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A Search Engine for mRNA: Algorithm Identifies Optimal Sequences to Improve COVID Vaccines

Friday, May 19, 2023

Messenger RNA vaccines proved their worth in the COVID pandemic, and new software stands to make the already transformative technology even more powerful.

Scientists developed an algorithm to identify the most stable, efficient mRNA sequences for vaccines. Tests show that the algorithm-derived mRNAs resist deterioration longer, produce more COVID spike protein, and dramatically increase antibody levels in mice compared to currently used mRNA vaccines. The results were reported in the journal Nature.

Study authors believe their tool will be valuable to companies that make mRNA vaccines and to research teams developing mRNA-based therapies for genetic disorders, cancer and a plethora of other diseases that can be treated by using mRNA to express a needed protein.

Searching for the Strongest mRNA

The COVID shots given throughout the pandemic have many advantages—scalable production, safety, efficacy—but suffer from some big drawbacks, including the need for ultra-cold storage and the resultant distribution challenges, and waning immunity. These limitations are due to the fact that mRNAs are inherently unstable and prone to degradation (they are constantly being “eaten” by enzymes present in cells).

The “secret sauce” for creating stronger mRNA sequences requires the right balance of two factors: structure and genetic code. Past research shows that mRNAs with a tight, rigid structure, as opposed to a floppy, unconfined structure, degrade more slowly (structure consolidates mRNAs and provides protection from hungry enzymes). Consequently, they stay in cells for a longer period and have more time to make the desired protein.

The mRNA used in COVID vaccines directs our bodies to make the COVID spike protein. The number of mRNA sequences that encode the spike protein is enormous—larger than the number of atoms in the universe. But, some of these genetic instructions are more efficient than others: one set may allow cells to churn out protein more quickly, while a different set might have redundancies that lead to sluggish protein production.

So, how do you find the right combination of structure and code? RNA expert David Mathews, MD, PhD and computer scientist Liang Huang, PhD, collaborated to create an algorithm that assesses both factors. Like a Google search for mRNA sequences, their algorithm spits out the top result for a specific protein amongst the almost infinite number of possibilities.

“Our tool is designed to identify the best sequence out of a huge space that you could never explore experimentally,” said Mathews, co-corresponding author of the Nature study and the Lynne E. Maquat professor of Biochemistry and Biophysics at the University of Rochester Medical Center. “Prior approaches did a poor job of searching this space. We hope this breakthrough will help companies to develop or improve their mRNA therapies.”

David Mathews Publishes Study in Nature on Algorithm to Optimize mRNA Vaccines

Thursday, May 4, 2023

The professor of Biochemistry and Biophysics partnered with an Oregon State University computer scientist to develop the algorithm to help research teams find the most stable, efficient mRNA sequences for vaccines and other therapies, such as monoclonal antibodies and anti-cancer drugs. Tested in COVID-19 mRNA vaccines, the algorithm substantially increased protein expression and antibody levels compared to currently used mRNA sequences.

Pulling the Plug on Viral Infections: CRISPR isn’t Just About Cutting

Thursday, April 27, 2023

Study shows how a Cas protein partners with a unique membrane protein to stop viral infection

CRISPR claimed scientific fame for its ability to quickly and accurately edit genes. But, at the core, CRISPR systems are immune systems that help bacteria protect themselves from viruses by targeting and destroying viral DNA and RNA. A new study published in Science reveals a previously unrecognized player in one such system – a membrane protein that enhances anti-viral defense – simultaneously broadening our understanding of and raising more questions related to the complexities of CRISPR.

Uncovering New Clues about CRISPR

CRISPR systems consist of two major components – a guide RNA that targets a specific viral DNA or RNA sequence and a Cas enzyme that cuts the targeted DNA or RNA, preventing a virus from replicating and spreading. A team at the University of Rochester Center for RNA Biology found that a specific Cas protein (Cas13b) not only cuts viral RNA, but communicates with another protein (Csx28) to augment its anti-viral defense.

In partnership with scientists at Cornell, the team discovered that the Csx28 protein forms a pore-like structure (i.e. it has a big hole in it). When they infected E. coli with a phage (virus that attacks bacteria) and deployed the CRISPR-Cas13 system to target and halt infection, they found that Cas13 signals to Csx28 to affect membrane permeability. Once this happens, Csx28 wreaks havoc in the infected cell, discombobulating membrane potential, crushing metabolism and hindering energy production. A virus can’t replicate under such unhospitable circumstances, leading to the team’s conclusion that Csx28 enhances CRISPR-Cas13b’s phage defense.

