This is the second time we are asking questions from an expert on COVID-19 pandemic, the first one was Prof. Guntaka Ramareddy, the discoverer of Hep B genome and its recombinant vaccine in India. In this interview with Dr Ram we are trying to know how he sees the biological pandemic like COVID-19 when he is currently working in Stockholm, Sweden.
Dr Ram Shankar Upadhayaya has 20+ years of experience of R&D in academia and industry in the field of Medicinal chemistry and Molecular Oncology. He has served Ranbaxy Research Ltd., Delhi, India, Lupin Ltd., Institute of Molecular Medicine, Delhi; TCG Lifesciences Pvt. Ltd.; Bioorganic Chemistry Department, Institute of Cell and Molecular Biology, Uppsala University, Sweden; Max Planck Institute (MPI), Berlin Germany.; Medical Research Council (MRC), London.; Head, Medicinal Chemistry at Bioimics AB, Uppsala, Sweden.
Dr. Ram is CEO of Laxai Life Sciences which is a flagship Contract Research Organisation based in Hyderabad, India. Dr. Ram is providing leadership and scientific expertise to global drug discovery research (Oncology, immunoncology and inflammation) within paradigm of Contract Research Organizations.
Dr. Ram is a veteran scientist who has been involved in development programmes for various novel drugs and has been instrumental in various drug development of clinical candidates in the field of infectious diseases (anti-viral and anti-bacterial) and Oncology candidates.
About Laxai, for last decade Laxai has been instrumental in driving various new drug development programmes for Indian & Foreign Pharmaceutical and Biotech Industry. Dr. Ram himself who was Chief Scientist in Laxai before he took the responsibility as CEO, has played key roles in various such programmes and has also been responsible for forging strategic partnerships between Laxai & Council of Scientific & Industrial Research (CSIR), Govt. of India. The partnership aims to accelerate the development of solutions for diseases of national interest such as COVID-19. As per Dr. Ram, this partnership will allow to bring expertise, experience & knowledge from the best of both worlds, creating an effective synergy which will lead us to effective & safe treatment for diseases such as COVID-19.
We would like to thank Dr. Ram for taking time for this discussion with us wherein we will take few perspectives from Dr. Ram, considering his viewpoint as a scientist and his suggestions on various aspects ofCOVID19 pandemic, treatment and what should be the future directions for our scientific community in India.
1. How did you become interested in COVID-19 research?
A pathogen is usually associated with a medical crisis. COVID-19 has disrupted the basic social nature of human life worldwide. Economies have gone for a tailspin, unprecedented rise in unemployment and above all the fear psychosis has ruined our normal life. As a scientist it is my duty to seek a solution or at least make a sincere effort to find a strategy to tackle this virus…!
2. Given the complexity of COVID-19 infection what are the post recovery complications?
One of the most intriguing observation is post-recovery organ damage in COVID-19 patients with severe disease presentation. Although lung damage is the most common reported occurrence post-recovery, yet reports of cardiac and neurological damage are in multitude. In the context of lungs several serious physiological perturbations have been reported. Syncytia formation leading to cellular fusion, alveolar clotting, heme dysregulation and fibrotic deposition are major areas of concern and may be probable reasons for post-recovery damage. Cardiac abnormalities were a disturbing finding from a study of 100 patients recovered from COVID-19 in Germany out of which nearly 66% had recovered at home. More than 75% of these subjects either had structural changes in their heart or had biomarkers relevant to heart attack even after two months post-recovery. Neuro-invasion by SARS-CoV-2 virus is a reason for neuronal complication. Post-recovery neurological abnormalities have also been reported. In a recent study published in Lancet, neurological symptoms were presented in 55% COVID-19 patients studied during a period of 3 months post-recovery. COVID-19 patients had statistically significantly higher bilateral gray matter volumes in olfactory cortices, hippocampi, insulas, left Rolandic operculum, left Heschl’s gyrus and right cingulate gyrus and a general decline of mean, axial and radial diffusivity, accompanied with an increase of the fractional anisotropy in white matter.
Are these damages irreversible and can they be treated? At the molecular level one is left to wonder the mechanisms responsible for such havoc created! The difference between SARS CoV and SARS-CoV2 is delineated at the base-pair level in the context of genomics, both being ~80% similar. But how the differences trigger such dramatic changes in pathogenicity is yet to be elucidated.
In summary, while I try to seek solutions for aiding recovery of patients, yet the post-recovery scenario is also a key area of my interest. The latter needs better and in-depth understanding of the pathophysiology of the disease at the molecular level!
3. What in your opinion are the challenges to tackle COVID-19?
COVID-19 is a recent scourge that has practically affected every part of our life. Though an effective vaccine is the need of the hour, however given the highly mutating nature of the coronavirus an effective long lasting vaccine may be an uphill objective to achieve. Another mutating virus, influenza virus, has made us to come in terms with different vaccines each year; depending on the prediction from WHO. This can also be a reality with COVID-19! There are at least 11 SARS-CoV-2 strains identified globally with six of them identified in India. Hence, the major question is can we have a treatment regime apart from the preventive vaccine regime? This is the third coronavirus attack after SARS and MERS and in all probability will not be the last one! Can we design drugs that can tackle future coronavirus variants? This is a futuristic approach that can spare humanity of another coronaviral crisis!
4. Why do you think drugs/vaccines are essential when the whole world is still waiting for a cure and putting all efforts to get a solution as soon as possible?
