Any machinery with the best of the designed parts will be damaged due to wear and tear over time. Gears catch, joints stiffen and engines stall unless they are lubricated with oil or grease. It is easy to forget that life, too, needed lubrication to get started.

In the early history of life, long before genes and proteins took centre stage, lipids may have quietly shaped the very possibility of living systems. Certain oily molecules, when placed in water, naturally arrange themselves into bubbles and sheets, forming compartments that can trap other substances inside. These self-organising structures are simple but effective. They offer one of the earliest known solutions to the problem of containment. Life needs a way to keep its chemistry separate from the world outside. Without that, even the most favourable beginnings would simply dissolve away.

As life evolved, lipids remained central to its workings. But the kinds of lipids that living things use are not all the same. One of the deepest differences among organisms lies in how their cell boundaries are built. Archaea, bacteria and eukaryotes all use lipids, which have a water loving hydrophilic head and a water repelling hydrophobic tail, to form a protective layer around themselves. However, archaeal membranes use chains which are often branched and cyclisedwhile bacteria and eukaryotes use straight chain fatty acids. These differences may seem trivial but they come from distinct biosynthetic pathways what cannot be easily switched.

These differences go all the way down to the enzymes involved and the raw materials they use. We believe the last universal common ancestor of all life had a kind of mixed membrane, containing both types of lipids, and over time, different groups specialised in one or the other. Interestingly, even though the cells of animals and plants are more closely related to those of archaea, they use the same kind of lipids as bacteria. This is likely because the ancestors of complex cells once absorbed a bacterial partner that provided not just energy but also an extra recipe for building its membranes.

Lipids, though, do much more than form membranes. Over time, they evolved into an astonishing variety of roles. Some became reservoirs of stored energy. Others took on signalling duties, helping cells talk to each other or respond to their environment. In animals, lipids became part of thermoregulation, sensory adaptation and waterproofing. In toothed whales, they took on a particularly striking function called sound shaping. These whales use echolocation to navigate and hunt, and they rely on a region of specialised cranial fat to focus and transmit their clicks. This acoustic fat is made from unusual lipids, waxy and branched, layered precisely to conduct sound. Understanding how these lipids work, or how they evolved, remains difficult. These molecules sit in tissues that are hard to access, and their functions depend on subtle physical interactions with each other that are only just beginning to be mapped.

Other animals show different innovations. Reptiles and birds, for example, have thick skin that protects them from water loss. This skin contains special lipids that form a kind of barrier. These adaptations allowed their ancestors to move away from water and into drier habitats. Some of these molecules were once thought to be unique to mammals, but are now known to appear in crocodilians and other reptiles as well. Still, these molecules do not fossilize, so piecing together their history means working backwards from what we find in modern species.

Plants, meanwhile, adapted differently. Instead of embedding fats within layers of skin, they developed a waxy surface coating made from very long-chain molecules, often even longer than those found in animals. While animal skin lipids typically have chains of around sixteen to twenty-four carbon atoms, plant surface lipids can extend beyond thirty, creating a dense, water-resistant layer that protects them from drying out.

Some algae and simple land plants make compounds that resemble the ones animals use in brain signalling, even though plants do not have the same kinds of receptors as animals do in their brains. In plants, these compounds appear when cells are under stress, and they have been linked to processes like injury response and growth regulation. The fact that they appear in very different groups of organisms suggests that in addition to them being present in a common ancestor, similar evolutionary needs in later species also led to similar solutions.

Still, despite the complexity, some patterns are clear. Across all life, lipids have been shaped by the pressures of the environment. Whether for surviving heat, resisting dryness, storing energy, communicating with other cells or navigating the deep sea, lipids have taken on new roles again and again. They are not just parts of the cell wall. They are flexible, adaptable molecules that keep changing with the needs of the organism.

What began as a simple oily film in the waters of early Earth has become one of the most versatile tools in biology. They may be harder to study than genes or proteins, but they carry a long and varied history written in the language of chemistry and shaped by the needs of survival. From archaea in hot springs to birds in dry forests and whales in the deep sea, lipids continue to evolve alongside life itself. It is perhaps not wrong to say that evolution is smooth, like a well-oiled machine.

From a healthy cell to a cancer cell

Every cell holds an instruction manual in the form of DNA — a blueprint that guides it to function, grow, and divide in an orderly fashion by producing the right proteins. However, the very ability of cells to grow and replicate comes with a cost. DNA, though resilient to changes, can sometimes be altered. These changes, or mutations, may result in faulty proteins that disrupt normal cell function.

