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An ocular microbiologist’s take on medical research and avoidable blindness in India

Dr Joveeta Joseph, PhD in medical microbiology, focuses her attention on ocular microbiology. She is a microbiologist at Jhaveri Microbiology Centre, L V Prasad Eye Institute (LVPEI), Hyderabad and is involved in diagnostic and research activities pertaining to ocular infections. She was the first one to describe the staining and electron microscopic features of ocular microsporidiosis. She has been honoured with various awards like G P Agarwal Young Scientist Award, DST Fast Track Scheme Grant, DST Women Scientist Scheme Grant, and recently the 2016 Young Scientist Award by Telangana Academy of Sciences. Being an active researcher in finding out ways to prevent avoidable blindness in India, she finds time out of her works to answer the questions posed to her from India Medical Times.

Dr Joveeta Joseph
Dr Joveeta Joseph

Please introduce yourself to our readers, about your career as a researcher, your aspirations and inspirations.

I started my research career in 2003 as a PhD student at the L V Prasad Eye Institute – BITS Pilani, soon after my Masters in General Microbiology. As often happens, the last few years of my graduate tenure were the most productive and yielded the most exciting discoveries of my thesis work, which focused on understanding microsporidia, an obligate intracellular parasite. I was able to demonstrate that different species of microsporidia possess a range of pathogenicity, tissue predilection and virulence to corneal tissue. In addition, I also worked on the significance of proteolytic enzymes in the pathogenesis of fungal keratitis. I later moved to the Indian Institute of Chemical Technology in 2008 wherein I was awarded the ‘Fast Track Scheme for Young Scientists’ by the Department of Science & Technology to work on investigation of microbial resistance among soil dwelling bacteria. It was a fantastic experience and provided a strong foundation for the span of my career. But I decided that I wanted to contribute to research in a field that would directly help people and thus when I was offered a faculty position as an ocular microbiologist at the L V Prasad Eye Institute, I immediately jumped ship.

In this journey, I realized the gravity of the problems associated with infections and diagnosis of infectious diseases as well as the role I could play as a professional microbiologist to directly combat these problems. Thus, where better than a centre of excellence in eye care services where basic and clinical research into eye diseases and vision-threatening conditions were being conducted for extending equitable and efficient eye care to underserved populations in the developing world. In addition, L V Prasad Eye Institute provides an academic environment wherein I have a chance to help educate the next generation on the facts and techniques in this fast changing field. In an attempt to move forward, I modelled my path after observing the passion for microbiology from Dr Savitri Sharma, who is currently Director of Laboratory Services of LVPEI network hospitals in India. With over 250 publications on ocular microbiology alone, along with several national and international grants, her diligence and professionalism have been my inspiration from the day I first stepped into this institute.

How did Ocular Microbiology specifically draw your attention and interests?

I came into the field of ocular microbiology twice. The first time, I had no other choices left to pursue my PhD, but the second time I found a purpose, having completed my PhD on understanding a pathogen that had been recently recognized as a causative agent of infective keratitis. It was then that we started publishing that microsporidia can cause ocular infections in immunocompetent individuals as well, a fact that was unheard of until then. My publications were among the first in the country and even today are the most cited. We have a global presence in this field. I realized that not only are we at a unique position to study these opportunistic pathogenic agents in ocular infections, the spectrum of infections in our country differ vastly than what is reported in western literature.

After joining back, along with infective keratitis, I started to focus on identification and characterization of mechanisms involved in vision loss and inflammation in endophthalmitis, an infection of the posterior segment of the eye. I noticed that out culture positivity in these cases have been between 30-40% but this did not correlate with the severity of infection and despite appropriate therapeutic and surgical intervention, there were cases of significant loss of vision (or the eye itself) within 1 to 2 days. This is an exciting field and there remains a lot to be studied. Ocular microbiology is one of the most under-recognized health professions but it remains an applied science wherein the advancements in molecular biology and the newer technologies pave the way for better understanding of ocular diseases.

Please tell us more about your research works.

