“Humans are not 70 kg rats,” remarked Thomas Hartung, Director, Centre for Alternatives to Animal Testing, John Hopkins University, USA, while describing the differences in the biology of widely used laboratory animal models and humans.
Humans share a high degree of genetic similarity with various animals. Hence, the usual paradigm to understand the effect of a chemical or a drug on humans involves testing them on specific animal species (such as rats and mice) and subsequently extrapolating the potential effects to humans.
However, scientists have increasingly observed that subtle genetic differences between animals and humans may contribute to pronounced differences in severity and features of human diseases. For example, in humans, similar groups of genes are employed in inflammation and stress response. In contrast, in mice, distinct sets of genes are involved in fighting different types of stress. Also, mice can be more resilient to inflammation compared to humans. For example, 30 nanograms/kg of endotoxin (a toxic compound usually found in the cell wall of gut bacteria) turns lethal in humans. In contrast, mice can tolerate almost a 1000 times higher concentration of the chemical.
Also, animals metabolise drugs differently from humans, leading to species-specific differences in how drugs are absorbed, distributed, metabolised, and transported.
Challenges associated with a data-rich era
The past decade has seen a rise in the development of miniature 3D tissues and organs-on-chips. These are miniature model systems that capture elements of human biology and are built using human cells that aim to mimic human organs. Also, new-age medical imaging and tracking tools are helping to visualise biochemical, molecular, and cellular changes occurring in the human body. These tools generate a vast amount of organism-level biological information. However, there is a need to connect such data and create a complete picture of how disease manifests and affects the human body.
A global resource that collects and organises such biological information is the Adverse Outcome Pathway (AOP). This platform is an open and crowdsourced framework promoted by the Organisation for Economic Co-operation and Development (OECD). Akin to a jigsaw puzzle, the AOP framework helps to piece together toxic effects of biological/chemical agents observed at various levels (e.g., molecular, cellular, or organ-level) to understand such effects at an organismal level. The information can be curated and organised further to build robust models for predicting human biological events.
Call for a national strategy
The Centre for Predictive Human Model Systems (CPHMS), Atal Incubation Centre-Centre for Cellular and Molecular Biology (AIC-CCMB), Hyderabad, along with the Humane Society International India, recently conducted a virtual event to discuss the advancement of human-relevant model systems and related frameworks to integrate such data in India.
The discussion initiated a dialogue between various stakeholders from academia, industry, and private funding bodies to address the challenges and promote emerging technologies that would make biomedical research more relevant to human biology in India.
The discussion’s focus was on advancements in three areas: new model systems based on human biology, crowdsourced databases that can integrate existing information, and computational systems that can use this organised information to develop predictive models of human diseases. While several research labs and start-ups in India have started working in these areas in the last five years, much research still occurs in silos. There is a lack of multidisciplinary cross-talk, which is essential for developing this area and bringing research closer to understanding human biology.
Rakesh Mishra, Director, CSIR-CCMB, Hyderabad, said “Innovative technologies based on human biology are no longer aspirational goals for a distant future but ready for implementation in India today.” He adds that advanced cell-culture methods and improved genomic understanding can lead to more precise drug discovery programs and better outcomes.
Promoting open access knowledge-integrative structures
With the advancement in ‘omics technology’ (a collective term for comprehensive analysis of cellular components such as molecules, metabolites, or genes), big data, and high-content imaging there is an explosion of collected data. There is a need for parallel development of frameworks and databases that can organise and collate this enormous amount of information.
The MANAV Human Atlas Project, a crowdsourced citizen science project launched by the Department of Biotechnology (DBT), is based on a similar idea to collate all available macro to micro-level information from life science literature and public databases to map how changes at the molecular level affect organs and the human body.
C. Ramachandran, Senior Principal Scientist at CSIR- Institute of Genomics and Integrative Biology (IGIB), suggested that data collation and integration should also be acceptable formats for publication in journals, which can serve as positive incentives for upcoming researchers. Indira Ghosh, Retired Professor, Jawaharlal Nehru University (JNU), New Delhi, and Shandar Ahmad, Professor, JNU, highlighted the need for context-based searching algorithms, guidelines on collecting and curating biological data for integration, and inter-institutional data managers who could collect, standardise, and classify the data.
Developing tools and technologies in India
Karishma Kaushik, Assistant Professor, Institute of Bioinformatics and Biotechnology, Savitribai Phule Pune University, and Indumathi Mariappan, Research Scientist, L V Prasad Eye Institute, Hyderabad, commented that establishing central facilities for manufacturing tools and instruments for creating organs-on-chip can reduce the dependence on international vendors and reduce the time and cost for Indian scientists. According to Jugnu Jain, Co-Founder and CEO, Sapien Biosciences, Hyderabad, “Leveraging India’s computational science and bioinformatics strength can help create a theoretical backbone for experimental results.”
Several panellists at the virtual discussion agreed that developing proof-of-concept and validating these emerging technologies are essential for acceptance by the regulatory bodies and the industry. V Radha, Emeritus Scientist, CSIR-CCMB and Ponnari Gottipati, Consultant — Grant Manager, LV Prasad Eye Institute, Hyderabad, suggested that dedicated centres of excellence, as established by the USA, the European Union, Canada, Japan, Korea, and Brazil, could provide the necessary infrastructure along with aiding collaborative science.
While there is a rise in the regulatory and funding initiatives worldwide to develop and validate these technologies, it is still a nascent field in India. Besides, new technologies are often viewed as risky investments, bringing down the private funding in these areas. Shirshendu Mukherjee, Mission Director, Program Management Unit (DBT- BIRAC-BMGF-Wellcome Trust), suggested an alternative to help reduce investor risks: a co-funding model that involves joint investments by the government, pharma companies, philanthropic bodies, and venture funds.
In his note, N Madhusudhana Rao, CEO, AIC-CCMB, remarked, “Sufficient traction for such emerging and human-relevant methodologies exists in India; however, the current activities remain highly fragmented and on a small-scale.”
As a way forward, in 2019, the Indian Council for Medical Research (ICMR) published a perspective paper and a roadmap on the need to promote alternatives to animal research in India.
On an ending note, the speakers collectively hoped that proposals that emerged from the initiatives by ICMR and this roundtable discussion could lead to actionable outcomes to bring biomedical research in India closer to human biology. These proposals include establishing centres of excellence and centralised facilities for tool development, including end-users and regulatory bodies in the technology development process, encouraging collaborative funding mechanisms, and promoting training and awareness amongst the student community.