How Curiosity-Driven Research Leads to Biomedical Breakthroughs

Fighting disease for scientists means something very different to what it means to a doctor or nurse. It is a comprehensive spectrum of research around how the human body functions. It encompasses fundamental science exploring the molecular and biological mechanisms of disease, the creation of advanced sensors, diagnostics and predictive screening tools for early detection, and the engineering of novel drugs, vaccines and living therapeutics that ultimately save lives.

In a Focus Talk at the 75^th Lindau Nobel Laureate Meeting on Wednesday 1 July, three Nobel Laureates described how their fundamental research led to treatments that have transformed the outcomes for countless people around the world.

From Fundamental Discoveries to Lifesaving Medicines

First up was Michael Levitt. He received the 2013 Nobel Prize in Chemistry alongside Martin Karplus and Arieh Warshel “for the development of multiscale models for complex chemical systems”. This pioneering research overcame the challenging task of bringing classical and quantum physics together to simulate proteins through multiscale modelling. “The first 20 years of my [academic] life were pure basic science,” Levitt confirms. “Looking at protein, RNA and DNA energetics, molecular dynamics, graph prediction, writing the first computer programs, and the first simulation of protein folding.”

Multiscale modelling laid the foundational architecture for computational structural biology, and in some ways paved the way for AlphaFold (an AI that predicts the complex 3D shape of a protein, and was the achievement that led to John Jumper and Demis Hassabis being awarded the 2024 Nobel Prize in Chemistry alongside David Baker). Levitt himself applied this new multiscale modelling technique to make progress towards therapeutics. “In 1987, I moved to Stanford… and became more involved in practical projects, one of which was humanising antibodies, early methods that led to cancer therapeutics that are still used today,” he shared. “Drugs like Avastin and Herceptin.”

Second to be introduced was 2006 Nobel Prize in Physiology/Medicine recipient Craig Mello. In 1998, Mello and Andrew Fire discovered RNA interference using the roundworm C. elegans. Contrary to the prevailing thoughts of the time, they found that gene silencing wasn’t driven by single-stranded RNA, but double-stranded RNA. For Mello, this was a true Eureka moment. “It was just such a surprise,” he shared. “These animals were so sensitive to double-stranded RNA that you could actually feed it to them, and they would silence a gene – the phenomenon itself was just inexplicable and strange and fascinating.”

In the early 2000s, Mello and collaborators confirmed that the same mechanism also exists in humans. From this, RNA interference (RNAi) has completely revolutionized biomedical research by giving scientists a universal light switch to turn off any human gene at will to see what happens. Today, RNAi has been successfully translated into a class of approved gene-specific drugs that are used to treat a small group of rare genetic disorders. And upcoming RNAi medications aim to target hypertension, hepatitis B and even Alzheimer’s disease.

The final panellist was Charles Rice, who received the 2020 Nobel Prize in Physiology/Medicine with Harvey Alter and Michael Houghton “for the discovery of hepatitis C virus”. Each played a pivotal role. Alter proved that a mysterious virus that was not hepatitis A or B was causing chronic liver disease via blood transfusions. Houghton cloned this virus’ genetic sequence. And Rice proved that this cloned genetic sequence alone could actually cause the disease.

This final step was actually one of the hardest, as creating a useful clone of the disease proved stubbornly difficult. “We tried to demonstrate a functional molecular clone repeatedly over almost a decade and failed, so when we first saw evidence of hepatitis C replication in a chimpanzee inoculated with synthetic genome RNA, that was pretty exciting,” he said. It would take until the mid-2010s before small molecule inhibitors for hepatitis C were used in people. Rice adds: “This gave rise to an interferon-free virologic cure for hepatitis C in more than 99% of the people that are treated”.

What each of these Laureates have in common is that their achievements relied on a healthy dose of curiosity mixed with a splash of serendipity. When they started out, none of them knew where their research would lead, but they persisted because they had a puzzle they had to solve.

In Safe Hands With the Next Generation

Similar traits were on display in the Young Scientists presenting their work at a Next Gen Science session on Monday 29 June. A particular highlight was the 10-minute talk from Yunchan Hwang (Massachusetts Institute of Technology, USA). This presentation described how optical coherence tomography (OCT) has advanced from its 1991 invention to its current status as a ubiquitous, contrast-agent-free retinal imaging tool. By developing advanced computational tools to measure micro-scale structural disruptions and track blood flow speeds in individual capillaries, Hwan explained how they took OCT a step further, showing its potential as a non-invasive diagnostic for various diseases, including but not limited to Alzheimer’s, hypertension and diabetes.

Another excellent presentation came from Zhanyi Xia (Chinese Academy of Sciences, China), whose study focused on Glycogen Storage Disease type 1, a rare metabolic disorder where the body cannot unpack glycogen from the liver and release it as glucose into the bloodstream. Using advanced single-particle cryo-electron microscopy, Xia mapped out the structural mechanics of two interacting membrane proteins whose mutations turn out to be the cause of the disease.

Perhaps the closest to application was the biosensor developed and described by Jaymi January (University of the Western Cape, South Africa). By replacing conventional antibodies with highly stable, engineered nanobodies paired with perovskite nanomaterials, the sensor January and collaborators have developed is capable of spotting exceptionally low concentrations of biomarkers for cancer and long COVID. And the best part is that by simply changing the nanobody recognition element in the sensor, the same sensing strategy could detect various different diseases, representing a highly versatile diagnostic platform.

Turning Immune Tolerance Into a Targetable Cure

Perhaps the most dramatic and recent example of curiosity-driven research leading to new and innovative medical breakthroughs came in Frederick Ramsdell’s Lecture on Thursday 2 July. Ramsdell received the 2025 Nobel Prize in Physiology/Medicine with Mary Brunkow and Shimon Sakaguchi “for their discoveries concerning peripheral immune tolerance”. In his talk, he delved into how his work has deciphered, harnessed and, most recently, shown the ability to enhance the human body’s adaptive immune response towards the goal of transforming the lives of people with autoimmune and inflammatory diseases. As he made clear in his address: “If the hypothesis is right, we should be able to restore normal immune function to these patients,” he said. “So we actually like to think about this as being a cure rather than a treatment.”

This cure involves regulatory T cells, whose role he and the other Prize winners discovered is vital for maintaining immune tolerance, acting as both anti-inflammatory shields and tissue rejuvenators. Though these properties made them an incredibly promising frontier for targeted cell therapies, in 2015, trials proved that infusing unaltered regulatory T cells back into patients was safe, but not curative.

But then, in 2020, scientists began genetically engineering these cells with specific receptors to migrate directly to sites of active inflammation. And early clinical trial results from the biotechnology company Sonoma Bio that Ramsdell co-founded were encouraging. Though only a very small sample size, and therefore far from conclusive, the trial revealed that patients with severe, highly refractory rheumatoid arthritis who had failed multiple biologic therapies showed dramatic drops in joint swelling, localized inflammation and pain. “We have patients who have been running for the first time in five years after getting the product,” he enthused. “We’re pretty encouraged by this.”

With other groups exploring engineered regulatory T cell therapy for multiple sclerosis, Crohn’s disease, type 1 diabetes, graft-versus-host disease and many more, Ramsdell is optimistic that this new technology will deliver genuine, long-term cures. “We’ve got a ways to go,” he concluded. “But we can see that on the horizon.”