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FfAME Our Team Elisa Biondi
Elisa Biondi

Principal Investigator & Fellow

Elisa Biondi

Elisa Biondi is an experienced biochemist and molecular biologist exploring how alternative genetic systems and synthetic nucleic acids can be harnessed to enable next-generation diagnostics and therapeutics, while also revealing clues to life's origins.
  • (386) 418-8085

Research Summary

My current research focuses on two main topics:

  1. The development of nucleic acids-based technologies with expanded and modified genetic alphabets for biomedical applications and translational research.
  2. The prebiotic formation and evolution of informational molecules and their building blocks in the context of the study of the origin of, and search for, life in the universe (astrobiology). 

Current projects include:

  • The development of AEGIS (Artificially Expanded Genetic Information System) and ERA (Expanded RNA Alphabet) technologies for the in-vitro evolution and characterization of aptamers (AEGISbodies, ERAbodies) targeting cancer and other disease biomarkers (such as PD-L1).
  • The development of AEGIS and ERA technologies for the in-vitro evolution and characterization of ribozymes (AEGIS and ERACleavers) capable of destroying proteins overexpressed in cancer and other diseases.
  • Applying AEGIS technologies to enhance the detection efficiency of aberrant epigenetic modifications in disease diagnostics.
  • Testing of RNA and DNA polymerases, kinases, and other enzymes evolved/modified to accept non-natural nucleotides from AEGIS and ERA pools.
  • The in-vitro evolution and characterization of catalytic molecules from standard and expanded nucleic acid libraries carrying different information contents, to understand sequence dynamics and information requirements during the prebiotic evolution of informational macromolecules.
  • The study of the interaction between mineral/geological surfaces and RNA molecules in prebiotic environments, including the prebiotic formation of RNA precursors and the chiral selection of RNA enantiomers.

Active Grants:

  • NIH-NCI, National Cancer Institute 1R61CA291117-01 (PI: Biondi) 7/2024 – 6/2027 “Evolved Molecules that Destroy Cancer Relevant Proteins”
  • NIH-NIGMS, National Institute of General Medical Sciences 1R21GM147764-01 (PI: Biondi) 9/2022 – 8/2025 “Technology to Create Spiegel ERAbodies on Demand: Biostable Universal Antibody Replacements”
  • NSF, National Science Foundation CHE-2108028 (PI: Biondi) 8/2021 – 7/2025 “Diverse evolutionary power of nucleic acid libraries carrying different information content”
Research Focus:
  • Synthetic biology
  • Nucleic acid-based technologies
  • Expanded genetic alphabets
  • Prebiotic chemistry
  • Astrobiology
  • Molecular evolution
Education:
  • BS in Molecular Biology, 110/110 Magna Cum Laude, University of Bologna, Italy (2002)
  • PhD in Genetics/Astrobiology, University of Florence, Italy (2007)
  • Postdoctoral Research Fellow, Astrobiology & RNA Biochemistry, University of Missouri-Columbia (2007-2012)
  • principal investigator & Fellow at the Foundation for Applied Molecular Evolution (FfAME), with a joint appointment at Firebird Biomolecular Sciences, LLC, in Alachua, Florida. (2012-present)
Awards:
  • ISSOL Fellow – Quito, Ecuador, August 2023
  • Travel awards: American Astronomical Society (2011), NASA Astrobiology Institute (2010), LSC-PGSA (2010, 2011), University of Missouri Postdoctoral Association (2008, 2010)
  • Training Fellowship: University of Missouri postdoctoral association-funded training on CEQ-SHAPE technology in Alain Laederach lab, Wadsworth Center, Albany, NY (2010)
  • Life Sciences Week first prize award (2009)
  • University of Missouri Life Sciences postdoctoral fellowship (2007-2009)
  • Training Fellowship: PAESMEM AAAS Mentoring Workshop, Washington, DC (2008)
  • Training Fellowship:  ICGEB training on “RNA Structure and Function”, Trieste, Italy (2005)
  • University of Florence postgraduate fellowship (2003-2004)

Publications

Kim H-J., Wenta A.J., Dobrzycki L.M., Biondi E., Benner S.A. ACS Chem Biol 20 (11) 2787-2797 (2025) PMID: 41197067, doi: 10.1021/acschembio.5c00724

The Watson–Crick-Franklin (WCF) rules describing nucleobase pairing in antiparallel strands of DNA and RNA can be exploited to create artificially expanded genetic information systems (AEGIS) with as many as 12 independently replicable nucleotides joined by six hydrogen bond pairing schemes. One of these additional pairs joins two nucleotides trivially designated as Z (6-amino-5-nitro-(1H)-pyridin-2-one) and P (2-amino-imidazo-[1,2-a]-1,3,5-triazin-(8H)-4-one). The Z:P pair has supported 6-nucleotide PCR to give diagnostics products, in environmental surveillance kits, and for laboratory in vitro evolution (LIVE) that has generated, inter alia, molecules that inactivate toxins, antibody analogs that bind cancer cells, therapeutic candidates that deliver drugs to those cells, reagents to identify targets on those cells’ surfaces, reagents to move cargoes across the blood–brain barrier, and catalysts with ribonuclease activity. However, the Z nucleoside is acidic, with a pKa of ∼7.8. In its deprotonated form, Z– forms a WCF pair with G. This leads to the slow replacement of Z:P pairs by C:G pairs during PCR or, in the reverse process, their introduction. Here, we examine analogs of Z that retain the same donor:donor:acceptor hydrogen bonding pattern as earlier generations of the Z heterocycle, still form a WCF pair with P, but have a higher pKa. Experiments with Taq polymerase show that the rate of loss of Z:P pairs decreases markedly as the pKa of the Z heterocycle increases. This provides direct support for the hypothesis that Z:P pairs are in fact lost via deprotonated Z–:G mismatches. Further, it provides a Z:P system that can be replicated with very high fidelity, with >97% retention of the Z:P pairs over 10,000-fold amplification.

