This week’s blog features another of our 2016 Student Voice Essay Competition submissions. Jungwoo Kang, a student at the Barts and London School of Medicine and Dentistry (QMUL), explores how rare diseases lead the way in medical research and clinical innovation.

Gaston Bachelard, a philosopher of science, made a simple premise – “the characteristic of scientific progress is our knowing that we did not know” (1). While there is myriad information that is currently unknown to science, Samuel Arbesman, a computational biologist, suggests the increasing difficulty of novel scientific discovery in recent years (2). As rare diseases by nature have peculiar pathogenic mechanisms which are uncommon, unfamiliar or unknown to the medical community, it is logical that rare disease research promotes medical progress despite the growing complexity in expanding scientific knowledge. Historically, the influence of rare disease on medicine has ranged from improved scientific understanding of physiology and pathophysiology, to paradigm shifts in approaches to treatment and public health. Whether it is the discovery of prion proteins and pathogenesis of migraine, or the development of revolutionary genetically-based therapeutics and advances in epidemic control, it is only fair to conclude that rare diseases greatly impact medical research and clinical innovation.

Rare disease research affects all fields of physiology – from molecular cell biology to wider pathogenic processes. Investigations into the aetiology of Creutzfeldt-Jakob disease (CJD) and similar neurodegenerative diseases, which single-handedly created a body of knowledge on prion proteins, embodies the effect that rare disease research can have on physiological discovery. Building on from prior animal research on scrapie agents, Stanley Prusiner identified the pathological prion protein (PrPSc­) to be the cause of CJD in 1982 (3), and subsequently recognised the normal cellular prion protein (PrPC) in 1985 (4). In CJD, the PrPSc was found to induce misfolding in PrPC, leading multiplication, aggregation, and eventually prion formation – the infectious and pathogenic agent (5). The prion was theorized to cause neurodegeneration through induction of neuronal apoptosis via direct action and microglial activation, which induces oxidative stress and a cytokine response leading to cell death. These misfolding processes are suggested to be pathogenic in both CJD and common neurodegenerative diseases such as Alzheimer’s disease, Parkinson’s disease and amyotrophic lateral sclerosis (5), demonstrating the wider effects of prion research in neurology. In addition, studies into the function of PrPC has uncovered its role in numerous physiological processes, including protection against apoptosis, synaptic transmission, and neuronal maintenance (6). Thus, it is apparent that rare diseases have enabled medical research progress in the case of CJD, as the novel discovery of prions and their physiological applications have had pertinent impacts in neuroscience and neurology. And considering the influence of Prusiner’s research, it is hardly surprising that he was awarded the 1997 Nobel Prize in Physiology for his contributions to science (3).

Furthermore, studies on rare monogenic forms of disease provide great insight for disease-gene discovery and perspective into the physiology of more common complex genetic disorders. For instance, a substantial body of knowledge about the pathophysiology of migraines, a neurological disorder characterised by severe episodic headaches (7), originates from research into familial hemiplegic migraine (FHM) an uncommon genetically-inherited form of migraine. FHM is an autosomal dominant disorder resulting from a mutation in the gene coding for the calcium channel Cav2.1 (FHM1), Na+/K+-ATPase (FHM2), or Na+ channel Nav1.1 (FHM3) (7). While there are 3 forms of FHM, they share a common pathophysiological pathway in impaired glutaminergic transmission – whether it is via increased activation or decreased inhibition of neurons (7). Not only did this consolidate the importance of glutaminergic activity in migraines (8), but also it delineated the need to explore the ionopathic nature of migraines. Consequent research has associated FHM ion channel mutations with an increased susceptibility to cortical spreading depression, a slowly propagating wave of brain electrical activity hypothesized to be the trigger of migraines (9), while a recent meta-analysis of over 375,000 individuals has also found 5 ion-channel related genes as migraine susceptibility loci (10). Evidently, research into FHM, a rare genetic condition, has both implicated and substantiated the role of ion channel defects in migraine aetiology, which emphasizes the role of rare disease research in understanding pathogenic and genetic mechanisms of their more common counterparts through the discovery of novel physiological processes.

In addition to physiological and pathophysiological discovery, studies on rare diseases also contribute to translational research. The most notable example of these contributions is the creation of genetic therapy, the treatment of disease through the repair of defective genetic material (11). While ideas of gene-based therapies were conceived decades prior, it was only in 1990 that the first successful genetic therapy was administered to a patient with adenosine deaminase-deficient severe combined immunodeficiency (ADA-SCID), a disorder arising from disturbed T-cell and B-cell development due to a lack functional of ADA. The therapy provided an alternative treatment to bone marrow transplantation, and with more than 75% of patients having no suitable donors (12), it was the only option other than complete isolation and frequent ADA injections. By using a virus to transduce the missing ADA gene into haematopoietic stem cells, the patient temporarily recovered – demonstrating the potential efficacy of gene therapy. In a subsequent phase 1-2 trial, with further developments in genetic technology, such as enabling the genetically-modified haematopoietic stem cells to establish a dominant cell population (13), 8 out of 10 patients required no further ADA replacement injections and had significant reductions in severe infections and number of hospitalisations (14). Utilising these technologies, the lead authors of the trial and GlaxoSmithKline have produced a therapy that was recently approved by the European Medicines Agency (12). However, the application of gene therapy is not isolated to ADA-SCID; early phase clinical trials have successfully treated rare and common disorders including childhood acute lymphoblastic leukaemia (15), HIV (16), sickle cell anaemia and β-thalassaemia (17). Although there are numerous hurdles to overcome in gene therapy, including fine-tuning its mechanisms and preventing detrimental side effects such as oncogenesis and autoimmunity (14), it is evident that there is incredible potential in its therapeutic application for both rare and common disease. With continual advancements in medical application and genetic technology, such as CRISPR, gene therapy has helped in causing the genomic medicine paradigm shift – all of which was made possible due to research impetus arising from the need to cure ADA-SCID and other rare diseases.

When discussing rare diseases, illnesses caused by uncommon infectious pathogens are often forgotten. Yet, outbreaks of rare viruses provide important lessons in public health on both national and international levels. For instance, the 2002-04 Severe Acute Respiratory Syndrome (SARS) epidemic, caused by the SARS coronavirus, delineated the need for international policy reform regarding epidemic response. Initiating in the Guangdong province of China, the SARS virus infected over 8000 patients and killed 774 in 37 countries (18). Whilst the infectivity of the virus cannot be ignored in explaining the spread of the disease, numerous mistakes in disease response and control severely exacerbated the epidemic. Firstly, during the early phases of the outbreak, deliberate misreporting (19), press censorship, and refusal of WHO access by the Chinese government lead to a delayed and inadequate government response (20). Furthermore, nosocomial outbreaks resulted from overcrowding of emergency rooms (21), improper hygiene, and a lack of transmission-based precautions in care systems of both developing and developed countries (22)(23). And although the epidemic came to a halt with strict quarantine and isolation, it emphasized the need to address these errors before a future outbreak of a more contagious and virulent virus. Consequently, the WHO published the International Health Regulations 2005 – a much needed revision of international law which aims to limit and control the spread of an outbreak (24). The resulting systematic approach in disease surveillance and international cooperation was crucial in rapidly mobilising the global response against the 2009 H1N1 flu pandemic as governments were more rapid and transparent in reporting new cases (25). However, with prevailing issues in the public health response, including the incapability of undeveloped countries to implement the new regulations and concerns around human right violations with aggressive quarantining (26), preparation in epidemic and pandemic response must continue to improve – especially considering the modern rise in prevalence of antibiotic-resistant bacteria and emergent viruses. As demonstrated by the acquired and applied knowledge from the SARS outbreak, it is clear that consistent challenges from rare infectious illnesses and retrospective examinations have, and will continue to strengthen the global response in containing disease.

Revisiting Bachelard’s premise, the principle of scientific progress being characterised by new knowledge, is exemplified through scientific and translational research uncovering the unique physiological mechanisms and effects of rare illnesses. From developments on the cellular level in prion discovery from CJD research and significant progress in genetic therapeutics arising from the need to treat ADA-SCID, to innovations in global health resulting from lessons learned from the SARS epidemic, it is clear that rare disease research has a widespread and penetrating impact on all fields of medicine. These effects are bound to multiply from impending technological advancements from the genetic revolution and research promotion through orphan drug policies. With pertinent effects in science and immeasurable benefit to patients, rare disease research must continue for medicine to progress. 

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