’ll get sick later in life. And, in those two cases, there are no effective treatments currently available. In some cases, though, such as certain kinds of cancer, an early diagnosis of a genetic predisposition can mean a cure. Certain cancers of the colon fall into this category.
BERT VOGELSTEIN: In about 80% of colon cancers there is no obvious family history.
JOHN HOCKENBERRY: Dr. Bert Vogelstein of Johns Hopkins University in Baltimore has been exploring the genetic links to colon cancers since the 1980s.
BERT VOGELSTEIN: But in approximately 20% of cases there is a family history and these cases can be loosely grouped as familial colon cancers. Some of the genes responsible for hereditary colon cancers have been identified. In the hereditary cases, patients often develop tumors at an early age, 40's 30's. We’ve seen patients develop tumors even before they are 10 years old in some of the most severe cases.
JOHN HOCKENBERRY: Now, keep in mind that the vast majority of colon cancers strike a much older population. The median age is in the mid to late sixties. And there is no known genetic link to approximately 80% of diagnosed colon cancer cases. But, for that 20% of the population in which there is a family history of the disease, Dr. Bert Vogelstein is a staunch advocate of predictive testing.
BERT VOGELSTEIN: Members of those families should be offered testing. Such testing can dramatically influence the way those families are managed and can, in fact, be life saving if applied correctly.
JOHN HOCKENBERRY: In families with a strong medical history of colon cancer, where sometimes there is a very early onset of disease, the issue of testing very young children comes up. In general, geneticists and bioethicists oppose genetic testing of kids, especially for a disease that won’t arrive until adulthood, and where there are no viable medical treatment options. But most make an exception for hereditary colon cancer.
DOROTHY WERTZ: Because at a certain point, you probably have to operate on that child to prevent cancer.
JOHN HOCKENBERRY: Dr. Dorothy Wertz is a senior scientist at the Shriver Center in Massachusetts. Wertz has written extensively about the issue of the ethics of childhood genetic testing.
DOROTHY WERTZ: They take out the colon, which will otherwise go cancerous. And it’s a question of when to do it. I’m told that testing as early as nine and certainly by the age of twelve may be justified in order to see whether you’re going to have to take that colon out.
SOUND OF NEWS REPORT: “About 6% of American Jews are at increased risk for colon cancer according to findings reported this week by John’s Hopkins researchers. The threat is posed by a subtle genetic mutation in a gene called APC. Researchers tested for it among Ashkenazy Jews, or Jews of eastern european descent.”]
JOHN HOCKENBERRY: In 1997, Dr. Bert Vogelstein’s research team identified a new colon cancer mutation. News reports including this one provided Johns Hopkins own new service, linked the mutation to people of Ashkenazy Jewish ancestry. The descendants of this group from central and eastern Europe make up about 90% of the American Jewish population.
BERT VOGELSTEIN: That doesn’t mean that only Ashkenazy Jews have such mutations. Probably lots of other populations have similar mutations.
JOHN HOCKENBERRY: However, as news of new genetic disease discoveries are reported, some members of the Jewish community have expressed concern that this will result in a kind of misleading labeling of certain populations. Dr. Vogelstein.
BERT VOGELSTEIN: There’s a more serious kind of discrimination that is not racially or religiously biased, but can affect anyone with a genetic defect that predisposes them to cancer or other diseases. And that’s job discrimination and insurance discrimination.
JOHN HOCKENBERRY: Is it possible to keep our genetic information private? George Annas is a professor of Health Law at Boston University and has written extensively on genetic privacy issues. He says that it’s essential that each of us control who has access.
GEORGE ANNAS: The DNA molecule, I think, can be analogized to a diary. It’s not a diary in the sense that you write things down when you’re young that you’re going to read about when you’re old. But, it’s a diary in the sense that it’s very private information that informs your younger self about your aging self, if you will. It’s your diary. It should be your decision whether to open it, whether to read it, and whether to share it with other people.
JOHN HOCKENBERRY: Dr. Gloria Peterson of Johns Hopkins University says that some of the families that she sees who are at risk for colon cancer want their genetic test results kept secret.
