Mobilizing Mutations: Human Genetics in the Age of Patient Advocacy

Mobilizing Mutations: Human Genetics in the Age of Patient Advocacy

by Daniel Navon

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Overview

With every passing year, more and more people learn that they or their young or unborn child carries a genetic mutation. But what does this mean for the way we understand a person? Today, genetic mutations are being used to diagnose novel conditions like the XYY, Fragile X, NGLY1 mutation, and 22q11.2 Deletion syndromes, carving out rich new categories of human disease and difference. Daniel Navon calls this form of categorization “genomic designation,” and in Mobilizing Mutations he shows how mutations, and the social factors that surround them, are reshaping human classification.
 
Drawing on a wealth of fieldwork and historical material, Navon presents a sociological account of the ways genetic mutations have been mobilized and transformed in the sixty years since it became possible to see abnormal human genomes, providing a new vista onto the myriad ways contemporary genetic testing can transform people’s lives.
 
Taking us inside these shifting worlds of research and advocacy over the last half century, Navon reveals the ways in which knowledge about genetic mutations can redefine what it means to be ill, different, and ultimately, human.
 

Product Details

ISBN-13: 9780226638126
Publisher: University of Chicago Press
Publication date: 09/20/2019
Sold by: Barnes & Noble
Format: NOOK Book
Pages: 384
File size: 2 MB

About the Author

Daniel Navon is assistant professor of sociology at the University of California, San Diego.

Read an Excerpt

CHAPTER 1

Genomic Designation: How Genetics Creates New Medical Conditions

But this order of the solid, visible body is only one way — in all likelihood neither the first, nor the most fundamental — in which one spatializes disease. There have been, and will be, other distributions of illness.

Michel Foucault, The Birth of the Clinic

From the clinical standpoint, [22q13 deletion] syndrome may be underdiagnosed because of the lack of a recognizable phenotype that would lead the clinician to request studies to rule out this specific chromosome 22 deletion.

Phelan et al., "22q13 Deletion Syndrome"

For sixty years now, we have been delineating medical conditions that are united not by observations of patients' bodies, evaluations of their psyches, or predictions of their fate, but by specific genetic mutations. Finding a mutation can lead experts to report a completely new category of human disease and difference. In other cases, it can result in the lumping together, splitting up, or recalibration of existing disease categories. This chapter introduces and defines this practice, which I call the genomic designation of medical conditions.

Genomic designation is the delineation and diagnosis of medical conditions strictly according to observations of abnormal genomes, be it whole chromosome duplications, tiny point mutations, or anything in between. When a newly discovered mutation does not line up with an existing condition and instead comes to designate a new disorder, we have a case of genomic designation. Most genomically designated conditions lack the phenotypic coherence or distinctiveness to be clinically diagnosable at all. Instead, the genome itself is the locus of classification.

Ever since 1959, genomic designation has been endemic to genetics research. As we explore in chapter 2, the ability to see, count, and distinguish between chromosomes under a microscope led almost immediately to the first cases of genomic designation. In the decades that followed, innovations in genetic testing quickly led to the discovery of new genomically designated conditions. Meanwhile, long-standing mutations have been rendered visible and more or less stable across different genetic testing platforms — from karyotype analysis to whole genome sequencing. Hundreds of conditions have now been discovered or reshaped through genomic designation. So far, however, only a much smaller number have become the sorts of categories that can truly transform people's lives. Beginning in this chapter, we are going to explore the varied history of carving up human difference through genomic designation.

For people with a genomically designated condition, having a genetic mutation means something that is at once crystal clear and deeply uncertain. Take one of our main case studies in this chapter: the microdeletion of genetic material at site 13.3 on the long arm of the twenty-second chromosome. Having this 22q13.3 chromosomal deletion means someone has 22q13 Deletion Syndrome (22q13DS — not to be confused with 22q11.2DS). Yet had the 22q13 deletion never been discovered, 22q13DS would be unthinkable. Even the researchers most responsible for establishing 22q13DS in the medical literature noted the "lack of a recognizable phenotype" that could even indicate genetic testing (Phelan et al. 2001:98).

