The recent explosion in the development and marketing of genetic-based medicine has signaled a new era of “precision medicine.” Once described as “personalized” or “individualized,” precision medicine today embodies the therapeutic approach of treating an individual based on genomic and other factors specific to that individual that may be identified through biomarkers and genetic mutations. The promise of precision medicine is that this strategy will augment, and eventually even replace, a “one-size-fits-all” or uniform therapeutic approach in which patients are prescribed a treatment based on diagnosis alone. Rather, precision medicine holds the hope for individually tailored treatment for patients with particular characteristics in a given set of circumstances, thus leading to a greater potential for effective therapy.
The clinical promise of precision medicine has been met with broad public and legislative support. In 2015, President Barack Obama announced the $215 million Precision Medicine Initiative, calling it “one of the biggest opportunities for breakthroughs in medicine that we have ever seen.” A year later, Vice President Joseph Biden launched “MoonShot 2020,” a five-year initiative aimed at completing a decade’s worth of progress in preventing, diagnosing, and treating cancer, including through the application of precision medicine research. This program will aggregate genetic data from more than one million volunteers to expand understanding and knowledge of genomes. Several institutions have begun their own contributions towards funding precision medicine, including universities, pharmaceutical manufacturers, and privately held companies.
Despite the momentum behind precision medicine, some public health experts and members of the scientific community have raised concerns about its practical and ethical implications, including about confidentiality and protection of data, fair and equitable access to genetic information, and the clinical utility of such information. These concerns are of particular importance in clarifying how precision medicine may affect population health. Specifically, critics contend that precision medicine holds promise for some, but that the notion creates and propagates unrealistic expectations and may even lead to harm.
The Promise of Precision: A Long Way Forward
The complex questions surrounding precision medicine were addressed at a Harvard Medical School consortium [1] featuring Sandro Galea, dean of the Boston University School of Public Health, and Calum MacRae, chief of cardiovascular medicine at Brigham and Women’s Hospital (BWH), facilitated by philosopher Spencer Hey, PhD, Research Fellow at BWH. Though both speakers were generally positive about precision medicine’s potential to advance scientific discovery and help patients in the future, both expressed caution about potential limitations of precision medicine, and argued that attention to the methods, environment, and ethics of the practice would be required to realize its promise.
Calling himself the “loyal opposition” to precision medicine, Dr. Galea, embraced the movement’s lofty goals of scientific advancement in health care, but questioned whether they are neatly achievable. “I am opposed to compelling ideas that do not advance health,” Galea said, offering three reasons for his skepticism.
First, Galea argued, that the hype of the precision medicine movement fails to account for the complexity of biology. “Precision medicine is a great idea, simple, compelling, but biology is much more complex than we give it credit for,” he said, adding that genetics are only one piece of the biological puzzle of disease. According to Galea, genetic variance corresponds less neatly to disease incidence than precision medicine accounts for, and that there are thousands of genetic variants for common diseases, such as high blood pressure, and they all have very small effects. Even when scientists find a genetic variant that corresponds to a given disease, many factors beyond that variant contribute to the disease. “That single variant alone reveals very little information about the disease or how to treat it,” he said.
Galea noted that there is little evidence for the efficacy of molecular targeting or treatment based on a patient’s individual genetic profile. Even if treatment based on genetics was demonstrably more effective than the current standard of care, Galea argued that “when discussing biology, we forget that we already have very good, precise markers that serve as indicators for disease, such as behavioral markers.”
Galea cited a 2003 New England Journal of Medicine study showing that obesity heightens the relative risk of developing various cancers. [2] “We know about these predictors, so precision medicine is just telling us something we already know,” he said.
Mind The Gap
The second limitation of precision medicine, according to Galea, is that it currently lacks sufficient precision regarding translation for population-level data to individual patients. Specifically, Galea noted that when researchers study populations and then apply their findings to groups of people, there is a gap between describing the health of particular individual and the health of the group.
“Our capacity to predict how populations are going to do as linked to particular genetic markers is dramatically different than our capacity to predict how individuals are going to do,” he said. This gap, according to Galea, is critically important in assessing the potential applicability of precision medicine for both individual and population health, emphasizing that the promise of precision medicine to “get a better treatment for me” is overstated.
Galea called a third problem with precision medicine the “fallacy of individual behavior change.” He countered proponent’s arguments that precision medicine can generate data that can help patients to modify their behavior to improve health, even if it does not lead to direct improvements to clinical care. “There is no evidence to show that awareness of DNA-based risk of disease actually changes individuals’ behavior,” he said.
Beyond academic debate, precision medicine, he argued, shifts attention away from other types of research that would have far greater impacts on population health. He cautioned against a misallocation of resources for precision medicine, at the expense of other research, explaining that the proportion of NIH-funded research, related to genetics, has increased by nearly ten percent over the past decade, while the proportion allocated to public health research has dropped from around four percent to less than one percent over the same timeframe. [3]
“There is plenty of reason to believe that we are nowhere near precision medicine working. This is a juggernaut that takes us away from what really matters,” he said.