The odds of a DNA sequence getting mutated are about 1 in 100,000. Fortunately, our cells are equipped with highly efficient DNA repair systems that quickly fix most errors. Damaged cells are often destroyed by the body’s own defense mechanisms. But on rare occasions, defective cells escape detection, multiply, and form an abnormal mass — a tumour.

A tumour becomes dangerous when it grows large enough to press on vital organs. If it invades nearby tissues, taking up space and consuming nutrients, and spreads to other parts of the body, it is classified as cancer.

The primary triggers for changes in the DNA and thus cancer can be environmental, biological, or lifestyle-related. Prolonged exposure to tobacco smoke, harmful radiation, or toxic chemicals can damage the DNA. Certain viral infections can also introduce mutations. An unhealthy lifestyle and chronic stress further strain the body, making DNA more vulnerable. Often, it’s a combination of these factors that sets cancer in motion.

Immunity against cancer

Our body is naturally equipped to defend against invading pathogens and other harmful agents, an ability known as immunity. This defense system is a highly coordinated, complex network of cells and molecules that detect and eliminate threats, keeping us healthy. It constantly performs surveillance, scanning for anything unusual. This same immune system is capable of detecting cancer cells. Those with weak immune systems have a higher risk of developing cancers.

When a healthy cell turns cancerous, it displays special signals called tumour-associated antigens like ID tags, that warn and activate immune cells. For example, specialized fighter cells such as Natural Killer cells and T cells can recognize and destroy these tagged cells.

But cancer is a master of trickery. Over time, these sneaky cells evolve and learn multiple tactics to evade detection, hiding from the immune system for years before they resurface. This ability to adapt and survive is a trait rooted in evolution itself, that explains why cancer can recur even after treatments.

How do cancer cells evade the immune response?

One way cancer cells disguise themselves as normal cells, is by producing protein markers of normal cells in abundance. These false cues can confuse immune cells, exhaust them, creating physical barriers that prevent an effective attack.

Another strategy is the formation of a protective shield known as the tumour micro-environment. This specialised environment shelters cancer cells and blocks immune cells from infiltrating or recognizing them. As a consequence, immune surveillance is weakened, and tumour cells can thrive unchecked.

Adding to their defense, research shows that some cancer cells can steal mitochondria—the energy-producing powerhouses of cells, from T cells. This deprives the T cells of the energy they need, rendering them ineffective and reducing the body’s anti-tumour immunity.

Such advanced escape mechanisms employed by cancer cells have pushed scientists to develop newer treatment strategies. While traditional approaches such as surgery, radiation, and chemotherapy aim to directly remove or destroy cancer cells, modern immunotherapies are designed to reawaken and empower the immune system, enabling it to combat a wide range of cancers more effectively.

Choices of Immunotherapies

Immunotherapy includes a range of strategies to harness the body’s own defenses against cancer.

One approach is to keep immune cells active for longer by blocking the checkpoints that normally dampen their activity. This frees them to attack cancer cells more aggressively. Another involves administering highly specific antibodies that act like guided missiles, homing in on cancer cells. In some cases, viruses are genetically modified to infiltrate and destroy cancer cells from within—a method known as oncolytic virus therapy.

Despite their promise, immunotherapies also have some caveats. An overstimulated immune system can trigger excessive inflammation, damaging healthy tissues.

A more advanced option that can circumvent these challenges, effective even when other immunotherapies fail, is CAR T-cell therapy—short for Chimeric Antigen Receptor T-cell Therapy. In this treatment, a patient’s own T cells are collected and genetically engineered to produce a special chimeric receptor: part of it comes from antibodies that recognize cancer cells, and part from T-cell proteins. This receptor works like a GPS, locking onto tumour-specific antigens and enabling T cells to bind to and destroy only cancer cells. Once modified and tested for efficacy against the patient’s cancer cells, these cells are multiplied in the lab, and infused back into the patient. Inside the body, they continue to replicate, patrol, and eliminate cancer cells. These CAR T-cells can remain active in the body, sometimes, for years.

CAR technology is not limited to T cells; other immune cells such as dendritic cells and natural killer (NK) cells can also be adapted, leading to CAR-NK therapies. Overall, CAR technology paves a way to highly personalized treatments tailored to individual patients, a hallmark of precision medicine.

