How would you explain your paper’s key results to the non-scientific community?
Our research published in EMBO reports explains the molecular basis of side effects caused by drugs, targeting a special type of receptor called G protein coupled receptors (GPCRs). Almost 40% of current drugs target these GPCRs for treating several clinical conditions. Therefore, the study has enormous implications in designing the next generation of safer drugs having very minimal side effects.
GPCRs are membrane proteins that act as a mailbox that receives several messages in the form of hormones or drugs and relays the information from the external environment to the cell machinery for a response in a coded massaging system inside the cell, which we call as signaling (Figure 1). GPCRs have two main partners who serve as a pivotal point for disbursing the signal viz. G proteins and beta-arrestins. GPCRs, upon receiving signal/massage undergo a modification called phosphorylation i.e., the addition of phosphate group on Serine and Threonine amino acids present in their terminal tail. This phosphorylation serves to act as a code that beta-arrestins recognizes and binds the receptor and initiates signaling in the cells.
Figure 1: GPCR behaves like a mailbox that receives messages from outside the cell and relays them to cell machinery by signaling.
Typically, GPCR signaling involves ERK1/2 MAP kinase proteins, which play an essential role in cellular growth and proliferation. For most of the GPCRs, lowering the level of beta-arrestins typically reduces ERK1/2 activation, but for some GPCRs, it leads to an enhancement. This phenomenon of opposing contribution of beta-arrestin in different receptors was inexplicable with our current understanding. It was quite a puzzling mystery in the field for more than two decades.
In this study, we took two such GPCRs vasopressin 2 receptor and bradykinin 2 receptor which is known to have an opposing effect in ERK activation upon beta-arrestin depletion. To unclutter this puzzle, we designed a smart and simple experimental approach whereby we changed the arrangement of the code i.e. position of Serine and Threonine amino acids in the tail of the human bradykinin receptor, a GPCR that is involved in cardiovascular regulation and pain sensation. By even a slight rearrangement of the code in bradykinin receptor C tail, we observed a dramatic alteration in the inhibitory contribution of beta-arrestin 1 in ERK1/2 activation to a more supportive role. We further discovered that such a change in the receptor C tail code does not affect the overall physical binding of beta-arrestin 1 to the bradykinin receptor but it rather changes its conformation (i.e. overall shape of beta-arrestin 1), which in turn determines beta-arrestin’s ability to support ERK1/2 activation in the cells (Figure 2).
Figure 2: Conformation of beta-arrestin (βarr) in vasopressin 2 receptor stimulates ERK signaling but a different beta-arrestin conformation in bradykinin 2 receptor is inhibitory to ERK activation but when Bradykinin 2 receptor mutant with a changed code, made similar to vasopressin 2 receptor now induce a conformation in beta-arrestin which again becomes supportive of ERK activation.
What are the possible consequences of these findings for your research area?
More than one third of all marketed medicines target the GPCRs to treat a wide variety of ailments. Understanding the details of GPCR signaling and regulation has critical implications for making smarter medicines with a minimized side-effect. Therefore, our findings now provide a previously missing piece of information about how conformation (overall shape) of beta-arrestins can control GPCR signaling, and therefore, have the potential to contribute towards improving GPCR targeting medicines in the future.
“[…] a paradigm-changing contribution to the field to understand beta-arrestin plasticity and related functions better.”
What was the exciting moment (eureka moment) during your research?
Conformation drives specific functions of beta-arrestin 1, which is a big finding of the study. Our preliminary study showed that beta-arrestin 1 exists in distinct conformation in different GPCRs first established in vasopressin and bradykinin receptor systems. It turned out to be a ‘Rosetta stone’ to decrypt this opposing beta-arrestin function in the other receptors. This is a paradigm-changing contribution to the field to understand beta-arrestin plasticity and related functions better. I feel this was the inflection point in the whole study, which made us so upbeat to follow this up to its logical conclusion.
What do you hope to do next?
Our next big aim is to identify the conformations of beta-arrestin, which favors biased signaling focused more towards the GPCR-beta-arrestin axis in different GPCRs, which will help us generate next-generation drugs with much lesser side effects in many more GPCRs. Our focus will be more towards those GPCR whose alternation is known to cause critical diseases in humans.
Where do you seek scientific inspiration?
Getting a new piece of data that crystallizes my hypothesis (in many cases opposing it) is a treat of delight, and this unsettles me (in the right sense, of course) and gives me the drive to chase it for months to come. Finally, when peers appreciate these discoveries makes me feel I am moving in the right direction.
How do you intend to help Indian science improve?
