Logic of metabolic sensing and network organization
Metabolism is central to life. Instead of viewing metabolism as rigid processes, we try to understand metabolism as the central form of dynamic information transfer in biology. Depending on the specific context, or “metabolic state”, a cell can undergo different fates ranging from growth, division, differentiation and autophagy to a commitment to cell death. This metabolic state of a cell is controlled by available nutrients, which are sensed by specialized metabolic sensors. To understand cell fate decisions, we work at the level of the metabolites, how these metabolites are sensed, and build a systems level understanding how this information is transferred within and between cells. More broadly, we are trying to re-imagine metabolism in the context of biochemical evolution, and are addressing what "metabolic costs" mean to a cell, in order to build organizational frameworks to understand the 'back end' of cellular resource allocations (see our publications page). In the lab, research is carried out in several areas, namely: (1) Logic and organizational principles of metabolic regulation and networks (2) "Special" metabolites that drive cell, and resource allocation strategies between cells. (3) Metabolism and resource sharing, cell specialization and division of labor in cell groups. (5) Extreme biology and synthetic biology to make complex metabolites. We use learning from these areas for synthetic-systems bioengineering, combining our understanding of metabolic and signaling networks to create strains and molecules for a variety of biotechnological uses. We are happy to work with start-ups and industry, please read more about all we have to offer here. |
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Our research team brings together multidisciplinary approaches, with strong foundations in biochemistry. We integrate mechanistic biology with analytical chemistry/mass spectrometry (metabolite and protein), systems level approaches, genomics, genome engineering, and physical/mathematical models. Our favorite model system is the budding yeast Saccharomyces cerevisiae, but our research spans mammalian cells, nematodes, and insect pests.
Research themes:
i) Special metabolites and organization of metabolic networks/outputs: Understanding why some metabolites are unique in their ability to control cell fates.
Related recent publications:
- Acetyl-CoA and quiescence-growth oscillations (Krishna & Laxman MBoC July 2018)*
- Methionine as a growth signal, setting up a hierarchically organized anabolic program (Walvekar et al MBoC Dec 2018).
- Trehalose controling spatial organization of cell groups, and phenotypic heterogeneity (Varahan et al eLIFE 2019)*
- Aspartate controling division of labor in cell groups (Varahan et al eLIFE 2020)*
ii) Metabolic sensing and systems-level management of resource allocations:
Related recent publications:
- A tRNA modification as an amino acid sensor and central regulator of metabolic homeostasis (Gupta et al eLIFE 2019 ).
- An ubiquitin E3-ligase that is required for proper glucose repression and gluconeogenic shut-down in cells (Vengayil et al J. Biol. Chem 2019)
- How cells balance metabolic supply with high translation during a (methionine-induced) growth program (Srinivasan et al. Plos Genetics 2020)
- How the TORC1 pathway, via Kog1/Raptor, controls the homeostatic function of the AMP Kinase/Snf1, and how cells balance carbon resource allocations (Rashida et al. Science Advances 2021)
- A theoretical framework to understand the integration of phosphates with carbon flux (Gupta eLIFE 2020)
iii) Metabolic determinants of collective cell behavior:
Related recent publications:
- Acetyl-CoA and quiescence-growth oscillations (Krishna & Laxman MBoC July 2018)*
- Metabolic constraints determining spatial self-organization of heterogeneous cell groups (Varahan et al eLIFE 2019)*
- Resource plasticity enabling metabolic specialization and division of labor in cells (Varahan et al. eLIFE 2020)*
These studies also require new tools, or developing methods or devices, such as quantitative metabolite measurements using mass spectrometry (methods papers for metabolic flux analysis: Walvekar et al Wellcome Open Research 2018 or Gupta Bio-protocol 2020), or novel micro-fluidic devices, imaging systems & software.
These studies can also be applied to microbial metabolic engineering, targeted towards channeling resources to produce specific products.
Research themes:
i) Special metabolites and organization of metabolic networks/outputs: Understanding why some metabolites are unique in their ability to control cell fates.
Related recent publications:
- Acetyl-CoA and quiescence-growth oscillations (Krishna & Laxman MBoC July 2018)*
- Methionine as a growth signal, setting up a hierarchically organized anabolic program (Walvekar et al MBoC Dec 2018).
- Trehalose controling spatial organization of cell groups, and phenotypic heterogeneity (Varahan et al eLIFE 2019)*
- Aspartate controling division of labor in cell groups (Varahan et al eLIFE 2020)*
ii) Metabolic sensing and systems-level management of resource allocations:
Related recent publications:
- A tRNA modification as an amino acid sensor and central regulator of metabolic homeostasis (Gupta et al eLIFE 2019 ).
- An ubiquitin E3-ligase that is required for proper glucose repression and gluconeogenic shut-down in cells (Vengayil et al J. Biol. Chem 2019)
- How cells balance metabolic supply with high translation during a (methionine-induced) growth program (Srinivasan et al. Plos Genetics 2020)
- How the TORC1 pathway, via Kog1/Raptor, controls the homeostatic function of the AMP Kinase/Snf1, and how cells balance carbon resource allocations (Rashida et al. Science Advances 2021)
- A theoretical framework to understand the integration of phosphates with carbon flux (Gupta eLIFE 2020)
iii) Metabolic determinants of collective cell behavior:
Related recent publications:
- Acetyl-CoA and quiescence-growth oscillations (Krishna & Laxman MBoC July 2018)*
- Metabolic constraints determining spatial self-organization of heterogeneous cell groups (Varahan et al eLIFE 2019)*
- Resource plasticity enabling metabolic specialization and division of labor in cells (Varahan et al. eLIFE 2020)*
These studies also require new tools, or developing methods or devices, such as quantitative metabolite measurements using mass spectrometry (methods papers for metabolic flux analysis: Walvekar et al Wellcome Open Research 2018 or Gupta Bio-protocol 2020), or novel micro-fluidic devices, imaging systems & software.
These studies can also be applied to microbial metabolic engineering, targeted towards channeling resources to produce specific products.
Funding and support: