Camilla Grondahl asked genetics researcher Gholson Lyon a simple, heartbreaking question: Was she carrying a lethal gene that might kill her unborn baby?
Grondahl, 29, didn’t want to terminate her pregnancy, which began in 2010. She just wanted to know what the scientist knew.
“It was just more stress and worry while I was waiting for my baby to be born,” Grondahl recalled. “What do you plan for? Do you plan for him going to college or for a funeral?”
Lyon said he couldn’t tell her. A few months earlier, Grondahl had given blood for a DNA study Lyon was conducting on her family. She signed a form that said she would be notified of findings that had “direct medical significance,” without defining what that meant.
Grondahl is one of thousands of people in the U.S. who have undergone DNA testing for research purposes and aren’t receiving the results, even when the information has life-or-death consequences. That’s prompting a burgeoning ethical debate that has led to soul-searching among scientists and doctors.
While DNA sequencing is becoming more widely available, most of the testing is done for research purposes at universities and large medical centers. Even when an individual wants to map his or her DNA, the cost can exceed $10,000 and is rarely covered by insurance. Physicians and researchers are using the technology to better understand and, in some cases, diagnose and treat cancer and other diseases.
As of last year, about 30,000 people have had their full genomes sequenced -- a complete analysis of their DNA -- up from just one in 2003. The vast majority of them were analyzed in research studies in which individuals, under standard research guidelines, signed consent forms waiving their rights to the information, said Alexander Wait Zaranek, a geneticist at Harvard Medical School.
‘Fork in the Road’
The possibility that scientists might have clinically important information about individual study participants that they aren’t sharing with them is the biggest ethical issue facing genetic research, said Susan M. Wolf, a professor of law and medicine at the University of Minnesota in Minneapolis.
“It’s very hard to defend a researcher knowing about an urgent, high-stakes finding that could be addressed medically, and not sharing it with a participant,” she said in a telephone interview. “There’s a fundamental fork in the road here.”
The consequences can be serious. At least 5,378 people have had genes sequenced through one National Heart, Lung and Blood Institute study, Zaranek said. A computer analysis of the data predicts that as many as 100 of them may have harmful mutations in genes that raise the risk of breast cancer, Zaranek said.
Researchers haven’t confirmed that the mutations are there, or informed participants that they may have elevated risk, said Christopher O’Donnell, a researcher at the institute who’s involved in the study. Deciding what to do with the information is one of the most important parts of the study, he said.
Researchers are struggling to understand what to do with genetic results that are discovered unexpectedly, called “incidental findings.”
Scientists are concerned that participants in their research projects risk finding out unwanted, unnecessary or incorrect information about themselves -- information that may induce fear and alter lives.
In a 1999 study in the American Journal of Human Genetics, about 1 percent of people who were diagnosed with Huntington’s disease, a fatal, genetic nerve disorder that usually occurs in mid to late life, attempted suicide or were hospitalized for psychiatric reasons.
Even when researchers are sure genetic data is correct, expertise in delivering the news is scant. There are about 1,300 clinical geneticists and 785 genetic counselors in the U.S., according to professional groups, or about one licensed and qualified person to explain genetic tests for every 150,000 Americans.
‘Pregnant and Sobbing’
“We have to take care with how we give people certain kinds of bad news,” said Harvard University genetics researcher Robert Green. “If you were going to tell someone they have inoperable cancer, you wouldn’t leave a message with their six- year-old child over the phone.”
When Angela Chiesa learned that her mother, who was diagnosed with dementia at the age of 57, carried the Apoe4 gene variant that boosts the risk for Alzheimer’s disease, she immediately felt a sinking feeling in her gut. The doctor told Chiesa that there was a 50 percent chance she, too, had inherited the gene variant, and might be vulnerable to Alzheimer’s disease as well.
“I was just sitting there, pregnant and sobbing,” Chiesa recalled. “It was such a devastating moment. It was just like someone punched me in the chest. I immediately started thinking about what this meant for my own children.”
Want to Know
Chiesa still hasn’t undergone a test for the gene, afraid of what she might find. She said she still might want to have it done in the future, if there was a chance if it might help her prepare for, or even avoid, Alzheimer’s.
Many research subjects want to know what their genetic testing shows, even when they’ve agreed to remain ignorant. A survey of 279 people published last year in the Journal of Empirical Research on Human Research Ethics found that 71 percent of those in the U.S. wanted all the results of genetic studies of their donated tissue. Even though there’s no therapy or prevention for Alzheimer’s disease, some patients say they would pay more than $1,000 to find out whether they’re at increased genetic risk, Harvard’s Green said.