I am not sure how I can improve Indian science, but I want to enhance or intend to improve the pharmaco-profile in the context of side effects caused by current GPCR drugs. By understanding the finer details of the beta-arrestin signaling paradigm, we can design much safer drugs with lesser side effects, which will bring relief to patients undergoing treatments with GPCR drugs. GPCR research has not picked up in India the way it should have been, especially keeping in mind India’s massive production output in global pharmaceutical manufacturing. This is quite a paradox really, and can be explained by the fact India does not discover or identify new GPCR drugs but rather produce the generic ones for foreign labels. This has to improve and can only be done by a higher focus in GPCR research in academia and the pharma industry. Let’s hope we only improve in the coming years.
Department: Biosimilars-Microbial MSAT (Upstream) Experience: 8+ years Qualification: BTech/ MTech- Chemical /Biochemical Engg
1. Experience in Process Engineering, Scale up fermentation and scientific Knowledge on microbial cell culture processes and controls 2.To manage MSAT Lab functions on routine basis for upstream related activities. 3. To ensure product life cycle management. 4. To handle continuous verification of process, deviation and out of specifications. 5. Contribute at team discussions of CMC and other decision-making forums for development, clinical and commercial manufacturing. 6. Review Technology transfer of manufacturing process to CMOS (outside parent site).
Zyla Health is looking for self-driven people with startup DNA who want to take up an entrepreneurial role at a rapidly-growing, high-impact startup. We are hiring immediately across teams.
Product/ TPM (3-5 yrs)
Performance marketing (2-4 yrs)
Strategic initiatives (3-7 yrs)
Engineering – Backend/ Full stack/ Devops (4-7 yrs)
Requesting interested folks/ referrals to share their CVs at firstname.lastname@example.org with subject line – [Role applying for from above][Current city][Years of experience]. We will reach out asap if we have an interesting role for you!
Deal Advisory is filling for strategy team. Strategy Group within Deal Advisory is looking for an Associate Consultant/ Consultant, with 2—5 years of experience in Pharma. Applicants should have a Master’s degree or equivalent, and proficiency in delivering sectoral strategy and research assignments. If you are interested, or would like to refer someone, please write to Varun Dabral (email@example.com).
Project Assistant (code PA-B: Positions 2): Essential Qualifications: M.Sc/M.Tech (Biochemistry/Biology/Biotechnology/Molecular biology/Microbiology or similar disciplines). Experience in Biosensors/Molecular recognition would be an advantage. Desirable is at least 1+ year experience in similar area.
Project Assistant (code PA-C: Positions 1): Essential Qualifications- M.Sc/M.Tech (Chemistry/Nanotechnology/Bioengineering or similar disciplines). Experience in Biosensors/Molecular recognition would be an advantage. Desirable is at least 1+ year experience in similar area.
We gained exponential growth in technology over the past few decades, but the field of drug discovery has remained relatively stagnant. There is a need for re-inventing the drug discovery process with disruptive innovations. The term “disruptive innovation” first coined by Clayton M. Christensen in 1995, describes the innovations that significantly affect the way a market or industry functions and changes the dynamics of the competitive market. These innovations are imperative to bring new players to the competition captured by big companies reluctant to innovate and few of these players successfully create their niche eventually creeping their way upmarket to topple the incumbent.
Focusing on biomolecular condensates as a druggable target is one such disruptive advancement which re-ignited the curiosity in drug discovery. Recently, drug-discovery particularly in the field of neurodegenerative diseases hit numerous roadblocks. Big pharma companies halted their ongoing drug discovery programs after successive disappointments to discover any lead molecule targeting amyloid plaques implicated in neurodegenerative diseases. The emergence of biomolecular condensates field changed the way we approach amyloid disease treatment.
Biomolecular condensates are membraneless organelles enriched in proteins and nucleic acids. These are involved in the diverse cellular processes and also implicated in diseases. Even though Prof. Edmund Beecher Wilson first mentioned liquid-like organelles in 1899, it took more than a century to clarify the concept of liquid-liquid phase separation (LLPS) as a fundamental physicochemical mechanism for cytoplasm organization described in Science paper (2009) by the lab of Prof. Anthony Hyman. This landmark discovery leads to the emergence of the biomolecular condensate field which is now explored by hundreds of labs across the world. Driven by multivalent interactions, these biomolecular condensates or phase-separated membraneless organelles play a critical role in regulating diverse cellular processes. a growing body of research suggests that these condensates are not only important for normal cellular homeostasis but implicated in complex conditions like neurodegenerative diseases, viral infection, and cancer. This opened up the new avenue for the drug discovery for targets considered as undruggable. With huge potential to identify entirely novel targets and unexplored ways to modulate these targets hidden within condensates brought new excitement to the field. With many pharma companies on the verge of closing their ongoing drug discovery programs especially for neurodegenerative diseases, the emergence of biomolecular condensate field is a breather much needed at this time than ever. With the intent to disrupt these condensates now considered as hot spots, many pharma companies jumped into the race without taking risks directly.
