When we fall ill, symptoms often seem to worsen as the sun goes down. The sudden spike in fever or the intensification of a cough during late hours isn't just a trick of the mind; it is a reflection of our immune system’s internal schedule. For a long time, the immune system was viewed as an ‘always-on’ surveillance team. However, we now know that it operates on a strict 24-hour cycle, leading scientists to ask: is our immunity actually ‘reduced’ at night, or is it simply changing its strategy?

Research indicates that the immune system is highly rhythmic. While certain protective barriers might be less active at night, other parts of the immune system are working overtime while we sleep. This rhythmic fluctuation is governed by our circadian clock—the same internal ticker that tells us when to wake and when to rest.

Chrono-immunology in plain language

Across the animal kingdom, biological processes are timed to coincide with the environment. Just as a flower opens during the day to attract pollinators, our immune cells move through the body in predictable waves. This field, known as chrono-immunology, reveals that our ‘defence budget’ is reallocated depending on the time of day.

During the day, when we are active and likely to encounter pathogens through food or social interaction, our immune system focuses on ‘immediate response’ cells in the blood. At night, the strategy shifts. The body moves its resources away from the ‘front lines’ and into the ‘training camps’—the lymph nodes—to process information and build long-term memory.

The ‘night shift’ of T-cells

One striking example of this rhythm involves T-cells, the specialised soldiers of the immune system. Research has shown that during deep sleep, the levels of T-cells in our bloodstream drop significantly. A study published in the Journal of Experimental Medicine found that this isn't because the cells have disappeared, but because they are migrating to the lymph nodes.

This migration is triggered by the drop in ‘stress’ hormones like adrenaline that occurs during sleep. When these hormones are low, T-cells are better able to ‘stick’ to their targets and move into lymphoid organs to memorise the signatures of viruses encountered during the day. Sleep acts as a master regulator that enhances the ‘stickiness’ of these cells, meaning that ‘reduced’ immunity in the blood at night is actually a sign of a highly efficient system moving into a specialised ‘repair and learn’ mode.

Molecular clocks: The BMAL1 regulator

The immune system’s rhythm is hardwired into our DNA. Nearly 8% of the genes in our immune cells fluctuate in activity based on the time of day. A central actor in this genetic play is a protein called BMAL1 (Brain and Muscle ARNT-Like 1).

BMAL1 acts as a master switch that regulates inflammation. In studies involving mice, researchers found that those with a ‘broken’ BMAL1 clock in their immune cells suffered from much more severe inflammation and higher mortality rates when infected with bacteria at night compared to the morning. This suggests that the body uses these molecular clocks to dampen inflammatory responses at specific times to prevent tissue damage. When the clock is disrupted—by shift work or jet lag—this regulation fails, leaving the body vulnerable to its own overactive immune response.

What could this mean for human health?

All of this raises a transformative possibility: ‘Time-of-day’ medicine. If our immunity follows a predictable schedule, we can time our medical interventions to catch the immune system at its most receptive.

There are several promising avenues:

• Vaccine timing: A cluster-randomised trial suggested that flu vaccines administered in the morning produce a significantly higher antibody response than those given in the afternoon, as the immune system is naturally gearing up for the day’s threats.

• Chronotherapy: Understanding when inflammatory pathways peak could allow doctors to prescribe anti-inflammatory drugs at the exact hour they are most needed, maximising efficacy while minimising side effects.

• Shift-work interventions: Recognising that a disrupted clock leads to ‘leaky’ immunity could lead to new light-based therapies or dietary schedules to protect the health of millions of night-shift workers.

The circadian rhythm of our immune system shows that biological timing is just as important as biological strength. Our defences are not simply ‘reduced’ at night; they are refined. By decoding the schedule of our internal ‘night shift’, biotechnology may turn these rhythmic cycles into a powerful tool for preventing and treating human disease.

Philosophy is written in that great book which is the universe, and it cannot be understood unless one first learns the language in which it is written. It is written in the language of mathematics, and its characters are triangles, circles, and other geometric figures”.

— Galileo Galilei

Long before mathematics became a technical discipline, numbers occupied a far deeper place in human thought. Across civilizations and philosophical traditions, numerical order was not merely calculated but contemplated. From Pythagoras’ conviction that numbers underlie harmony and form, to Platonic and Neoplatonic reflections on intelligibility, to theological traditions that discerned in numerical order a trace of divine reason, numbers consistently crossed the boundaries between science, philosophy, and religion.

This vision was later broadened rather than diminished by mathematical developments that moved beyond rigid Euclidean forms. The emergence of fractal geometry, with its recursive patterns and scale-dependent order, along with Fibonacci sequences and the golden ratio in growth processes, challenged purely linear and reductionist accounts of form. These structures suggested that mathematics could describe not only static objects, but processes of dynamic becoming—growth, proportion, and self-organisation.

Yet in modern education and practice, mathematics is often encountered as a lifeless technique: an instrument of calculation rather than a mode of perception. The quiet persistence of constants and patterns across nature, however, continues to invite an older intuition—that number does not merely measure reality, but reveals the intelligible order through which it unfolds.

From the stripes of zebras and the spots of giraffes to the rhythm of the human heart, from planetary orbits to quantum oscillations, disparate natural phenomena are governed by shared mathematical constraints. Wherever space curves or cycles close, the constant π appears—an infinite, non-repeating number whose universality transcends scale and substance.

π is rarely defined, though it is endlessly used. In schools, it is introduced as a convenient constant for calculating areas, volumes, and circumferences, as though it were merely a tool of mensuration. Yet π is not fundamentally about measurement. It is the constant relationship between straightness and curvature—the ratio that emerges whenever linear extension bends into enclosure. Wherever space closes upon itself, π appears.

What makes this constant extraordinary is not only its universality, but its nature: π is irrational, infinite, and non-repeating. It has no final digit, no terminating form, no complete representation. No matter how advanced our computational power becomes, π cannot be exhausted, because it is not a quantity to be completed but a structure that never resolves. Within its endless sequence, every finite pattern is expected to arise—not by design, but by necessity—making π a mathematical object that is at once precise, inexhaustible, and deeply enigmatic.

Once π is understood as a constant governing curvature rather than a mere tool of measurement, its pervasive presence in physics becomes unsurprising. Wherever forces radiate, fields propagate, or symmetry is expressed in space, π emerges naturally within the mathematical form of physical laws—from Newtonian gravitation to electromagnetism, wave mechanics, and quantum field theory. This recurrence does not indicate coincidence, but necessity: physical reality unfolds in curved, continuous space, and π is the invariant ratio that such space demands.

What is more unexpected, however, is that this same constant reappears not only in the abstractions of physics, but in the formation of living forms themselves. When Alan Turing turned his attention to biological morphogenesis, he showed that the emergence of stripes, spots, and spatial patterns in organisms could be described by reaction–diffusion equations whose solutions are constrained by geometry and curvature. In this moment, π crossed a conceptual boundary—from governing the structure of space and force to quietly shaping the visible architecture of life.

When π reappears in biological morphogenesis, it does so not as a numerical curiosity but as a structural constraint that governs how form may arise. In reaction–diffusion systems, pigmentation does not assemble arbitrarily; it stabilises into stripes, spots, and bands whose spacing and closure are constrained by curvature, growth, and enclosure. π does not dictate the pattern, but it tunes the space in which pattern becomes possible. As bodies grow and surfaces curve, global geometry filters local chemical interactions, allowing order to emerge without prescribing sameness. The result is a striking synthesis: species-level regularity alongside individual-level uniqueness. No two organisms share identical patterns, yet none escape the same geometric laws.

π is also woven into biological periodicity. It appears in mathematical descriptions of oscillatory processes such as cell-division timing, cardiac rhythms, respiratory cycles, and circadian clocks governing sleep–wake behaviour. Across scales, from cellular dynamics to organismal physiology, π recurs wherever cyclicity, resonance, and enclosure intersect.

Taken together, the role of π in biological form suggests that life unfolds within a mathematically intelligible order—one that precedes and exceeds blind randomness. This order does not impose rigid outcomes, nor does it require interventionist design. Rather, it renders form possible through lawful constraint, allowing order and individuality to arise together. π thus reveals a world that is not merely calculable, but meaningfully structured: a world in which life arises not by accident alone, but within an intelligible geometry that quietly governs how form comes to be.

The artist who renders visual form from mathematical formulae does not translate mathematics into art so much as reveal what is already latent within it. The equations do not instruct the artist what to draw; they constrain what can appear. In a similar way, biological morphogenesis does not encode π as information, nor does it calculate geometry in any conscious sense. Life instantiates π because it unfolds within continuous, curved space governed by abstract constraint. Yet instantiation itself implies something prior—a field of intelligibility that precedes material expression.

Plato recognised this when he argued that forms are not created but participated in. Augustine echoed the same intuition in a theological register, insisting that numbers are not human inventions but eternal truths. Whether expressed philosophically or theologically, the claim is the same: mathematics is not a language we merely devised to describe the world, but a structure through which the world becomes describable at all.

In this light, nature does not invent mathematical order; it realises abstract potentiality. Biology, like art, gives visible form to an intelligible order that was already there.

The time is 9 AM. People are rushing to their offices, school vans are racing toward their destinations, and pedestrians are waiting impatiently at the zebra crossing for the signal light to turn red. Every individual, though moving with purpose, is subtly influenced by the presence of others – their paths altered, movements constrained, their interactions more frequent. Over time, each entity learns to navigate the intricacies of proximity and interaction within finite space – a scenario strikingly analogous to the microscopic world inside a living cell.

For decades, scientists carried out experiments in pristine lab buffers. But the reality of a cell is entirely different. Within cells, a dense, dynamic environment hosts a myriad of biophysical and biochemical processes simultaneously, including protein-protein interactions, protein folding and unfolding, aggregation, enzyme catalysis, etc.

Such complexity is driven by extremely high concentrations (approximately 400 g/L) of various macromolecules, viz., proteins, nucleic acids, and polysaccharides, which together occupy roughly 30-40% of the cell volume, along with small molecules and ions. This crowded setting restricts available space and offers only a limited portion for carrying out essential biological activities.

To replicate this constricted environment – termed the ‘excluded volume effect’ – researchers are rewriting the rules of how biology works!