Our laboratory is working on research projects related to investigating microbial pathogenesis and physiology, microbial susceptibility to drugs, immune defence system and the host-pathogen interface in a range of infectious diseases of the eye. The research activities are supported through research grants received from national agencies and industries, including the Council of Scientific and Industrial Research (CSIR), Department of Biotechnology (DBT), Department of Science & Technology (DST), Indian Council of Medical Research (ICMR) as well as international agencies such as Asia Cornea Society, Singapore; Bausch & Lomb International Research Programme; British Contact Lens Association etc. Some of them are outlined below:

Corneal diseases are a major cause of blindness worldwide and corneal infections are a substantial cause of blindness in Asia. We are one of the participating institutes in the Asia Cornea Society Infectious Keratitis Study (ACSIKS) study, conducted under the auspices of the Asia Cornea Society. ACSIKS is a supranational, three-year multi-centre study on infectious keratitis involving 11 clinical sites from major ophthalmic institutions in eight Asian countries with the aim to develop improved strategies for prevention and treatment, with the ultimate goal of reducing ocular morbidity and corneal blindness related to infectious keratitis in Asia.

One of the most challenging tasks faced by an ophthalmologist is to overcome antibiotic (antifungal) resistance in ocular pathogenic fungi, which are responsible for nearly half of the total corneal ulcers. Our laboratory is interested in characterizing Candida species (a common cause of fungal infections worldwide) isolated from ocular infections. This study aims to also investigate the virulence factors associated with these Candida strains. In addition, we are also interested in assessing the biofilm formation potential of ocular Candida albicans and to correlate the potential with antibiotic susceptibility by identifying the genes involved in biofilm formation in ocular Candida albicans. The results of this study would help understand the pathogenicity and clinical course of various Candida species associated with ocular infections, and would help us to achieve good treatment outcomes.

The human eye surface microbiome study aims at establishing both the gut and ocular surface microbiomes of normal individuals and individuals with keratitis using next-generation sequencing (NGS) as a foundation tool. The acquired knowledge would help to unravel and understand ocular health in the context of how gut microbiome changes could alter host–microbiome interactions to mitigate disease.

Using molecular methods we recently recognized a corneal pathogen Pythium insidiosum that was probably lurking around earlier unrecognized. Through our research we have now mastered a simple laboratory method to recognize this organism and the condition is increasingly being diagnosed in our laboratory. Our focus is now on studying the clinico-microbiological profile of patients with Pythium insidiosum keratitis. Resistance to treatment with antifungal drugs has made this condition of special concern to cornea specialists. Active research to address this issue is one of our recent engagements.

After eye surgery, trauma, or injury, there’s a potential that patients may develop nasty infections, either from the bugs that are present on the ocular surface, or from contamination, the environment, or pollution. When these bacteria get into the back of the eye, where the retina lies, they initiate an acute inflammatory response. The inflammation is good, as an early innate response to protect the host, but it must be resolved quickly or it will cause damage to the retina. What we are trying to understand is, what are these pathogens that get into the eye, and what kind of immune response they generate during endophthalmitis? We are also interested in looking at inflammatory mediators, like cytokines, as well as anti-inflammatory molecules. Our research programme provides insights and publications in the areas of ophthalmology, microbiology and immunology.

Please elaborate on this Vision Chip that the institute had been involved in developing?

Dr Savitri Sharma, Director of Laboratory Services of LVPEI network hospitals, was involved in the development of the Vision Chip (XCyton DNA chip) for the molecular diagnosis of various eye infections under a grant from CSIR (New Millennium Indian Technology Leadership Initiative or NMITLI) and a patent applicant for the same. XCyton DNA chip is a diagnostic product of collaborative research of four ophthalmic centres viz Vision Research Foundation, Chennai; L V Prasad Eye institute, Hyderabad; Dr Rajendra Prasad Centre for Ophthalmic Sciences, AIIMS, New Delhi; Centre for Cell & Molecular Biology, Hyderabad; and industrial partner, XCyton Diagnostics Ltd, Bangalore.

