Long

Against the Idea of ‘The Cure’

200-year-old anatomical wax model, La Specola, Florence. Credit: Konrad Laker.
200-year-old anatomical wax model, La Specola, Florence. Credit: Konrad Laker.

Ideas of health, its pathogenesis, and disease have radically evolved throughout the history of medicine right up to the emergence of modern evidence-based medicine. Yet, in each period of medical culture, the consultation of those in pain with those offering a cure was the prototypical medical encounter. The hope for a cure, a renewed absence of disease, is still one of the central legitimizing forces in the project of medicine. The promise of a cure inspires hope in patients and motivates doctors and researchers. But is it really a useful concept for guiding medical research and assessing the success of medical treatment?

The idea of a cure is simple enough to be useful irrespective of different concepts of health and disease. Whether disease is understood as divine punishment, an imbalance of internal processes in the form of humours, an external entity, a germ, or an aberrant internal process, the cure is the promise of resolution. Its apparent ahistorical character and indifference to other conceptual frameworks within which it operates, seems to empty the idea of much concrete content. But the cure cannot be understood as a vacuous placeholder for what is deemed medical success at a given time. It is surprisingly a deeply problematic concept within the framework of modern medicine.

Precision

The precision of modern medicine in localizing or mapping disease processes in the body presents a serious challenge to our common sense idea of the cure. In a popular understanding, modern medicine arose from increasing knowledge of the spatial constitution of the body (anatomy), the many systems encapsulated within this for maintaining homeostasis (physiology), and the role disease plays in disturbing them (pathology). Elucidations of the chemical interactions explaining many of these features (biochemistry and molecular biology) and the information coding for the molecular constituents of the body (genomics) have arisen much more recently. By fracturing the body into ever smaller constituent parts, the physical substrate of a person can increasingly be described with precise numbers and measures, and denoted on a minute scale.

Whether it is the voxels of the MRI machine, the specific folding pattern of a crucial protein, the base pair composition of our DNA or its methylation pattern, the number of parts the body can be divided into is ever increasing. At each level, the medical sciences ask two questions: “Does this explain the pathology of the disease experienced by a person” and “If we were to inhibit, replace or enhance this process, would it cure the disease?” A causal link is established between the person sitting before me in a hospital gown, in pain, discomfort or mortifying anxiety, and an object unimaginably small. Most diseases in this light are not unified entities anymore, but radically dispersed through the body.

Dispersal and heterogeneity

Dispersal itself is not a new problem in describing disease entities. For a long time we have understood that colonies of microorganisms—e.g. bacteria living in tissues that cannot tolerate their presence—cause pathology. However, their susceptibility to strong therapeutic agents such as antibiotics made them appear to be a single entity. If we can find their weak spot, target something specific to them and not present in us, their dispersal would not pose a problem in combating them. This magic bullet theory of pharmacological treatments still captures the public imagination. If we think of a future cure, we hope it will be like the antibiotics: taken for a brief time and followed by a swift return to health with no lasting impairment.

The importance we placed on antibiotics as the prototypical drug stands in stark contrast to the huge crises antibiotics face today. The last major class of antibiotics was discovered three decades ago[i] and many pharmaceutical companies have shut down research into new antibiotic agents. This is partially due to the hope for more profitable drugs for other diseases, but also to our understanding that bacterial colonies cannot only disperse through the body but display radical heterogeneity. Bacteria possess a plethora of methods to exchange genetic information, both intragenerational and intergenerational, allowing them to quickly propagate effective methods to combat antibiotics throughout a colony.[ii] Heterogeneity, or greater genetic flexibility, led to the eventual emergence of antibiotic resistance. This inevitability is the true crisis in antibiotic research. But is this only a problem with this specific type of cure? Or does it point to a more fundamental problem with the idea itself?

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The problem

Dispersal and heterogeneity of the disease entity are compounded by the precision of our body maps. As we dig deeper into the undergrowth of molecular biology, we can map out the normal and pathological in ever greater detail. But this precision entails an increase in entities that can be identified as normal or pathological. If to be cured means an absence of the disease-causing entity—in contrast with remission, a temporary diminution in severity—we are increasingly faced with a situation in which the number of points to be sampled exceeds practical means. Establishing an absence is statistically difficult if we deal with a complex object like the body, divided into many different compartments, with many different tissues made up of even more specialized cells. Furthermore, the heterogeneity of the pathological entity makes it incredibly difficult to map it in its entirety.  Paradoxically, increasing precision, or a higher resolution of our body maps, makes the ascertainment of a cure ever more difficult as it increases the number of entities to be sampled.