“Incorporating crowding effects early in drug discovery can dramatically improve the physiological relevance of screening assays. It enhances predictive accuracy, reduces attrition rates, and accelerates the path from hit to lead – ultimately saving time and resources”, saysSaravanan Thangavelu, an expert in this field and Assistant Professor at the School of Chemistry of University of Hyderabad.

Why does macromolecular crowding matter?

In vitro studies conceptualise the effects of macromolecular crowding primarily through the excluded volume effect. Textbooks often present proteins folding neatly and enzymes catalysing reactions under ideal buffer conditions. But in real biology, no ideal rules truly apply. On one hand, excluded volume effects are often stabilising, while on the other, chemical interactions between crowders and biomolecules can either stabilise or destabilise. Artificial crowding can significantly influence the cellular environment in undefined ways – a protein may stabilise or aggregate, a drug may diffuse freely or remain trapped, and a catalytic reaction may proceed rapidly or come to a halt.

Consider driving. On an empty highway, the ride is smooth and predictable. But in the middle of rush hour (not to forget the potholes and speed breakers to test one’s driving skills), every turn on a busy or crowded road depends on the traffic flow – sometimes stable, sometimes slow, sometimes encountering unexpected collisions. Crowded, noisy and bumpy roads may be frustrating, but they mirror the real conditions inside a living cell far better than smooth open highways.

From theory to therapy

Recent advancements in the field show macromolecular crowding is not just a fundamental curiosity but a powerful influence on drug discovery and clinical therapeutics.

• Bio-engineered models for bio-mimicry –Development of therapeutic drugs reached new heights when macromolecular crowding was introduced in vitro. It enhances physiological fidelity in cell culture and the building of scaffolds – the architectural framework of tissues. These crowded blueprints now inspire regenerative therapies and more predictive drug screening.

• Vesicle encapsulation – Crowding agents help in packing large biomolecules into vesicular carriers, maintaining uniformity between the solutes during formation. A recent ACS Synthetic Biology study reported almost 40% increase in encapsulation efficiency in a crowding milieu. The vision? Insights into predicting therapeutic carriers’ payloads and limitations in crowded, heterogeneous, physiological environments. These vesicles have immense potential as drug delivery capsules, navigated with precision.

• Nanocarriers and pharmaceutical formulations – As compared to the non-crowding condition controls, polymer matrices and nanocarriers fabricated under crowded conditions behave differently. Porosity, drug release rates, binding specificity and targeting efficiency often shift unpredictably. This variability has disappointed pharmaceutical giants who were testing polymeric nanocarriers for targeted drug delivery. To overcome it, scientists are designing molecularly imprinted polymers (MIPs) that can efficiently survive critical conditions – tailoring molecular assemblies to function optimally in crowded biological systems.

• Tumour-associated 3D models – The extracellular matrix (ECM) is a network of biomolecules – providing mechanical support to organs and tissues, influencing cell proliferation, differentiation and migration – plays a pivotal role in the tumour microenvironment (TME). When researchers at Trinity College, Dublin, mimicked ECM deposition on crowded breast cancer models, they observed that standard chemotherapy drugs became less effective. Crowding shielded tumour cells from oxidative stress, making them more resistant to therapy. This finding suggests that some drug resistance may not be genetic at all, but simply a matter of cellular conditions – a question to be addressed by the oncologists.

Thangavelu mentions, “Crowding-aware models can better simulate patient-specific cellular environments, enabling more precise predictions of drug behaviour. This opens avenues for tailored therapeutics that reflect individual molecular landscapes, especially in complex diseases”.

Challenges in tying up the loose ends

Macromolecular crowding today is both enabling and limiting – a stabiliser and a disruptor!

Biomimicking a living cell to create artificial systems doesn’t always replicate the outcomes of the excluded volume effect. Both physiological and synthetic crowders complicate experiments with higher viscosity, poor signal quality, and enhanced background noise. These challenges make experimental systems harder to interpret but incrementally bring us closer to in vivo reality.

“Funding agencies could initiate targeted calls to support crowding-based proof-of-concept studies in academic labs. These foundational efforts can then be translated into industrial pipelines through collaborative grants or public–private partnerships,” Thangavelu answers when asked about the challenges and funding of crowding-based proof-of-concept studies.

On one hand, crowding stabilises proteins, enhances physiological fidelity, and improves drug encapsulation and release. On the other hand, it can just as easily trigger unwanted aggregation or hinder diffusion. The challenge is to implement rigorous quality-assessment strategies along with sophisticated engineering so that crowding becomes a better tool rather than a hurdle in next-generation biomedicine.

Vision: A future built on crowding

Despite the high road, drug discovery is in urgent need of realism. The leap from petri dish to patient has always been treacherous, partly because our models oversimplify reality. With crowding, it is a path forward – not a perfect fix, but, in many cases, a necessity.

As synthetic biology and bioengineering surge ahead, crowding may help us design better artificial cells, smarter drug vehicles, and even biofunctional microdevices responsive to logic signals in real time. To be able to match this pace, we must develop systematic ways to quantify, predict, and harness crowding – not merely tolerate it.

Thangavelu lastly mentions,

The next decade will see crowding integrated with AI-driven simulations and high-throughput screening platforms. This convergence will refine our understanding of intracellular dynamics and unlock new strategies for rational drug design”.

The science is clear: No molecule moves in isolation.

The future of drug delivery may well depend on how well we learn to navigate immediacy inside the cell, maintaining the required precision.

They thrive in every way except the one nature usually values most: Reproduction. These are sterile hybrids, the products of the mating of two distinct species. They're generally stronger, tougher, and better adapted to their environment than either of their parents. A mule. A dzo. Even a pizzly—the rare offspring of grizzly and polar bear intermixture. Once-only wonders of nature.

For decades, they were seen as evolutionary mistakes, biological detours with no destination. But today, that's changing. Scientists are beginning to view them as biological outliers—animals that demonstrate the fine machinery of survival, compatibility, and the limits of reproduction itself.

Why sterility occurs

In order to reproduce effectively, chromosomes need to pair well during meiosis, the biological process by which sperm and egg cells are produced. In hybrids, however, they do not typically match. They fail to pair or cannot align, so cell division is not completed.

The outcome is a fully developed and functioning organism—sometimes even superior to both parents—but with a nonreproductive system. It has neither eggs nor sperm, leading to a cessation of lineage. It is not a defect in the traditional sense; rather, it is a biological constraint.

The paradox of performance

Sterile hybrids not only live—they thrive! Consider the mule, prized for its strength, endurance, and disease immunity. It labours longer, consumes less, and is healthier than either horse or donkey. Or the dzo (yak-cattle), best suited to the hardships, high elevations of the Himalayas. In aquaculture, researchers grow triploid fish, intentionally sterile but more rapidly growing and more efficient than their fertile counterparts.

These hybrids are not mistakes of evolution; they are biological upgrades. They illustrate an effect called heterosis, or hybrid vigour, in which the combination of genes creates a strengthening of characteristics. Yet, their inability to reproduce defies the expected norm of evolutionary success.

From natural fluke to scientific tool

What happened before in nature by chance is now a planned tool in science. In vector control, the sterile insect technique uses laboratory-reared male mosquitoes released into city environments. They copulate, but no offspring are produced. Within generations, entire disease-spreading populations collapse—no insecticides, no ecological spillover.

Sterile hybrid mice in genetic labs have taken over vasectomy models through surgery in the field of reproductive study. These animals make embryo transfer studies possible with absolute predictability—no surgery, no hormone manipulation—just a pure, reproducible biological system.

Genetically sterile bees are being used in precision agriculture to manage pollination. They target specific crops, do their job, and vanish from the ecological balance. In genetically sensitive orchards and seed farms, their sterility functions as a biological firewall.

Triploid salmon in fish farms are designed to carry an extra set of chromosomes. They grow more rapidly, are better able to fight parasites, and can't reproduce with wild fish if they escape. These traits make fishery operations more effective. Wild genes remain intact. Even conservation technology finds scientists experimenting with sterile hybrid crops to keep invasive plant species from cross-breeding with native flora—essentially creating a living ecological barrier.

Throughout these industries, sterility no longer indicates malfunction. It allows for control, containment, and clean biological intervention. Where fertility disperses risk, sterility imposes precision. In a world where genetic borders are dissolving, sterility is becoming one of science's most advanced tools.

Evolution's unintended experiments

They are sites where species meet, bifurcate, or intersect in ways that test the boundaries of compatibility. Even if these animals do not contribute to future lineages, they reveal to us sites where evolutionary paths become uncertain and where resistance transiently manifests in unlikely conjugations.

They serve as models for the study of the mechanisms of infertility, gene expression modulation, and molecular conflict that arise between incompatible genomes. In doing so, they provide us with representative insights not only into reproductive biology but also into the mechanisms of speciation itself.

These are unreplicated experiments that hold value not because of their duration, but because of the information they convey. Each one is a unique biological experiment, showing how life will sometimes produce something special—perhaps only once.

Whether found in untapped ecosystems or observed through the prism of controlled environments, these organisms remind us that nature is not made up entirely of legacy.

It is also composed of experimentation, impermanence, and the quiet process of adaptation at the boundaries of possibility.

On 9 January 2025, Prime Minister Narendra Modi unveiled the Genome India Project, a groundbreaking initiative representing the sequencing of 10,000 genomes from 83 distinct population groups across India’s vast demographic landscape. This landmark achievement is a significant step toward a health genomics revolution in the country.

Human health-focused genetics and genomics research relies heavily on harnessing genetic diversity to identify genetic variants that influence disease susceptibility or resilience. This knowledge enables accurate diagnosis, prognosis, the development of novel therapeutics, and the tailored application of precision medicine. Unfortunately, non-European ancestry groups are severely underrepresented in genomic databases globally. A 2022 study revealed that participants of European ancestry accounted for 86.3% of genome-wide association studies (GWAS)—a method for identifying genetic markers linked to diseases or traits—while South Asian populations contributed a mere 0.8%. Expanding representation in genomics databases is crucial to ensuring biomedical research and precision medicine are inclusive and beneficial for Indian populations.

