By Daniel Tarade
When studying disease, it easy to get caught up in the concept of normalcy. For example, it is normal for hematopoietic stem cells to give rise to white blood cells, to replace those that have become damaged or have died. It is abnormal for these same progenitor cells to divide uncontrollably and we call this disease – leukemia. It is normal for blood to flow through the circulatory system to aid in the delivery of oxygen and nutrients. It is abnormal for plaques to obstruct said flow of blood and we call this disease – heart disease. Countless examples can be enumerated, all of which highlights the propensity of scientists to categorize bodily functions and processes as normal or abnormal, healthy or diseased.
The purpose of this categorization system is multifold. The identification and categorization of normalcy is central to and in many ways entangled with the diagnosis of disease. Establishing normalcy allows for pathologists and physicians to delineate diagnostic criteria. It is normal for a human to have between 3500 and 10,500 white blood cells per microliter of blood. It is abnormal to have more than 10,5000 white blood cells per microliter of blood, particularly immature blast cells that typify leukemia.[i] Following diagnosis, a benchmark of normalcy also informs the preferred method of treatment. When a patient presents with blast cells in the blood stream, they can be treated with various chemotherapeutics to try and eliminate these blasts. The concept of normalcy also serves an additional function of directing research efforts. The term ‘disease’ cries out for the development of a cure.
The concept of disease ultimately contains a list of symptoms, diagnostic criteria, and suggestions for treatment. As used currently, disease is defined in a both descriptive and prescriptive sense: this is how you deviate from the norm and this how medicine can correct these abnormalities. However, it is important to remember that disease and health are context-dependent. Something that Siddhartha Mukherjee reminds us in his latest book, The Gene, is that the nomenclature of biology and biochemistry does not refer to an ‘essential’ ‘normalcy’ but is instead statistical in nature.[ii] Rather than focusing on what is normal and abnormal, geneticists, biochemists, and molecular biologists rely on the descriptors ‘mutant’ and ‘wild-type.’ Wild-type, recall, simply describes an allele or variant that is more common in the wild. It is therefore an inherently relative term. What is wild-type among people of European ancestry might be considered a mutant allele amongst those with Sub-Saharan ancestry. Also important to remember is that the terms ‘wild-type’ and ‘mutant’ in themselves do not suggest anything about the nature of the allele, whether it is beneficial, detrimental, or simply different. The terms are simply statistical in nature – any normative claims arise from the scientists and physicians who study these genes.
Rather than defining disease as mutant and normal as wild-type, disease ought to instead be thought of as a mismatch between genotype, regardless of the ‘wild-type’ or ‘mutant’ status of an allele, and the environment. A disease-causing allele is one that prevents a person living a satisfying and reasonable long life. Disease is not the lack of normalcy but a condition of incompatibility between an individual and the environmental or social conditions in which they live. Leukemia in this sense is not a disease because it is abnormal but because it causes pain, wastes away the body, and results in premature death
For most research questions, this context-dependent view of disease is not requisite. There are very few imaginable circumstances where metastatic lung cancer, cystic fibrosis, or polycystic kidney disease can be considered beneficial. It requires incredible imagination to think up a scenario where such diseases can be highlighted as context-dependent. Just about all contexts of human existence can be seen to be worsened with the addition of Huntington’s Disease or Amyotrophic lateral sclerosis. However, there are scenarios when what is defined as disease can turn out to be beneficial, even lifesaving. Consider the ending of the M. Night Shyamalan film Signs, in which an asthmatic child encounters an alien capable of dispensing toxic gas from slits in its wrists. What normally would result in death was instead prevented by the asthmatic condition – the child’s lungs were closed off and inaccessible to the lethal vapours. In that specific context, admittedly a fictional scenario, asthma is advantageous and the distinction of health and disease is inverted, albeit temporarily and only for the duration of the alien encounter. Do we need to necessarily rely on a typified M. Night Shyamalan twist ending to highlight the context-dependence of disease?
