Sudipto ROY - Merit Prize in the Asian Scientist Writing Prize 2015
It is not common knowledge that cilia, finger-like projections from the surface of eukaryotic cells, were the first organelles to be discovered by Antonie van Leeuwenhoek way back in the 16th century. We now know that these microtubule-based structures are important hubs for a large number of developmental and physiological signaling pathways. Moreover, some cilia are motile – they can beat rhythmically and function to drive fluid flow over epithelia (for example, mucus clearance from our airways) or facilitate cellular locomotion (swimming movement of spermatozoa). My interest in cilia was triggered several years ago by our discovery that the transcription factor FoxJ1 is the master regulator of motile cilia differentiation. We found that FoxJ1 regulates the expression of a whole suite of genes required for proper ciliary differentiation and motility. Most interestingly, we realized that many of the target genes of FoxJ1 are mutated in patients suffering from a disease called Primary Ciliary Dyskinesia (PCD). Due to the lack of proper ciliary motility, individuals with PCD suffer from severe recurrent airway disease, infertility and sometimes a peculiar anatomical abnormality called heterotaxy or situs inversus, where the major visceral organs are positioned anomalously within the body cavity (for instance, heart on the right side and liver on the left). There is no cure for PCD, and diagnosis and management of the disease is very challenging. While significant progress has been made in these directions in the west, PCD is largely neglected in Asia. When I noticed the story writing competition launched by Asian Scientist, I realized that this may be a good forum to write about PCD. One important criterion for this competition was that the story must be written in an aspirational manner and must focus on an issue that is currently not well recognized in Asia. My intention with the story about PCD that I wrote for the Asian Scientist Writing Prize was to create awareness for this disorder in the region. I am indeed deeply grateful and honored for receiving a merit prize in this competition, and I hope that my story will help inspire the establishment of proper PCD diagnostic and treatment facilities in Asia for the benefit of numerous PCD patients in this part of the world.
To read more about contest: please see http://www.asianscientist.com/2015/07/topnews/asian-scientist-writing-prize-2015-winners/
Mirror, mirror on the wall
Amina has been sick as long as she can remember. Born with severe respiratory distress syndrome, she has been plagued with chronic sinusitis and respiratory problems. She has persistent purulent cough and ear infections that come and go. It depresses her to be sick all the time, especially when she sees her friends having all the fun in the world that children of her age typically have. Amina is not the only ailing child in her family of six siblings. Her younger brother, Abedin, has been sick since he was born, and suffers from the same spectrum of symptoms. Their father works as a laborer in the paddy fields. During the monsoon season, he is barely to be seen at home – toiling in knee deep waters transplanting young rice saplings. Monsoon is also the most uncomfortable season for Amina and Abedin. They hate the seasonal flu and secondary infections that break out during this period. It makes their sickness a lot worse, and they dread the time they spend cooped up in their little one room hutment, unable to go to school or play with their friends.
No one seems to know why Amina and Abedin have this illness. The village aurvedic doctor, who they see most often, usually gives them a foul tasting concoction of herbs. It helps in clearing the mucus that accumulates in their sinuses and lungs. They have also visit the government hospital in Chennai a number of times, when infections get particularly bad. Dr. Bala, who sees them there, will always shake his head and give them a large strip of capsules to swallow with water after food. Both Amina and Abedin know that they always feel better after taking Dr. Bala’s medicines. But what they like most is to make boats with the large strips of silver foil that are left behind once all the capsules have been consumed. They float their silver boats in the sewer that runs past their home, which swells and gargles with madly rushing water from the monsoon rains. But what haunts Amina the most is the plaintiff wail of her mother, Noor Begum, as it drifts through the thick evening air, ever since her eldest brother suddenly died. Noor’s grief is inconsolable. Abdul, like Amina and Abedin, also suffered from respiratory problems, but he also had bouts of breathlessness that Amina and Abedin doesn’t. Abdul loved playing football, and as a lad of 18 years, he was a formidable player for his opponents. Sadly, he had collapsed and passed away at a school football game a few months ago, much to the horror and shock of his family. Noor had hoped that despite his illness, Abdul will be able to get a job in the city, and turn around the fortune of her family. She is immensely pained at his loss, but the thoughts of raising a large family of young children, with two chronically ill, weighs down upon her shoulder.
