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.