This makes 22q13DS quite unlike most well-known genetic disorders — Huntington's disease, cystic fibrosis, Down syndrome, and so on — or genomic risk factors like the BRCA variants. In all of those cases, established medical conditions were found to have a significant relationship with genetic mutations. By contrast, 22q13DS reverses this sequence of genotype-phenotype association. This syndrome is actually one of the most consistently severe conditions discussed in this book. Even so, it could never have been conceived of until after the identification of the 22q13 (pronounced twenty-two-q-one-three) chromosomal deletion. Hence, the 22q13 deletion became a subject of scientific investigation around 1988, some thirteen years before the syndrome named after it was proclaimed and the 22q13 Deletion Syndrome Foundation was formed. The patient population and its clinical profile depend entirely on the people found to carry a 22q13 deletion and what they are like. Today, knowledge about 22q13DS — now known as Phelan-McDermid syndrome (PMS) — and the work of the renamed Phelan-McDermid Syndrome Foundation have a powerful impact on the lives of patients and their families. This very clear process of discovery, delineation, and mobilization captures the essence of genomic designation.

A New Front in the Social Studies of Genetics and Medicine

While genomic designation establishes an unusual level of certainty at the level of etiology, it often does so at the expense of clinical specificity. In most cases it is unlikely that diagnosis could, even in principle, take place on the basis of what someone is actually like (i.e., their phenotype). Conditions like 22q13DS therefore go beyond the matter of social action undertaken on the basis of reductionism or risk, which in one form or another has been the focus of most of the social scientific literature on genetics and medicine (e.g., Callon and Rabeharisoa 2003; Hacking 2006a; Hedgecoe 2001; Lippman 1991b; Rabinow 1996; Rose 2007b). In this way, genomic designation builds upon but also powerfully subverts the "clinical gaze" (Foucault 1973; Rose 1998b) — the nosological relationship between the observed and the unobserved that privileges localized anatomo-clinical observation — which has dominated medical classification since the nineteenth century. In conditions like 22q13DS, genetic mutations take on great meaning, not as a proxy in the form of a predisposition or an essentializing explanation, but as the core referent of a new category of human difference. The sociological interest in genomic designation therefore goes beyond the study of a bunch of new disease entities, or what Hacking called "human kinds." Instead, it extends to the emergence of a new kind of human kind that can reconfigure the way we understand and act on difference, illness, and disability.

Grappling with genomic designation forces us to rethink the relationship between genetics, medical classification, and human difference. Existing research has shown how discovering explanatory mutations may or may not reshape diagnostic protocols for conditions like Huntington's and Cystic Fibrosis, how finding a mutation in a seemingly normal patient can create a "patient in waiting," and how it takes a network of experts to simultaneously understand the clinical and biological significance of mutations. Looking at genomic designation, however, shows us how knowledge about genetic mutations can be used to carve out novel medical conditions and communities, not just refine, destabilize, or help us understand old ones.

Genomic designation therefore both challenges and extends three seminal concepts in social studies of genetics: biosociality, geneticization, and the molecular gaze. Abby Lippman's work on geneticization helped spark an explosion of interest in the "ongoing process by which differences between individuals are reduced to their DNA codes, with most disorders, behaviors and psychological variations defined, at least in part, as genetic in origin" (1991a:19). Scholars have paid particular attention to the way this process of geneticization essentializes differences between persons, sometimes in ways that contribute to stigmatization (see Phelan 2005; see also Hedgecoe 2001 on "enlightened geneticization").

