December 14, 2020
A coronavirus uses a protein in its membrane - shown here in red in a molecular model - to bind to a receptor - shown in blue - on a human cell to enter the cell. Once inside, the virus uses the cellular machinery to make more copies of itself. (Juan Gaertner / Source of Science)
Rochester's research on the structure and function of RNA provides important information for developing treatments for the coronavirus.
The US Food and Drug Administration recently granted an emergency use authorization for aCOVID-19 vaccine developed by Pfizerand the German pharmaceutical company BioNTech.
The vaccine made history not only because it reported a 95% effectiveness rate in preventing COVID-19 in clinical trials, but because it is the first vaccine to be approved by the FDA for human use and based on RNA technology.
"The development of RNA vaccines is a great boon for the future of infectious disease treatment," he says.Lynne Maquat, J. Lowell Orbison Distinguished Service Alumni Professor of Biochemistry and Biophysics, Oncology and Pediatrics at Rochester and Director of the Rochester Center for RNA Biology.
COVID-19, short for "Coronavirus Disease 2019", is caused by the novel coronavirus SARS-CoV-2. Like many other viruses, SARS-CoV-2 is an RNA virus. This means that the SARS-CoV-2 genome is encoded in ribonucleic acid (RNA), unlike humans and other mammals. Viral RNA is sneaky: its properties cause the human protein synthesis machinery to mistake it for the RNA produced by our own DNA.
For this reason, several of the leading vaccines and treatments for COVID-19 are based on RNA technology.
A contingent of researchers from theUniversity of Rochesterstudy the RNA of viruses to better understand how RNAs work and how they are involved in disease. This RNA research forms an important foundation for the development of vaccines and other drugs and therapies to stop the virus and stop infections.
"Understanding the structure and function of RNA helps us understand how we can throw a therapeutic wrench into what the COVID-19 RNA is doing - creating new viruses that can infect more cells of ours and of other people as well."
What does RNA mean?
RNA stands for ribonucleic acid.
What is RNA?
RNA delivers the genetic instructions contained in DNA to the rest of the cell.
What does Covid mean?
Covid-19 stands for “coronavirus disease 2019”.
As scientists have realized in recent decades that genetic material is largely regulated by the RNA that encodes it, that most of our DNA makes RNA, and that RNA is not only a target but also a tool for disease therapy," o The world of RNA research has exploded," says Maquat. "The University of Rochester understood this."
Maquat was founded in 2007The Center for RNA Biologyas a means of interdisciplinary research on the function, structure and processing of RNAs. The center includes researchers from the River Campus and Medical Center and combines expertise in biology, chemistry, engineering, neurology and pharmacology.
“Our strength as a university is our diversity of research expertise combined with our highly collaborative nature,” she says.Drache Fu, Associate Professor of Biology at River Campus and member of the Center for RNA Biology. "We are surrounded by outstanding researchers advancing our understanding of RNA biology and a medical center that offers a translational aspect where knowledge gained from RNA biology can be applied to therapeutics."
How is RNA related to disease?
AChart created by The New York Timesillustrates how the coronavirus that causes COVID-19 enters the body through the nose, mouth or eyes and attaches itself to our cells. Once the virus is in our cells, it releases its RNA. Our hijacked cells serve as virus factories, reading the virus's RNA and producing long viral proteins to weaken the immune system. The virus makes new copies of itself and spreads to other parts of the body and to other people through saliva, sweat and other body fluids.
“Once the virus is in our cells, the entire process of infection and reinfection depends on the viral RNA”, says Maquat.
One of the reasons viruses pose such a challenge is that they change and mutate in response to drugs.
This means that every time a new strain of virus emerges, new treatments against the virus and vaccines must be developed. Armed with groundbreaking research into RNA fundamentals, scientists are better equipped to design and test therapies that directly target RNAs and processes critical to a virus's life cycle.
How do RNA vaccines work?
Conventional vaccines against viruses like influenza inject inactivated viral proteins called antigens. Antigens stimulate the body's immune system to recognize the specific virus and produce antibodies in response, in the hope that these antibodies will fight off future viral infections.
RNA-based vaccines - such as those developed by Pfizer/BioNTech and the American biotechnology company Moderna - do not introduce an antigen, but inject a short sequence of synthetic messenger RNA (mRNA) encapsulated in a specially designed lipid nanoparticle. This mRNA instructs the cells to produce the virus antigen themselves.