“Ultimately most genetic information should be freely available for anyone who wants to find out information about themselves,” said Green, who’s conducting a number of studies of how to give such data back to people. “We still need evidence demonstrating that doing so isn’t harmful.”
‘Odd Little Things’
Debra Leonard, a pathology professor at Weill Cornell Medical College in New York, wants to know. She enrolled a few years ago in a government study that involves an analysis of all her protein-making genes. She signed a consent form in which she gave up her rights to the data from the sequencing.
Leonard, who oversees all the clinical laboratories at Weill Cornell Medical Center and New York-Presbyterian Hospital, has asked the researcher running the study whether her sequencing is finished so many times that he has joked about avoiding her at scientific meetings, she said. The committee overseeing human research at the National Institutes of Health forbids releasing all her data to her. She said she has considered demanding the results under the Freedom of Information Act.
“I’d like to look at my genome and see if I can figure out odd little things like why I have such a strong reaction to caffeine,” she said. “Sometimes I get severe cramps in my feet and legs, and I’d like to see if there are underlying variants that might explain that. My children are also entering their childbearing years, and I’m wondering if I’m carrying any rare diseases that might affect my grandchildren.”
Leslie Biesecker, chief of the genetics disease research branch at the National Human Genome Research Institute, who leads the study, declined to discuss Leonard’s case. One of the goals of the study is to examine how to share genetic data with participants, and it’s important for the study to treat people consistently, regardless of their qualifications, he said.
“We all want to get to the answer of what is the right way to give large-scale genetic information to individual patients,” Biesecker said in a phone interview. “I don’t think it’s practical to imagine taking an average patient and dumping on them their genome and all the variants in the genome.”
Decades-old regulations that govern studies of people haven’t kept pace with the “evolving human research enterprise,” according to the Office for Human Research Protections, the U.S. Department of Health and Human Services division that oversees ethics panels. As part of an effort to modernize these rules, HHS has asked for public comment on the issue of returning results to study participants, said Jerry Menikoff, office director.
A committee formed by the American College of Medical Genetics and Genomics is developing a list of disease-linked mutations that laboratories should report when a patient’s DNA is found to sharply increase the risk of breast cancer, colon cancer, or sudden heart failure, for example. The report would go to the doctor who ordered the test for the patient.
“A mutation on the list would have to be the kind of thing that a person would want to know, or absolutely has to know, to prevent an adverse event,” said Robert Nussbaum, a geneticist at the University of California, San Francisco, who’s on the organization’s committee.
Camilla Grondahl and her husband live in a small, one-story brick home in Ogden, Utah’s second largest city. One end of their street is crammed with stores and fast-food restaurants; at the other end lie the foothills of the Wasatch Mountains.
Boys Kept Dying
Enclosed by a chain-link fence, their front yard is filled with the toys of their 2 1/2-year-old daughter, Chloe, and signs advertising the costume jewelry that Grondahl sells from her house. Eric Grondahl works nearby, installing windshields and glass in cars.
The Grondahls dreamed of having several children. Yet they knew that for 30 years, the baby boys in the family kept dying.
Camilla Grondahl’s mother, Halena Black, suspected something was wrong soon after Camilla’s oldest brother, Kenny Rae, was born just under five pounds on Thanksgiving Day in 1979. His skin was wrinkled, he had eczema, and his pediatrician noted that he grew slowly.
“By the time he was five months old, the doctor said ‘There’s something not quite right with your son,’” Black said. “’I don’t know what it is, I can’t put my finger on it.’”
While tests showed nothing wrong, Kenny Rae was clearly sick. He stopped breathing once and had to be resuscitated. In 1980, on the night before Halloween, he went into cardiac arrest and died.
The Blacks went on to have three healthy daughters, along with one girl who was stillborn, before Hyrum was born in 1987. At more than 6.5 pounds, Hyrum was bigger than Kenny Rae, yet the wrinkled skin and sunken eyes were unmistakable. He looked just like his brother.
The family was at Sunday church services when Hyrum had his second cardiac arrest. Black had been through it often enough that she thought she could hear the baby make a distinct sound, like a gurgling cough, as it began. She put Hyrum on the floor of church and began trying to resuscitate him as hundreds of parishioners looked on. Just 9 1/2-months-old, Hyrum was rushed to the hospital. He died the same day.
When the Blacks had a healthy baby boy in 1990, they thought their troubles were behind them. Then their second daughter, Sesha, gave birth to Corbin, and he looked just like his two uncles who died so young.
Corbin lived five months.