So, genomic designation could be understood as a radical form of geneticization: it is, if nothing else, built on the premise that we should parse human difference according to genetic abnormality. Many of the concerns Lippman raised when she introduced geneticization to the social sciences — the power of genetics to define abnormality and disability, the social implications of prenatal testing, and the resurgent specter of eugenics — may even be more likely to emerge through genomic designation than the gene-for model. And yet, genomic designation does not simply reduce existing categories to genetic mutations: it produces new categories of disease and difference.

Paul Rabinow's (1996) discussion of biosociality was a similarly formative moment in the social sciences' engagement with genomics (Hacking 2006a). Rabinow foresaw biosociality playing out on two dimensions. First, there was the potential for altering human DNA in pursuit of socially derived ends — hardly a novel topic. Second, and far more innovative, was the idea that social action and network formation might occur on the basis of a perceived genetic predisposition or risk for developing a clinical disorder. As Rabinow ([1992] 1996:102) presciently argued, "It is not hard to imagine groups formed around the chromosome 17, locus 16,256, site 654,376 allele variant with a guanine substitution." He even predicted these groups "will have medical specialists, laboratories, narratives, traditions, and a heavy panoply of pastoral keepers to help them experience, share, intervene, and 'understand' their fate." In this way, he explained, "Older cultural classifications will be joined by a vast array of new ones, which will cross-cut, partially supersede, and eventually redefine the older categories" (103). However, Rabinow's discussion of this new biosociality was clear that the social power of genomic difference would remain limited to questions of risk for something else. Observations of the genome, he averred, "carry with [them] no depth; ... it has no meaning" (102).

Cases like 22q13.3 deletion allow us to extend the incredibly productive concept of biosociality. Mutations can acquire meaning when networks of knowledge production and social mobilization are assembled around them. Knowledge about genetic mutations can give rise to entirely new categories of human difference and therefore forms of identity that go far beyond mere risk factors. Furthermore, I show how these networks powerfully shape the course of biomedical research and the very knowledge produced about genetic mutations. Knowledge about the genome can set new forms of biosociality in motion, as Rabinow presciently recognized, but biosociality can also transform the way we understand the mutations themselves.

Genomic designation also represents a clear realization of what Nikolas Rose has called the "molecular gaze" (2007b, 2007a). Rose outlined the transformation of contemporary biomedicine's "style of thought" (Ludwik Fleck, cited in Rose 2007a:12) via an array of techniques aimed at understanding the body at the molecular level. By turning to molecular processes, Rose argues, contemporary biomedicine has begun to supplement the "clinical gaze" famously documented by Foucault (1973), with its focus on localized bodily observation as the basis for medical classification (Rose 2007b:11–15). To take just a couple of examples, previously indistinguishable forms of breast cancer have been differentiated on genetic grounds, and disjunct diseases have been found to share a genetic etiology, leading researchers to draw distinctions and see underlying unities that would not have been possible on a clinical basis (see Loscalzo, Kohane, and Barabasi 2007). In sum, the hegemony of anatomoclinical classification is facing a serious assault from researchers armed with new molecular technologies.

Still, it is genomic designation that represents a molecular gaze in the true Foucauldian sense. Rather than localized anatomo-clinical observation (Foucault 1973:3–4), disease is increasingly classified according to genetic mutations that are usually found in every cell of the body. Knowledge about these mutations is being used to carve out medical categories, bringing about what Foucault (1973:195) called a "syntactical reorganization of disease in which the limits of the visible and the invisible follow a new pattern," and bringing previously unthinkable categories of illness into view. To be clear, I argue that genomic designation thrives when it enters into a productive interface with the prevailing clinical modes of classification. Anatomo-clinical medicine may have achieved a rapid and decisive victory over its predecessor, at least as told in Foucault's forthright account in Birth of the Clinic (1973; see Armstrong 2011 for a more circumspect account). By contrast, there is no foreseeable prospect of genomic designation quickly or straightforwardly supplanting what came before.

