Chronicling the Cutting Edge: Ethics and the Promise of New Genomic Medicine
from the Spring 2015 issue of Early Developments
FPG senior scientist Debra Skinner has a front-row seat to study what happens at the intersection of the design and practice of a new science. On the cutting edge of clinical medicine, diagnostic genomic sequencing offers the opportunity to better understand and address current illnesses and to peer into the future. Here, ethics are racing to keep pace with the availability of a new magnitude of information for people seeking answers about their health.
“There are famous chronicles of the discovery of the double helix or of the making of penicillin,” Skinner said. “This is one of those times: I get to chronicle genomic medicine as it’s being formed.”
For three years, Skinner and FPG post-doc Kelly Raspberry have worked on the North Carolina Clinical Genomic Evaluation by Next-Generation Exome Sequencing (NCGENES) project at UNC, which is establishing best practices for the use of genomic technologies in medical practice. They study the social and cultural aspects of clinical exome sequencing, a new option for medical professionals that sequences their patients’ DNA in order to diagnose the genetic cause of illnesses and their potential courses of treatment.
Analysis of the whole human exome, which constitutes about 1% of the genome, costs less than analyzing the entire genome while offering most of the same clinically relevant information. Not only can whole exome sequencing provide insight into patients’ current conditions, it can even forecast conditions patients may suffer from later.
“The clinical application of genomic knowledge is just beginning,” Skinner explained. “When we started the project, this application mostly was being done as research, but in the last three years, it’s moved into clinical medicine.”
NCGENES brings whole exome sequencing to a wide variety of children and adults, including underrepresented populations. “These are people affected by a disease,” said Skinner. Other tests have failed to diagnose the cause of the conditions of the several-hundred patients enrolled in the project, each of whom researchers suspect has a genetic disorder. “These are people who’ve already been through other forms of genetic testing, and NCGENES researchers are trying to discover that rare genetic variant that points to an explanation.”
From a one vial of blood, whole exome sequencing can examine tens of thousands of genetic variants and find one that causes a single, particular disease.
“Here at UNC, they’re really building genomic medicine,” said Skinner (below). Key scientists with NCGENES include UNC’s James P. Evans, Jonathan Berg, Gail Henderson, Karen Weck-Taylor, and Kirk Wilhelmsen. “When the project started, a tremendous amount of labor went into developing the sequencing pipeline and determining how to interpret the genetic variants. NCGENES investigators are a central part of the national effort that is producing genomic medicine and standards for it. We’re seeing science in action.”
Not only is the project evaluating the usefulness and effectiveness of whole exome sequencing—and diagnosing many previously un-diagnosable patients along the way—NCGENES is documenting the effects on patients who sometimes learn new and potentially life-altering information in addition to their diagnostic result.
This is where Skinner’s expertise comes into play. As a sociocultural and medical anthropologist, she captures what she calls “the ethnography of the result.” She and Raspberry catalog the social and technical factors that go into the making of a genomic result, following that result as researchers interpret it and clinicians communicate it to patients—and documenting its impact on patients’ lives.
Skinner, director of FPG’s Qualitative and Ethnographic Analysis Core, has taken on many seminal roles on projects that have helped young children and their families—including earlier projects that looked at the implications of genetic disease for families and their children. On the NCGENES project, she has been privy to insider discussions from the start as researchers worked to devise standards and best practices related to clinical exome sequencing.
“There has been a tremendous amount of labor in deciding what genetic variants to report to patients,” she said. “Do we report only the pathological variants related to the person’s illness? What’s our obligation to look for secondary findings—variants unrelated to the person’s illness but that could cause another disease?”
From the beginning, the project team has been aware of the ethical questions raised by the magnitude of potential information available through sequencing.
“It’s a fascinating process that requires so many decisions about what to filter out—what genes to look at closely because of their association with disease, what variants within those genes are potentially pathological,” Skinner said. “The variants they find are classified into different categories related to how likely they are to cause disease. Some variants are known to be pathological; some are highly suspected to be; some are known to be benign. For those that are suspected, experts sit down as a group and consult multiple databases to make a final decision. Do we report this back or not? Does this rise to the level of clinical significance?”
The considerations can become extremely complicated, especially because sequencing generates secondary or incidental findings—information that wasn’t the object of a diagnostic search. It’s one thing for a patient participating in NCGENES to learn the cause of his or her disease, but what happens when exome sequencing turns up five other things for which the patient might be at increased risk or even information that is far worse—a dread disease that they are very likely to suffer from?
“What to do with secondary findings is a huge issue in genomic medicine right now,” Skinner said. “What’s the obligation of a person in the lab running the test, or a researcher or primary care physician to search for secondary findings that aren’t the purpose of what you ordered the test for? Should they look for and report back other conditions that are medically treatable? And many patients want to know other conditions they are at risk for, even if they’re not considered treatable through medical means.”
And then there are the test results that cannot yet be interpreted—when nothing or little is known about the genetic variants—but which might provide valuable, even lifesaving information at some point in the future. As medical knowledge accrues, what happens when progress means the unknown might become known or the untreatable becomes treatable?
“Our people at UNC have been very instrumental in classifying the information that whole exome sequencing generates,” Skinner said. “For the diagnostic information they ask: can this variant explain your disease, or do I reasonably think it can? They also look for and return other secondary information for conditions that are medically treatable. NCGENES participants are told that if sequencing detects these conditions—for example, a mutation that’s 80% likely to cause colon cancer and early death—they will be informed, because screenings can be done that may well prevent the cancer’s onset.”