At present, the widely used method for detecting the infecting organisms is microbial culture. However, this process is time-consuming and the results are not immediately available to clinicians for making treatment decisions. Scientists have exploited the fact that by deploying the PCR (Polymerase Chain Reaction) method it is possible to detect the unique regions on a pathogen’s DNA, which can then be used as a signature as PCR based methods are more sensitive and rapid. The DNA chip method combines multiplex PCR with DNA hybridisation and aids in the diagnosis of several ocular clinical conditions. The advantages of the vision chip are that a single chip can detect probable infectious organisms and detection is done by naked eye. Though this is PCR-based technique, a trained medical laboratory technician can perform the test with ease. Even laboratories at the district level hospital can introduce this test. Our institute has specifically highlighted its use in the diagnosis of a previously unknown aetiology for infectious uveitis.

What is your take on the prevention of avoidable blindness in India? Is Vision2020 working? How would you explain the state of community ophthalmology in India?

We are one of the fastest growing economies in the world today; ironically, we also shoulder one of the largest populations of the visually impaired. The reasons behind avoidable blindness run deeper than the eye diseases that cause them, from socio-economic conditions to the availability of health and eye care services. In rural communities with better economy, improved nutrition, and sanitation, corneal scarring is less of a problem, with cataract being the major cause. In populations with good healthcare cataract is not a major cause of blindness, although significant numbers of people have visual impairment from untreated cataract, and age-related macular degeneration, glaucoma and diabetic retinopathy are the major reasons.

Vision 2020 envisages collaboration between governments, the World Health Organisation (WHO), the International Agency for the Prevention of Blindness (IAPB), funding agencies, international and private non-governmental organisations (NGOs) that collaborate with the WHO in the prevention and control of blindness. Vision 2020 has identified certain conditions, which require immediate attention in India; these include cataract, childhood blindness, refractive errors, corneal blindness, diabetic retinopathy and glaucoma. They work to ensure that people who are visually impaired or blind have access to preventive, curative and rehabilitative services without financial hardship. With a strong national standing, operational presence in several states and alignment with national issues, Vision 2020 in India is transitioning from a regional structure to a unified national organisation. It has brought increased public awareness, professional and political commitment to the prevention of blindness. This is also evident from recent figures that indicate there has been a genuine improvement in eye care resulting in less blindness from avoidable causes. However, there is still much to be done not only in treating these disease conditions, but also to mobilise human and financial resources to implement Vision 2020 at the rural and community level.

Community ophthalmology is traditional individual patient-based clinical practice of ophthalmology to the assessment and facilitation of good eye health in the population as a whole. India being a signatory to global call of Vision 2020: The Right to Sight Initiative, the government is working towards making society free from all causes of avoidable blindness by the year 2020. Some of the challenges are lack of local leadership, inadequate coordination between departments, poor communication, incomplete or under reporting and pro-active community interventions. Nevertheless, we have been making and consolidating gains and expanding in difficult to reach areas and long-term and sustainable impact will be evident in times to come.

About eye donation and corneal transplants, what do you think is the level of awareness about this in India?

While there is no doubt that the rate of eye donations has picked up recently, the myths associated with eye donation is still holding back many from contributing to the cause. On an average, our country needs 200,000 corneas in a year, and only 44,806 are collected. Out of these, only about 40-45% are utilized for sight restoration, as the others do not meet the standards for transplantation. As a result, the patient line-up and wait to get a corneal transplant keeps getting longer with each passing day. Furthermore, the cost of cornea transplant in addition to unavailability for corneas makes it practically impossible for underprivileged people to access these medical remedies. Therefore, creating awareness amongst the masses and encouraging them to pledge their eyes for donation is critical. Voluntary eye donation is a result of the realization of one’s social responsibility towards the corneal blind. Many times, though families are aware about the pledge, grief would give them little time to think about the donation. In such time, eye donation counsellors step in to speak to the family and motivate them. While this has been successful in Tamil Nadu, Andhra Pradesh and Gujarat etc, there are few states in India where there is no active eye donation programme and cornea collection figures are very poor. The eye donation awareness and cornea retrieval programmes still have a long way to go.

You work mainly on corneal infections, but what do you think is the possibilities of advanced technologies like stem cell transplantation, bionic eye and other such innovations in helping reduce the other causes of blindness in our country?