The Genome India Project marks an important first step in this direction but remains far from comprehensive. Programs like the USA’s All of Us initiative aim to enroll at least 1 million participants from historically underrepresented populations, representing 0.3% of the national population. Similarly, the UK’s 100,000 Genomes Project represents 0.15% of the country’s diverse population. By comparison, Genome India currently covers only approximately 0.007% of the population, and 2% of India’s documented 4,600 population groups, leaving significant gaps in representation that must be addressed for the project to achieve its full potential.

The genomic data generated through the Genome India Project is now centrally housed at the Indian Biological Data Centre (IBDC) and is intended to be made accessible to researchers worldwide. However, India's unique population dynamics and the absence of robust data protection laws necessitate a cautious approach. Moreover, genomics data differs from personal data in several critical ways. Furthermore, the global good data practices have laid down the CARE framework for ensuring that data is collected and used in a responsible, equitable, and transparent manner, particularly in the context of indigenous data sovereignty. This refers to the inherent right of the vulnerable communities, especially indigenous people, to control, govern, and even manage sharing of their own data. Therefore, governance frameworks and privacy guidelines for genomics data must be tailored to address these complexities, as well as encompass global standards for data sharing and governance.

Genomics data – why should we be concerned?

Between 1990 and 1994, researchers from Arizona State University collected DNA samples from the Havasupai tribe to study type-II diabetes, a condition with high prevalence in the community. Approximately 400 members consented to participate. However, in 2003, a tribe member discovered the samples had been used in unrelated studies on migration, which contradicted the tribe’s oral history of their origins and posed potential legal risks to their land claims. Evidence also emerged that the samples were intended for mental health research without the tribe’s knowledge, raising concerns about perpetuating stigmatising stereotypes.

In 2004, the Havasupai tribe sued the Arizona State Regent, alleging misuse of their genetic data. Researchers argued that broad consent, allowing subsequent studies, protected them legally. However, this consent was obtained in English, a second language for the tribe, further questioning its validity. After a six-year legal battle, the court ruled in favour of the Havasupai in 2010, awarding monetary compensation and ordering the return of the DNA samples.

This landmark case underscored the complexities of genomic data governance, particularly for marginalised communities. Unlike personal data, genomic data carries both individual and collective implications. It reveals personal traits, disease risks, and ancestry while also containing information about relatives, ethnic groups, and populations, raising ethical questions about data ownership and consent.

Genomic data's long-term relevance further complicates governance. Unlike other data, it remains biologically significant throughout a person’s life and across generations, necessitating robust safeguards for its storage and use.

Moreover, genomic findings often intersect with cultural beliefs, ancestry, and identity, potentially conflicting with traditional narratives or impacting legal claims.

The misuse of genomic data can harm entire communities, leading to stigmatisation or exploitation, particularly for Indigenous populations. Informed consent poses additional challenges, as the potential future uses of data may be unknown at the time of collection. The collective nature of genomic data also means that decisions about one person’s data can affect others without their explicit consent.

Indian population structures – and what needs to be done?

The practices of consanguineous marriages and endogamy—marrying within one’s caste—has created a distinct genetic structure across India. This has resulted in limited gene flow between groups, effectively forming genetically "endogamous" populations. Consequently, genomic data from a few individuals can reveal their community, making improper use of such data a potential source of harm or stigma for entire communities, particularly vulnerable indigenous groups. While including these populations in genomics research is essential to extend biomedical benefits, misuse of their data risks perpetuating stereotypes, undermining cultural identities, and causing long-term harm.

To mitigate these risks, a set of robust principles and governance models is required to ensure the ethical and equitable use of genomic data.

Privacy and long-term protection

Strong anonymisation protocols are crucial to safeguard individual, familial, and community privacy. Techniques like pseudonymisation and noise addition can obscure identities while preserving data utility. Privacy protections must be designed for long-term relevance, aligning with the enduring nature of genomic data. Strategies must account for decades, not just the initial years, of data security.

Informed consent and the right to withdraw

Informed consent is fundamental but must go beyond one-time, broad agreements. Consent should be a continuous, iterative process, and in local languages, particularly for new analyses or secondary use of existing data.

Since genomic data implicates families and communities, consent mechanisms should extend beyond individuals. Additionally, individuals and communities must have the "Right to Withdraw," allowing for the complete erasure of their data at any point.

Community data governance

For indigenous and marginalised groups, community-driven governance is essential. Implementing the CARE Principles (Collective Benefit, Authority to Control, Responsibility, and Ethics) ensures respect for cultural values and data sovereignty. CARE prioritises community empowerment, cultural sensitivity, equitable benefit-sharing, and long-term trust.

Adopting CARE in Indian genomics programs

To integrate CARE into initiatives like Genome India:

1. Engage communities at every research stage through Community-Based Participatory Research (CBPR).
2. Ensure communities retain authority over their data.
3. Develop mechanisms for equitable benefit-sharing, including healthcare and economic opportunities. These should particularly be given consideration when making this data available for research with private sectors or across borders.
4. Establish ethical oversight bodies to enforce CARE adherence and suggest alignment of national biomedical research or genomic data policies with CARE principles.
5. Implement federated data-sharing models, enabling regional centers and universities to locally manage data, with mentorship from institutions like IBDC or IGIB.

By embedding these principles, India can advance genomics research while safeguarding the rights and dignity of its diverse communities.

Conclusion

Indian genomics programs are at a nascent stage, offering policymakers a chance to embed ethical and equitable practices. By adopting participatory governance models and frameworks like the CARE Principles, these programs can empower communities, safeguard cultural values, and ensure sustainable outcomes. Stringent regulations are crucial to protect community interests and enable responsible data use. With the right strategies, India can advance healthcare, foster scientific innovation, and establish a globally recognised model for sustainable and inclusive genomics research.

Traditional drug ingestion is passive, meaning medications often affect the entire body, with a few exceptions. A contrasting approach, using principles from active matter physics, is to evolve a branch of therapeutics aimed at directed drug delivery. By harnessing autonomous movement and response to local cues, this approach aims to ensure that medications are released precisely at the target site—whether a tumour, an infected area, or a specific organ. Ideally, this would minimise the side effects, says Sriram Ramaswamy, Honorary Professor, Indian Institute of Science (IISc), Bangalore.

The Bangalore Science and Technology Cluster (BeST), established under the Office of the Principal Scientific Advisor to the Government of India, works to enhance and educate better healthcare management in the city of Bengaluru. As part of its initiative, BeST recognises the need to understand and integrate active matter therapeutics within the community. Given the relative novelty of research and clinical trials, there exists a significant knowledge gap in the community.

Active matter therapeutics: A new era in medicine

The idea of using active matter for targeted drug delivery isn’t entirely new, notes Ramaswamy. Researchers have studied chemical gradient-based drug delivery (commonly called gradient swimmers) for a long time now. However, these early methods had limitations.

One of the main drawbacks was the unpredictability of these chemical reactions, which could sometimes be imprecise, leading to negative outputs. However, the recent advancements in robotics and nanotechnology have propelled the field of directed drug delivery with more accurate and effective drug delivery via nanobots.

Nanobots: The “Magic Bullet” of modern medicine

Nanobots are revolutionising drug delivery approaches worldwide. These microscopic robots are capable of moving across surfaces, locating and delivering medications directly to the target site. At the forefront of this cutting-edge research is Ambarish Ghosh, Professor at the Centre for Nano Science and Engineering (CeNSE) at IISc. Ghosh explains, “nanobots are programmed to search for specific targets such as cancerous tumours or sites of infection”. This level of precision, once unimaginable in medicine, holds the potential to vastly improve patient outcomes.

Ghosh further emphasises that the success of nanobots lies in their ability to autonomously navigate through the body and their potential to work collectively in swarm-like behaviour to enhance therapeutic effects.

Ghosh explains, “Motion is an important aspect in the functionality of these nanobots”. By harnessing external stimuli such as light, magnetic fields, or chemicals, researchers power the movements of these nanobots with a high degree of accuracy. This versatility makes them adaptable and customisable to fit the specific needs of the treatment. Additionally, with newer concepts, such as untethered/ tethered swarm movements using hundreds of nanobots, the effectiveness of the treatment can be amplified.

The promise of nanobots in medicine

The potential applications of nanobots in medicine are vast, with several success stories already making waves in the scientific community. One of the most promising areas of research is the use of nanobots in cancer treatment. Ghosh highlights, “Nanobots aren’t just designed to skim the surface of a tumour, but now can penetrate inside the tumour and destroy cancer cells from inside.” This not only increases the effectiveness of the therapy but also reduces the risk of recurrence.

In addition to cancer, nanobots have shown promising results in different fields of the medical industry, including treatments and diagnostics.

Ghosh and his team have made remarkable strides in dentistry with their magnetic nanobots in clearing bacterial infections of the teeth. Chronic hepatitis, anaemia, and diagnostic procedures in the peritoneal cavity and gastric area are some of the other areas making progress in the area of drug delivery using nanobots. These developments reflect the growing potential of nanobots to revolutionise many aspects of healthcare.

Several startups are actively working towards advancing the field of active matter therapeutics. Bionaut is dedicated to working towards a cure for neurodegenerative disorders. Another notable player, Nanobots Therapeutics, focuses on treatments against bladder cancer. Additionally, Theranautilus, a homegrown Indian startup, was founded by Ghosh and his associates to provide cutting-edge solutions for drug delivery and medical procedures. These companies are front runners in pushing boundaries in targeted drug delivery approaches.

Challenges and the future of active matter therapeutics

Despite its promising applications, active matter therapeutics face significant challenges. One of the biggest obstacles in this field is navigating the complex tissue surfaces of the human body. The body's intricate internal structure, combined with varying properties, presents a significant challenge while designing nanobots. For example, paving the way through the complex large intestine. Another critical issue is ensuring the safe removal of nanobots from the body after they complete their task. Ongoing research aims to overcome these challenges, and Ghosh remains optimistic about the future of this technology.

The future of active matter therapeutics is incredibly exciting, with clinical trials already underway for several promising treatments. Ghosh’s work on root canal treatments is one example of how active matter therapeutics is already transitioning from research to real-world applications. With continued research and development, it’s likely that nanobots will become an integral part of medical treatments in the near future, offering a safer, more efficient way to deliver drugs and treat various diseases.

Active matter therapeutics represent a paradigm shift in how we approach healthcare.

