# The Principles of Regulatory, Conformational and Evolutionary Adaptation

> **NIH NIH R35** · CALIFORNIA INSTITUTE OF TECHNOLOGY · 2023 · $754,365

## Abstract

Project Summary
A hallmark of living organisms is their ability to adapt to the world around them. Such
adaptation takes place across many different scales in both space and time. On cellular
time scales, molecules in individual cells enable them to regulate metabolic genes and
thrive despite changing carbon sources. Over generations, cells evolve and adapt to
stresses such as antibiotics. In the work proposed here, we will uncover principles of
such adaptation over the functional hierarchy from molecules to cells to populations. To
achieve this goal, our laboratory will use our tradition of integrating precise
measurements with biophysical theory on specifically constructed biological systems.
Our first research thrust is built on the recognition that despite the amazing successes
of molecular biology and genome science over the last half century, we still know next
to nothing about how genes are regulated for more than 65% of the genes in the
commensal gut bacterium E. coli, which is arguably biology's best-understood
organism. With this award we will create a first draft of the regulatory genome for the
entire E. coli genome - including the binding energies and identities of every
transcription factor and the genes or operons that they regulate. A second thrust
focuses on a key way that living organisms respond to intracellular and environmental
signals: through conformational changes in individual allosteric proteins and in
assemblies of proteins, such as those found in the spindle responsible for chromosome
segregation. Using a system we developed to finely control cytoskeleton-motor
interactions using light, we seek to discover a predictive theoretical framework that
guides and constrains how we view assembly and adaptation. The third thrust in our
study of adaptation will build upon the previous two threads by providing a rigorous
examination of how genomes and the proteins that interact with them evolve. The
specific case studies will focus on the evolution of transcriptional regulation with special
emphasis on the response of pathogenic bacteria to antibiotic drugs. The cell is the
fundamental organizational unit of living organisms and the work proposed here will
provide a far-reaching but detailed view of how cells adapt. The approach we adopt is
ultimately biophysical; we insist that our analysis of the cell be at once quantitative and
predictive, sharpening our questions and deepening our understanding in a way that
can ultimately be parlayed into new strategies for improving human health.

## Key facts

- **NIH application ID:** 10683092
- **Project number:** 5R35GM118043-08
- **Recipient organization:** CALIFORNIA INSTITUTE OF TECHNOLOGY
- **Principal Investigator:** ROB PHILLIPS
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $754,365
- **Award type:** 5
- **Project period:** 2016-05-10 → 2026-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10683092

## Citation

> US National Institutes of Health, RePORTER application 10683092, The Principles of Regulatory, Conformational and Evolutionary Adaptation (5R35GM118043-08). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10683092. Licensed CC0.

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