While 80% of visual impairment can be prevented or cured, there remain 20% of the cases for which there is currently no cure. Thanks to medical advances and expanding treatment, it’s no longer just a dream, Scientists are trying to restore vision in a number of exciting ways. Gene therapy focuses on correcting the biochemical abnormalities that lead to the death of retina cells in patients with Age-related Macular Degeneration (AMD). This approach is highly specific and probably several hundred treatments would need to be developed in order to treat the full range of retinal degenerative diseases.

Comparatively, the stem cells are considered to be the fourth pillar of healthcare and have immense potential for treatment of currently incurable conditions like diabetes, Parkinson’s disease, and a variety of degenerations. Our scientists at the Sudhakar and Sreekanth Ravi Stem Cell Biology Laboratory have been exploring the feasibility of applying cell-based therapy for the treatment of various ocular disorders affecting the corneal and retinal tissues. While the usefulness of cultured limbal epithelial transplantation (CLET) for the treatment of over 800 patients with limbal stem cell deficiency (LSCD) has been demonstrated for over two decades, more recently our clinician scientists, Dr Virender Singh Sangwan and Dr Sayan Basu have innovated an alternative simple limbal epithelial transplantation (SLET) procedure wherein a small piece of healthy limbal tissue is harvested from the normal eye of a patient, cut to smaller pieces and transplanted onto the affected eye in a single surgical procedure thus eliminating the need for a tissue culture lab.

The discovery of multi-potent stem cells in the corneal stroma has opened up the possibility of developing a stem cell-based approach for treating corneal stromal scars, as an alternative to corneal transplants. In a murine model of corneal opacity, human stromal stem cells were found to be effective in remodelling stromal scars, and our scientists (Dr Sayan Basu and Dr Vivek Singh’s group) have already started testing the usefulness of this technique in an investigator-initiated, pilot clinical trial. However, unlike cornea, the adult retinal tissues do not have stem cells for regeneration. Therefore, to address the problems of retinal degenerative diseases, Dr Indumathi Mariappan’s group has been exploring the applications of human embryonic stem cells (hESCs) and induced pluripotent stem cells (iPSCs) as alternative sources of stem cells for generating retinal tissues. Towards this effort, the group has established the technique of converting skin cells into iPSCs and also worked out protocols for differentiating these stem cells into mature retinal pigmented epithelial (RPE) cell sheets and complex retinal tissue organoids. The group has injected pure cultures of iPSC derived RPE cells in immune compromised mice models and confirmed that these cells are safe and do not induce any undesirable tumours. To test if these cells can help either in delaying disease progression or in recovering the lost visual function, the group is now planning to conduct sub-retinal transplantation studies in dystrophic rat models and the research is ongoing.

Another set of people who had lost virtually all of their sight due to a rare, incurable genetic disease called retinitis pigmentosa have been able to see again for the first time in years with the Argus II “bionic eye.” Their restored vision isn’t much like what we’d consider normal, but they can see edges and outlines of figures they couldn’t before, which significantly improves their quality of life. The Argus II is a rough replacement for lost photoreceptors. It translates video images from a camera into electrical signals, which it then feeds to electrodes on a chip that’s been surgically implanted on a patient’s retina. That chip stimulates nerve cells that connect to the part of the brain that interprets visual information, just as healthy photoreceptors would.

In addition, research is also on to replace human cornea by artificial corneas for transplantation but immune related issues remain. Such barriers—and similar ones affecting stem cells and bionic implants—won’t fall overnight. Most gains will be hard-won and incremental. Right now it’s unsteady—but strong enough to support our weight if we move carefully in our quest to end untreatable blindness.

There are technologies which involve using a contact lens to sense and monitor the blood glucose levels and such similar entities. While holistically they would help the body what do you think will be the adverse effects of such lens on the eye itself? Will it cause more infections?

The smart contact lens is one of the most anticipated medical technologies this year. While it will look like a regular contact lens, it comes with a sensor that can track the blood sugar level of the user non-invasively through their tears and correct vision in a new innovative way. Users put it on in the morning, take it off at night, and clean it just like a normal contact lens. I believe that the risk of infection would be similar to normal daily wear contact lenses and would be linked to the care of the lens. Chances of infection are likely to increase with overnight lens wear and improper care. In general, diabetics are more prone to infection; however, the question of them causing more infections remains unanswered. Maybe scientists could perfect their work towards instilling the lenses with antimicrobials, giving contacts yet another new role — miniature germ fighters.

It’s been a common practice to use contact lens for cosmetic purposes. It’s also a well-known fact that frequent handling of the eye results in the possibility of infections. As an ocular microbiologist, what’s your opinion on this?

Our tears are anti-bacterial in nature and blinking helps to wash off bacterial organisms or any foreign bodies from the surface of the eye. However, when you wear contact lenses, the effectiveness of both these functions is compromised. Thus, bacteria, fungus and parasite can bind to the surface of the contact lens that sits against the eye. If those organisms infect the corneal surface they can destroy the delicate corneal cells, which can lead to infection and vision loss. To make matters worse is the influx of cosmetic lenses, which are sold everywhere, legally or illegally. These lenses carry the same or even higher set of risks than a typical contact lens, as people tend to handle them carelessly.

Poor methods of usage include sharing the lenses, wearing ones that are either too big or hard and some even may dye their own cosmetic lenses. Negligence in the manufacturing process, careless handling, inadequate disinfection, prolonged overnight wear etc are potential predisposing factors for developing eye infections and may lead to irreversible blindness.

What’s your take on the current scenario for medical research in India? How conducive or challenging it is for medical researchers?

An interesting question but difficult to answer. India has a huge potential for medical research and is considered as a preferred site by the Indian and international pharmaceutical companies for the conduct of global clinical trials. India also offers qualified, skilled and experienced doctors and healthcare professionals; large treatment naïve population, high enrolment rates, cost efficient trial conduct and diverse patient pool. In addition, the research guidelines and regulations are in harmony with the international guidelines. The misconception of Indian population being used as guinea pigs, unethical research practices, concerns around compromises with the participant rights and safety is the lack of awareness about clinical research among the masses.

People need to be informed that clinical research is medical research involving human subjects which aims to understand causes, development and effects of diseases and is vital in the reduction of mortality and morbidity rates, improved quality of life, increased life expectancy, advancements and breakthrough in the field of diagnostics, therapeutics and preventive medicine. The sense of doing social good would invite more participation. People should know that as a participant they are not deprived of the standard of care, if available but the new interventions are prescribed in conjunction with the best available medical standard of care in most of the trials. Also, they can refuse participation and can withdraw from the study any time with no effect on their usual medical care, if participated. Being acquainted with the facts like respect for privacy and confidentiality of the records and participant identity, medical management and compensation in case of related injury or death, right to raise medical concerns to the investigator and concerns regarding participation to the ethics committee hold paramount importance.

Government and regulatory bodies are acting jointly to make stringent regulations for clinical research activities to safeguard the rights and health of the public. Once the grey areas and contentious issues are addressed, the clinical research in our country will quickly scale up in a much safer, regulated and enabling environment. The scientific community is extremely thankful to those volunteers who participate in trials, through them they are learning more all the time about how to deal with a whole range of medical conditions – and make some real breakthroughs that will affect thousands of lives.

What’s your message for budding medical researchers in India?

As India is one of the fastest growing economies in the world, the global health sector industry is finding huge market in the Indian population. Better clinical trials conducted in India on Indian population can yield useful data pertinent to the country and will find application towards enhanced medical care and better health promotion. Medical research in collaboration with biomedical engineering will revolutionize various aspects of medical care, ranging from automated diagnostics, computer modelling of drug molecules and imaging technologies to minimal access and robotic surgeries. There are tons of data yet to be pulled out and a lot to be learnt. In addition, the country has long battled infectious diseases such as tuberculosis, malaria and dengue, but is now facing rising numbers of non-communicable illnesses, including diabetes and coronary heart disease. This puts further demand on applied research for developing new drugs, tests, imaging techniques, surgical modalities etc, especially because the increasing population burden and longer lifespan have generated novel health issues that were not so critical even a few decades ago. We need to initiate and establish a more stable and interactive dialogue between the clinical and basic scientists and also involve technological experts in translating basic bio-medical research into real applications. Medical research in general is in an exciting place. Technology is moving so fast, our understanding is moving so fast that I think the future holds a great promise.

by Usha Nandini

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