With nanobots leading the charge, the potential for targeted drug delivery is greater than ever. As the field continues to evolve, we may soon see a future where personalised medicine is the norm and nanobots are a common tool in the fight against diseases. The road ahead is not without its challenges, but the progress being made today offers hope for a healthier tomorrow.

Towering Pine trees of the Pfynwald alpine coniferous forest enveloped me. Golden yellow specks flew around like stars sprinkled on a canvas. The golden spots are a visualisation of the volatile organic compounds released by trees, in the ‘Atmospheric forest’ exhibit at the ‘Critical Zones: In search of a common ground’ exhibition housed on the third floor of the Science Gallery Bengaluru (SGB). It is an adaptation of the exhibition ‘Critical zones: Observatories for earthly politics’, originally conceived and showcased at ZKM, Centre for Art and Media Karlsruhe (2020-2022). The exhibition was the brainchild of Bruno Latour, French philosopher and sociologist and Peter Weibel, an Austrian artist.

What is the critical zone?

"What is the critical zone?" a curious visitor asked. “It's the thin layer of Earth where all life exists," said the mediator. It is everything from the ground beneath our feet, the hidden world of underground rivers and tiny creatures, all the way up to the air we breathe. It is the ‘life support system’ of Earth that makes life on Earth possible. "Think of the earth as an orange - the critical zone would be just the peel", explained the mediator.

The critical zone may be thin, but it holds a surprising variety of landscapes and water forms – and these change rapidly over geological time. The Sahara desert, for example, was once a vast ocean. Thematic maps visualise these shifts which shows how a place's landforms have transformed over different eras. The "Physical Atlas" exhibit is a thematic map that represents the landforms of a location over different periods in horizontal sections. Although critical zones have always been changing due to natural forces, in the ‘Anthropocene’ era humans are the dominant force shaping geography, climate and ecology. The critical zone now faces unprecedented challenges as a result of our actions.

Health of the critical zone

Scientists are concerned about the health of our planet’s critical zone. Humans have altered over half of the Earth’s land surface, pushing the planet’s life support systems beyond sustainable limits. To assess the ‘health’ of the critical zones, scientists have made field stations that monitor various environmental parameters. The ‘Critical Zone Observatory’ (CZO) exhibit showcases artwork inspired by CZOs in France, Switzerland and the Indian Institute of Science.

At the CZOs instruments track measures like soil moisture, groundwater level, and streamflow. This data helps analyse how resilient the critical zone is to change.

The mangrove ecosystem has also become a site of destruction, as explained by the exhibit ‘Critical membrane’ by Sonia Mehra Chawla. The artist worked with scientists at the M S Swaminathan Research Foundation (MSSRF) in Chennai, India. They collected soil and water samples from mangrove ecosystems. Scientists at the MSSRF, known for their research on the role and preservation of mangroves, then grew microbiological cultures from these samples. The MSSRF is also studying traditional fishing techniques used in these areas, as these techniques create networks of canals that contribute to the health of the mangrove ecosystem.

Fransesca Romana Audretsch, art mediator at the Center for Arts and Media, Karlsruhe, says,

The exhibition is not about the climate crisis. It is about finding ways to coexist with all forms of life on Earth. It is about finding common ground, about how we can identify ourselves with living forms around us rather than as nations, and making people think.

The ’Cloud studies’ exhibit by Forensic architecture further underscores the vulnerability and interconnectedness of the critical zone. It captures the drastic changes clouds face due to air pollution and chemical emissions, highlighting the impact of human activities on even the seemingly distant sky.

We are all interconnected

The exhibition introduces the concept of ‘Ghost acreages’ and asks us an uncomfortable question- Do we live where we are? We depend on international trade, coal and oil sourced by displacing local communities for our sustenance. The land we live in is not the land we live from and there is profound interconnectedness in the critical zone. "Soil Affinities" by Uriel Orlow reveals the complex story of European food production relying on industrial farms in West Africa, established during colonialism. Meanwhile, "Raiz Aerea" by Edith Morales showcases an indigenous Mexican maize variety, uniquely capable of self-fertilization. This plant, with its nitrogen-fixing aerial roots, has been nurtured by indigenous communities for millennia. However, in 2018, scientists and corporations took notice, potentially putting its intellectual property at risk. This raises critical questions about biopiracy and the exploitation of indigenous knowledge.

Every element, from water and soil to gases and minerals, has been shaped by living organisms, exemplifying the concept of Gaia – how life forms create and sustain the conditions for other life to exist. Such interconnectedness can lead to profound experiences, as was the case with the artist Cemelesai Dakivali. Years ago, a group of young people from Dakivali's tribe in southern Taiwan fell ill with a strange disease after conducting research in their ancestral lands. This incident echoed the warnings of tribal elders who believed certain areas should remain untouched. Inspired by their wisdom, Dakivali created large-scale artworks depicting not invasive species, but the viruses and creatures unleashed from the wilderness in response to human intrusion. This powerful reversal of perspective challenges the traditional narrative, highlighting humans as the disruptive force facing retaliation from the natural world.

The exhibition introduces us to the concepts of critical zones, interconnectedness in the critical zones and the urgency to act to save our life support systems from reaching the tipping point. To do so, it proposes a paradigm shift- that humans should move away from national identities and focus on building a shared understanding of our place on earth. It invites visitors to join this ongoing process of finding new ways to exist and thrive on Earth.

By engaging with the "Critical Zones" exhibition and its message of interconnectedness and shared responsibility, we can collectively move towards a more sustainable and harmonious future for all life on Earth.

The critical zones exhibition is open to the public free of cost till 17 March 2024. More activities, talks, film-screenings and workshops are lined up as part of the exhibition.

This article was first published by Editage Insights, which recently concluded their Peer Review Week 2022 celebration.

The increasing number of publications and journals is widening the chasm between the number of peer reviewers required and the number of reviewers willing to review. Many researchers reject reviewing opportunities because they are pressed for time and need to meet their own publication and funding requirements. The burden to perform competent peer reviews, therefore, often rests on a small number of academics, leading to agonizing waits for authors hoping to have their papers published.

Moreover, expectations from peer reviewers themselves can vary by journal, discipline, and region, and with other changes in the academic and publishing landscape. All of this places pressure on the current peer review system and may call into question the effectiveness of the process in maintaining the quality and integrity of published research.

These challenges notwithstanding, the integral role of peer review in academia cannot be denied. Quality assurance in some form or the other will always be a crucial cog in the machine of scholarship, and the academic community is actively trying out new models, signaling hope and change in the way peer review is conducted.

Novel peer review models

The formats of scholarly dissemination keep evolving. From print-only, subscription-based traditional journals, we have now moved to an era of digital publication and open access (OA). There is a thrust toward open science and open data, particularly in the face of global crises such as COVID-19 and climate change.

In response, peer review models have not remained static. For example, during the current pandemic, academic journals followed fast-track systems for COVID-19–related content to hasten review and publication. Academic publishing and communications organizations such as PLOS and eLife created a Rapid Reviewer Initiative to maximize the efficiency of peer review of COVID-19 research. This was an unprecedented and “uncommon moment of scholarly publishers collaborating to gather useful insights on the performance of the scholarly communication system.” Meanwhile, preprints provide unique opportunities for open and effective peer review. The last few years have witnessed a spurt in new forms and ideas for peer review to meet different evolving needs and expectations. Let’s look at some notable developments in the last few years.

Open peer review

Open peer review (OPR) aims to make reviews and publishing decisions more transparent. There is no clear definition for OPR, but it broadly refers to a peer review model wherein elements of the peer review process are made publicly available before or after publication. This system hinges on combinations of the following:

Open identities: Reviewer identity is known.

Open reports: Peer review reports are published alongside the relevant article.

Open participation: The paper is open to scrutiny and feedback from the community.

OPR in various flavours has been implemented by several journals and scholarly platforms. TheEMBO Journal allows pre-publication interaction among reviewers, who comment on each other’s reports before the editor makes a decision. Frontiers journals have an interactive collaboration stage involving the authors, reviewers, and Associate Editor, which enables quicker arrival at a consensus.

Making review reports open means that the research community can evaluate the review process. Open review reports are also amenable to reviewer recognition (see later in this article).

Pros

• OPR can address problems like lack of accountability and unethical review practices, which can otherwise occur under a veil of anonymity.
• Open identities encourage reviewers to be more meticulous and constructive in their evaluations.

Cons

• A single, clear definition of open peer review is not available.
• Some reviewers (especially early-career researchers) might be guarded or hesitant to give critical feedback when reviewing manuscripts by established researchers.

Post-publication peer review

When an article is published before peer reviewers are sought, it is called post-publication peer review (PPPR). PPPR can also bring in much needed transparency. By allowing anyone in the scientific community to evaluate a paper after it has been made public, PPPR extends the window of scrutiny beyond the publication date.

PPPR can take a number of forms, such as Letters to the Editor, blog posts, and social media posts. Some publication platforms like eLife have pioneered this model. According to Michael Eisen, Editor-in-Chief of eLife, and his colleagues, eLife tries to “replace the traditional ‘review, then publish’ model developed in the age of the printing press with a ‘publish, then review’ model optimized for the age of the internet.”

Twitter peer review may be considered a type of PPPR. Many scientists today spend at least some time daily on social media platforms like Twitter. On Twitter, numerous researchers deconstruct papers and their limitations, strengths, and conclusions—often in lay terms, sometimes even infusing humor and memes! The Twitter “thread” is fast becoming a way to explain complex concepts and phenomena. In a Twitter thread, one is not restricted by a 280-character limit.

That being said, Twitter cannot be a formal system of peer review but can serve as a channel to draw attention to grave issues and amplify important messages.

PPPR in various forms might continue to be a part of the academic landscape, diversifying into newer and important models.

Pros

• PPPR allows rapid publication.
• It can spark meaningful discussions between researchers and a wide range of contributors.
• Critiquing on Twitter can draw attention to aspects of a published paper when it is difficult to do so via traditional channels.

Cons

• Quick publication without prior peer review could lead to poor-quality research being widely disseminated.
• Twitter reviews can be misinterpreted by persons outside the scholarly community.
• The tone of a Twitter review can make it feel like an attack.

Results-masked review

An interesting new form of peer review is “results-masked review” or “results-blind review,” wherein a manuscript is judged based on the research question and methodology rather than the results. In this form of peer review, manuscripts without the results, discussion, or conclusion are first sent to peer reviewers for scrutiny, and only when they are accepted after this stage do they move to the next, where the full manuscripts are reviewed.