Currently, two startups Aquinnah Pharmaceuticals and Dewpoint Therapeutics are leading the drug discovery race for targeting biomolecular condensates. Aquinnah pharmaceuticals was founded in 2014 by Dr. Glenn Larsen and Prof. Ben Wolozina. Company rely on their discovery of the connection between stress granules and neurodegenerative disease. It received funding from Takeda Pharmaceuticals, Pfizer, Abbvie and grants from National Institute of Neurological Disorders and Stroke (NINDS) and The Tau Pipeline Enabling Program (T-PEP) for developing new therapies for Amyotrophic lateral sclerosis (ALS) and Alzheimer’s disease (AD). Despite early start, Aquinnah failed to impress investors over the past six years and probably missed to achieve milestones. With small funding at their dispel, the company struggled to push any molecule to clinical trials and no official updates on current status from the company since January 2019.
Another startup Dewpoint Therapeutics founded in 2018 by Prof. Richard Young and Prof. Anthony Hyman is making inroads at a faster pace. With already two big deals with Bayer and Merck for different modalities encompassing cardiovascular, gynecology and viral diseases apart from an exciting future portfolio including neurodegeneration, cancer, inflammation, infectious disease, metabolic disease and rare genetic disorders. With a growing team of scientists based in Boston and Dresden and good financial support, Dewpoint is setting up an example by “translating the condensate biology into much-needed medicines”.
With ample opportunities available for drug discovery, over time, the usefulness of targeting biomolecular condensates will be undermined. As we know that not every disruptive path leads to a triumph, it will be interesting to see whether this emerging curiosity in targeting biomolecular condensates will sustain and prove to be a disruptive innovation.
The idea for the setup of this center dates back to 2018 when the first edition of summer immersion program (Media coverage: Times of India and VoxPopuli) was started by Faculty In-Charge Prof. Amitabha Bandyopadhyay (IIT Kanpur) and Dean of innovation & Cardiologist Prof. Rishi Sethi (KGMU). The first part of this program involved seven IIT Kanpur students (engineers and PhDs) who stayed at KGMU and under the supervision of Prof. Rishi Sethi interacted with doctors from different specialties. Different ideas were discussed and few ideas were selected to pursue further at IIT Kanpur. Two week stay also involved Hackathon where the team of doctors and engineers together presented solutions to medical problems to the audience consists of doctors from KGMU and professors from IIT Kanpur. With further discussion and deliberation on selected ideas at IIT Kanpur, two ideas were selected for design and product development. Products were shown at Abhivyakti IITK 2019.
One product is “Electrosurgical Cautery with Suction Inbuilt” designed to prevent doctors & patients from carcinogenic & mutagenic effects of surgical smoke, produced during surgeries. It has been granted Design Registration No. 320342-001.
This set-up the blueprint for a future edition of the program which is now officially announced as part of SIB-SHINE center. The program shares similarity with Stanford-India Biodesign program launched in 2007 as a collaboration between Stanford University, the All India Institute of Medical Sciences (AIIMS), and the Indian Institute of Technology (IIT) Delhi. With many success stories this school transitioned to School of International Biodesign (SIB) based at AIIMS/IIT Delhi in the year 2014 with support from DBT and Ministry of Science and Technology (Government of India) in collaboration with QUT Australia and Hiroshima University, Japan.
Considering the growing need for similar program to tap the unmet needs of the healthcare sector and recent success stories from IITK incubation center, SIB-SHINE centre will take innovation to the next level. With ample indigenous resources available, this center will provide a unique one-year fellowship to doctors and engineers. Fellows will stay at KGMU to understand the issues faced by clinicians daily and to design and develop solutions for identified problems at IIT Kanpur. Institute now harbors Medical Device Rapid testing facility & EMI/EMC testing facility, funded by BIRAC and newly established Centre for Engineering in Medicine, funded by Mehta Family Foundation to support prototype/product development. The product development process will be accelerated by testing by devices in the clinical setup at KGMU which will help in better quality product development before clinical trials. SIB-SHINE centre is the right stepping stone at the right time when India needs more efforts for “Make in India” and “Make for India“. Looking forward to hearing numerous success stories from this center.
Biological condensates or bio-condensates or protein droplets are membrane-less organelles formed as a result of proteins liquid liquid phase separation or demixing. It is important phenomenon which was recently discovered and now not only considered important for normal biological functions but also linked to pathological conditions like neurodegenerative diseases and cancer. Considering importance of this natural phenomenon, I have compiled list of sources providing video/movie of formation of biological condensates or describing this phenomenon in detail.
Three video lecture series by Prof. Cliff Brangwynne gives glimpse of protein liquid phase separation process. Lectures are also available on iBiology and Youtube.
P-bodies and the mRNA Cycle: This YouTube video by Prof. Roy Parker (University of Colorado, Boulder) is second part of lecture series “The Life of Eukaryotic mRNA: Localization, Translation, and Degradation” on iBology provide an overview of why the regulation of translation and mRNA degradation is an important aspect of the control of gene expression in eukaryotic cells and how P-bodies and stress granules play role to achieve this.