A more real-world example, although still involving a potentially unreasonable amount of conjecture, is related to my own research project. One focus of our lab involves study of hypoxia (i.e. low oxygen) and the bodies adaptation to such low oxygen conditions. In addition to studying how cells can adapt to hypoxia, we also study how diseases can arise from the mutation of genes normally involved in the hypoxic response. One such ‘disease’ that I study is familial erythrocytosis, a condition of abnormally elevated red blood cells counts. The particular form of familial erythrocytosis that I study is driven by inheritance of a faulty allele of HIF-2alpha, a transcription factor involved in the co-ordination of the cellular response to low oxygen conditions.[iii] With a list of symptoms that includes headaches, dizziness, shortness of breath, and an elevated risk of developing potentially life-threatening clots, it is easy to see how familial erythrocytosis falls into the category of disease; it is not impossible to live a satisfying and long life with an inherited erythrocytosis but it is definitely more difficult. However, if you change the context, it is possible to see how this condition can actually be beneficial and subvert its classification as disease. Based on actual hypotheses by climate scientists, by the year 2100, amidst rising global temperature, the levels of oxygen on Earth may decrease due to die-off of vegetation (particularly oceanic plankton).[iv] Instead of our ‘normal’ context of 21% atmospheric oxygen, we may find ourselves choking on air. Those who inherited a faulty copy of HIF-2alpha, rather than diagnosed with erythrocytosis, might find themselves the beneficiary of a circulatory system than can more efficiently deliver oxygen. Rather than these people being candidates for gene therapy (i.e. CRISPR mediated DNA editing) to fix their genetic lesions, they instead may be the inspiration for gene therapy to introduce HIF2alpha ‘mutants’ to individuals to increase oxygen carrying capacity – to allow for continued survival of people in a world fundamentally altered by run-away climate change. In this scenario, what is normal (21% atmospheric oxygen) become abnormal, resulting in re-classification of disease and health, such that they no longer align with the wild-type and mutant classification of HIF2alpha alleles.
There is no current research exploring how patients with familial erythrocytosis will actually fare under chronic hypoxic conditions. However, a particular mutation in EPOR, another protein important for the organismic response to low oxygen, results in a mild form of familial erythrocytosis.[v] The ‘disease,’ as defined in a seminal research article, results in increased hemoglobin levels but is not associated with any undesirable symptoms or shortened lifespan.[vi] In fact, one of the afflicted individuals was a dominant cross-country skier - Eero Mäntyranta - who had won seven Olympic medals, including three gold medals. It is speculated that the EPOR mutations resulted in an increased oxygen carrying capacity, which aided in endurance sports.[vii] As a result, researchers have speculated about the possible therapeutic possibilities of this ‘disease.’
The example serves, however, to explore the relative nature of disease and health. Many conditions of disease involve an elevation or depression of some normal function. In these cases, it is conceivable of some context in which a depression or elevation of some function may actually be beneficial. Our current categorization of disease may be a toolbox for the adaption of humans to the unexpected scenarios of the future. Future human civilizations may one day find themselves inhabiting as of yet indescribable planets, new homes for which our ‘normal’ genes and proteins will not necessarily be best suited. Disease is potentially driven by variation in DNA. Variation in DNA is fodder for selection on the basis of natural fitness. As Darwin astutely observed, fitness is dependent on situation. The disease of today can be the driver of increased fitness in the future. It is important to remember that as genome altering technologies continue to develop that we, as researchers and clinicians, are not limited to correcting mutations but can explore these ‘mutant’ variants for their potentially beneficial properties as we explore ways of modifying the human genome to aid people in their quest for fulfilling lives.
[i] According to the Mayo Clinic, http://www.healthline.com/health/wbc-count?m=0#overview1
[ii] Mukherjee. (2016) The Gene: An Intimate History, Scribner.
[vi] Juvonen et al. (1991). Blood 78: 3066-3069.