But what if a patient does not want to learn of this sort of incidental information? Skinner told the story of a clinician who couldn’t understand this very scenario, in which he wouldn’t be allowed to inform a patient about an illness he could treat. “You can see some of the ethical dilemmas,” she said. “Patient autonomy and choice can clash with clinical ethics—the clinician’s sense that I could save this person’s life.
As for the other secondary information that is not medically treatable, we’re doing a lot of work in order to give people informed choices on what types of information they may want, or not.”
It’s a daunting issue: do patients really want to find out they will develop Alzheimer's or another severely debilitating disease without a current treatment?
“What if I tell you that you have Lou Gehrigs’s disease? That’s a condition that you can’t do anything about, and it progresses to death,” she said. “The researchers at NCGENES realized early that it wasn’t a simple question about whether patients want to learn their secondary information. Some do. Some only initially may think they do. That’s why the researchers separated the information into categories by severity, and educated the patients about the categories before they let them choose which ones they wanted to know. We were worried about how much harm could come from patients just saying they want to know everything they can, without really having thought about it.”
Skinner added that some people may want to know about a looming disease even if it cannot be treated so they can live life differently, or be aware of medical advances as they occur and proactively manage their condition, if possible. “But other people don’t want to know, and you have to respect that.”
Bioethicists and others joined the discussion when the NCGENES team was developing a plan for sharing with patients the information that sequencing could find. “From the beginning, there was an awareness the project had to really help patients to understand and consider their options,” said Skinner.
How is it even possible to contextualize the information available to families? Skinner explained that given the nature of the choices that adult patients in the NCGENES project must consider, the researchers ask them not to decide immediately what categories of non-treatable secondary findings they want to learn about.
“I’m present when the clinicians are outlining the choices for people, in those sessions when they’re educating people about the categories,” she said. “NCGENES requires the patients to go off and think about it. After the patients consider it all, they actually have to make another call back to request their secondary findings.”
She also emphasized that the categories of available information are fluid, which introduces another level of complexity to the process. Some results from whole exome sequencing could well carry a different meaning at a later time.
“Variants for which there is little known today might in the future become known causes of particular diseases, and diseases that aren’t medically actionable now might be treatable down the road,” she said. “That’s why there’s a really big push for current sequencing projects to build a general database, one that pools and includes all the available information and evidence, in order to make better informed judgments about the associations between variants and diseases.”
While the clinicians face a formidable challenge in communicating complex genomic information to patients, the families tasked with understanding it all obviously do, too. According to Skinner, FPG’s long history of studying children with disabilities, including children with genetic disorders, dovetails nicely with her work with families in the NCGENES project. At FPG, Skinner previously has studied parent experiences in a pediatric genetics clinic, and last year she wrapped up work on a project that examined families’ responses to newborn screening for Fragile X Syndrome.
“We’ve had—and continue to have—many projects at FPG that conduct family studies and look at the development of children with disabilities, and my role on NCGENES fits squarely into that tradition,” she said. “The parents enrolled in NCGENES have had a lot of experiences with their child’s disabilities, but they don’t know what the genetic cause is. We want to know what difference getting the diagnostic results from sequencing makes for them. And how do they use that information?”
For Skinner, the families’ perspectives also are central to a series of important research questions on the secondary findings. Do people actually request this incidental information? What categories of information do they request? Why do they request it? If they don’t, why not?
“We interview people about it,” she said. “Are you glad you did it? What have you done with the information? Did you find it useful?”
NCGENES behavioral scientist Christine Rini and her team are analyzing those responses now. Skinner said people have requested incidental findings for which there is no medical treatment out of curiosity or a sense of wanting to feel prepared, however, the majority of patients haven’t requested the information. “It’s also interesting that a lot of people will say they’re going to request the information, and then they actually don’t. But the project isn’t over yet.”
Skinner also said that, for several reasons, few, if any, of the study participants have expressed regret at learning their secondary results. Patients receive a negative finding about life-threatening illnesses as good news, even though sequencing cannot detect all such diseases, and positive findings about such illnesses are rare. Some of the other secondary information “isn’t particularly useful or earth-shattering.” A patient might discover, for instance, that he or she is at a slightly increased risk for diabetes or leprosy.
“Some people are interested in knowing that kind of information, but it’s often not relevant on a practical level,” Skinner said. “Nor is learning about being a carrier of some disease. Everybody is likely to carry 5-6 recessive conditions, but the other biological parent has to carry the same recessive gene for this to be important, and that’s unlikely.”
Over her long career at FPG, Skinner has conducted numerous studies on families’ understandings of childhood disabilities and on the broader cultural, economic, and political contexts of their beliefs and practices. She has developed theoretical models and methods to assess personal identity and parental beliefs, and her research has included family and poverty studies in urban and rural areas. But the rise of whole exome sequencing means that at this moment she is riding the wave of new medical science as it crests.
Her role as the chronicler both of the day-to-day inner workings at NCGENES and of the reactions of its patients remains central to understanding the ethnography of the result—and to applying what the project learns on a much broader basis. She continues to record the story of how patients, clinicians, and researchers wrestle with ethical issues and medical uncertainty one diagnosis at a time.
“Nobody’s got all the answers,” she said. “The geneticists will tell you there’s still so much we don’t know.”
Debra Skinner, Senior Scientist
UNC's Frank Porter Graham Child Development Institute
1. DNA Double Helix, courtesy of the NIH.
2. Debra Skinner, FPG Photo Archives.
3. DNA Double Helix, under a CC BY-SA 3.0 license (http://commons.wikimedia.org/wiki/File:A-DNA,_B-DNA_and_Z-DNA.png).
4. Inside FPG's former child care center, FPG Photo Archives.