Pros

• It is a great step to avoid publication bias favoring positive findings only.
• It places a greater focus on methodological rigor.

Cons

• It has not been widely adopted.
• It may not be applicable to articles that do not have an experimental section, e.g., review articles.

Other recent trends in peer review

Incentives for reviewers

Stakeholders in academia are realizing the need to recognize peer review reports as scholarly outputs. For example, on the ScienceOpen platform, all reviews are openly available and have DOIs to make them fully citable to allow recognition in the review process. Review histories can be cited in CVs.

Initiatives like Reviewer Credits and Publons (now part of Web of Science) confer benefits and reviewer “credits” (e.g., access to non-OA journal content) to reward researchers for their inputs as peer reviewers.

Diversity and inclusion in peer review

Peer review by individuals with diverse backgrounds is essential to prevent biases, promote development, and increase scientific rigor. Journals are becoming increasingly cognizant of the importance of diversity, equity, and inclusion (DEI) in their editorial boards and reviewer pools and are actively trying to include academics of different genders, geographical backgrounds, and career stages. Academic publishers are now committed to developing and implementing ways to improve DEI in peer review, which will be crucial in diversifying and improving science.

Peer review assisted by artificial intelligence

Artificial intelligence (AI)-powered tools for language checks, plagiarism detection, and journal compliance checks are in use by authors and publishers alike. There might even be exciting possibilities for AI in peer review. AI technologies may be used to select reviewers and summarize the conclusions of a manuscript to ease the load on a reviewer. The use of AI in peer review can simplify and semi-automate pre–peer review screening and some aspects of the peer review process.

Looking ahead

Peer review has come a long way since the inception of science publishing with Philosophical Transactions in 1665. The flexibility of peer review was recently demonstrated in the way academic content was processed during the pandemic. This is testament to how versatile and amenable to change the process can be. Every innovation in peer review has the potential to dispel the limitations and criticisms of the traditional system. Suffice it to say, we can look forward to speedier and more transparent ways of assessing scholarly content, which might become the norm rather than exception.

Proteins are the workhorses of living cells, and genes determine how these proteins are faithfully manufactured. Fundamentally, a protein is a string of amino acids (simple organic molecules) arranged in a specific sequence that decides the structure and function of the protein. During protein translation — the process of making proteins — a cell chooses amino acids from a set of twenty chemically distinct ones. Each of them is carried by a specific adaptor molecule called tRNA. Enzymes aid the amino acids in binding to their respective tRNAs. They are then taken to the protein translation site, where they are picked and incorporated into a new protein.

Sometimes, cells pick the wrong amino acids, as many have only minor chemical differences. But cells also have many proofreading enzymes to correct the mistakes, and such editing abilities have been key to the survival of organisms over millennia. Scientists are actively researching the details of these correction processes.

Rajan Sankaranarayanan, Outstanding Scientist, CSIR-Centre for Cellular and Molecular Biology (CCMB), Hyderabad, is one of them. As a structural biologist, he studies the structures of enzymes down to their atomic detail and correlates them with their functions in cells. Over the last two decades, he has delved deep into the proofreading and editing enzymes involved in protein translation in bacteria, archaea (the oldest unicellular life forms on earth) and eukaryotes (uni-or- multicellular organisms, evolved from the union of bacterial and archaeal cells).

Sankaranarayanan’s exhaustive work has unravelled a few mysteries of a class of enzymes that play a vital role in the error-free translation of proteins, advancing our knowledge of these life-controlling mechanisms.

Here is a brief account of his research journey.

A serendipitous discovery leads to a deep dive

In the early 2000s, Sankaranarayanan discovered that one of the protein translation enzymes in bacteria performed a dual role: it attached amino acids to their tRNA and corrected the wrong ones (if any). In addition, he found a specific region, called an editing domain, on the enzyme’s molecular structure that was performing the editing function.

Sankaranarayanan wanted to understand this novel editing mechanism more, so he moved to CCMB in 2002 to start his research group. First, he set up a state-of-the-art X-ray diffraction facility there. Then, the group began making crystals of various protein translation and editing molecules and studying their structures.

When studying a protein translation enzyme in archaea, they found that this enzyme, too, had an editing domain just like in the bacterial enzyme discovered earlier. But the structures of the two were different. Excited, they searched for other enzymes across organisms that might have a structurally similar domain. If they found one, it would give them a clue about the domain’s function.

The work took an unexpected turn in 2005 when they found it to be similar to another editing enzyme, called the D-aminoacyl-tRNA Deacylase (DTD) in bacteria.

The master selector

Until then, DTD — a poorly-understood enzyme — was known to be only an amino acid chirality selector. Chirality is a structural feature of amino acids, where the amino acids are found in two mirror-image-like forms, L (for levo) and D (for dextro). Chemically, L and D chiral forms of amino acids are the same, but their 3D molecular arrangements are mirror images of each other. (Just like the structure of our palms). Nineteen amino acids exist in L and D forms except for glycine.

However, not much experimental evidence of DTD’s functions existed, and scientists were unaware that D-amino acids were present widely inside cells. Over time, reports of D-amino acids’ role as neurotransmitters and hormone regulators came; they were also components of bacterial cell walls and antibiotics, making it clear that cells had copious amounts of D-amino acids but proteins do not contain them. It was evident that cells were fishing out L-amino acids and then incorporating them into proteins.

Sankaranarayanan thought the likeness in editing domains (in bacterial and archaeal enzymes) hinted that, different organisms used similar mechanisms to remove D-amino acids from tRNA. But the actual enzyme action was in the dark. So, he and his team started looking at crystals of DTD and D-amino acid structures bound to tRNA.

After screening hundreds of crystals for structure determination, they realized how the two interact.

A cleft in the structure of DTD fitted into a matching structure in D-amino acid bound to tRNA. When the two latched, a chemical reaction separated the D-amino acid from the rest of the complex. In contrast, the complex with L-amino acids has a structure that does not fit into the cleft and hence gets selected for protein making. For glycine (the amino acid without chirality), tRNA enters the DTD cleft but stays intact.

DTD’s fine ability to distinguish between glycine’s tRNA and other amino acids comes from identifying one position on the tRNA – called the discriminator base. However, in glycine-tRNA, the discriminator base is structurally different from all other tRNAs and hence, has a separate identity. Thus, Sankaranarayanan deciphered the mechanistic details of how DTD selects one of the mirror images for protein translation in cells.

“There are other chiral checkpoints too in the protein translation machinery in a cell. But DTD is unique because it selectively rejects binding to L-amino acids; all others known choose binding to L-amino acids,” says Sankaranarayanan.

By now, it was also evident that every living organism has DTD enzymes. Although they differ structurally, their function is common — to remove D-amino acids from the selection. Sankaranarayanan’s team saw enough examples to infer that DTD and tRNA have co-evolved in unexpected scenarios.

The molecule’s multiple roles in the evolution of life

They found that DTD in eukaryotic organisms evolved from bacterial DTD. The difference lay in their choice of discriminator base on glycine tRNAs. This difference allows the modified bacterial DTD to work with archaeal tRNA. This change in DTD was necessary for protein synthesis in eukaryotic cells formed from the symbiosis of bacteria and archaea.

As the eukaryotes evolved into multicellular organisms, they noted the chances of mismatch were more between amino acids and tRNAs. Also, they found that ATD, an animal-specific DTD-like enzyme, minimized such mistakes. “Evolution of ATD and the start of multicellularity happened around the same time. So, it looks like ATD helped organisms overcome the challenges in protein translation caused by multicellularity,” says Sankaranarayanan.

In plants, the team found another enzyme called DTD2 (which had a different structure). It played the part of DTD, helping the plant roots survive underground in low-oxygen conditions by removing the detrimental effects of acetaldehyde in root cells. Acetaldehyde disrupts protein translation machinery’s function.

Sankaranarayanan’s studies compelled biologists to think of the role of DTD enzymes in the broader context of evolution. “tRNA is considered important in the evolution of life because it can pick amino acids and build proteins. Our studies now show DTD enzymes have worked with tRNA in key evolutionary steps – for the success of eukaryotes, multicellular organisms and land plants – a feat not known for any other enzyme,” remarks Sankaranarayanan.

LS Shashidhara, Distinguished Professor of Biology and Dean of Research at Ashoka University, Delhi NCR, says: “Sankaranarayanan’s work in protein quality control, with a special focus on chiral selection, is elegant, pathbreaking and qualifies to enter classical textbooks on foundations of biology.”

What is a community?

A community is a group of co-occurring and interacting species at a given time and place. It is a dynamic entity, with members interacting within the population as well as with their surroundings. A community has some chief characteristic elements. It comprises a group of individuals, has a defined boundary, has a level of similarity amongst the members, uses various communication methods, and possesses skills and resources that can be utilised by its members.

Behaviours in a bacterial community

The qualities of a community also apply to bacterial communities. Bacterial species are the most diverse organisms. They are found everywhere, even in the most extreme environments such as glaciers, ice caps, thermal springs, hydrothermal vents, and ocean floors. Bacterial species are rarely found in isolation. Often, they survive as part of a population which comprises multiple species. Interactions occur between various species through behaviours such as neutralism, commensalism, amensalism, mutualism, parasitism, and competition. Years of co-evolution has led to a large variety of these relationships.

These interactions have been studied in a pairwise setup. However, a stable community is the result of all the collective behaviours. In other words, the aggregate activity of individual cells determines the ability of a community to accomplish a particular function. It is a very difficult process to observe community dynamics in real time. However, computer simulations have often been performed on two-species systems, which have shed light on changes in population structures. Under identical parameter conditions such as nutrients and space, it has been observed that behaviours such as neutralism and mutualism show balanced population structures. These so-called symmetrical interactions have almost the same abundance of both species. Co-operation is thus seen as a fundamental requirement in bacterial communities, and such communities can have several positive effects.

Is a diverse community better?

The co-operation within a diverse community has far-reaching consequences. Bacterial diversity has proved important for ecological balance. Soil nutrient cycling is important for maintaining crop growth, and studies have shown that diverse bacterial populations are a necessary requirement for a good crop yield. A higher enzyme activity and increased mineralization are some characteristics of a bacterial community, which can lead to better plant growth. In fact, a study points out that plant species richness is directly proportional to the soil bacterial diversity. A strong relationship exists between bacterial diversity and stability of the environment. The impact of a diverse community on several ecological processes is more significant than previously thought.