GLORIA PETERSON: People are choosing to cover their costs themselves and not ever let their insurance company know about it. And, in some instances, I think they’re not even letting their physician put it into their medical charts. They may be verbally telling their physician what may have resulted but not allowing it to be put into their chart.
LISA GELLER: I think most people actually don’t know to do that or don’t think to do that, or their physicians don’t necessarily suggest it.
JOHN HOCKENBERRY: Lisa Geller is a bioethicist who works for a Boston law firm as a technology specialist. Back in 1996, she co-authored a Harvard Medical School study that documented cases of genetic discrimination. Geller thinks that as time goes on, more people will try to keep their genetic information a secret.
LISA GELLER: There’s legal risk though, because once you have the insurance, that’s one thing. Although, if there is some clause where they can cancel it, you could be in trouble. But withholding information, you’ve signed a contract with the company saying that you are not withholding information. So, there is risk if you do that.
JOHN HOCKENBERRY: Susan Van Gelder, Chief of Staff for the Health Insurance Association of America, says there’s no reason for people to withhold genetic information from their insurers – that there is nothing to be afraid of.
SUSAN VAN GELDER: It’s an unfounded fear. I mean they have coverage. They can’t lose that coverage. They can’t have their insurance premiums go up based on the results of a genetic test. It’s unfounded and I believe sort of fed by this media frenzy trying to gin up some problem in this area.
JOHN HOCKENBERRY: She’s right so long as you are covered by a big group plan or if you’ve left a job with such coverage and kept up the premiums yourself. But if you’re between jobs, this is a costly proposition. What if you were an individual applying for health insurance on your own? A predictive genetic test has told you that you are at high risk for a certain disease, and you decide to tell the truth about it when you apply for coverage?
SUSAN VAN GELDER: Yes, an insurer would take that information into account, if it were known, if that test were taken, just as it would take into account high blood pressure, high cholesterol levels, because they need to be able to price adequately for the resulting claims that could occur from that potential policy holder.
JOHN HOCKENBERRY: Professor George Annas of Boston University says that health insurers would probably run afoul of the Americans with Disabilities Act if they denied coverage outright.
GEORGE ANNAS: But it doesn’t prevent them from charging very high rates for that. Rates that wold be prohibitively expensive for most people. So that’s not a solution.
JOHN HOCKENBERRY: And while most of us get our health insurance through our jobs, the kind of insurance coverage we are offered is changing. Most of us used to be covered by what’s called fee for service: the doc says you need a test or a procedure and the company paid for it without question. Now more and more of us are part of the managed care medical model. You want a test or a specialized treatment, the insurer gets to say yes or no.
BAYLA: I have fears about that, because I see people to whom that’s going to happen. For me what would have happened would have been in the eventuality of maybe three or four years, I wouldn’t have been alive.
KATHY MCANALLY: I met Bayla 20 years ago. She was bald from chemotherapy. She was determined to prove the doctors who’d given her six months to live, wrong. And she was positive that breast cancer was written in her genes.
BAYLA: My mother was one of six sisters. They all died of breast cancer, and my father died of breast cancer, and those were all my first line relatives. The other people in my family, aunts, uncles, then my cousins, there is four of us who are alive and have had breast cancer and or ovarian cancer. There is a lot of people in my family who have died of cancer. It’s been incessant.
MARY CLAIRE KING: The existence of families in which many women have had breast cancer, and indeed in many such families, ovarian cancer as well, is not new.
KATHY MCANALLY: Dr. Mary Claire King of the University of Washington, first posed the theory that a gene could be found that was linked to susceptibility to breast cancer. Twenty years ago, many of her fellow geneticists found King’s idea laughable. Her current work focuses on unlocking the mysteries of the two known breast cancer mutations – BRCA1 and BRCA2.
MARY CLAIRE KING: It’s clear that ancient mutations in BRCA1 and BRCA2 have occurred in many populations in Europe. There’s one mutation in BRCA2 which is found specifically in Iceland, is ancient in Iceland, and is responsible for virtually all of familial breast cancer in Iceland. In Southern Sweden, there are three glacial valleys. There’s a BRCA1 mutation specific to each glacial valley.
