Perspectives in 2022

The ‘predictive validity’ of decision tools such as disease models that are used in drug research and development (R&D) — the degree to which the output from a tool correlates with clinical utility in people — has a major influence on R&D productivity. This article explains this influence and discusses methods to evaluate and improve the predictive validity of decision tools, with the aim of supporting the application of more effective tools and catalysing investment in their creation.

Emerging understanding of biomolecular condensates — transient liquid-like droplets made up of proteins and nucleic acids — in normal and aberrant cellular states is providing new insights into human diseases. This Perspective proposes that such insights could enable a previously unexplored drug discovery approach based on identifying condensate-modifying therapeutics, and discusses the strategies, techniques and challenges involved.

Evidence for a fluid clearance pathway in the central nervous system known as the glymphatic system has grown in the past decade. Nedergaard and colleagues overview the evidence for the glymphatic system and its role in disease, and discuss opportunities to harness the glymphatic system therapeutically; for example, by improving the effectiveness of intrathecally delivered drugs.

This Perspective article discusses the mechanisms used by tumours to evade the immune system, collectively called adaptive immune resistance (AIR), and why defining AIR mechanisms in the tumour microenvironment is key in immunotherapy development.

Phenotypic drug discovery has re-emerged over the past decade as an approach to systematically pursue drug discovery based on therapeutic effects in realistic disease models. This article discusses recent successes with this approach, and considers ongoing challenges and strategies to address them.

Psychedelic drugs such as psilocybin and lysergic acid diethylamide (LSD) have emerging therapeutic potential for neuropsychiatric diseases such as depression and anxiety. In this Perspective, McClure-Begley and Roth discuss the promises and pitfalls of psychedelic pharmacology, including complex activity profiles beyond canonical 5-HT_2A receptor activation that continue to be elucidated. They consider progress and challenges for clinical studies, as well as prospects for parsing the therapeutic from psychedelic effects of this class of compounds to develop ‘cleaner’ drugs.

Many drugs that target amyloid-β in Alzheimer disease have failed in clinical trials. Karran and De Strooper analyse clinical trial data for these drugs in the light of drug properties that could affect their clinical performance. They propose that amyloid plaque would need to be reduced to a low level to reveal significant clinical benefit and that there will be a lag between the removal of amyloid and the potential to observe such a benefit.