When it comes to human health, research on the positive effects of bacterial diversity has brought out interesting observations. In a recent study by Rebecca M. Rodriguez et al., a higher bacterial diversity shows correlation with the overall survival of cancer patients. The highly-diverse bacterial community that inhabits our body has a positive effect on inflammation and immune responses. A study by Ying et al. shows the effect of a diverse community on the mortality rate in hematopoietic stem cell transplantation. A substantial disturbance in these communities can disturb the maintenance of a healthy state and directly increase the risk of diseases.

Thus, the aggregate of positive interactions in a bacterial community can be seen as beneficial, not only for the community itself but also the surroundings it interacts with.

Our takeaway

The observations from these micro-level environments can be representative of higher order functioning. Our understanding of community functioning leads us to believe that ‘diversity’ can be an innate social virtue and perhaps bacterial communities are not the only ones benefiting from it.

What exactly is the benefit?

Similar to bacteria, humans too have inherited many traits, leading to the current social structure. Studies show that in the last one million years, humans have evolved the ability to learn from each other to promote a cumulative society. The natural selection of pro-social motives has built an inclusive architecture. The process of cooperation involves reframing one’s perceptions and thought processes, being open to critiques and alternative explanations, performing better as a moral agent, and being tolerant and peace-loving in challenging situations. This can be seen from the fact that humans spend a great amount of time and energy in coping with challenging emotions and challenging others. It helps (in an ideal set-up, it should) individuals to become better persons – intellectually and morally (by practicing and cultivating virtues). In comparison, in a homogenous society, there would be less number of such challenges and hence, less scope for improvement.

This is similar to results from studies on micro-level cooperative traits in bacterial populations. In this regard, there are many lessons yet to be learned from our microscopic friends.

Early morning on a Sunday, my grandfather went for a walk. He realized that his right leg was stiffer and less flexible when he wanted to move fast. He has been suffering from this condition for quite a long time. He became very tired and returned home worrying about his problem. He was confused about whom to approach for getting it screened and diagnosed. We consulted doctors, who suspected arthritic joint disease – a type of autoimmune disease. They based their diagnosis on a recent, advanced diagnostic method that uses cell-free circulating deoxyribonucleic acid (DNA) in the blood.

Diagnosis, using such cell-free molecules, is non-invasive. Neurodegenerative diseases and cancers can be detected using this technique even before the onset, primarily by using blood samples. An interesting study by Vishnu Swarup and team from the All India Institute of Medical Sciences, New Delhi discovered that in Friedreich's ataxia, which is a type of neurodegenerative disease, there was a three-fold increase in the plasma DNA levels in suspected individuals compared to the normal category. This reinforces the fact that these cell-free DNA molecules are crucial biomarkers.

The novel discoveries of many years of effort by researchers have played a pivotal role in revolutionizing advanced diagnostic techniques. Multiple groups of scientists have demonstrated that the levels of nucleic acids such as DNA, ribonucleic acid (RNA), micro RNAs (miRNAs), mitochondrial RNAs and long non-coding RNAs are enhanced in the blood of affected individuals. These molecules, referred to as cell-free DNAs and RNAs, are not detected in healthy tissues.

Often, these nucleic acids are modified by the addition of specific molecules (called methyl marks) on their surfaces. These are like crowns on the king and queen that visually signify their importance. This is scientifically termed as epigenetic modification. Adding an extra methyl group to DNA on specific genes regulates the protein expression, resulting in altered levels of proteins in the tissues. The addition of methyl groups is performed by an enzyme known as DNA methyl transferase (DNMT) present inside the nucleus of the cell where DNA is located. Specifically, the cytosine (C) base of DNA gets modified into different forms such as 5-methylcytosine (5mC), 5-hydroxymethylcytosine (5hmC), 5-formylcytosine (5fC) and 5-carboxylcytosine (5caC). The type of modification varies based on the tissue of origin and the type of disease. Based on this, the severity of the disease is known and accordingly, the treatment regimen can be planned for patients.

The methyl marks on DNA surfaces are identified using laboratory-based assays such as methylLight, methyl-specific polymerase chain reaction (PCR), methylation-sensitive high-resolution melting and MIRA (methylated CpG island recovery assay). Here, DNA is isolated from the collected tissue sample and subjected to PCR following bisulfite treatment. This treatment can only convert unmethylated cytosine in DNA to uracil (one of the four nucleobases in the nucleic acid RNA). The regions that are methylated remain unchanged during PCR-based sequencing and can be easily detected. In methylLight, which is a fluorescence-based technique, methylation-specific fluorescent antibodies are used to detect modified DNA marks. Such techniques have resulted in ease of diagnosis for health care providers, which ultimately help in efficient disease management.

This diagnostic method—using cell-free DNA—has recently shown promise for prenatal diagnosis as well. Such diagnosis is important in detecting early signs of abnormal pregnancy, including genetic diseases such as Down’s syndrome, Edward’s syndrome and Turner’s syndrome. Fetal-specific DNA marks can be easily distinguished, even though maternal blood is used for clinical testing.

In addition to autoimmune diseases and prenatal diagnosis, the method can be used to diagnose diabetes, inflammation, stroke, trauma, neurological disorders such as Alzheimer’s and Parkinson’s diseases, mitochondrial disorders and metabolic syndromes. Moreover, with the advancement in technologies such as artificial intelligence and machine learning, large-scale data-rich repositories such as The Cancer Genome Atlas (TCGA), BLUEPRINT, and the Encyclopedia of DNA Elements (ENCODE) provide the necessary computational platforms to support relevant diagnostic techniques. These tools and databases will help the future growth of precision medicine and personalized care for patients. The simultaneous developments in molecular diagnostics and disease-specific database repositories will benefit the healthcare system, ultimately creating patient awareness for early prevention and healthy living.

Long-term close interactions between living organisms abound in nature. Observing these associations – such as the mutualistic interactions between insects and plants among numerous others – imbues the minds of the researchers with curiosity. For instance, a bee feeds on nectar – a sugary fluid – present in the flowers of a plant, and in return, aids in the plant’s pollination. Such exchanges occurring in nature are known as ‘mutualisms’.

A mutualism is essentially a type of interaction between two parties in close proximity, where there is an exchange of rewards and services between them. The partnership is mutually beneficial to both the parties, with minimal costs incurred on both sides. This stable relationship is based on a fine equilibrium in which one partner provides just enough rewards to get the required service, and nothing more.

Ecologists now believe that almost every species on earth is directly or indirectly involved in one or more such interactions. Fascination for such systems has inspired several researchers from the Indian Institute of Science (IISc), Bengaluru to explore the rich flora and fauna at its lush green campus and the nearby Western Ghats – one of the global biodiversity hotspots – and study these systems closely. The inquiries of some of these researchers into two such mutualistic systems have revealed the ways in which the partners have co-evolved to perform the balancing act in their complex relationships.

The fig tree and the wasp

A fig fruit (Fig. 1a) contains clusters of tiny flowers that form a unique enclosed flower arrangement, called a ‘syconium’. Hidden inside it, specialised fig wasps (Fig. 1b) help in pollen exchange between male and female flowers. In return, the fruit bestows them with nourishment and a safe haven for the wasps’ eggs. Each wasp community is completely dependent on its specific host fig tree species to complete its life cycle.

Vignesh Venkateswaran, a former Integrated-PhD student at IISc, currently a Postdoctoral researcher at the Max Planck Institute for Chemical Ecology, studied this mutualism between fig tree species – Ficus racemosa, Ficus hispida and the fig wasp communities associated with them. Venkateswaran began his PhD journey sitting near fig trees on the IISc campus for long hours to watch the fig wasps arriving from other trees at different time points, wondering about how the fig wasp’s flight abilities have evolved in connection to distance between fig trees.

While F. racemosa trees grow spaced apart from each other, F. hispida trees grow clumped together. Venkateswaran showed that the wasps that visited F. racemosa had higher energy levels enabling them to fly longer distances compared to wasps that visited F. hispida. “The fig wasp communities have been able to evolve, adapt and match their dispersal abilities with the distribution of the plants; thus, mirroring how the fig trees are spaced,” he explains. This exemplifies how mutualists co-evolve with respect to one another.

The fig tree also houses tiny nematodes (roundworms) that hitch a ride in the fig wasp’s abdomen to move from tree to tree (Fig. 1c). When Satyajeet Gupta, a former Integrated-PhD student at IISc and currently a Postdoctoral researcher at the Swedish University of Agricultural Sciences, chanced upon the fig-fig wasp mutualistic system, he wondered what strategies are employed by a third party such as these hitchhiking worms to survive in this mutualism.

Gupta identified three species of fig nematodes residing inside the gut of the female pollinator fig wasp associated with the fig tree F. racemosa. “It used to be quite fascinating to see nematodes wriggling and moving around inside the fig [wasp], every time I opened one,” says Gupta. He found that if there are too many worms boarding a wasp, they turn into parasites and affect both the wasp and the tree. Although this third-party intervention can negatively affect the mutualism, the mutualism still persists. “This is possible as the nematodes are parasitic in nature only in large numbers. At lower numbers, they probably do not harm the fig-wasp mutualism at all,” explains Gupta.

Gupta also discovered that the worms tend to board wasp ‘vehicles’ with less crowded guts using chemical cues. A worm that chooses a heavily crowded gut of a wasp would never be able to propagate itself, as the much heavier wasp would face difficulty in reaching the fig fruit of the next distantly located fig tree and most likely would get eaten by predators during its journey. After all, survival of not just the two mutualists but also the third party is important for the functioning of the ecosystem.

The Humboldtia plant apartment and its tenants

If a three-way relationship seems complicated, how might a four-way interaction look like? To find out, we hike over to the hills of the Western Ghats, where grows a unique plant known as Humboldtia brunonis (Fig. 2). This plant has special structures on its leaves that produce nectar for ants. The plant also has special shelters – hollow swollen tube-like chambers in its stem, known as ‘domatia’ (Fig. 2a), where the ants reside. In return, the ants act as security guards and protect the plant from being eaten by herbivores. “I was blown away by the idea that there is a plant somewhere in the rainforests of the Western Ghats which has a friendship with ants, and that this plant is endemic to these rainforests”, says Joyshree Chanam, a Postdoctoral researcher at the National Centre for Biological Sciences, who studied this unique ant-plant mutualism in her PhD at IISc.