Way back in 1935, Ludwik Fleck presciently explained how "the modern concept of disease entity ... [is] by no means the only logical possibility. As history shows, it is feasible to introduce completely different classifications of diseases" (Fleck [1935] 1981:21; my emphasis). Likewise, Foucault insisted (1973:3) that "this order of the solid, visible body is only one way — in all likelihood neither the first, nor the most fundamental — in which one spatializes disease. There have been, and will be, other distributions of illness." Genomic designation is precisely such a new way of locating and classifying disease. When genetic mutations such as the microdeletion at 22q13.3 come to serve as more than explanations for disease categories like hypotonia or autism and instead become the essential referents of new medical conditions like Phelan-McDermid syndrome, we begin to see geneticization, biosociality, and the molecular gaze writ large.

Clarifying Genomic Designation

What exactly do I mean by genomic designation? It is not a concept that one finds in the genetics literature, some recent discussion of "genotype-first" disease discovery notwithstanding (see chapter 8). So, because genomic designation has not previously been recognized as a distinct form of human classification, conditions have to be identified on a case-by-case basis. My criteria are straightforward: a condition is genomically designated if it is delineated and diagnosed strictly according to a genetic mutation. In other words, the observation of a specific genetic mutation is necessary and sufficient for diagnosis. The phenotype of the condition is then tabulated post factum by studying people if and only if they have the mutation in question.

In the clearest cases of genomic designation, like Triple X syndrome, 22q13DS, or ADNP syndrome, the mutation is discovered, and a brand-new condition is delineated on its basis. In less straightforward cases, a mutation that is strongly associated with an established clinical disorder ends up radically reshaping medical classification by lumping, splitting, and/or recalibrating more long-standing categories. We will return to the different varieties of genomic designation later in this chapter after exploring a couple of case studies.

Many hundreds, perhaps even thousands, of genomically designated conditions have been reported in the genetics literature. As a sociologist, however, I am especially interested in the cases where a genomically designated condition becomes a category of practice and social action — where it gives rise to the kind of clinical guidelines, specialist centers, advocacy organizations, and support groups that make it a bona fide medical and social category.

There are at least twenty-five clear-cut genomically designated conditions that match this ideal type, ranging in size from a mere handful to many thousands of diagnosed patients. They are all radically different from any preexisting clinical diagnosis, and they all have some sort of registered foundation or formal advocacy group established in their name (see table 1.2below).

A key question for genomic designation moving forward is this: How many of the countless mutations and genomically designated conditions reported in the literature — a list that grows with every passing week — will join that vanguard? Countless other syndromes do not fulfill all these conditions perfectly, but, as we will see below with the 16p11.2 Deletion Syndrome and Williams syndrome, they should be understood in terms of genomic designation nevertheless. Once we recognize its clearest cases, genomic designation becomes useful as a broader conceptual tool for investigating the impact of contemporary genetics research. Indeed, thousands of genetic mutations are best thought of in these terms: they do not line up with preexisting clinical categories, and the extent to which they give rise to new disease entities in the medical literature, inform clinical practice, or become objects of social mobilization is an empirically open question. A typology of genomic designation is outlined below. First, where did genomic designation come from?

(Continues…)


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Table of Contents

Acknowledgments

Introduction: From Mutations to New Kinds of People

1              Genomic Designation: How Genetics Creates New Medical Conditions
2              Immobile Mutations: Nowhere to Go in the 1960s and 1970s (and the Exception That Proves the Rule)
3              Leveraging Mutations: Going from the Rare to the Common in Human Genetics
4              The Loops That Tie: Mutations in the Trading Zone of Autism Genetics
5              Assembling a New Kind of Person
6              Mutations in the Clinic: Reframing Illness and Redirecting Medical Practice
7              Remaking the Normal versus the Pathological in Genetic Medicine
8              The Future for Genomic Designation and the New Prenatal Testing Landscape

Conclusion

Notes
References
Index
 

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