KATHY MCANALLY: Inherited breast cancer mutations have been tracked to a small area in Scotland and throughout eastern Europe.
MARY CLAIRE KING: This mutation in America has been found primarily in families of Ashkenazy Jewish ancestry. Now, of course, it shows up in families of eastern European ancestry, whether Jewish or Christian. So, we are the consequences of mutations and the patterns of movement and marriage of our ancestors.
KATHY MCANALLY: In the early 1990s, a race was on to find the exact location of the breast cancer mutations. Dr. King and her colleagues had done the groundbreaking early research and were very much in the running. But the winner was Dr. Mark Skolnick, then of the University of Utah.
MARK SKOLNICK: We were able to find BRCA1 first by studying large Utah pedigrees, and these pedigrees are unusual that in the last half of the 19th century, the Mormon pioneers often had multiple wives and six or seven children per wife. And this was documented by genealogical data so that we were able to study the descendants of these pioneers, often dozens of children, hundreds of grandchildren, thousands of great grandchildren, and tens of thousands of individuals in the present generation.
KATHY MCANALLY: Researchers were able to pinpoint a gene to a specific chromosome, then look for the variation in the families being studied.
MARK SKOLNICK: When we find a gene that has such variations, we know that we have found the gene that we’re looking for. In the case of breast cancer susceptibility, BRCA1.
KATHY MCANALLY: Susceptibility means more likely. Dr. Mary Claire King.
MARY CLAIRE KING: A woman who inherits a mutation in, for example, BRCA1 is just fine. Just absolutely nothing wrong with her at all by virtue of having inherited that mutation. However, if and when any of the epithelial cells lining her breast ducts undergo a mutation or a loss of the remaining normal copy of the BRCA1 gene or if that same event happens in a cell in her ovarian epithelium, that is the other remaining normal copy of BRCA1 is lost, then there’s no remaining normal copies of BRCA1 present. Both are gone. And when that occurs, a tumor begins to develop.
KATHY MCANALLY: DR MARK SKOLNICK.
MARK SKOLNICK: About five to ten percent of breast cancer occurs in individuals who have the susceptibility to BRCA1 and BRCA2. So, the vast majority of people who get breast cancer do not have these highly penetrant genes.
KATHY MCANALLY: In other words, more than 90% of all breast cancers have no known inherited genetic component. They don’t carry a little mistake, a specific genetic mutation that greatly increases the risk of breast and ovarian cancer. [Sound of explanation in lab.] Dr. Mark Skolnick has made the diagnosis of those highly penetrant genes his business. He’s the chief scientific officer for Myriad Genetics in Salt Lake City, Utah. Myriad owns the patent rights for the susceptibility test for BRCA1 and 2.
MARK SKOLNICK: It’s very important for women who might be at high risk to have the knowledge to decide whether they want to be tested or not. I see thousands of women dying each year from BRCA1 and BRCA2 whose lives could be saved if they knew early enough that they were affected.
[more lab background explanations]
KATHY MCANALLY: A positive test result doesn’t provide any clear-cut answers as to what to do next. One option is to have more frequent mammograms. Dr. Michael Kaback.
MICHAEL KABACK: There is no data on this but what, if any, are the risks of increased mammography in woman who carry mutations in BRCA1 and 2? We don’t know the answer to that.
KATHY MCANALLY: The other, much more radical, option is to remove the breasts and ovaries surgically. But, says Dr. Neil Holtzman, an expert on genetic testing issues, prophylactic mastectomy doesn’t guarantee a future free of breast cancer either.
NEIL HOLTZMAN: I don’t personally believe there’s enough evidence to say that prophylactic mastectomy or overectomy -- that we know enough to say that the benefits of those surgical procedures are better for a woman at the age of 30, 35 or 40 than periodic mammography, particularly with some of the new mammographic techniques. We just don’t know. The studies haven’t been done. I mean it puts women at a bind, and I think many women, particularly where there is a severe family history, will have their breasts removed. They will probably lower their chance of having breast cancer perhaps more than if they were to have mammography, but I don’t think that evidence is in.
KATHY MCANALLY: What is the definition of a severe family history? Dr. Mary Claire King.