Apart from the ants, Chanam discovered another tenant in these domatia – the arboreal earthworm, Perionyx pullus (Fig. 2b). She wondered how these earthworms repaid the plant for their housing. The answer was – with their droppings! The organic waste generated by these worms is absorbed by the domatia wall and becomes nutrition for the plant. “We initially thought that these domatia inhabitants are opportunistic interlopers, but it turns out that – they are mutualists,” states Chanam.

Chanam further observed a thin fungal layer in the inner walls of the domatia (Fig. 2 d). Arkamitra Vishnu, a Postdoctoral researcher at IISc, currently Program Manager at the National Centre for Biological Sciences, identified this fungus and investigated its role in this unique ant-plant mutualism. Humboldtia trees often have both earthworms and ants cohabiting in the same domatia. Vishnu found that in such cases, the ants started building a strong thick wall-like-structure called ‘carton’, made from the diverse fungal network commonly available on the plant surface and Humboldtia plant tissues – to create a partition in the housing space inside the domatia.

Staying on one side of the carton is important to the ants as well as the wall fungi, because the secretions from the earthworms can be harmful to both of them. “The wall fungi cultivated by the ant tenants may also play a role in the ant’s nutritional requirements. In return, the fungi are able to thrive in the protective environment of the domatia. Therefore, it behaves as a structural mutualist in this ant-fungus mutualism,” Vishnu explains. Similar instances of multiple mutualisms co-existing in one natural system are quite common in nature. Microbes are ubiquitously present everywhere and therefore, it is crucial to understand the roles they play in the various long-term interactions such as mutualisms.

Investigating the interactions encapsulated within mutualistic systems and deciphering the mechanisms and the hidden complexities in these long-term interactions leave ecologists utterly spellbound in the most amazing ways. Pursuing such nature-inspired projects help to not only unravel the mysteries of the natural interactions around us, but also appreciate the grandeur in the life forms amidst us.

Infectious diseases are one of the leading causes of death worldwide. Of these, bacterial infections form a major category. The serendipitous discovery of penicillin, and the subsequent advancements in research and development of antibiotic drugs proved to be a remarkable remedy for bacterial infections. But the abuse of antibiotics over the years has led to the emergence of antibiotic resistance (ABR). Some predominant examples of antibiotic-resistant bacteria include methicillin-resistant Staphylococcus aureus (MRSA), multi-drug resistant Mycobacterium tuberculosis (MDRTB) and vancomycin-resistant Enterococci (VRE), among others.

Antibiotic resistance: a global problem

Major international and national health agencies, including the World Health Organization (WHO), the Centers for Disease Control and Prevention(CDC) and the Indian Council of Medical Research (ICMR), have warned against the dreadful effects of the rapidly-escalating threat of ABR to global health and economy. According to the UN Ad hoc Interagency Coordinating Group (IACG) on Antimicrobial Resistance, at least seven lakh people die every year due to drug-resistant diseases. It is estimated that, by 2030, up to 24 million people would be thrust into extreme poverty due to antimicrobial resistance. ABR further weakens the languishing healthcare systems in developing countries. For example, without effective antibiotics, the duration of medical procedures like organ transplantation, chemotherapy and surgeries are extended.

Types of antibiotic resistance

Bacteria can be inherently resistant to certain antibiotics or acquire resistance through genetic mutations or gene transfer to survive antibiotics. Such acquired genetic changes could modify the composition of bacterial membranes to permit less or no antibiotics into the cell. Thus, the bacteria effectively resist antibiotics and survive treatment.

Alternatively, they could inactivate or degrade the antibiotics, or change the structure of their target (inside the cell) to which the antibiotic would bind and subsequently, destroy the bacteria. Two other forms of ABR include ‘cross-resistance’ – bacterial strains gaining resistance to a class of antibiotics that act using similar mechanisms, and ‘multi-drug resistance’ – the same bacteria resisting multiple drugs. Of these, it is most important to control acquired resistance where bacteria acquire changes that can help them survive in the presence of an antibiotic. Such changes include reduction in membrane permeability such that the bacteria take up lower amounts of antibiotic, synthesis of enzymes that can inactivate or degrade antibiotics, increase in the number of pumps to flush out the antibiotic, and structural alteration of the molecule that is targeted by the antibiotic to ultimately kill the bacteria.

Contributing factors

The main factors that contribute to the rise in ABR include excessive or deficient consumption of antibiotics, improper disposal of medical waste (like disinfectants and expired drugs), unhygienic sanitation systems, excessive use of antibiotics in animal husbandry, and international travel/migration. For instance, migrants or travellers may carry infectious diseases depending on the living conditions in their countries. Some of them, who have medical conditions, may be especially prone to infection by drug-resistant bacteria during their travel. The movement of patients from one country to another — for medical treatment — contributes to the risk of ABR increase in that country.

In line with Darwin’s theory of evolution, bacteria acquire ABR for survival as a part of the natural selection process. When several antibiotic drugs that are designed to kill or restrict the growth of a broad range of different bacteria are used for treatment, the few surviving bacteria develop resistance against all similar drugs. Such bacteria are called multi-drug resistant bacteria. These bacteria transfer their genetic material to others that are susceptible, thereby helping them gain resistance to the drugs and survive treatment. Thus, these different factors lead to the emergence of new bacterial strains that are resistant to antibiotics.

To interpret the onset of ABR, it is necessary to identify and understand the genes and proteins that confer bacteria with antibiotic resistance, their distribution and modes of action.

Fight against ABR

The ICMR, WHO and CDC have been taking measures to combat ABR. For instance, ICMR is actively involved in research and funding projects that develop new drugs. This includes initiatives and action plans undertaken by ICMR for the study and surveillance of antibiotic contamination and resistance. In 2015, WHO outlined a global action plan to handle antimicrobial resistance. The main aims were to spread awareness among people, and conduct research and surveillance programs. The WHO has established Working Groups for coordination, surveillance and research in regard to ABR in developing as well as developed countries. The Global Antimicrobial Resistance Surveillance System (GLASS), Global Antibiotic Research and Development Partnership (GARDP), and Interagency Coordination Group on Antimicrobial Resistance (IACG) are some of the groups working on this major global crisis.

Despite these measures, many people are not completely aware of ABR. Therefore, it is necessary to disseminate the relevant information to curb antibiotic resistance. Policymakers must have strict regulations in place to monitor the use of antibiotics. Scientists and clinicians must collaborate and approach the problem in a multi-disciplinary manner to eliminate this threat of multi-drug resistance. Further, personalized medicine and appropriate antibiotic therapy for patients can be new interventions. It is essential to conduct antibiotic resistance profiling of patients before prescribing antibiotics. This could be done using a combination of molecular techniques and well-maintained patient databases to identify the antibiotic-resistance genes present in the microbiome of a patient and prescribe drugs accordingly.

There is a serious need for medical practitioners to appropriately indicate the dose and mode of using drugs. A proper prescription combined with a change in public approach to antibiotic use would help in the fight against ABR. In summary, a multi-disciplinary approach is required to fight against ABR.

The coronavirus SARS-CoV-2 and COVID-19, the disease it causes, continue to be enigmatic. There are some who do not even realize that they are carrying the virus while others can not survive its attack. As India unlocks, the virus is reaching further pockets of the country with frailer healthcare systems. This makes it important to identify the potential sources of infection, and protect the vulnerable communities.

In the context of this article, we consider the most vulnerable communities to be those with the most aggressive symptoms, often needing hospitalization. On the other hand, those who carry the virus asymptomatically are the ones most difficult to detect, and are considered to be one of the primary sources of the virus. Had there been an affordable way to detect the presence of a virus by a personal device like those used to check blood sugar or blood pressure, things might have looked different for COVID-19 management. Unfortunately, in the absence of such technology, testing for coronavirus is done via multiple methods, each with different implications.

How do you detect a virus?

Looking for something as small as a virus is tricky. We can indirectly trace an infection by the symptoms it causes. But the symptoms of COVID-19 are varied, with symptoms like fever and cough that are not specific to SARS-CoV-2. So instead, we look for fragments of the virus in patient samples, which we can detect via molecular biology techniques. These fragments can be the viral proteins or genome - ribonucleic acid (RNA) - both of which can be found in nasal or throat swabs or sputum samples. Viral RNA can also be found in faecal samples of a small proportion of patients.

Our bodies react to infections by developing antibodies. The immune systems in our bodies detect pieces of the foreign (viral in this case) proteins, called antigens. Against these, our body makes a set of targeted proteins - antibodies - which are released into the bloodstream. This opens up the possibility of detecting viral infections through a blood test by looking for these antibodies or antigens.

RT-PCR - The gold standard method

The RNA sequence of the virus became available in February 2020. This allowed researchers to develop probes to look for specific sequences that could serve as a ‘signature’ for the novel coronavirus. In the Reverse Transcriptase-Polymerase Chain Reaction (RT-PCR) technique, the probes and enzymes amplify these sequences, which can be visualised and detected. These tests have been estimated to have at best 70% sensitivity. That means 30 out of every 100 positive samples can turn up as false negatives.

This test also requires facilities to have specialised PCR machines, trained personnel, and reaction kits that are largely imported – all adding to the cost of the process. Since the samples contain live viruses, testing is limited to facilities with Biosafety Level 2 or higher and is both labour- and time-intensive. All of these make RT-PCR a non-optimal choice for testing large numbers of people.

Antigen-antibody testing methods

Mass testing works best with techniques that require minimal infrastructure or training and are as fast and cheap as possible. Time-tested methods for these include testing for antigens or antibodies. Since antibodies bind to their respective antigens specifically, with a stock of antibodies, one can look for their antigen in blood samples, and vice versa. Both of these can be produced in large quantities, extracted and purified. Following purification, they can be immobilized on a plate or a paper strip for long-term storage and point-of-care usage. Antigen-antibody binding can be detected in multiple ways, and such tests have been deployed in diagnostics of various infectious diseases globally.