Vaccine development is usually a long term affair, though due to the current emergency many rules are being relaxed. A new drug discovery project consumes at least 6-8 years on a fervent pitch and mankind cannot witness the rising death toll silently.
As an alternative why not try existing approved drugs prescribed for other indications against COVID-19? There are a plethora of drugs and based on their molecular properties many have the potential to target COVID-19. There are more than 15 anti-cancer drugs, nearly 4 anti-helminths, nearly a dozen anti-inflammatory therapies that can potentially be harnessed to treat COVID-19 associated complications.
The objectives for both new drug discovery and drug repurposing are same with respect to targets. Either viral or host factors are targeted. Viral factors like RDRP are targets for drugs like Remdesivir and Favipiravir. Targeting host factors largely involve host proteins that facilitate viral entry and replication and contribute to the cytokine storm. Multiple existing drugs are now being tested both to arrest viral replication and control the debilitating ARDS. While drugs like Nafamostat, Umifenovir and HCQ are touted to inhibit viral replication by inhibiting fusion processes, other drugs like colchicine, dexamethasone and budesonide are being harnessed to arrest the cytokine storm and ARDS. On the new drug discovery front the viral mPro has emerged as a plausible target and multiple organisation worldwide are deep into R&D to develop drugs against this target.
As a matter of fact, drug repurposing is the best bet at this time and periodically news of old drugs as effective therapies is popping in. Dexamethasone, Remdesivir, Favipiravir, Tocilizumab and Itolizumab are already approved examples and many more are to follow. Moreover, combinatorial therapies addressing multiple facets of COVID-19 infection is a silver lining in this repurposing era!
5. How your Personal background/upbringing/early education and motivation to pursue research career can help to find the answers of your questions?
I have always been fascinated by the overlap of multi-disciplinary science when it comes to human welfare, health in particular. Being an organic chemist and having done my doctoral study in medicinal chemistry, I developed a profound interest in drug discovery. Its a unique platform where multiple wings of science work in tandem in the true spirit of R&D. I have been associated with and have led multiple successful drug discovery projects in the field of infectious diseases and oncology. This R&D journey of two decades has transformed me to always ask questions and seek the answers which can benefit mankind!
6. What is the role of biotechnology in your job?
In spite of great research, we still don’t have a concrete answer as to why this virus is associated with a vast spectrum of pathobiology. The virus infection in overwhelming numbers results in asymptomatic cases, triggers mild symptoms like anosmia while in some patients, life threatening strokes and ARDS are reported. To decipher this nexus, understanding the viral machinery vis-a-vis the host requires tremendous application of biotechnology. Elucidation of signalling pathways, protein dynamics, epigenetics of regulation require cutting edge biotechnology tools. Better understanding of these processes will translate into effective drugs and vaccines. I believe biotechnology can also be used to analyse any genetic predisposition towards disease severity.
7. Can you tell us Milestones of your research till now and in particular in COVID-19 R&D?
My research work has yielded novel interventions against TB, Leishmaniasis and HIV. Apart from this, my research work has translated into novel molecules targeted against cancer. In recent times my activities in COVID-19 research includes both new drug discovery as well as repurposing. Laxai Life Sciences, whom I presently represent as CEO, has entered into collaboration with CSIR-IICT, Hyderabad to reduce the import dependency for active pharmaceutical ingredients (APIs) and key intermediates.
Apart from this we have collaborated with CSIR, Govt of India to conduct clinical trials of combinatorial therapies against COVID-19. Through your platform, I wish to convey my sincere thank to Dr. Shekhar Mande (DG-CSIR), Dr. Ram Vishwakarma (Ex-director-IIIM, Jammu, Advisor-CSIR) and Dr. Chandrashekar (Director-IICT) for all the support that we have got up until now due to which Laxai has been able to make significant leaps to make both novel and repurposed drugs for COVID-19. It is because of the continuous support received from CSIR that we are now in the clinical phase of testing programme for few of our target molecules for COVID-19 treatment.
8. What aspects of your work do you think could be described as Indian science?
Personally, I believe science should not have any geographical boundaries. Yet scientific research in India is really making impact worldwide! Notwithstanding, a noteworthy aspect of my research has been to minimize foreign dependencies. We have covered a broad spectrum of activities; and conceptualising ideas has been the distinguishing aspect of my research activities. On a translational aspect, developing smarter molecules and making them in India at affordable price has been my top priority.
9. Can you tell us about future goals of your lab?
My lab is dedicated to ‘seek and deliver’ from India. We are chasing a handful of human diseases to develop novel therapies. I strongly believe that right from elucidation of the mechanistic pathways and target selection to a clinical candidate nomination can be done in India. The lab is dedicated towards this mission, collaborations are needed but they will be a truly “IDEATED & MADE IN INDIA” endeavour!
10. Sir, Any message to global Life sciences community and in particular to India?
The world has witnessed how efficiently a 1.3 billion population has stood up against a deadly virus. Despite having limitations in the healthcare facilities to deal with such a large population,the rate in India is one of the lowest globally. India has the top 2 vaccine candidates for the earliest entry (though one is in collaboration with Oxford University). India has the world’s largest vaccine producer churning out 1.5 billion doses annually. Given the depth of our manpower, both intellectually and otherwise, India can be the hub of pharmaceutical research. The right will and the zeal to deliver can make us a world leader in scientific research and development.