“This finding upends the idea that CRISPR systems mount their defense only by degrading RNA and DNA in cells and really broadens our view of how CRISPR systems may be working,” said corresponding author Mitchell O’Connell, PhD, assistant professor of Biochemistry and Biophysics at the University of Rochester Medical Center (URMC) and a member of the UR Center for RNA Biology. “When we think about CRISPR, we see Cas proteins such as Cas9 or Cas13 as the big hammer doing all the damage, but that might not be the case; we found that Cas13 and Csx28 are working together to effectively extinguish a virus.”

“When you read this paper you think to yourself…‘what?’ This is such a weird mechanism and not the way I would have predicted that bacteria would work,” added John Lueck, PhD, assistant professor of Pharmacology and Physiology at URMC. “It is really impressive that the team identified this pore-like protein that doesn’t resemble anything else we’ve seen before, and now that we know that this mechanism exists people will start to look for it in other systems. This is exciting because in science, when you scratch the surface, you often find that there is an entirely new world behind it.”

2023 RNA Institute Symposium: UR Talks and Awards

Tuesday, April 4, 2023

Photo of the co-organizers The 2023 RNA Institute Symposium, a collaborative event hosted by The RNA Institute at the University at Albany (UAlbany) and the University of Rochester (UR) Center for RNA Biology, was held March 16-17, 2023, at UAlbany. This two-day event was co-organized by Lynne Maquat, PhD, Dave Matthews, MD, PhD, Eric Wagner, PhD from the UR Center for RNA Biology, and J. Andrew Berglund, PhD and Marlene Belfort, PhD from The RNA Institute at UAlbany.

The large-scale event provided a forum for faculty and students to present their research and network with colleagues, featuring speakers from companies with origins in UAlbany and UR research programs, including Codomax, SupreMEtric, Scriptr, and sxRNA.

The Symposium, hosting ~260 attendees, featured 8 trainee talks, 28 lightning talks, 122 posters from students and postdocs/research faculty, and several invited talks by faculty and industry representatives – including Douglas Anderson, PhD of the Aab CVRI and Scriptr Global and Lynne Maquat, PhD, Director of the Center for RNA Biology and Professor in the Department of Biochemistry & Biophysics. Participants from the UR included 38 graduate students, postdocs, and faculty.

As a co-organizer of this event, Dr. Maquat also hosted the Award Ceremony with Thomas Begley, PhD (Associate Director, The RNA Institute at UAlbany). Details on the student talks and the awards given to UR participants are shown below. The overall Symposium schedule and highlights can be found on the event site: https://www.albany.edu/rna/rna-symposium.

UR Participant Photos

Talks

UR Student Talks (8 mins + 2 mins Q&A)
Lily Cisco Graduate Student, Lueck Lab, CMPP	Benefit of Verapamil on Myotonic Dystrophy Bi-Channelopathy
Xueyang He Graduate Student, Boutz Lab, BSCB	Modeling the Effects of Cancer-Associated Spliceosome Mutations and Identifying Driving Intronic Features using Deep-Learning Neural Networks
Madeline (Maddie) Jensen Graduate Student, Wagner Lab, BMB	Identification and Structural Basis of a Novel Licensing Factor of the Integrator Cleavage Module

UR Student and Postdoc Lightning Talks (2 mins + 1 slide)
Elizabeth Abshire, PhD Postdoc, Maquat Lab, DBB	AKT Constitutes a Signal-Promoted Alternative Exon-Junction Complex that Regulates Nonsense-Mediated mRNA Decay
Sara Ali Graduate Student, Mathews Lab, BSCB	Mutate2test: New Algorithm and Software for Mutational Design
Diego Arévalo Graduate Student, Miller Lab, CHEM	Expanding the Known Structure Space for RNA Binding: A Test of 2,5-diketopiperazine
Dakarai Esgdaille Graduate Student, Boutz / Mello Labs, BGG	Defining the Regulatory Role of Nuclear Paraspeckles in RNA Splicing in the Context of Pancreatic Tumors
Justin Galardi Graduate Student, Kielkopf Lab, BMB	HIV-1 Rev Regulates Host Transcription and RNA Processing Factor TatSF1 to Promote HIV-1 Infectivity
Omar Hedaya Graduate Student, Yao Lab, BMB	Secondary Structures that Regulate mRNA Translation Provide Insights for ASO-Mediated Modulation of Protein Expression
Wooree Ko Graduate Student, Lueck Lab, CMPP	Anticodon-Engineered Transfer RNA for the Treatment of Nonsense-Associated Cystic Fibrosis
Adrian Molina Vargas Graduate Student, O’Connell Lab, BGG	Development of New Strategies for the Design of Ultrasensitive Cas13a-Based RNA-Diagnostic Tools with Single-Nucleotide Mismatch Sensitivity

Awards

Only two total Trainee Speaker Awards were given out, one of which was presented to a UR participant:
Lily Cisco Graduate Student, Lueck Lab, CMPP	Benefit of Verapamil on Myotonic Dystrophy Bi-Channelopathy