For example, once a vaccine mRNA is in our body, it "instructs" the protein synthesis machinery in our cells, which normally makes proteins from the mRNAs derived from our genes, to make a piece of the SARS virus. -CoV-2 spike protein. Since the SARS-CoV-2 virus spike protein is foreign to our body, our body will produce antibodies that inactivate the protein.
“If the virus enters our body from an infected person, these antibodies bind to the virus and inactivate it, binding to its spike proteins, which coat the outside of the virus capsule”, says Maquat.
An RNA-based vaccine therefore acts as a code, instructing the body to make many copies of the viral protein - and the resulting antibodies - on its own, leading to an immune response.
Unlike more traditional vaccines, RNA-based vaccines also have the benefit of eliminating the need to work with the real virus.
"Working with a live virus is expensive and very labor intensive, requiring researchers to use dedicated biosafety labs and wear bulky personal protective equipment so that the virus is 'biocontained' and nobody gets infected," says Maquat.
Developing a vaccine from a live virus also takes much longer than making an mRNA-based vaccine, but "no one should think the process is easy," says Maquat of Pfizer/BioNTech Vaccine. "As it's the first of its kind, a lot had to be worked on."
How is the Rochester RNA research applicable to COVID-19?
Researchers Douglas Anderson, Dragony Fu and Lynne Maquat are among the University of Rochester scientists studying the RNA of viruses to better understand how RNAs work and how they are involved in disease. (Photos University of Rochester / Matt Wittmeyer / J. Adam Window)
Maquat has been studying RNA since 1972 and was part of the first wave of scientists to recognize the important role that RNA plays in human health and disease.
Our cells have multiple ways of fighting viruses, which can be seen as an "arms race" between the host and the virus. One of the weapons in our cells' arsenal is an RNA surveillance mechanism discovered by Maquat called Nonsense-Mediated mRNA Decay (NMD).
"Nursery-mediated mRNA degradation protects us from many genetic mutations that could cause disease if NMD were not active to destroy the RNA that harbors the mutation," she says.
Maquat's discovery has contributed to the development of drug therapies for genetic diseases such as cystic fibrosis and could be useful in developing treatments for the coronavirus.
"NMD also helps us fight viral infections, which is why many viruses inhibit or bypass NMD," she adds. “The genome of the COVID-19 virus is a positive-sense single-stranded RNA. Other positive-sense single-stranded RNA viruses are known to avoid NMD by having RNA structures that prevent NMD from degrading viral RNAs.”
Maquat's lab collaborated with a lab at Harvard University to test how viral proteins can inhibit the NMD machinery.
His recent work focuses on the SARS-CoV-2 structural protein called N. Laboratory experiments and datasets from infected human cells indicate that this virus is unusual in that it does not inhibit the NMD signaling pathway, which controls many of our genes and some of the Viruses regulate the genes. Instead, the viral N protein appears to promote the signaling pathway.
“SARS-CoV-2 reproduces its RNA genome much more efficiently than other pathogenic human viruses,” says Maquat. “Perhaps there is a connection; we will see."
At the Faculty of Biology, Fu andJack Weren,Nathaniel and Helen Wisch, Professor of Biology, received accelerated grants from the National Science Foundation to apply their expertise in cellular and evolutionary biology to the study of proteins involved in COVID-19 infection. The funding was part of NSF's Rapid Response Research (RAPID) program to mobilize funds for high-priority projects.
Werren's research will be important in alleviating some of the possible side effects of COVID-19 infections, including blood clots and heart disease, while Fu's research will provide insight into the potential effects of viral infection on human cellular metabolism.
"Our research will provide insight into the possible effects of viral infection on host cellular processes," says Fu. "Identifying which cellular functions are affected by the virus could help reduce some of the negative effects of COVID-19." Green = said twice.
Douglas Anderson, an assistant professor of medicine at the Aab Cardiovascular Research Institute and a member of the Center for RNA Biology, studies how RNA mutations can cause human disease and found that alternative therapies such as CRISPR gene-editing technology could also "lead a new approach to the way we fight and fight infectious diseases”, he says.
In recent years, Anderson's lab has developed tools and delivery systems that use RNA-targeted CRISPR-Cas13 to treat human genetic diseases that affect muscle function. CRISPR-Cas13 is like molecular scissors that can target specific RNAs for degradation using small, programmable guide RNAs.