Though this may sound simple and straightforward, the reality of making a new antigen or antibody testing kit is different. To make an antigen-testing kit for SARS-CoV-2, one needs to select an antigen specifically expressed in this virus. To induce antibodies, it must be expressed in large enough quantities and should be visible to the immune system. These antibodies are generated in laboratory animals, extracted, and used for making antigen-detecting kits.

For an antibody-testing kit, we need to produce SARS-CoV-2-specific antigens using cells grown in the laboratory. This method allows large-scale production of the antigens but does not fully guarantee mimicking the native structure of these antigens. In such a case, it is difficult to predict whether they would bind with the antibodies produced in human bodies. Also, if the viral load is too low, the antigen test does not pick it up. A negative result in the antigen-test needs to be validated by RT-PCR – still the most reliable technique available.

Antibody-testing kits are known to be low on specificity. While designed to detect SARS-CoV-2, they can also detect antibodies produced against other coronaviruses. Antibodies against SARS-CoV-2 are elicited around two weeks after the symptoms appear in an infected person. So, if tested too early, one might not test positive though they carry the virus. An estimated 10% infected people do not test positive for antibodies. We don’t yet clearly know how long the antibodies against SARS-CoV-2, once formed, persist in the bodies. This means we don’t yet know how closely antibody-tests represent the present reality of the community’s health.

The Spike (S) and the Nucleocapsid (N) proteins of SARS-CoV-2 are the most preferred proteins to use as antigens in the antigen/antibody-testing kits. The N protein is the most abundant protein on this virus and thus induces antibodies easily. The S protein is the most specific protein to distinguish SARS-CoV-2 from other coronaviruses that can infect humans.

Different methods for mass surveillance

With economies opening up in the coming months, it is imperative to keep an eye on the community’s health through non-invasive, volunteer-independent surveillance techniques. This is especially important for a country like India with a large population earning its livelihoods through daily wages and pockets of high population density.

Mumbai, Pune, Delhi and many other cities have tested for antibodies via door-to-door collection of blood samples in select communities and extrapolated those results for the entire cities. These tests are increasingly being deployed in the country for large-scale testing. These results provide a basis for the local governments to evaluate the efficacy of their COVID-19 management strategies but depend on volunteer participation.

A non-invasive and volunteer-independent strategy involves checking for viral particles released into air or water by the infected individuals. Majority of this release is via respiratory droplets. But 30-60% of those infected also release non-infectious viral RNA through their faeces. While methods of air surveillance are still under development in India, sewage surveillance has already been done in cities like Chennai and Hyderabad. City sewage treatment plants record the quantity of sewage received and their geographic origins. The concentration of viral RNA in sewage water samples can be measured by RT-PCR. Through this, researchers can indirectly estimate the number of infected people in the city.

Pieces of SARS-CoV-2 RNA in faeces of infected persons can be found up to 35 days after the onset of symptoms. Thus, testing sewage containing faecal samples of a community, at any given time, paints a picture of the entire previous one month.

Why should we know this?

The results of these different testing methods are not always directly comparable. When Hyderabad’s sewage surveillance results were released, there was a lot of discussion about the unexpectedly large estimate of infected people in the city. However, the debates missed the intrinsic differences between direct and indirect testing methods that allow the latter to test much greater numbers of people.

Sewage surveillance can estimate infection levels in large communities at a negligible cost. However, it is largely limited to urban settings in India. On the other hand, healthcare workers are used to blood-based antibody tests, and the strategy can work in both urban and rural settings. These tests also give individual results, which can help in targeted demographic strategies for different genders, age groups and socio-economic backgrounds. But since these depend on people’s voluntary participation, they also tend to introduce bias in data. The study conducted in Mumbai, for example, had fewer women who got tested, which should be kept in mind by the policymakers who use the surveillance data to design their strategies in the coming months.

It is easy to be confused with all the different kinds of tests that are being done. The choice of tests is often made on the basis of tools and expertise available to a region. Their objectives can also span from individual to community management. Given the varying specificity and sensitivity of each of these tests, the estimated numbers of infected people in communities will differ in each method. With this article, we hope that if you or your community get tested, you will understand what is exactly being tested, its methodology, and interpret the results with clarity.

The COVID-19 pandemic drastically affected science and technology across the world. Conversely, it has also created many new scientific opportunities. Global scientific communities have been cooperating to further the progress of novel coronavirus (SARS-CoV-2) research and to identify new scientific activities to fill certain critical gaps. The need for continuous access to scientific data and learning is essential during this pandemic period.

Creative Commons and the Open COVID Pledge

Creative Commons (CC) is an organization that provides an open license to copy, distribute, and use intellectual property rights (IPR)-protected work. Recently, the CC organization implemented a call to promote open access in science to combat the COVID-19 pandemic. It requested scientists to follow zero embargo periods for their publications and adopt a CC BY and CC0 waiver for their research data.

CC0 means “no rights reserved”, which enables scientists to place their findings for free in the public domain. This allows others to freely enhance and reuse such works for any purposes without restriction under copyright or database law. CCBY enables researchers to remix, transform, synthesize derivatives, and rebuild the material for any purpose provided that they give appropriate credit to the original license holder and indicate what changes were made to the original material.

Restrictions in the usage of patents, copyrights, and other intellectual property rights (IPR) might end up costing lives during this pandemic. The Open COVID Pledge is an effort comprising scientists, advocates, entrepreneurs, and volunteers committed to resolving IPR-related obstacles in order to further the progress of research related to therapeutics and diagnostics for COVID-19.

The Open COVID Pledge calls for pharmaceutical industries, academic institutions and other organizations across the world to make their patents and Intellectual Property Rights (IPR) available free of charge for use in inventing new diagnostics, therapeutics, vaccines, equipment, and software solutions against COVID-19.

Further, the Open COVID Pledge requests individuals to raise awareness about the Pledge in their organizations and networks using the hashtag #OpenCovidPledge. Several big industries have already joined this pledge. IBM has shared their supercomputing power and AI for virus tracking and created a consortium to give researchers free access to over 400 petaflops of computing capacity. Furthermore, IBM has offered free access to its patent on touchscreens that use UV light for preventing pathogen transmission.

RADVAC, Mitsubishi Electric Research Laboratories, NASA-Jet Propulsion Laboratory at CalTech, Sandia National Laboratories, New Jersey Institute of Technology and many other laboratories and organizations have pledged their patents and copyrights under the Open COVID Pledge.

Open access for COVID-19 related publications

Several scientific publishing houses have been providing free access to scientific publications related to SARS-CoV-2 infection. Elsevier, a major scientific publisher, made its research and data related to COVID-19 freely available from March 13, 2020, at PubMed central and WHO COVID database. Further, Elsevier Connect created a COVID-19 Information Centre with the latest research information on SARS-CoV-2 and made more than 19,500 articles freely available via the ScienceDirect platform.

Moreover, Elsevier clinicians have also been curating data from Elsevier medical journals, textbooks, clinical information, as well as resources from other information providers and major health and government organizations for use by researchers, clinicians, and healthcare professionals. Similarly, other leading scientific publishers like the American Chemical Society and Springer Nature have also committed to supporting direct access to research and data available on their platform by the global scientific community.

Springer Nature has enabled free access to over 60,000 research articles, book chapters, and assay protocols on their platform. During this period, it has published about 10,000 new research/review articles on the COVID-19 pandemic and made all the underlying experimental data sets freely available for re-use.

The United Nations Educational, Scientific and Cultural Organization (UNESCO) has also partnered with several organizations to enable open science in the fight against COVID-19. The UNESDOC Digital Library, a part of UNESCO, recently released a set of policy guidelines for the development and promotion of open access.

The COVID-19 Universal REsource gateway (CURE) was recently established by the Indian Statistical Institute (ISI) in India, and Redalyc in Mexico. These organizations verify the relevance and accuracy of openly-licensed scientific data about the virus from different sources. The Stephen B. Thacker Center for Disease Control and Prevention (CDC) Library also maintains an up-to-date COVID-19 database. This CDC library allows researchers to search for and download research articles on COVID-19 from multiple databases.

The iSearch COVID-19 Portfolio is a comprehensive, expert-curated source for publications related to COVID-19 maintained by the NIH. WHO's COVID-19 research article database also allows searching through multiple databases and downloading articles. The Public Health Genomics and Precision Health Knowledge Base provides up to date genomics and precision health information on COVID-19.

Preprint publications

Preprints are full research papers that are shared publicly before they are peer-reviewed and accepted by a journal. Major preprint servers like bioRxiv and medRxiv have posted thousands of studies related to SARS-CoV-2 since the pandemic’s outbreak. Chemistry-related preprint servers like ArXiv and ChemRxiv have also shared several papers on COVID-19.

Preprints are initially examined by in-house staff and volunteer academics for plagiarism, biosecurity risk and completeness. After scrutiny, these preprints are published publicly within 2-3 days. The medRxiv publication duration is usually five days as it maintains a more in-depth screening process given that its publications are more directly relevant to human health.

However, there is also a global concern about non-peer-reviewed publications as they may influence public health policy decisions. For example, there have been instances of entirely computation-based analyses for COVID-19 treatments, publications with conspiracy theories, publications contradicting widely accepted public-health advice, as well as those using unprofessional language, eliciting severe concern about preprint servers.

Conclusion

There exist a multitude of scientific responses to the COVID-19 pandemic. Considering the cost of lives, several companies and investigators have waived off the usual IPR protections and restrictions through the Open COVID Pledge. Moreover, many scientific publishing companies have made COVID-19 related publications freely available online during this time. Furthermore, many researchers took advantage of the expedited framework for preprint publications during this period. However, additional scrutiny and scepticism are required while considering preprint servers as a resource for clinical applications.

Further Reading

• Bagdasarian, N., G. B. Cross, and D. Fisher. 2020. “Rapid Publications Risk the Integrity of Science in the Era of COVID-19.”BMC Medicine
• Glasziou, Paul P., Sharon Sanders, and Tammy Hoffmann. 2020. “Waste in Covid-19 Research.”The BMJ
  
• Kwon, Diana. 2020. “How Swamped Preprint Servers Are Blocking Bad Coronavirus Research.”Nature.
  
• McCreary, Erin K. and Jason M. Pogue. 2020. “COVID-19 Treatment: A Review of Early and Emerging Options.”OFID