For decades, molecular biology has operated on a powerful paradigm: a protein's specific amino acid sequence dictates its unique three-dimensional structure, which in turn determines its function. Yet, a persistent paradox has haunted the field. Up to 20% of the proteome consists of so-called low-complexity domains (LCDs)—stretches of repetitive, seemingly "nonsensical" sequences that lack a stable, folded structure [1, 2]. Long dismissed as functionless "junk" or mere linkers, these intrinsically disordered regions posed a fundamental challenge: how does the cell harness this apparent chaos to perform some of its most critical tasks?
The journey to understanding LCDs began in the 1980s with two parallel, seemingly unrelated observations. Researchers, including a young Steven McKnight, noted that potent transcriptional activators contained bizarre, repetitive domains that defied structural logic but were essential for function [3]. Frustrated by their enigmatic nature, many, including McKnight, temporarily abandoned the problem [4]. Simultaneously, cell biologists studying the nuclear pore complex (NPC) identified that its central channel was lined with nucleoporins containing repetitive phenylalanine-glycine (FG) motifs—a classic type of LCD [2]. This FG-repeat meshwork was the gatekeeper of the nucleus, but the physical principle behind its remarkable selective permeability remained a deep mystery. The field was left with a tantalizing question: was there a common biophysical language hidden within these simple sequences?
The 2025 Lasker Basic Science Award, celebrated in a recent PNAS perspective, honors the two scientists who, from different starting points, cracked this code: Steven McKnight and Dirk Görlich [1]. Their work revealed that LCDs drive a fundamental process of cellular organization known as liquid-liquid phase separation (LLPS), creating dynamic, functional compartments without the need for membranes.
McKnight's return to LCDs was sparked by serendipity. In 2012, a "fishing" experiment to find the cellular target of a small molecule, isoxazole, went spectacularly awry, pulling down hundreds of proteins [2, 4]. Instead of a failure, it was a revelation. The precipitated proteins were overwhelmingly RNA-binding proteins known to form cellular granules, and their common feature was the presence of LCDs [5].
This led to a bold hypothesis: the LCDs themselves were mediating a phase transition. McKnight's team elegantly proved this by showing that purified LCDs from these proteins could spontaneously self-assemble into hydrogels in vitro [5]. Using X-ray diffraction, they found these gels were composed of cross-beta fibers, structurally similar to the pathological amyloid plaques seen in neurodegenerative diseases. However, there was a crucial difference: unlike pathological amyloids, these LCD-driven fibers were fully reversible [5, 6]. This "virtue of weakness"—the ability to form and dissolve weak, transient interactions—was the key to their biological function, allowing for the dynamic assembly and disassembly of cellular machinery for processes like transcription [1].
Working in parallel, Dirk Görlich was tackling the NPC puzzle. In 2001, he proposed a revolutionary "selective phase" model: the FG-repeat LCDs within the NPC coalesce to form a gel-like phase that acts as a selective barrier [2]. He posited that nuclear transport receptors could "dissolve" into this phase and pass through, while other large molecules would be excluded.
In a series of landmark experiments, Görlich's lab provided definitive proof. In 2006, they demonstrated that purified FG domains could indeed form a hydrogel that perfectly mimicked the selective permeability of a native NPC—blocking inert molecules while allowing transport receptors to pass through at physiological speeds [7, 8]. The culmination of this work came in 2021, when his team built a functional, selective transport barrier from a single, simple synthetic peptide containing only repeated GLFG motifs [9]. This minimalist system irrefutably established that phase separation driven by LCDs is the core mechanism of the nuclear pore's function.
The convergence of McKnight's and Görlich's work has catalyzed a paradigm shift in cell biology. It has unveiled a new layer of cellular organization based on dynamic, self-assembling "membraneless organelles" or "biomolecular condensates." This principle explains the formation and function of numerous cellular bodies involved in RNA processing, stress response, and signaling.
Furthermore, this discovery has profound implications for human disease. The work showed that disease-causing mutations in proteins associated with neurodegenerative conditions like ALS and frontotemporal dementia often occur within LCDs. These mutations disrupt the delicate balance of reversible phase separation, tipping the scales toward the formation of irreversible, pathological solid aggregates [1, 6]. This reframes these conditions as disorders of phase transition, opening entirely new avenues for therapeutic intervention.
The future of the field lies in dissecting the complex regulatory code that governs LLPS in vivo and in learning to engineer it for therapeutic and biotechnological purposes. Systematically mapping the sequence-to-phase-behavior grammar of LCDs will require screening vast combinatorial libraries. This is a task where autonomous screening platforms, which can link expression to survival and generate structured data for AI-driven design, could dramatically accelerate discovery.
In conclusion, the pioneering research of McKnight and Görlich transformed our view of cellular "dark matter." What was once dismissed as junk is now understood as a fundamental language of life, a code that uses the physics of phase separation to orchestrate the dynamic, intricate dance of the cell. Their discoveries have not only solved decades-old puzzles but have also laid the foundation for a new and exciting era of biological inquiry.
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