UR Poster Awards (Recipients of cash awards)
Hironori (Hiro) Adachi, PhD Staff Scientist/Postdoc, Yu Lab, DBB	Targeted Pseudouridylation: An approach for Suppressing Nonsense Mutations in Disease Genes
Sara Ali Graduate Student, Mathews Lab, BSCB	Mutate2test: New Algorithm and Software for Mutational Design
Dakarai Esgdaille Graduate Student, Boutz / Mello Labs, BGG	Defining the Regulatory Role of Nuclear Paraspeckles in RNA Splicing in the Context of Pancreatic Tumors
Jordana Schmierer Graduate Student, Takimoto Lab, IMV	Host Adaptative Mutations in the pH1N1 PA CTD Affect Genome Replication
Elinore VanGraafeiland Graduate Student, Miller Lab, BMB	Targeting Programmed Ribosomal Frameshifting in SARS-CoV-2 with a Resin-Bound Dynamic Combinatorial Library

UR RNA Society Awards (recipients of one-year RNA Society Memberships)
Elizabeth Abshire, PhD Postdoc, Maquat Lab, DBB	AKT Constitutes a Signal-Promoted Alternative Exon-Junction Complex that Regulates Nonsense-Mediated mRNA Decay
Wooree Ko Graduate Student, Lueck Lab, CMPP	Anticodon-Engineered Transfer RNA for the Treatment of Nonsense-Associated Cystic Fibrosis
Jessica Perciaccante Graduate Student, Anderson Lab, BGG	The CARDINAL lncRNA Represses TCF-SRF-Mediated Gene Transcription by Co-Occupying SRF-Bound Gene Promoters in the Heart

NYS Center for Excellence in RNA Research and Therapeutics (CERRT). This Symposium reflects an ongoing commitment between the University of Rochester Center for RNA Biology and The RNA Institute at the University at Albany-SUNY to train the next generation of RNA Scientists. This endeavor is occurring in real-time and alongside the NYS Biotech industry to develop an academic pipeline to fuel NYS efforts in harnessing RNA as a therapeutic tool and target.

CALL FOR ABSTRACTS: 2023 Young Investigator Symposium on RNA Biology (hosted by Dr. Xin Li)

Friday, March 10, 2023

Register (free!) and, postdocs/research-track faculty, submit your abstracts by March 20th: 2023

2023 Young Investigator Symposium on RNA Biology

Dates: March 24-25, 2023
Venue: VIRTUAL via Zoom Webinar. Please register to obtain the link.

Application Deadline: March 20th, 2023
Register and/or Apply Here (All virtual attendees and talk applicants must register.)

Event Website

The 2023 Young Investigator Symposium on RNA Biology is co-organized by Xin Li, PhD, Associate Professor at the University of Rochester, the RNA Medical Center of Zhejiang University, and the University of Rochester Center for RNA Biology. The Symposium is free to attend and is focused on talks by dedicated postdocs, instructors, and young (associate) researchers from around the world, in addition to the keynote by Yi-Tao Yu, PhD, Professor of Biochemistry & Biophysics at the University of Rochester. The symposium will feature over 20 scholars, each presenting their cutting-edge research for 30 minutes. It will also feature two career sections on networking and job hunting.

Schedule

Friday, March 24th: Virtual format, opening remarks and then talks, starting at 8:20 am EDT
Saturday, March 25th: Virtual talks and Keynote for a half day, starting at 8:30 am EDT
The symposium will also include two virtual career sections on networking and job hunting. Please see the event website for updates on the program and speakers.

Speakers:

(KEYNOTE) Yi-Tao Yu, University of Rochester
Title: Nonsense suppression induced by RNA-guided RNA modification

Qinqin Cui, Zhejiang University
Title: Diverse CMT2 neuropathies are linked to aberrant G3BP interactions in stress granules

Junnan Fang, Emory University
Title: Isoform expression and the post-transcriptional regulations of centrosome Plp mRNA

Wenxia He, University of North Carolina at Chapel Hill
Title: The Degradation Complex on the 3’ End of Histone mRNA

Yanqiang Li, Harvard Medical School
Title: Low RNA stability signifies increased post-transcriptional regulation of cell identity gene

Ling Liu, University of Manitoba, Canada
Title: Mechanism of Adaptive Splicing Controlled by DNA Methylation

Jianjun Luo, Institute of Biophysics, Chinese Academy of Sciences
Title: Systematic Identification and Functional Studies of Long Noncoding RNAs and SEPs

Yicheng Luo, California Institute of Technology
Title: Maternally inherited siRNAs initiate piRNA cluster formation

Maria Mavrikaki, Harvard Medical School, Beth Israel Deaconess Medical Center
Title: Severe COVID-19 is associated with molecular signatures of aging in the human brain

JingRong Zhao, University of California
Title: Molecular profiling of individual FDA-approved clinical drugs identifies modulators of nonsense-mediated mRNA decay

