BIIE Faculty Dr. Chase Beisel Leads International Team Awarded a Prestigious ERC Synergy Grant to "Resurrect" Ancient Proteins for Gene Therapy

An international team led by Chase Beisel at the Botnar Institute of Immune Engineering (BIIE) has been awarded a European Research Council (ERC) Synergy Grant of over €10 million for a groundbreaking project: traveling back billions of years in evolutionary time to solve modern medical challenges.

The four-research group collaboration—spanning Switzerland, the United States, and Spain—will computationally "resurrect" ancient versions of proteins from CRISPR immune systems and selfish jumping genes called transposons in bacteria, where the underlying RNA-guided proteins share a common ancestry. Their end goal is to overcome fundamental limitations in today's gene-editing technologies. Joining Beisel are Samuel Sternberg (Columbia University), Raúl Pérez-Jiménez (CIC bioGUNE), and Israel S. Fernández (Biofisika Institute).

"Think of it as combining archaeological excavation and technology development," explains Beisel, who will coordinate the six-year project from Basel. "We're excavating the genetic past to build the medical future."

When Older is Better

The project, "RGNcestry – Tracing and Harnessing the Ancestry of RNA-Guided Nucleases," stems from breakthrough research principally by the Pérez-Jiménez group, published in Nature Microbiology (2023) and Nature Biotechnology (2024). When Beisel and Pérez-Jiménez reconstructed ancient CRISPR proteins dating back 2–3 billion years, they discovered that these evolutionary ancestors exhibit profound properties distinct from their modern counterparts, such as recognizing a broader range of DNA targets or cleaving other nucleic acids upon activation.

Current CRISPR tools require specific DNA markers (PAM sequences) to function, meaning many disease-causing mutations cannot be targeted. The ancient proteins tested so far hadn't yet specialized for specific bacterial needs, retaining broader capabilities that could prove therapeutically valuable.

"Evolution optimized proteins for specific bacterial needs," explains Prof. Pérez-Jiménez. "Ancient proteins retained broader capabilities we can now harness for biotechnology."

These broadened activities raise fundamental questions about how these proteins functioned in early life and how they could serve as starting points to adapt these proteins for tailored applications. 

Aligned with BIIE's Mission

The team will develop two applications directly aligned with BIIE's mission to improve global child and adolescent health:

• Gene Therapy: Developing PAM-free editors for childhood genetic diseases currently untreatable with existing CRISPR tools, including addressing immunogenicity challenges that can limit therapeutic use.

• Point-of-Care Diagnostics: Creating ambient-temperature diagnostic tests for detecting infections in children, particularly in resource-limited settings where refrigeration is unavailable.

"Every project at BIIE connects to improving global child and adolescent health," says Beisel. "These technologies could enable gene therapy for childhood genetic diseases currently beyond CRISPR's reach and diagnostic tools that work anywhere in the world."

Complementary Expertise

The collaboration brings together essential specialties: Beisel's rapid CRISPR screening methods available at BIIE, Sternberg's transposon biology expertise, Pérez-Jiménez's computational reconstruction capabilities, and Fernández's structural biology prowess.

"We assembled a fantastic team uniquely equipped to reveal the biology of ancient RNA-guided nucleases and how they can be harnessed as a new paradigm for technology development," says Beisel. "I'm excited to get started and see what we can accomplish together."

"Chase's team at BIIE has pioneered rapid CRISPR characterization methods," adds Sternberg. "Combined with our transposon expertise and Israel’s structural biology capabilities, we have a truly unique collaboration to explore ancient biology and create new tools."

The team will reconstruct a comprehensive evolutionary map spanning 4 billion years, characterize ancient proteins using high-throughput systems at BIIE, determine atomic structures via cryo-electron microscopy, and engineer optimized variants for medical use.

A Notable Achievement for BIIE

The ERC Synergy Grant—with an acceptance rate of 9% and only 66 awarded across all disciplines in 2025—specifically funds research requiring deep collaboration between complementary experts. For the newly founded BIIE, securing such a high-profile grant represents a major success, demonstrating that the excellence of its research programs is already recognized by Europe's premier research funding body.

The project builds on successful collaborations between team members. Beisel and Pérez-Jiménez co-authored the 2024 ancestral Cas12a study in Nature Biotechnology, while Beisel and Fernández previously published multiple structural studies including one in Nature (2022). The application was initiated while Beisel was at the Helmholtz Institute for RNA-based Infection Research before he joined BIIE.

The project begins in 2026 and will run for 72 months, coordinated from BIIE's state-of-the-art facilities in Basel.

Additional information about the ERC Synergy grant and this year's winning projects and grantees can be found in ERC's Press Release.

Image: © European Commission