Precision Medicine: Ethics, Politics, and Culture Project: Mobilizing Mutations

Ari Galper, Supriya Kapur, and Glenn Wolther
June 10, 2021

In his presentation “Mobilizing Mutations: How Precision Medicine is Blurring the Line between Normality and Pathology,” Sociology Professor Dan Navon provided an overview of his work examining how research on people with genetic mutations is destabilizing long standing modes of measuring, categorizing, and managing human difference. The presentation was divided into three primary sections, each addressing a particular subset of these processes.

The first section of the talk focused on the ways in which genetic testing is reshaping medical classification and practice. One of the dominant trends in genetics is what Professor Navon calls “genomic designation,” or the practice of discovering, delineating, and diagnosing disease strictly according to genetic mutations. Because many genomically designated conditions can encompass enormous phenotypic heterogeneity and are not clinically diagnosable, genomic designation is challenging the assumption that a particular mutation lines up perfectly with an existing disease category. Professor Navon calls this assumption the “gene-for” approach to human difference, and it underlies foundational concepts in genetics. However, experts and patients have begun to interrogate this approach. Contestation around genomically designated conditions is giving rise to vibrant interdisciplinary networks of researchers, caregivers, medical management guidelines, specialist clinics, pharmaceutical trials, support groups, foundations, and patient advocacy programs. For instance, groups like the 22q Family Foundation are helping patients and parents navigate the medical maze that comes along with a diagnosis of 22q11.2 deletion syndrome, as well as educate them about the import and various manifestations of 22qDS.

The second section of Professor Navon’s talk focused on the evolving boundary between “normal” and “pathological.” One example of this evolution is how genetics is destabilizing thresholds of clinical significance developed in other fields. For instance, the characteristics of people with conditions like 22qDS are often coded as symptoms of their genetic disorder regardless of whether they meet the usual thresholds for clinical significance (Navon 2020:884). Given the rise of genomic designation, mutations no longer have to meet the criteria created in other disciplines in order to be considered real, powerful, or important; people can be seen as affected even when clinical presentation is within normal range. How, then, do we understand the people who have these mutations and the challenges they face? Some researchers are turning to endophenotypes and deep phenotypes. By attending to more subtle forms of human difference than traditional phenotypes, researchers have been able to establish stronger correlations between what people are actually like and genetic variants. Deep commonalities can thus be seen in people with the same mutation even when their medical records are widely divergent (Navon 2020:881-2).

In the third and final section of his presentation, Professor Navon addressed how genomics and the work of various social groups is increasingly challenging our understanding of penetrance, pathogenicity, and carrier status. For instance, because people with carrier variants often present with mild or late onset phenotypes, the notion of a carrier variant is not as clear of a category as it used to be. One example is Fragile X. The heterogeneous manifestations of Fragile X were only discovered because there was a community of researchers and caregivers, medical management guidelines, support groups, influential foundations, and patient advocacy programs that coalesced around the syndrome. As a result of these groups’ efforts, the ‘Fragile X’ label is increasingly considered to designate a family of disorders rather than a clear-cut carrier mutation or a straightforward set of phenotypes caused by a particular genetic mutation. Dr. Navon’s presentation made clear how the implications of this community’s work involves rethinking mendelian genetics altogether.

Following the presentation, PMEPC hosted a discussion session attended by Professor Navon and members of the PMEPC working group. This discussion provided an opportunity for Professor Navon to dive deeper into his work with BabySeq, an NIH sponsored clinical trial, as well as an opportunity for the PMEPC community to explore questions of use and implications surrounding the BabySeq project and more generally, sequencing. Professor. Navon introduced the BabySeq project, emphasizing that unlike a typical trial, it was not a test of a specific treatment or intervention, but rather a trial of the application of newborn genetic sequencing. Further details on the trial and results can be found in the article “Interpretation of Genomic Sequencing Results in Healthy and Ill Newborns: Results from the BaySeq Project'' (Ceyhan-Birosy et al. 2019). Professor Navon focused in on the question of whether more harm than good can be done from the information given by newborn genome sequencing, noting that information from genomic sequencing can be extremely helpful for early disease intervention, but can have psychosocial impacts that may be harder to address.