Zhengjie Zhou, The University of Chicago
Title: Vascular targeted mRNA therapies treating cute Respiratory Distress Syndrome

Please send any questions to Xin Li, PhD

Study: Yi-Tao Yu, Paul Boutz Harness Power, Precision of RNA to Make Mutations Invisible

Monday, March 6, 2023

Scientists have discovered a new way to suppress mutations that lead to a wide range of genetic disorders. A study in the journal Molecular Cell describes a strategy that co-opts a normal RNA modification process within cells to transform disease genes into normal genes that produce healthy proteins. The findings are significant because they may ultimately help researchers alter the course of devastating disorders such as cystic fibrosis, muscular dystrophy and many forms of cancer.

Negating Nonsense

Around 15 percent of mutations that lead to genetic diseases are called nonsense mutations. Aptly named, nonsense mutations occur when an mRNA molecule contains an early “stop” signal. When the mRNA takes genetic instructions from DNA to create a protein, this early stop sign orders the cell to stop reading the instructions partway through the process. This results in the creation of an incomplete protein that can lead to disease.

Team members of the Yu lab

Led by Yi-Tao Yu, PhD, a team of researchers from the University of Rochester Center for RNA Biology designed an artificial guide RNA – a piece of RNA that can modify other types of RNA – to target mRNA molecules that contain early stop signals (also called premature termination codons). Guide RNAs are a natural mechanism that cells use all the time; Yu’s team altered this already existing process.

Like DNA, RNA is made up of molecular building blocks that are represented by the letters A (adenine), G (guanine), U (uracil), and C (cytosine). Premature termination codons always have the building block U in the first position (for example, UAG, UAA or UGA). The team’s artificial guide RNA was designed to modify the U in the first position, changing the molecular makeup of the targeted mRNA so that the stop signal is no longer – or less well – recognized by the cell.

Paul Dunman Elected Fellow of the American Academy of Microbiology

Tuesday, February 28, 2023

The professor of Microbiology and Immunology and Ophthalmology is one of 65 scientists selected for the 2023 fellowship class. Dunman uses Staphylococcus aureus and Acinetobacter baumannii to study how bacteria cause disease, with the goal of developing new therapies to treat bacterial infections.

RNA Biologist Lynne Maquat Awarded 2023 Gruber Genetics Prize

Thursday, February 23, 2023

Lynne E. Maquat, PhD, the founding director of the Center for RNA Biology at the University of Rochester, has been awarded the 2023 Gruber Genetics Prize for her discovery of nonsense-mediated mRNA decay or NMD in humans. The Gruber International Prize Program, administered by Yale University, honors scientists from around the world whose groundbreaking work leads to fundamental shifts in knowledge and benefits mankind.

Maquat has spent her career deciphering the many roles that RNA plays in sickness and in health, and is best known for elucidating the complexities of NMD in mammalian cells and human disease. One of the major surveillance systems in the body, NMD protects against mistakes in gene expression by targeting and eliminating deleterious mRNAs that could lead to the production of incomplete and potentially toxic proteins. Maquat’s lab also revealed that NMD helps our cells adjust to changes in development and in their environment, and more rapidly respond to certain stimuli.

“Lynne’s scientific prowess and steadfast commitment to her research is exemplary and has helped catapult the field of RNA biology to the forefront of medicine over the past decade,” said Mark B. Taubman, MD, CEO of the University of Rochester Medical Center and dean of the School of Medicine and Dentistry. “This is an exciting time, as Lynne and other scientists are putting her mechanistic findings related to NMD to use to design treatments. She is incredibly deserving of this honor.”

Work pioneered by Yi-Tao Yu highlighted in new studies

Thursday, February 16, 2023

Rewriting the message: Harnessing RNA pseudouridylation to tackle disease

Matias Montes, Nicole M. Martínez DOI:https://doi.org/10.1016/j.molcel.2023.02.001

Two recent papers in Molecular Cell made strides toward two worthy goals: (1) site-specific modification of RNAs with pseudouridine (Ψ) for functional studies of the epitranscriptome and (2) correction of disease-causing PTCs through Ψ-mediated stop codon readthrough. Both studies build on pioneering work from Yu and colleagues that first showed the potential to engineer small nucleolar RNAs (snoRNAs) for targeted pseudouridylation of stop codons in yeast and discovered that pseudouridylated stop codons suppressed translation termination when artificially introduced in mRNAs.

Yi-Tao Yu and Paul Boutz highlighted on the URMC social media channels

Thursday, February 9, 2023

Studies in Molecular Cell are being highlighted on the University's Twitter and LinkedIn pages. Check them out.

https://twitter.com/URochester_SMD/status/1623715711905308678

https://www.linkedin.com/feed/update/urn:li:activity:7029483715420401664