Gholson Lyon, the geneticist and a psychiatrist with an interest in the genetic underpinnings of mental illness, moved to Utah from New York in 2009. He heard about the family’s unusual deaths and decided to investigate.
Just before Thanksgiving in 2010, Lyon drove 45 minutes north from his office in Salt Lake City. He met the family in the Blacks’ living room, where eight or nine relatives crowded in to give blood samples. Like Camilla, the others signed consent forms.
Lyon, a young scientist and doctor who studied at the University of Cambridge in the U.K. and earned his M.D. and Ph.D. degrees in New York, worked feverishly.
50 Percent Chance
Focusing on the X-chromosome -- of which men have just one copy, while women have two -- Lyon led a team of scientists and in just a few months identified a previously unknown gene mutation that was responsible for the continued cases of heart failure in the family’s boys.
All the women who had given birth to the ill boys carried the potentially deadly gene. Every baby boy had a 50 percent chance of inheriting the gene mutation and dying.
In the meantime, Grondahl had become pregnant with her second child, a boy. Lyon had already sequenced her blood sample and knew what the results showed.
“She called me about four months into her pregnancy and said, ‘You took my blood, and I heard you may have found something in my sisters,’” Lyon recalled. “’Is there anything you can tell me?’”
Lyon agonized over what to tell Grondahl. While the results of his research were clear, he says he didn’t have a government- approved test that would confirm the finding. Congress passed a law in 1988 requiring government approval for all clinical lab tests after some women got incorrect results from Pap smears, and suffered cases of cervical cancer that might have been prevented. His procedure didn’t satisfy the requirements of that law, he told the Grondahls.
Alan Rope, a medical geneticist who has followed the Black family since 2009 and helped with Lyon’s research effort, said he e-mailed a member of the research ethics committee at the University of Utah. One member told him that the panel probably would have permitted the results to be given to the Grondahls, he said.
“We knew what we were dealing with,” Rope said. “There was no question we were on the right track.”
Lyon said he doesn’t recall hearing from Rope about what the ethics panel member said at the time. Human research ethics panels, called institutional review boards, are still struggling to understand the issues in genetic research, he said.
Sutter and Max
“I don’t want to be somebody who sells or gives stuff back to people without the proper approvals,” Lyon said in an interview. “That would make me no different than someone who’s in a ‘60 Minutes’ expose for giving stem cells without FDA approval to somebody.”
Grondahl awaited the birth of her son. A year earlier her sister Kimberly gave birth to a son, Sutter, born with the gene defect. He lived about 15 months, dying on Oct. 16, 2010.
A few months later, on Feb. 2, 2011, Grondahl’s son was born. They named him Max.
His father, Eric, saw signs of hope. Max’s body was swollen, so he didn’t seem to have the characteristic wrinkles and sunken eyes that marked the boys who had died.
Five days into Max’s life, the swelling went down. The Grondahls sat with Max and watched a video of baby Corbin, who had died before Max was born.
“Max looked just like him,” Eric Grondahl said. “I lost my boy on that day.”
On Father’s Day, June 19, 2011, at the age of 4 1/2 months, Max died.
That same week, Lyon and Rope published a paper in the American Journal of Human Genetics describing the fatal condition, which they named Ogden syndrome, and the gene that caused it.
Three months later -- too late for Camilla Grondahl and her family -- the U.S. Centers for Medicare & Medicaid Services approved the test for the gene Lyon had found, meaning it could be used to tell people whether they carried the fatal mutation. The test is available through ARUP Laboratories in Salt Lake City.
Since then, Lyon has become an outspoken advocate for changing practices that don’t allow study participants to learn what scientific studies have said about their own genes. He’s published several articles and spoken at conferences on how important it is for scientists to prepare themselves to return important sequencing results to subjects.
He still believes he did the right thing under the current guidelines. Yet, he says it’s unethical to conduct genetic tests under conditions that don’t allow medically important results to be returned, he said.
“It is ethically and morally unacceptable to sequence living humans only in a research setting, without providing means for participants to get access to the results,” he said.
Grondahl says she isn’t upset that Lyon didn’t inform her of the test results. Even if she had known that the baby would be afflicted with Ogden syndrome, she wouldn’t have ended her pregnancy. Now that the test is approved, it may be used to test future pregnancies in the family.
“After all these years of not knowing why your brothers died and your son died, it gives you some closure,” she said. “You can move on with your life.”
To contact the reporter on this story: John Lauerman in Boston at firstname.lastname@example.org
To contact the editors responsible for this story: Jonathan Kaufman at Jkaufman17@bloomberg.net