Promise Versus Actualization
The second speaker, Calum MacRae, began by acknowledging that true precision medicine is difficult to achieve. He tried to define and contextualize the concept, by referring to the genetic foundations of medicine, challenging the advancement of precision drug development, and questioning if any achievements had really been made.
Considering the basic inferences of precision, MacRae outlined three fundamental parameters that define the concept of precision medicine: new timing, scale, and resolution. First, new timing highlights a deviation from health to disease onset in the continuum of a person’s life. The notion of precision comes into relevance within a “competitive space,” during which the trajectory of disease onset can be modified. Second, the clinical development timeline—including drug discovery, preclinical studies, and phased human trials, to FDA approval— now has a twelve- to fifteen-year timeline. A major disconnect exists between the rapid pace of scientific discovery and the slow process of clinical translation, according to MacRae. Third, he distinguished a reductionist approach to science that utilizes individual scales, from holistic approaches that are characterized by emergent and integrated systems that function as a unified whole.
MacRae argued that realistic medicine, not precision medicine, is needed, describing precision medicine’s failure to meet the expectations and objectives of scientific discovery due to mismatch between promise and actualizing discovery in treatment. “In the process from identifying disease mechanism to therapeutic discovery, the model requires the researcher to take multiple shots on the goal,” he said. Translating this metaphor to science would mean including large populations in clinical studies; the larger the number of people affected by the disease, the more shots the researcher would have to meet the goal of finding a therapy to cure a disease. With precision medicine, the output is far less rewarding for MacRae because the method yields “low therapeutic signals,” or distracting noise, for drug discovery.
He contrasted the present model of precision medicine with a model that translates discovery into parallel mechanisms and outputs, using multiple genetic factors from a single individual. It is imperative, MacRae said, to define broader genetic frameworks that also take into account epigenetic and environmental factors in determining disease outcomes.
A Need for Deeper Methodology
“Today, genetics alone are not predictive of scientific and therapeutic targets for discovery,” MacRae said. First, he argued that not all key risk factors are genetic, for example, smoking as a risk factor for lung cancer. Second, at present the wrong endpoints are measured to determine the predictive value of therapies. Third, genotype selection is not complete. Finally, the integrated role and function of the genotypes studied remain unclear. To illustrate these points, MacRae observed the limitations in the current understanding of chronic diseases with significant impact on public health, citing diabetes, cardiovascular disease, and cancer. Other diseases also have “little in the way of a rigorous quantitative basis,” he added, noting the absence of standardized assays and diagnostic measures.
MacRae emphasized that a broad approach to achieving greater precision medicine requires a deeper methodology. For MacRae, medicine can achieve the goals of precision medicine by including more comprehensiveness, regaining a perspective on the “whole” patient, incorporating phenomes, and proposing a computable “physical exam.” The most influential factor, for the future of precision medicine, MacRae suggested, is competition. Specifically, he argued that new workflows, data streams, and delivery systems would usher in technologies and revenue models that could shift the focus from broad genetic models to fully integrative and precise medicine.
The underlying ethical consideration, for MacRae, is the possible futility of “precision” treatments. He asked generally whether individual precision treatments would work, and for whom. True precision medicine, he concluded, requires integration of research and clinical care from genomes to populations. To do so, would require breaking down medical silos through more efficient and relevant data and adopting a holistic assessment of disease, by way of prevention and wellness, developing innovative partnerships and systems, and fostering a foundational reliance on “traditional clinical and scientific values.”
The discussion concluded with both Galea and MacRae acknowledging the vast possibilities of precision medicine, yet advising temperance of that enthusiasm with a level-headed [better yet, data-driven] assessment of the likelihood of deriving clinical benefit from this avenue of research and care. Both speakers expressed hope in actualizing the goals of precision medicine but cautioned clinicians, researchers, policymakers, regulators, and others in attendance, to contextualize their hopes within the current scientific and clinical landscape.
Sarah R. Bates, MBE '17 and Jeffrey S. Gruenglas, MA, MBE '17, can be reached at BioethicsJournal (at) hms.harvard.edu.
[1] The Harvard Medical School (HMS) Center for Bioethics Health Policy and Bioethics Consortium. The event was part of a series organized by the HMS Center for Bioethics in conjunction with the Program On Regulation, Therapeutics, and Law (PORTAL) at Brigham and Women’s Hospital, with financial support from the Oswald DeN. Cammann Fund at Harvard University.
[2]Calle, Eugenia E., Carmen Rodriguez, Kimberly Walker-Thurmond, and Michael J. Thun. "Overweight, Obesity, and Mortality from Cancer in a Prospectively Studied Cohort of U.S. Adults" New England Journal of Medicine (2003): 348, 1625-1638.
[3] NIH RePORTER. Search results for projects for which funding data is available. Accessed on November 20, 2014.
