Andrew Folkmann, Ph.D.
Assistant Professor, Biochemistry
Emergent Properties and Function of Biomolecular Condensate
Research Keywords: biomolecular condensates, phase separation, soft matter, cellular compartmentalization, chemical microenvironments, interfacial regulation, emergent properties, molecular transport, single-molecule biophysics, quantitative microscopy, super-resolution microscopy.
Research Specialty: Soft-matter and chemical regulation of biomolecular condensate
Research Description: Cells must organize thousands of biochemical processes within a crowded and constantly changing cytoplasm. Membrane-bound organelles solve part of this problem by enclosing reactions within lipid barriers. Biomolecular condensates create a fundamentally different form of compartmentalization. They assemble through collective interactions among proteins and nucleic acids to form dynamic, membraneless compartments. In this sense, condensates are a form of biological soft matter: materials whose organization, dynamics, and mechanical properties emerge from the collective behavior of many interacting molecules. This soft-matter nature allows condensates to remain deformable, responsive, and compositionally dynamic while still creating distinct intracellular environments.
The Folkmann laboratory investigates how these emergent material properties give rise to biological function. We ask how molecular-scale interactions generate larger-scale behaviors such as viscosity, elasticity, internal organization, selective transport, and responsiveness to environmental change, and how these physical properties influence the biochemical activities carried out within condensates. Condensates can also create distinct chemical microenvironments that differ from the surrounding cytoplasm. Their interiors can alter local concentrations, pH, hydration, ion partitioning, and molecular mobility. We investigate how these chemical properties arise from collective interaction networks and how they influence protein activity, RNA regulation, molecular transport, and biochemical reactions.
A major focus of the laboratory is the condensate interface. Although condensates lack a lipid membrane, the boundary between the condensed and dilute phases can act as a selective and highly regulated zone. Interfacial protein assemblies can nucleate condensate formation, control condensate growth and stability, and determine whether molecules remain at the surface or enter the interior. We seek to understand how charge, molecular architecture, post-translational modification, and cell-cycle regulation reshape this boundary and thereby control condensate composition and function.
The long-term goal of the Folkmann laboratory is to establish how cells use the physical and chemical properties of biomolecular condensates to regulate biological processes across scales, from molecular interactions to cellular organization and animal development.
Current Projects in the Laboratory:
- Defining the chemical environments created by biomolecular condensates, including differences in pH, hydration, ion partitioning, molecular concentration, and solvent organization.
- Determining how condensate microenvironments influence biochemical function, including protein activity, RNA behavior, molecular recognition, and reaction kinetics.
- Mapping the collective interaction networks that generate emergent material properties, internal heterogeneity, and distinct modes of molecular transport within condensates.
- Establishing how condensate interfaces regulate assembly and molecular access, including nucleation, growth, selective recruitment, surface retention, and entry into the condensate interior.
- Understanding how cell-cycle signals, kinase activity, stress, and post-translational modifications tune condensate properties and function.
- Connecting condensate physical and chemical properties to biological function, in living cells and during elegans development.
- Developing reconstituted and computational models that connect sequence-level molecular interactions to the emergent behavior of entire condensates.
Approach: We use a multidisciplinary approach combining C. elegans genetics, CRISPR genome editing, cell biology, in vitro reconstitution, quantitative microscopy, chemical microenvironment sensors, biophysical measurements, single-molecule tracking, super-resolution microscopy, microrheology, and computational modeling. By moving between purified systems, living cells, and developing organisms, we can determine how principles discovered at the molecular scale produce biological function across larger spatial and temporal scales.
Significance: The presence of a biomolecular condensate does not, by itself, explain its biological function. The central challenge is to determine how condensation changes the physical movement, chemical state, and biochemical activity of the molecules it contains. By treating condensates as responsive soft materials with structured interiors, distinct chemical environments, and regulated interfaces, our work seeks to uncover general principles by which cells build adaptive compartments without membranes. These principles will explain how emergent material properties are harnessed to control cellular chemistry in space and time and how disruption of those properties can interfere with normal biological function.