However, CAR-based therapies also come with a few challenges. Unlike many treatments, CAR T-cell therapy cannot be tested in animal models before human use. It is expensive—often costing up to 10 times more than conventional cancer treatments available today. They may still cause severe immune-related side effects in some patients. And, so far, they have no success against solid tumours. Currently, they are approved mainly for certain blood cancers, which are easier for immune cells to access because they circulate throughout the body.

Nevertheless, CAR T-cell therapy remains a powerful form of immunotherapy. Custom-designed for each patient, it mounts a stronger and more targeted attack against cancer. It typically requires only a single infusion and can offer long-term protection. With ongoing research and advancements, CAR-cell therapy holds great promise and may one day replace conventional chemotherapy as a front line cancer treatment.

For that is what the Western Ghats can seem like to those of us used to the gentle curves of the plains – a wall of trees that is eerily silent save for the droning of the cicadas. Every year, thousands of people travel to nondescript towns and villages in Maharashtra, Karnataka, Kerala and Tamil Nadu to trek, birdwatch, film, and in cases like ours, research. What makes the Ghats a haven for nature lovers is also why we study them- it is one of the 36 ‘biodiversity hotspots’ in the world. According to the highly cited original paper, this means that it contains more than 1,500 ‘endemic’ plant species (species that are found nowhere else in the world). Furthermore, more than 70% of its forest cover has been lost, making the region a top priority for conservation biology.

So how much biodiversity does the Western Ghats really have? The research is ongoing. But, we do have estimates for some organisms – approximately 100 species of mammals (of which 11% are endemic), 200 species each of amphibians and reptiles (78 and 62% respectively are endemic), 300 species of freshwater fish (41% are endemic), 500 species of birds (4% are endemic) and 600 species of trees (56% are endemic). But for scientists interested in tropical mountain chains, the real headscratcher is this – why is there so much biodiversity in the Western Ghats, and where did it come from?

From an evolutionary biology perspective, three processes ultimately determine the distribution of biodiversity- speciation, dispersal and extinction. Speciation refers to the creation of new species from pre-existing ones, whereas dispersal is the movement of species into an area from others. Both act together to increase the number of species in a region. Alternatively, extinction, which refers to the death of a species, decreases the biodiversity of a region.

What happened in the Western Ghats:

Most of the examined animal diversity of Peninsular India (roughly below 23° N latitude), of which the Western Ghats is a part, dispersed into India within the last 65 million years, following which speciation events took place. One example is that of toads, which likely dispersed from elsewhere in Asia, with subsequent speciation probably promoted by the diverse habitats and heterogenous landform of the Ghats. A well-studied case of how speciation can be facilitated by separating organisms from each other, is the Palghat Gap: a 30-km stretch of land at 200 m elevation that cuts through the mountains (which rise to 2 km on either side). Researchers speculate that the gap has promoted the separation of populations of a single species into different species over time.

On the other hand, the Western Ghats also contains some groups of animals that have remained there since their origin! A recent study of ours’ shows that an ancient group of long-legged centipedes called scutigeromorphs have existed in the peninsular region of India for approximately 125 million years, eventually evolving into multiple species in the Western Ghats. Such species are called ‘Gondwanan relicts’ as their ancestors were present on Peninsular India back when it was attached to Africa, South America and Australia as part of the supercontinent Gondwana, more than 200 million years ago.

Despite a century-old battle to eradicate malaria, it remains one of the leading causes of global morbidity and mortality. WHO reported an estimated 247 million cases of malaria and more than 0.6 million malaria-associated deaths in the year 2021 in 84 malaria endemic countries. A majority of these cases are reported in countries of the African region. Within India, malaria incidence and deaths are higher in the states of Odisha, Chhattisgarh, Jharkhand, Meghalaya and Madhya Pradesh. The disease predominantly affects children under the age of 5 and pregnant women. Patients show symptoms such as irregular fever, chills, headache and malaise. Under severe disease conditions, complications arise, leading to renal failure, cerebral malaria, pulmonary oedema or haemorrhage.

The shape-shifting Plasmodium parasites

To date, more than 200 species of Plasmodium have been described, which cause malaria in a diverse range of vertebrate hosts. 5 strains are known to cause disease in humans. The parasites have a complex life-cycle, both within the mosquito vector, through which the disease is transmitted, and the human host.