Following Professor Navon’s comments on the BabySeq project, a discussion took place centering on the topics of inequality, recommended use for newborn sequencing, and the greater societal impacts surrounding our increasing ability to diagnose genetic variants and mutations. Regarding inequality, because there are limited resources for intervention and treatment, the information given by genetic sequencing may only be actionable to some. Interesting comments on this topic included the assertion that implementing genetic sequencing with a broad stroke, as done with the BabySeq project, could eliminate the prospect of only certain groups having access to genetic information. However, this still leaves the issues regarding funding possible interventions on the table. Additional comments on the use of variants and mutations to intentionally demote certain groups seemed to represent the very real possibility that information from genomic sequencing can work to further existing inequality. On the topic of the recommended use of sequencing, comments first addressed the fact that the Hastings Center recommends that genetic testing for newborns be limited to only specific circumstances relating to confirming suspected diagnoses or aiding in current screening criteria. These specific regulations of where and when genomic sequencing can be used were thought to address some of the psychosocial issues that could arise from widespread newborn sequencing, removing potential stigmatization. However, clinical recommendations and commercial sector applications often differ, and the possibility of direct-to-consumer newborn sequencing, though out of line with the Hastings Center’s recommendation, could likely become a reality as biotech companies continue to move forward. Lastly, the discussion dove deeper into one of Professor Navon’s chief talking points: the increasing distinction “between the normal and the pathological” (Navon 2020:870) . Questions were raised regarding the possible over-scrutinization of childrens’ actions, as common personality traits or behavior patterns such as shyness can be seen as symptoms of disease, rather than normal childhood traits. The broader question of how to avoid such over-identification of symptoms proved--like most other questions brought up during the discussion--difficult to definitively answer.

Evident from both the talk and discussion, Navon's principal point is that globally, research on rare mutations is destabilizing systems of classification and reshaping medical classification. Navon's chief concern centers around genomic designation: as genetic screening tests increase more individuals will be informed of the possibility that they have a risk for a pathogenic phenotype occurring, which can lead to a cascade of medicalization, including over-inclusion, pathologizing, anxiety, large medical bills, and raise red flags for insurance companies (Knapp et al 2019). Further, as science delves deeper into the genetics underlying non-mendelian complex pathology, this situation will only grow more acute. Navon asserts that such an outcome is not the intended purpose of either genetics or precision medicine. Navon pointed to the enterprise of precision medicine that is driving the phenomena to research across the sciences--from basic research in biology and genetics all the way up to clinical application. Yet, from the perspective of genetic counseling, commentators have argued that the blurring of the line separating Mendelian and chromosomal disorders has occurred in tandem with technology that has enabled better assessment of genetic pathologies (Clark 2020:68-69). In order to assess the impacts of medicalization it will be important to distinguish among research in biology, genetics, psychiatric & behavioral genetics, and precision medicine while also evaluating the impact that patients presenting consumer testing results to their doctors has.

Overall Navon's talk suggests that we must proceed with nuanced awareness and caution (cf Johnston 2018). Maintaining the traditional system of medical classification based upon either the location of the pathology or the symptoms that are manifested is likely over time to give way to genetic diagnosis. Therefore, the solution to the problem of medicalization lies partly in the circumstances in which people are genetically screened, and partly in public education. The Hasting Report makes clear, direct to consumer commercial screening should never be used. Relatedly, the public needs to be better educated about genetics as a whole, and both, (a) the complexities of even 'simple' classical, one gene, Mendelian, disorders and (b) the far more complex processes of 'complex' multiple gene disorders. (Id.)

