A new generation of radiotherapies for cancer, and why we sigh

On the Science podcast, Robert Service discusses a surge in radiopharmaceuticals for cancer, covering how radioactive isotopes are linked to targeting molecules, the differences between alpha and beta emitters, and the complex supply chains needed to deliver short-lived isotopes like lutetium-177 and actinium-225. The conversation highlights receptor targets such as PSMA in prostate cancer and somatostatin receptors in neuroendocrine tumors, along with advances in linker chemistry to limit kidney exposure. The episode also delves into production scale-up, including Oak Ridge's actinium work and a new Utah linear accelerator, emphasizing the growing commercial interest in these therapies. The second segment reveals how sighing affects the lung surface and surfactant, altering interfacial properties to maintain lung compliance.

Radiopharmaceuticals and Cancer Therapy: An Emerging Field

The episode opens with a clear view of how radiopharmaceuticals work, explaining that radioactive atoms are linked to molecules that specifically bind to cancer cells. This targeting is a practical realization of the lock-and-key concept, leveraging cancer cell surface receptors such as PSMA in prostate cancer and somatostatin receptors in neuroendocrine tumors. The host notes the long history of radiotherapy and how targeted radiopharmaceuticals represent a refinement that aims to maximize tumor destruction while minimizing normal tissue damage. A key example discussed is the use of iodine for thyroid conditions in the 1940s, which demonstrated the feasibility of tissue-specific radiation delivery and helped set the stage for modern approaches.

"Every single radioisotope is unique, and it has to have its own supply chain." - Robert Service

Isotopes, Half-lives, and the Choice Between Alpha and Beta Emitters

The conversation moves to the properties of different isotopes. Beta-emitters, like lutetium-177, travel further in tissue, making them suitable for larger or diffuse tumors, while alpha-emitters deliver a concentrated punch over a short distance, enabling highly localized tumor cell kill. The half-life of isotopes shapes logistics: lutetium-177, with a half-life of about 6.5 days, requires careful planning for production, shipment, and clinical use. The potential of actinium-225 is highlighted for its potent alpha emissions, but its supply chain is less developed, prompting ongoing efforts to create scalable production and distribution networks. The host emphasizes that isotope choice is a balance of therapeutic efficacy, safety, and practical logistics.

"it's like you're shipping ice cubes around, so these things are melting as you go." - Robert Service

Supply Chains, Production, and Scaling Isotopes

The discussion shifts to how radiopharmaceuticals are produced and distributed. Short-lived isotopes cannot be stockpiled; they must be produced, attached to targeting agents, and shipped rapidly to patients. The podcast stresses the challenges of creating reliable supply chains for different isotopes, noting that while lutetium-177 has a healthy supply chain, actinium-225 requires new infrastructure and processes. The Oak Ridge National Laboratory experience—where thorium decay yields actinium-225 via thorium cows—illustrates a legacy source that must be scaled up. A new linear accelerator in Utah is highlighted as a technology designed to produce multiple medical isotopes more efficiently, potentially enabling large-scale Actinium-based therapies. The segment underscores that progress in both research and manufacturing is driving broader clinical adoption.

"There has been enough positive results and frankly commercial success that then drives the market forward." - Robert Service

Targeting Molecules, Linkers, and Safety Considerations

Researchers continue to hone targeting molecules that distinguish cancer cells from normal tissue, using receptors that are upregulated in tumors but may be present in normal tissue as well. The episode discusses the use of precise receptor targeting and the development of novel linkers that improve safety by facilitating clearance of the radiopharmaceutical from non-target tissues. A notable example is designing linkers that kidney enzymes can cleave to speed elimination while preserving tumor-killing activity. The dialogue emphasizes that even with strong targeting, off-target effects remain a concern, prompting ongoing work to optimize both the targeting component and the linker chemistry to reduce renal exposure and systemic toxicity.

Clinical, Economic, and Future Prospects

The segment closes with reflections on the clinical pipeline and market dynamics. The host notes ongoing trials and the arrival of approved therapies like lutetium-177–based treatments, while acknowledging persistent supply chain constraints as competing research programs scale up. The broader message is one of cautious optimism: the combination of compelling clinical results and the ability to scale production is catalyzing investment and collaboration across academia and industry. The episode then transitions to a completely different topic focused on sighing and lung surfactants.

"There has been enough positive results and frankly commercial success that then drives the market forward." - Robert Service

Anatomy of a Breath: Sighing and the Lung Surface

The second half of the podcast explores sighing and the lung surface. The guest explains the alveolar air-liquid interface, where a thin liquid layer meets air and surface tension is shaped by surfactant. This film, composed of lipids and proteins, lowers surface tension and allows the lungs to expand and contract efficiently. The discussion recounts the neonatal context where surfactant replacement therapy is used for premature infants, illustrating how surfactant reduces breathing difficulty and supports lung development. The researchers then introduce the concept of multilayer surfactant structures and how breathing dynamics influence their organization. A key finding is that deep breaths cause a restructuring of the interface, enriching saturated lipids, which improves the ability to compress and expand the surface during respiration.

"it seems to be enriching in the saturated lipids." - Maria Clara Nova Silva

Measuring the Interface and the Role of Breathing Deformations

Using neutron reflectometry and compositional analysis, the researchers show that normal tidal breathing does not markedly alter the interface, but deep breaths lead to a larger, reorganized multilayer structure. Saturated lipids appear to concentrate at the interface under deep-deformation conditions, while unsaturated lipids and proteins appear to regulate this process. The work posits that sighing serves a regulatory purpose for maintaining surface stress and lung compliance, particularly when mechanical ventilation alters natural breathing. The researchers caution that translating in vitro findings to in vivo settings requires careful validation, but the data suggest that periodic deep breaths may be important for maintaining a healthy lung surface. The episode also notes the typical sigh frequency in everyday life is around a dozen per hour, illustrating how regular breathing patterns could influence lung mechanics in healthy individuals.

"the rate is around a dozen sighs per hour" - Maria Clara Nova Silva

Clinical Implications and Future Research

The discussion ends with potential translational implications for therapies and devices that could mimic or encourage the beneficial restructuring of the surfactant interface, particularly in patients on mechanical ventilation or those with conditions like ARDS. The researchers emphasize that while the in vitro results are promising, in vivo testing is essential to understand how sighing and interface restructuring translate to patient outcomes. They also suggest that reframing how clinicians think about surfactants—not just as a chemical supply but as a dynamic interfacial system with time scales—could influence future treatments for lung diseases and neonatal care.

"There has to be careful testing in vivo, but this framework could shift how we think about surfactants in disease and therapy." - Robert Service

Top-line takeaways from this episode include the rapid growth of radiopharmaceuticals as a cancer therapy, the centrality of supply-chain logistics for short-lived isotopes, the nuanced decision-making around alpha versus beta emitters, and the potential for new linker chemistries to improve safety. In the sighing segment, the research highlights how breathing patterns interact with the lung surface at the nano-scale, offering a fresh perspective on surfactant function and possible clinical applications for ventilation strategies and neonatal care. The episode invites continued cross-disciplinary collaboration among chemists, biologists, clinicians, and engineers to translate these insights into scalable therapies and improved patient outcomes.