MARY CLAIRE KING: For women in families in which more than four women have developed breast cancer already, or both breast and ovarian cancer had appeared, that there was a quite high likelihood that a BRCA1 mutation would be found, and we’ll see what the BRCA2 story is next.
KATHY MCANALLY: Dr. Mark Skolnick goes with the recommendation of the American Society of Clinical Oncologists as to who is a candidate for testing.
MARK SKOLNICK: Women who are at a 10% risk of being positive for BRCA1 or BRCA2 should be tested. And this turns out to be women with breast cancer or ovarian cancer if the breast cancer occurred below age fifty, or ovarian cancer at any age, or if they have one relative with breast cancer.
KATHY MCANALLY: The definition of who exactly is at high risk, how many familial cases of breast or ovarian cancer it takes to reach that unfortunate plateau depends on who you talk to. My friend Bayla has little patience with those who hover over statistical tables, trying to figure out who should and should not be tested. Bayla has metatastic breast cancer.
BAYLA: Women have to make lots of decision with this. I think she’s the only person who should be able to make the decision about it. I think the people who are the most rowdy, the most sort of obnoxious and rude to their doctors and just saying, I’m doing this, I need to do this for me, and I don’t care what you say, you know, I want it, and if you can’t be my doctor, then you can’t be my doctor.
KATHY MCANALLY: DR. MARY CLAIRE KING:
MARY CLAIRE KING: As a woman and a consumer, I want the right to be tested if I am convinced that it is the right thing for me. Period. End of story.
KATHY MCANALLY: But the scientist in Dr. King says that gene testing for breast cancer susceptibility is medically appropriate in only a small percentage of the population. That inherited breast cancers count for only five to ten percent of the disease. And remember also that a negative test result doesn’t meant that a woman won’t get breast cancer. And that tests are marketed to doctors by companies that stand to make a profit.
LORI ANDREWS: We’re at an interesting juncture in society in that we’ve lost our neutral experts on this.
KATHY MCANALLY: Professor Lori B. Andrews is an expert on genetics and the law. She teaches at Chicago Kent College of Law.
LORI ANDREWS: It used to be that places like the National Academy of Sciences had governmental or other scientists they could turn to to ask about the efficacy of testing and the appropriateness. Now, it seems though, that the very people working on the test all have a financial self interest in spreading it as far as possible.
BARBARA KOENIG: We wouldn’t want to stifle innovation, and I think the real issue is this overlap between the basic science and commercialization.
KATHY MCANALLY: Barbara Koenig is an anthropologist who co-directs the program on genomics, ethics and society at Stanford University.
BARBARA KOENIG: It’s a big shift, and I don’t think that individuals in companies who are developing these kinds of technologies are doing it out of any ill motivation. I think they actually believe that they’re going to be saving lives and giving people more choices. I don’t think that there’s anything nefarious going on.
CNN news report: “A public interest law firm claims Lawrence Berkeley National Laboratory subjected employees to secret medical tests.”
JOHN HOCKENBERRY: September 1995, a lawsuit is filed by a group of black and Hispanic employees at the Lawrence Berkeley Laboratory. They are asking a federal court to find that the lab violated their constitutional right to privacy as well as their civil rights by subjecting them to medical and genetic tests without their knowledge or consent.
MARIA BLOODSAW NORMAN: My parent’s reaction was this is something that happened to them during the Jim Crow laws when blacks were tested to keep them from getting positions.
JOHN HOCKENBERRY: In 1994, employee Maria Bloodsaw Norman requested a copy of her medical records and was astonished to learn that she’d been tested for a venereal disease.
DANA HAWKINS: She asked her colleagues to request their medical records so they could compare notes.
JOHN HOCKENBERRY: Dana Hawkins, an associate editor at U.S. News and World Report, wrote several articles about the case.
DANA HAWKINS: And eventually she and several of the other employees went to the Legal Aid Society of San Francisco and they were able to get the records of about seventy more employees.
JOHN HOCKENBERRY: According to Dana Hawkins, the lab confirmed that it retested its black and Hispanic employees periodically. Why? The lab’s lead attorney Douglas Barton had this explanation.