While the Mendelian model of heritability--one gene for one phenotype--has long been understood within the medical, genetics & biological communities as being inadequate to explain complex genetic heritability, expanding that understanding to other disciplines and the public at large has remained a challenge. (Passamani, 2013:193-194) Individuals who are presented with the results of genomic sequencing are likely to have an incomplete understanding of the significance, actionability, and implication of the test results. And even within clinical practice to date, there appears to be little to no good evidence that physicians in general (Johnson 2017), let alone lay members of the public, are in a position to reasonably evaluate the results of a genetic screen. At a more granular level, the issue is twofold. First, physicians need to be better trained and educated regarding genomics diagnosis. Second, direct to consumer genetic testing presents a multitude of issues, not the least of which, is interpretation. Any uncertainty in genetic test results is best interpreted and assessed by clinical geneticists in conjunction with genetic counselors.  In clinical practice, within the realm of genetic variants, mutations are labeled as benign, pathogenic, or unknown significance. Yet, the same genetic material, given to different labs, may result in different interpretations, leading to a different classifications, for example benign rather than pathogenic or vice versa. The American College of Medical Genetics and Genomics has generated guidelines in an attempt to avoid these issues (Richards et al 2015).

At Columbia University, as part of its Precision Medicine Initiative*, any genomic diagnosis requires more than simply sequencing and genetic report. Rather, it involves an interdisciplinary team of clinicians, geneticists, genetic counselors, and a finding will not become a diagnosis that goes into a patient’s medical record until agreed upon by a pathologist with a clinical genomic diagnosis. (Goldstein 2018) For other institutions with considerably fewer resources, this may be difficult. At Columbia’s Medical Center, personalized medicine is the act of delivering the care via genetic, biological, and clinical insights developed in the collective enterprise of precision medicine. (Maniatis, 2015)

Classification schemes serve an important purpose in enabling clinicians, laboratories, and researchers across different areas of scientific investigation to pool research, data, and conduct experiments, which lead to increased knowledge in patient assessment, care, and treatment. Yet, any classification scheme can potentially either unite or divide us. As with any such endeavor, unintended consequences occur. Overall, as we move toward new classifications with genomic designation, we should be mindful of the unintended consequences of broad phenotypic variability. Currently, furthering education of people within medical practice and the public as a whole about genetics while also avoiding consumer genetic testing are two of our best weapons in avoiding unintended consequences of the enterprise of precision medicine.

*PMEPC is under the umbrella of Columbia University's Precision Medicine Initiative

Works Cited:  

Ceyhan-Birsoy, O., Murry, JB., Machini, K., et al. Interpretation of Genomic Sequencing Results in Healthy and Ill Newborns: Results from the BabySeq Project. Am J Hum Genet. 2019;104(1):76-93. doi:10.1016/j.ajhg.2018.11.016

Clarke, A. (2020) Harper's practical genetic counselling, 8th Ed. CRC Press

Goldstein, D., Columbia University’s Zuckerman Institute. (2018a, 20:00-21:45 April 10). Finding the Right Medicine One Patient at a Time [Video]. YouTube.

Johnson, L.-M., Valdez, J. M., Quinn, E. A., Sykes, A. D., McGee, R. B., Nuccio, R., et al. (2017). Integrating next-generation sequencing into pediatric oncology practice: an assessment of physician confidence and understanding of clinical genomics. Cancer 123, 2352–2359. doi: 10.1002/cncr.30581

Johnston, J.D. Lantos, A. Goldenberg, F. Chen, E. Parens, B.A. Koenig, members of the NSIGHT Ethics and Policy Advisory Board Sequencing newborns: A call for nuanced use of genomic technologies Hastings Cent. Rep., 48 (Suppl 2) (2018), pp. S2-S6 doi: 10.1002/hast.874

Knapp, B., Decker, C., and Lantos, J. D. (2019). Neonatologists’ attitudes about diagnostic whole-genome sequencing in the NICU. Pediatrics 143 (Suppl 1), S54–S57. doi: 10.1542/peds.2018-1099J

Maniatis, T., Columbia University Irving Medical Center. (2015, 00:00-01:18 January 30). Dr. Tom Maniatis explains precision medicine [Video]. YouTube.

Navon, D. (2020). '"The gene didn't get the memo": Realigning disciplines and remaking illness in postgenomic medicine'. ​Critical Inquiry. 46(4): 867-890

Richards, S. et al. Standards and guidelines for the interpretation of sequence

variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet. Med. 17, 405–423 (2015). doi: 10.1038/gim.2015.30