This heterogeneity also plays a role in the identification of infectious agents and the effectiveness of our drugs against them. It is a greater problem for ascertaining the cure of many non-infectious diseases. Cancer, for example, is now understood to be a principally genetic disease, which commonly develops over a lifetime through the gradual accumulation of mutations.[iii] As there are many innate safeguards against carcinogenesis a large number of genetic “hurdles” need to be overcome before a tumor becomes pathological. (Strongly hereditary cancers occurring early in life represent a relatively rare exception to this model.) A tumor is not necessarily a genetically homogenous mass of cells, but is likely to include a larger number of cells with different mutations and properties. As mutagenesis is one of the hallmarks of cancer,[iv] a clear identification of what is normal and pathological may not be easily achieved, especially if genetic changes have no simple phenotypic expression. Although the genome is constantly being repaired, we now understand that it is not a static blueprint that is simply read out. Many levels of control modifiable by environmental factors play an important role determining the constituents of the body.[v] Hence, the normal is itself in flux, even if we were to assume that change occurs only at the epigenetic and regulatory level.  This heterogeneity and our inability to clearly delimit the boundaries of the normal and pathological within this, represent an additional level of complexity when trying to diagnose a cure.

An additional problem for the cure is that scientific tests have error bars and varying sensitivity to what they are meant to establish.  Absence must always be described as falling below the lowest detectable level. As a result we can only ever estimate the presence of absence rather than ascertain it with any precision. The precision with which the body is mapped in the life sciences and the more limited techniques of clinical practice, may mask this to a certain extent. It is the absolute nature of the cure that makes the concept extremely difficult to delineate precisely in scientific medicine.

Some may want to argue that the modern notion of a cure already incorporates these epistemological problems of scientific medicine. In HIV research[vi], for example, a distinction exists between the development of a functional and a sterilizing cure. A functional cure describes the ability of a patient to discontinue antiretroviral therapy without suffering any adverse consequences. A sterilizing cure describes the complete eradication of the HIV virus from the body. The idea of a functional cure allows us to declare someone cured without knowledge about the exact localization of the virus. Does it matter that we are unable to ascertain an absence of the virus, if we can describe someone as functionally cured?

A functional cure

HIV infection is a peculiar disease insofar as most patients experience a long period following initial infection during which they display no symptoms. The virus is present in their blood, they are infectious to others, but it is only when a sufficient number of CD4+ lymphocytes have been depleted, that AIDS manifests itself as a drastically diminished ability to fight common infections. Being cured of HIV therefore would mean to be certain not to be infectious to others and assurance that AIDS will not develop. The cure is essential not for relieving acute symptoms, but for quelling the potential to develop the disease.

HIV infection is diagnosed by the number of infectious HIV copies or, more commonly, by the presence of specific antibodies to the virus. [vii] The HAART drug regimen, a cocktail of potent antiretrovirals, is highly effective in reducing the number of HIV copies to a level where they are practically undetectable.  However, these patients are not considered to be functionally cured, since a cessation of the drug regimen results in a rapid rebound of the HIV copies in the blood. This is believed to be due to the presence of latently infected cells that are capable of producing new HIV copies. Latent infection means that HIV, as a retrovirus, inserts its own genome into the host cell’s genome, where it may or may not be expressed to produce the functional virus particle. Cells that do not express the virus are not easily identifiable by the immune system and present a reservoir from which new viral particles can be generated when reactivated. This is complicated by the fact that the mechanism HIV uses to insert itself into the host genome is highly error-prone, accounting for the heterogeneity of the virus. A complete cure, then, necessitates the eradication of the virus particles from the blood stream and, critically, the destruction of all HIV genome sequences capable of producing new virus particles. The dispersal of the infection and the heterogeneity of the target may serve as theoretical explanations for why a HIV cure has remained elusive.

A number of functional cures have now been reported, where patients have ceased to take drugs and have not experienced a rebound in the number of HIV copies in their blood. In the famous case of the “Mississippi baby”[viii], a neonate was infected during birth, but a high dose of antiretroviral drugs was administered within 30 hours. Antiretroviral medication was continued until the 18th month, when therapy was interrupted by the mother for unknown reasons. Five months later, the mother returned with the child, but HIV was no longer detectable in the girl’s blood. After several tests and continued observation the patient was declared to be functionally cured. Unfortunately, during more recent tests the virus was again detected in the blood, overturning the belief that the girl was effectively cured by the high dose of antiretroviral drugs following birth.

The idea of a functional cure does not capture our expectations of what it really means to be ‘cured’. If being HIV positive is about the potential to infect others and the development of AIDS in the future, a functional cure cannot provide certainty without ascertaining an inability of HIV to replenish itself in the future. As there are no symptoms to relieve, a functional cure is unlikely to alleviate anxiety about the potential to develop the disease and infect others.