Bang Wang, Xiaoshu Pan, I-Ting Teng, Xiaowei Li, Firas Kobeissy, Zo-Yu Wu, Jiepei Zhu, Guangzheng Cai, He Yan, Xin Yan, Mingwei Liang, Fahong Yu, Zunyi Yang, Elisa Biondi, William Haskins, Y. Charles Cao, Steven A. Benner, Weihong Tan, Kevin Wang Angew. Chem. Int. Ed. (2024) e202402007, https://doi.org/10.1002/anie.202402007

Pathological hyperphosphorylation and aggregation of microtubule-associated Tau protein contribute to Alzheimer's Disease (AD) and other related tauopathies. Currently, no cure exists for Alzheimer's Disease. Aptamers offer significant potential as next-generation therapeutics in biotechnology and the treatment of neurological disorders. Traditional aptamer selection methods for Tau protein focus on binding affinity rather than interference with pathological Tau. In this study, we developed a new selection strategy to enrich DNA aptamers that bind to surviving monomeric Tau protein under conditions that would typically promote Tau aggregation. Employing this approach, we identified a set of aptamer candidates. Notably, BW1c demonstrates a high binding affinity (Kd = 6.6 nM) to Tau protein and effectively inhibits arachidonic acid (AA)-induced Tau protein oligomerization and aggregation. Additionally, it inhibits GSK3β-mediated Tau hyperphosphorylation in cell-free systems and okadaic acid-mediated Tau hyperphosphorylation in cellular milieu. Lastly, retro-orbital injection of BW1c tau aptamer shows the ability to cross the blood brain barrier and gain access to neuronal cell body. Through further refinement and development, these Tau aptamers may pave the way for a first-in-class neurotherapeutic to mitigate tauopathy-associated neurodegenerative disorders.

Jerome, C.A; Hoshika, S.; Bradley, K.M.; Benner, S.A.; Biondi, E. Proc. Natl. Acad. Sci. USA (2022) 119(44). DOI: 10.1073/pnas.2208261119

The ability of nucleic acids to catalyze reactions (as well as store and transmit information) is important for both basic and applied science, the first in the context of molecular evolution and the origin of life and the second for biomedical applications. However, the catalytic power of standard nucleic acids (NAs) assembled from just four nucleotide building blocks is limited when compared with that of proteins. Here, we assess the evolutionary potential of libraries of nucleic acids with six nucleotide building blocks as reservoirs for catalysis. We compare the outcomes of in vitro selection experiments toward RNA-cleavage activity of two nucleic acid libraries: one built from the standard four independently replicable nucleotides and the other from six, with the two added nucleotides coming from an artificially expanded genetic information system (AEGIS). Results from comparative experiments suggest that DNA libraries with increased chemical diversity, higher information density, and larger searchable sequence spaces are one order of magnitude richer reservoirs of molecules that catalyze the cleavage of a phosphodiester bond in RNA than DNA libraries built from a standard four-nucleotide alphabet. Evolved AEGISzymes with nitro-carrying nucleobase Z appear to exploit a general acid–base catalytic mechanism to cleave that bond, analogous to the mechanism of the ribonuclease A family of protein enzymes and heavily modified DNAzymes. The AEGISzyme described here represents a new type of catalysts evolved from libraries built from expanded genetic alphabets.

Craig A. Jerome, Hyo-Joong Kim, Stephen J. Mojzsis, Steven A. Benner, and Elisa Biondi Astrobiology (2022) http://doi.org/10.1089/ast.2022.0027

Reported here are experiments that show that ribonucleoside triphosphates are converted to polyribonucleic acid when incubated with rock glasses similar to those likely present 4.3-4.4 billion years ago on the Hadean Earth surface, where they were formed by impacts and volcanism. This polyribonucleic acid averages 100-300 nucleotides in length, with a substantial fraction of 3',-5'-dinucleotide linkages. Chemical analyses, including classical methods that were used to prove the structure of natural RNA, establish a polyribonucleic acid structure for these products. The polyribonucleic acid accumulated and was stable for months, with a synthesis rate of 2 x 10-3 pmoles of triphosphate polymerized each hour per gram of glass (25°C, pH 7.5). These results suggest that polyribonucleotides were available to Hadean environments if triphosphates were. As many proposals are emerging describing how triphosphates might have been made on the Hadean Earth, the process observed here offers an important missing step in models for the prebiotic synthesis of RNA.

Rajamani, S., Biondi, E. Nature Physics, Springer (2022) https://doi.org/10.1038/s41567-022-01549-4

The transition from chemistry to evolvable molecular systems is at the core of origins of life studies. Now, the acidic dew–liquid water dynamic cycling inside simulated Hadean rock pores is found to possibly provide a confined environment for strand separation, replication, mutation, and the evolution of nucleic acids.
All My Publications