The parasite grows in female Anopheles mosquito and in humans, jumping between the two through mosquito bites. Within the human host, sporozoites navigate their way to the liver. They infect liver cells to form thousands of merozoites. These enter the blood stream, infect red blood cells (RBCs) and develop to give rise to ring, trophozoite and schizont forms. Mature schizonts rupture infected RBCs. This allows several merozoites to come out, which then infect fresh RBCs to continue the cycle. During this stage, some of the merozoites also get programmed to form male and female gametes, which are then picked up by mosquitoes.

Once in the mosquito’s mid-gut, the male and female gametes fuse to form a zygote. It matures to form a motile ookinete, which traverses the epithelial lining of the mosquito to form an oocyst. A single oocyst gives rise to close to a thousand sporozoites, which traverse to the salivary gland of the mosquito, and are now ready to find new hosts.

Those developing vaccines against the Plasmodium are interested in understanding this complex life-cycle of the parasite. That is because, there is a huge diversity in the proteins on the cell surfaces of the parasite during its developmental stages. And these proteins are the primary target of the immune system.

For example, PfEMP1 (P. falciparum erythrocytic membrane protein 1) is a protein expressed in at least 60 different combinations and targeted to the surface of parasite infected RBCs. While host immune system can identify one form of the protein, allowing it to clear these parasite infected RBCs, this immunity is lost when the parasites switch to express a different form of PfEMP1. These complexities make it challenging for the host immune system to keep a check on these enigmatic parasites, unable to target them at the right stage.

Malarial vaccines – One step at a time

Out of 133 malaria vaccines that have been in clinical development, two vaccines have been prequalified and recommended by the WHO – RTS,S/AS01E and R21/Matrix-M. We will focus on these two while others are still in trials or did not meet the WHO-set criteria.

Vaccine development requires identifying a part or whole of the pathogen, which will not cause an infection but help the immune system in identifying the pathogen quickly in case of a real infection. These are called as antigens.

Initial efforts of malarial vaccine development used radiation-inactivated sporozoites. They don’t cause infection but still elicit immune responses. But this helped in achieving only partial protection. However, the researchers found that most of the antibodies produced through this vaccine was against the circumsporozoite protein (CSP), a major surface protein on sporozoites. This showed that the immune system acted the most against this protein, and CSP became the antigen of choice in malarial vaccine development.

The first effort was in collaboration between GlaxoSmithKline and Walter Reed Army Institute of Research, which resulted in the development of RTS, S vaccine. It is a designed like a virus. It contains 18 copies of a part of the CSP, called the repeat regions. These are attached to a hepatitis viral surface antigen, which helps in presenting CSP on virus-like particle’s surface. More access to CSP ensured better immune response.

This vaccine also contains adjuvants; substances that promote immune response, decrease the dose of antigen required and prolong the duration of protection. It uses a combination of liposomes and saponins (detergents) obtained from the Chilean soapbark tree, also known as Quillaja saponaria Molina, as its adjuvant.

Meeting the then WHO set goal of >50% efficacy, RTS, S/AS01 also known as Mosquirix^TM was the first to be approved in 2021 by the WHO for large scale production and trials.

Not all was sorted still. Clinical trials revealed that protection against malaria after administration of this vaccine is partial and wanes over time, leading to the recurrence of the malaria cases. We still needed vaccines with prolonged protection and improved efficacy.

Next came the R21/Matrix-M^TM vaccine developed by Oxford University. Similar to the RTS, S vaccine, the R21 vaccine is also a virus-like particle, based on CSP. This, however, had reduced amount of viral antigen used in RTS, S vaccine.

This vaccine also used an advanced Matrix-M^TM adjuvant. Developed by Novavax, it is composed of fractions obtained from the bark of Quillaja saponaria tree, mixed with cholesterol and phospholipids to give rise to unique nanostructures that enhance the host immune responses. It met the revised target of reaching >75% efficacy. And in 2023, WHO approved the vaccine for use in children aged 5 to 36 months.

The next obvious step is to produce and distribute the vaccine at a large scale. A cost-effective vaccine will be important for mass-scale vaccination in malaria prevalent countries of Africa. Serum Institute of India Pvt. Ltd. (SIIPL) has now been granted the licensure for production and distribution in Ghana. Current production capabilities at SIIPL are estimated to be over 200 million vaccine doses annually. They played an important role in developing affordable vaccines against many diseases, including COVID-19. And it remains to be seen if they transform malaria management.

Until then, mosquito bed nets, anti-mosquito sprays, rapid diagnostic tools for detection, and antimalarial therapies remain our most viable tools to use.