Susan Sontag said that “everyone who is born holds dual citizenship in the kingdom of the well and in the kingdom of the sick.”[ix] The cure is the implicit promise of returning to a previous life to join the perpetually healthy. However, these cultural connotations rely on the ability to give a certain diagnosis with the precise tools of modern medicine. If the conceptual problems the cure faces cannot be resolved, the cultural promise cannot be fulfilled. What does this mean for the idea and possibility of medicine without the promise of a cure at its center?

New norms

“In any case no cure is a return to biological innocence. To be cured is to be given new norms of life, sometimes superior to the old ones.” Georges Canguilhem, The Normal and Pathological, [x]

The promise of a cure inspires hope in patients and motivates doctors and researchers. Should we dismiss the idea because of an epistemological technicality in spite of its apparent social utility? At this point it is important to note that I have not tried to make predictions about the future. It is likely that more cures will be developed and I make no attempt to dismiss the great achievement this represents. The question posed here is whether the cure represents a useful concept in guiding medical research and assessing the success of medical treatment. The focus on the cure, given that it has become a concept with a very fuzzy operational definition, has many negative consequences.

The promise of the cure divides patients into those with curable and incurable diseases, or more conventionally into those with acute and chronic conditions. For those deemed incurable, the chronically ill, there is only the promise that further medical research, by developing a cure, will let them break out of their condition. The number of the chronically ill is increasing, whether from high blood pressure, diabetes, psychiatric conditions or incurable cancer. The increasing number of elderly patients suffering from a number of co-morbidities is likely to increase even more, with little hope that medicine will return them to perfect health.[xi] It is not possible to generalize the experience of chronic illness, the different expectations and anxieties a patient may develop. Nevertheless, how we conceptualize disease and, conversely, the possibility of a resolution, impacts the way treatment is administered. Many doctors may resign to the fact that most treatment is not curative and may be reluctant to declare a patient cured. Yet ‘the cure’ remains at the center of medical culture and may distort priorities for patients and doctors alike in trying to find a solution. How many patients seek out or receive excessive and unnecessary treatment for the abstract promise of being cured?

If the cure is a problematic concept within modern medicine, other ways for patients to conceptualize their own situation may arise. For medicine as a whole, the withering away of the promise of the cure could open up new avenues to organize the encounter between patient and doctor. Rather than seeing the inability to treat a patient as a failure and nuisance to be rectified by medical progress, we may be able to redefine medical progress by returning the cure to its etymological root.

cure |kjʊə, kjɔː|

verb [ with obj. ]

ORIGIN Middle English (as a noun): from Old French curer (verb), cure (noun), both from Latin curare ‘take care of’, from cura ‘care’. The original noun senses were ‘care, concern, responsibility’, in particular spiritual care […]. In late Middle English the senses ‘medical care’ and ‘successful medical treatment’ arose, and hence ‘remedy’.[xii]

 


[i] http://kingsreview.co.uk/magazine/blog/2013/05/18/death-by-tonsillitis-imagining-a-world-without-antibiotics/

[ii] Giedraitienė A(1), Vitkauskienė A, Naginienė R, Pavilonis A, Antibiotic resistance mechanisms of clinically important bacteria, Medicina (Kaunas). 2011;47(3): 137-46.

[iii] Eric R. Fearon, Bert Vogelstein, A genetic model for colorectal tumorigenesis, Cell, Volume 61, Issue 5, 1 June 1990: 759-767

[iv] Douglas Hanahan, Robert A. Weinberg, Hallmarks of Cancer: The Next Generation, Cell, Volume 144, Issue 5, 4 March 2011: 646-674,

[v] http://www.lrb.co.uk/v23/n05/adrian-woolfson/so-much-for-genes

[vi] http://www.amfar.org/three-types-of-hiv-cure/

[vii] Murray Longmore, Ian Wilkinson, Andrew Baldwin, and Elizabeth Wallin, Oxford Handbook of Clinical Medicine, OUP, 2014: 413

[viii] http://www.nature.com/news/hiv-rebound-dashes-hope-of-mississippi-baby-cure-1.15535

[ix] http://www.nybooks.com/articles/archives/1978/jan/26/illness-as-metaphor/

[x] Georges Canguilhem, The Normal and Pathological, Zone Books, 1998:. 228

[xi] http://www.theatlantic.com/features/archive/2014/09/why-i-hope-to-die-at-75/379329/

[xii] Oxford Dictionary of English, OUP, 2010

 


Konrad Laker is studying clinical medicine at University College London. He completed his pre-clinical studies at Wolfson College, Cambridge and previously read philosophy at UCL.