When the health crisis became apparent in Wuhan, China, researchers in Anderson's lab focused on developing a CRISPR-Cas13 therapeutic targeting SARS-CoV-2. Using already available knowledge about coronavirus RNA replication, they developed unique CRISPR guide RNAs capable of targeting any viral RNA produced in a cell infected with SARS-CoV-2. Using a new cloning method developed in Anderson's lab, multiple CRISPR guide RNAs can be packaged into a single therapeutic vector (a genetically engineered transporter) to simultaneously target multiple viral RNA sites. The multipronged targeting strategy can be used as a therapy to protect against virus-induced cellular toxicity and to prevent the "flight" of viruses that may have mutated.
"Infectious viruses and pandemics seem to come out of nowhere, which has made it difficult to quickly develop and track traditional small molecule therapies or vaccines," says Anderson. "There is a clear need to develop alternative targeted therapies such as CRISPR-Cas13 that can be rapidly reprogrammed to combat emerging pandemics."
Although many new treatments are being considered for the new coronavirus, one thing is certain, says Maquat: "Targeting the RNA or proteins it produces is essential to therapeutically combat this disease."
What role will RNA play in the future of vaccines and disease treatments?
Most people living in the US today have only read about the 1918 flu pandemic and the relatively new RNA viruses like Ebola or Zika that are prevalent in other countries.
"RNA treatments are likely to be a wave of the future for these and other emerging diseases," says Maquat. "Epidemiologists know that new infectious agents are emerging because of how small the world has become due to international travel, including to and from places where humans and animals are in close contact."
Bats, in particular, are reservoirs of viruses.. Given bats' unusual physiology, many bat species can live with viruses without suffering ill effects. However, if these bat viruses mutate so they can infect humans, new diseases will emerge, says Maquat.
“It's just a matter of when it will happen and what virus it will be. The hope is that with the new pipelines in place for COVID-19, we will be ready and able to develop vaccines against these new viruses.”
This story was originally published on April 28, 2020 and updated on December 14, 2020.
FDA approves emergency use of Pfizer's coronavirus vaccine
Researchers and volunteers in Rochester have been involved in the Pfizer/BioNTech vaccine trial since May, and the technologies used in vaccine development may have their roots in decades of infectious disease research conducted in Rochester.
Bats offer clues on how to treat COVID-19
Bats carry many viruses, including COVID-19, without getting sick. Biologists at the University of Rochester are studying the immune system in bats to find possible ways to mimic this system in humans.
Rochester biologists selected for 'quick survey' on COVID-19
Rochester biologists are studying how the coronavirus interacts with cellular proteins to cause COVID-19 as part of an NSF priority program.
Tag: RNA Biology Center,COVID 19,Institute of Biochemistry and Biophysics,Department of Biology,Douglas Anderson,Drache Fu,featured post,Lynne Maquat,medical Center,School of Arts and Sciences
To trigger an immune response, many vaccines put a weakened or inactivated germ into our bodies. Not mRNA vaccines. Instead, mRNA vaccines use mRNA created in a laboratory to teach our cells how to make a protein—or even just a piece of a protein—that triggers an immune response inside our bodies.Is Covid DNA or RNA virus? ›
Coronaviruses (CoVs) are positive-stranded RNA(+ssRNA) viruses with a crown-like appearance under an electron microscope (coronam is the Latin term for crown) due to the presence of spike glycoproteins on the envelope.How long does mRNA stay in the body? ›
mRNA, which is the technology used in the Pfizer and Moderna vaccines, degrades in the body naturally after a few days, and the spike protein it creates only stays for a couple weeks .Which COVID vaccines are not mRNA? ›
- Pfizer-BioNTech and Moderna COVID-19 vaccines are mRNA vaccines.
- Novavax COVID-19 vaccine is a protein subunit vaccine.
- Johnson & Johnson's Janssen (J&J/Janssen) COVID-19 vaccine is a viral vector vaccine and can be given in some situations.
