# Using directed evolution to study the origins of multicellular development.

> **NIH NIH R35** · GEORGIA INSTITUTE OF TECHNOLOGY · 2023 · $384,498

## Abstract

ABSTRACT
Little is known about how novel multicellular developmental programs arise in evolution, largely because
multicellularity arose deep in the past and early steps have been lost to extinction. The PI has circumvented this
constraint by creating a new model system, using directed evolution to directly study the origin of multicellularity
and development. The proposed research will help resolve two major knowledge gaps in the field of
developmental biology: 1) How does development evolve de novo? 2) What are the long-term evolutionary
consequences of development? After thousands of generations of directed evolution, the PI has observed the
evolution of autonomous cell type specification in snowflake yeast, his model system of early multicellularity.
Specifically, snowflake yeast form multicellular groups that are far more mechanically tough by adaptively
differentiating into two cell types, in which cells deep in the cluster interior change their budding angle by 90
degrees and interlock neighboring cellular branches. In this model system (and in most simple multicellular
organisms), a cell’s age provides key information about its location, allowing temporal changes in gene
expression to drive spatial patterns of cellular differentiation. Preliminary data suggests that the chaperone
protein Hsp90 has been co-opted to act as an age (and thus location)-dependent developmental switch,
regulating the transition between cell types. The proposed research will further examine the evolution of this
novel developmental mechanism, and will contextualize these wet-lab experiments with both 3D biophysical
simulations and evolutionary models, allowing the PI to derive general principles from these experimental
results. The proposed research will also examine how stochastic cellular behaviors can be co-opted for symmetry
breaking, allowing snowflake yeast to evolve more complex multicellular structures. Finally, the proposed
research will examine the evolutionary consequences of development: namely, how cellular differentiation can
entrench a lineage into a multicellular state. This work will examine how cellular differentiation strips cells of
their evolutionary autonomy by limiting the potential for reversion to unicellularity. Development would thus
have a doubly-profound impact on an organism’s evolutionary dynamics: opening new avenues for increased
multicellular complexity while closing off opportunities for ancestral, unicellular behaviors.

## Key facts

- **NIH application ID:** 10630828
- **Project number:** 5R35GM138030-04
- **Recipient organization:** GEORGIA INSTITUTE OF TECHNOLOGY
- **Principal Investigator:** William Croft Ratcliff
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $384,498
- **Award type:** 5
- **Project period:** 2020-08-01 → 2025-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10630828

## Citation

> US National Institutes of Health, RePORTER application 10630828, Using directed evolution to study the origins of multicellular development. (5R35GM138030-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10630828. Licensed CC0.

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