It was the visit of Noor’s brother, Latif, which brought in a ray of hope for the Amina and Abedin. Once the excitement of seeing their uncle after a long time and hearing all the stories of their cousins back in Lahore had subsided, Amina and Abedin poured over a newspaper cutting that Latif produced, describing the story of a Pakistani family whose children had a disease that seemed so much similar to what was scourging Amina and Abedin. They read with interest how these people got to know of a doctor in London who was able to provide them some help. They learnt that their disease is likely to be a condition called Primary Ciliary Dyskinesia, but could not follow the rest of the medical jargon that explained how it develops. But, what was striking in the newspaper article was a X-Ray image of a diseased individual that showed the positions of all the major organ systems in his body - the heart, stomach and liver – all switched to the opposite side, in what seemed to be a complete mirror image reversal!
Primary Ciliary Dyskinesia (PCD) is a genetic disease that arises from mutations in genes that encode proteins required for the differentiation or function of tiny hair-like cellular organelles called motile cilia. Motile cilia line the airways, from the nasal cavities all the way to down to the lungs, and they beat continuously in a rhythmic manner to clear mucus that traps inhaled pathogens and pollutants. In PCD, patients carry mutations in genes that are required for the structure and function of the motile cilia. Consequently, PCD patients have defective motile cilia that impair mucus clearance from the airways, causing chronic respiratory problems like sinusitis and bronchitis. Improper management of this condition leads to bronchiectasis or permanent damage of the lung and the airways. Since sperm cells use a long cilium, called the flagellum, for swimming towards the egg for fertilization, PCD afflicted male individuals are often sterile. But the most unusual, and at times insidious aspect of PCD, is the abnormalities in the left-right disposition of visceral organs. This arises due to defects in the motility of a very special group of cilia that decorate a transient pit-like structure called the ventral node during embryonic development. Directional fluid flow within the node cavity, driven by the beating of these cilia, is the initial cue that directs developmental signals to initiate the proper asymmetric formation of organ systems – for example, the heart positioned on the left and liver on the right. About half of PCD patients have abnormalities in the disposition of the visceral organs – some have complete reversal, a condition called situs inversus, whereas others have heterotaxy or randomization of organ asymmetry. While situs inversus is a dramatic developmental anomaly, surprisingly, despite being on the wrong sides, all the organs can function normally without any detrimental consequences. Heterotaxy, however, is a serious condition that can be life-threatening. For example, heterotaxy patients often have severe congenital heart disease due to improper positioning of the heart and the associated great vessels. Without proper diagnosis and follow-up corrective surgery, such a condition can be fatal.
Diagnosis of PCD is challenging. Even though respiratory problems are apparent at birth, the condition is often confused with other respiratory conditions such as cystic fibrosis and asthma. Traditional methods of diagnosis involve measurement of exhaled nitric oxide levels and electron microscopy to evaluate the integrity of the respiratory cilia. Lately, videomicroscopy of live ciliated cells obtained by nasal brushing as well as studies of localization patterns of different ciliary proteins have complemented the traditional procedures. The final recourse is genetic screening, but with more than 30 different PCD genes that have now been identified, this is not a readily available service. Given the sophisticated nature of these diagnostic procedures, it is unsurprising that PCD diagnosis services are currently only prevalent in a handful of western countries. This means, as for Amina and Adebin, the large population of the Asian nations is completely deprived of awareness of this disease, and more importantly, access to clinics specialized for diagnosis and treatment. This is even more alarming when one considers the incidence of PCD. It is estimated to be in the range of 1:10,000 – 20,000 in the general population, but frequencies as high as 1:2500 have been reported in highly consanguineous communities, many of which reside in the Asian region. This is indeed the case for Amina’s parents, who are first cousins, explaining the preponderance of the disease phenotype among their children.
Studies in the west have clearly underscored the merits that early diagnosis of PCD can have on the well being and prognosis of lung damage progression in patients suffering from this disease. Early diagnosis will ensure reasonably normal life through routine physiotherapy to clear mucus build up in the lungs and very aggressive antibiotic treatments to control infections as and when they occur. Without these interventions, PCD patients almost invariably progress to severe end stage lung disease, with lung transplantation being the only remaining solution. Early diagnosis of PCD also ensures early diagnosis of associated congenital heart disease, which can then be rectified with appropriate corrective surgery. Knowing all of this information about PCD, one can begin to piece together facts about Amina and her brothers’ illness. Abdul likely died of an undiagnosed congenital heart condition, and who knows, an ultrasound scan may surprise Amina or Abedin with a mirror image reflection of their viscera!
The key challenge, then, is to bring in awareness and comprehensive PCD diagnostic and care services to Asia, which will be a tremendous benefit for patients suffering with this rare but morbid and often life-threatening genetic disorder. Can Singapore lead the way?
For more information on Sudipto ROY's laboratory, please click here.