The advantage of mRNA technology compared with conventional approaches is that it allows for faster development and scale-up of production. Vaccine development has traditionally been measured on the timeframe of a decade. It's an amazing scientific accomplishment to be where we are right now.What are examples of RNA viruses? ›
1.1. RNA Viruses. Human diseases causing RNA viruses include Orthomyxoviruses, Hepatitis C Virus (HCV), Ebola disease, SARS, influenza, polio measles and retrovirus including adult Human T-cell lymphotropic virus type 1 (HTLV-1) and human immunodeficiency virus (HIV).Is coronavirus an RNA virus? ›
Coronaviruses (CoVs), enveloped positive-sense RNA viruses, are characterized by club-like spikes that project from their surface, an unusually large RNA genome, and a unique replication strategy.What are the symptoms of RNA virus? ›
Symptoms include cough, fever, sneezing, nasal congestion, sore throat, fever, and headache and usually last 7–10 days after an initial 48-h viral incubation.How does mRNA get out of your body? ›
The cells make copies of the spike protein and the mRNA is quickly degraded (within a few days). The cell breaks the mRNA up into small harmless pieces.Can you reverse mRNA vaccine? ›
Preclinical studies of COVID-19 mRNA vaccine BNT162b2, developed by Pfizer and BioNTech, showed reversible hepatic effects in animals that received the BNT162b2 injection. Furthermore, a recent study showed that SARS-CoV-2 RNA can be reverse-transcribed and integrated into the genome of human cells.
- Muscle pain.
Previous studies have found that two doses of inactivated whole-virus vaccines elicited lower antibody titers and conferred less protection against SARS-CoV-2 infection than two doses of mRNA vaccines.What is an example of mRNA vaccine? ›
Both the Pfizer-BioNTech and the Moderna COVID-19 vaccines use mRNA . Vector vaccine. In this type of vaccine, genetic material from the COVID-19 virus is placed in a modified version of a different virus (viral vector).When were mRNA vaccines invented? ›
The concept of mRNA vaccines was first developed in the early 1990s (Schlake, 2012).What is the conclusion on RNA viruses? ›
RNA viruses exhibit a high mutation rate and are very frequent in recombination thus having unique evolutionary capacity. RNA viruses adapt to rapid environmental changes, such as shifts in the pharmacological challenge or immune pressure.
The genetic material of a virus can be either DNA or RNA. The viruses that contain DNA as their genetic material are called the DNA viruses. RNA viruses, on the other hand, contain RNA as their genetic material.Why do viruses use RNA instead of DNA? ›
Unlike DNA viruses which must always transcribe viral DNA into RNA to synthesize proteins, RNA can skip the transcription process. Furthermore, some RNA molecules can act as mRNA being translated directly into protein.What does the medical term RNA mean? ›
RNA is also the genetic material of some viruses instead of DNA. RNA can be made in the laboratory and used in research studies. Also called ribonucleic acid.What is the meaning of RNA virus? ›
Definition and Basic Properties of RNA Viruses
RNA viruses replicate their genomes using virally encoded RNA-dependent RNA polymerase (RdRp). The RNA genome is the template for synthesis of additional RNA strands (a molecule of RNA is the template and molecules of RNA are produced).
RNA viruses have higher probabilities to infect new host species because of their exceptionally shorter generation times and their faster evolutionary rates.
RNA viruses generally have very high mutation rates compared to DNA viruses, because viral RNA polymerases lack the proofreading ability of DNA polymerases. The genetic diversity of RNA viruses is one reason why it is difficult to make effective vaccines against them.Can RNA virus affect DNA? ›
It is apparent, however, that many RNA viruses can also induce significant DNA damage, even in cases where viral replication takes place exclusively in the cytoplasm.Can RNA viruses infect humans? ›
There are 180 currently recognised species of RNA virus that can infect humans and, on average, 2 new species are added every year.Would our bodies be able to make proteins without mRNA? ›
Without it our genetic code would never get used by our bodies, proteins would not be created and ultimately our bodies would not be able to perform its necessary functions.What prevents mRNA from entering the nucleus? ›
Upon translocation to the cytoplasm, the transport receptor is dissociated from the export complex to prevent the mRNA cargo from returning to the nucleus.Can mRNA leave the nucleus? ›
This mRNA can undergo processing in the nucleus. And once this is complete, the mature mRNA can then exit the nucleus through the nuclear pores to enter the cytoplasm. In the cytoplasm, the mRNA can bind to a specialized organelle called the ribosome.Are there cardiac side effects after Covid vaccine? ›
Myocarditis has been considered a rare but serious potential side effect from COVID-19 vaccination, more often after a second dose than after the first, according to the Centers for Disease Control and Prevention.How is COVID vaccine differ from other vaccines? ›
While other vaccines trick the body's cells into creating parts of the virus that can trigger the immune system, the Novavax vaccine takes a different approach. It contains the spike protein of the coronavirus itself, but formulated as a nanoparticle, which cannot cause disease.