DANA HAWKINS: He says that their intentions were entirely honorable, and that he notes that employees of all races were tested for a number of health problems. And he claims that the focus was to assist people to maintain good health.
JOHN HOCKENBERRY: That justification isn’t believed by Dr. James Bowman who watched blacks face discrimination because of sickle cell testing programs back in the 1970s. He was horrified to learn about the Lawrence Berkeley Lab’s secret tests.
JAMES BOWMAN: I think that was absolutely horrible. And as far as I’m concerned, that was a racist act. It was obvious. It’s astonishing that they did that. Astonishing they did that. I was absolutely shocked because it was just as if we were way back in the early ‘70s.
GEORGE ANNAS: People care a lot about whether individual employers, the government, other people are testing them for conditions without telling them about it.
JOHN HOCKENBERRY: Boston University Professor George Annas lauds the 1998 court decision which found Lawrence Berkeley National Laboratory in the wrong.
GEORGE ANNAS: That’s exactly right. That’s what’s intolerable, is for other people to know more about you than you know about yourself, and to gather that information without your consent.
JOHN HOCKENBERRY: Do you want others to know about your genetic future? Most of us would say no, absolutely not. Professor George Annas advocates strict laws that protect genetic privacy.
GEORGE ANNAS: We can prevent employers from using genetic information against someone and we an prevent health insurance companies from using genetic information to deny health insurance.
JOHN HOCKENBERRY: Perhaps most of all, the decision to have predictive genetic testing is a personal decision. It couldn’t be more personal to Dr. Nancy Wexler, the Huntington’s disease researcher who is at risk for the disease.
NANCY WEXLER: I wouldn’t even say absolutely that I either haven’t been tested or I wouldn’t get tested in the future. These are decisions that are fluid. They change over time and they change with your situation.
JOHN HOCKENBERRY: Biologist Robert Weinberg of the Whitehead Institute, Massachusetts Institute of Technology.
ROBERT WEINBERG: There’s a certain kind of fatalism, a genetic determinism which says in certain people’s minds, that whatever they are and whatever they will do is dictated totally by the genes they happen to have inherited from one’s parents. They will say that whatever they do good or bad is the fault of their genes rather than their own personal responsibility.
JOHN HOCKENBERRY: You know, there’s an old saying: A little knowledge is a dangerous thing. And perhaps the most important idea to take away from these stories is that at the current state of technology, predictive genetic testing still represents just a tiny bit of knowledge about an extremely complex subject – our genetic makeup. The problem is, there couldn’t be more at stake for everyone – insurers, researchers, the courts, and, above all, the actual people who will live with the consequences of knowing or not knowing even a little bit about their genetic future. They ultimately, even under the best scenarios, after all the genetic counseling and financial support, will be on their own. So, do you really want to know your future? Right now it’s your call.
Credits for The DNA Files:
The DNA Files is produced by SoundVision Productions, in Berkeley, California, and is made possible through the generous contributions of the National Science Foundation, the Department of Energy and the Alfred P. Sloan Foundation.
JOHN HOCKENBERRY: You’ve been listening to The DNA Files. I’m John Hockenberry.
For more information, and for an interactive look at some of the issues behind this program, go to our web site at www.dnafiles.org. For tapes and transcripts of this program and this series, contact VisABILITY at 303.823.8000. That’s 303.823.8000. To contact The DNA Files, send your email to firstname.lastname@example.org. Today's program, Predictive Genetic Tests: Do You Really Want to Know Your Future?", was produced by Kathy McAnally. The editor was Catherine Stifter and the engineer was Ed Herrmann.
The DNA Files’ Executive Producer is Bari Scott. The Project Director is Jude Thilman.
Managing Editors of The DNA Files are Loretta Williams and Catherine Stifter. Production manager is Catherine Gollery. Technical Director is Robin Wise. Adi Gevins is Director of Research and Creative Consultant. Sally Lehrman is Content Consultant. Original music composed and performed by Bill Frisell. Introductory Feature produced by John Rieger and edited by Gary Covino.
This has been a SoundVision production.
This program is distributed by NPR – National Public Radio.