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AWARD-WINNING RESEARCH: The development of two RNA-based COVID-19 vaccines spotlighted the potential for RNA biology to improve human life. Maquat has been recognized as a pioneer in RNA biology for four decades. (Source: Matt Wittmeyer for the University of Rochester)

When the US Food and Drug Administration approved emergency use authorization for the Pfizer/BioNTech COVID-19 vaccine, the vaccine made history, not only because of its high efficacy rate at preventing COVID-19 in clinical trials, but also because it was the first vaccine ever approved by the FDA for human use that is based on RNA technology.

Traditional vaccines against viruses like influenza inject inactivated virus proteins called antigens. The antigens stimulate the body’s immune system to recognize the specific virus and produce antibodies in response, with the hope that the antibodies will fight against future virus infection.

RNA-based vaccines, however, do not introduce an antigen but instead inject a short sequence of synthetic messenger RNA, which provides cells with instructions to produce the virus antigen themselves.

The world is only beginning to pay closer attention to the importance of ribonucleic acid (RNA) in disease treatment. That’s in part due to the research that Lynne Maquat, director of Rochester’s Center for RNA Biology, has been working on for decades.

Maquat, the J. Lowell Orbison Distinguished Service Alumni Professor in Biochemistry and Biophysics and a professor of oncology and of pediatrics at Rochester, was part of the earliest wave of scientists to realize the important role RNA plays in human health and disease. She says she “never questioned” whether or not RNA was important: “Every time I looked at something, it seemed to go to RNA.”

This year, as the first-ever RNA-based vaccines are having such a profound effect—promising to end the pandemic that has put the world close to a standstill for more than a year—Maquat is heartened that RNA is finding its time in the spotlight.

And it’s just the beginning: “The development of RNA vaccines is a great boon to the future of treating infectious diseases,” she says.

‘Fundamental discoveries in RNA biology’

Maquat joined the Medical Center in 2000 after 18 years in the Department of Human Genetics at the Roswell Park Cancer Institute in Buffalo. She has spent her 40-year career studying messenger RNA (mRNA), RNA molecules that receive genetic instructions from DNA and create proteins that carry out functions within our cells. Her research has contributed to the development of drug therapies for genetic disorders such as cystic fibrosis and may be useful to developing advanced treatments and therapies for COVID-19.

Messenger RNA has taken on new promise during the pandemic with the development and approval of multiple COVID-19 vaccines—including those developed by Moderna and Pfizer/BioNTech—that use RNA as a vehicle for the body to produce disease-fighting antigens.

This year, Maquat was awarded the 2021 Wolf Prize in Medicine from Israel for her “fundamental discoveries in RNA biology that have the potential to better human lives.” The acclaimed international award is presented to outstanding scientists from around the world for achievements that benefit humanity.

While she has spent her career deciphering the many roles of RNA, Maquat is internationally known for her discovery of non-sense-mediated mRNA decay, or NMD. One of the major surveillance systems in the body, NMD is a quality-control mechanism that removes flawed messenger RNA molecules that can lead to mistakes in gene expression and, consequently, disease. According to the Wolf Prize Committee, her work has “furthered our understanding of the molecular basis of human disease and provides valuable information to help physicians implement ‘personalized’ or ‘precision’ medicine by treating the disease mutation that is specific to each individual patient.”

“Lynne Maquat has been a true pioneer in an important aspect of eukaryotic gene expression—nonsense-mediated mRNA decay—that is extremely important for medical implications,” says Joan Steitz, the Sterling Professor of Molecular Biophysics and Biochemistry at Yale University, who shares the 2021 Wolf Prize in Medicine with Maquat. “Understanding this molecular mechanism is providing the basis for developing therapeutics for diseases such as Duchenne muscular dystrophy. Maquat’s tenacity, creativity, and insight in this challenging area, as well as her exceptional record of training and service, have had great impact on the field of RNA research.”

A major surveillance system

As a biology undergraduate at the University of Connecticut, Maquat took a cell biology course where she first learned about protein synthesis.

“I thought it was so cool,” Maquat told the Wolf Prize Committee in a recent interview. Working in the lab of her cell biology professor, she studied messenger RNA and continued this work—researching mRNA in bacteria—as a graduate student at the University of Wisconsin–Madison, where she received her PhD in biochemistry.

“I continued to study messenger RNA in the context of human diseases and was able to show that human diseases can be due to mutations in DNA that cause misprocessing of precursors to mRNAs or unstable mRNAs,” she says.

In 1980, she traveled to Hadassah Hospital in Jerusalem to retrieve and begin processing bone marrow samples from children suffering from a severe form of an inherited blood disorder known as thalassemia major. The bone marrow of people with the disease is unable to produce beta-globin protein, which is necessary for the oxygen-carrying function of red blood cells. Maquat wanted to find out why.

DNA in the nucleus of our cells is like a genetic instruction manual, while RNA is the vehicle that puts the genetic instructions into action: genetic instructions in DNA are transcribed into precursors to mRNAs that are then processed to mRNAs, which in turn, travel out of the nucleus to deliver the instructions to ribosomes. From there, the ribosomes translate the information into proteins, which carry out functions throughout the body.

Normally, once RNA’s instructions have been read from start to finish by the ribosome, a stop signal appears to indicate that all of the information has been translated into a full-length, functional protein. Disease is gene expression gone awry, and a common flaw in gene expression is the introduction of an early “stop” signal, which prevents the instructions from being read completely.

Similar to baking a cake but only completing half the recipe, early stop signals can lead to undesired results: a protein might not be produced at all, or a truncated protein may be produced, either of which can cause disease.

Maquat helped reveal one of the most important mechanisms behind gene expression: quality control, or what has been called “nonsense-mediated mRNA decay.” Her studies documented how NMD works as a surveillance system to detect and destroy mRNAs that contain bad copies of instructions. By eliminating the production of potentially toxic truncated proteins, NMD can act as a cellular weapon to combat disease.

Her 1981 breakthrough manuscript, published in the journal Cell, documented her research on thalassemia and was the first manuscript to reveal the role of NMD in human cells. The paper opened an entirely new field of research into how mRNAs are monitored and regulated.

A vehicle for COVID-19 treatment

Throughout her career, Maquat has figured out the rules by which NMD functions to reduce the expression of unwanted mutations in the human genome. The research is vital to better understanding and combating COVID-19.

Like many other viruses, SARS-CoV-2 is an RNA virus, meaning that the genetic material for SARS-CoV-2 is encoded in RNA. The virus’s features cause the protein synthesis machinery in humans to mistake the virus’s RNA for RNA produced by our own DNA.

Researchers have shown that viruses with a genome similar to that of COVID-19 evade NMD by having RNA structures or producing proteins that prevent NMD from degrading viral RNAs.

“SARS-CoV-2 reproduces its RNA genome with much higher efficiency than other pathogenic human viruses,” Maquat says. “Maybe there is a connection there with evading NMD; time will tell.”

In the meantime, she says, “RNA treatments will most likely be a wave of the future for relatively recent RNA viruses and other emerging diseases.”

RNA-based vaccines, for instance, are beneficial in that they inject mRNAs that instruct our cells themselves to produce antigen molecules, which then stimulate the production of antibody proteins to fight disease. RNA-based vaccines have other advantages over traditional vaccines: they eliminate the need to work with an actual virus and are quicker to develop than traditional vaccines, although “no one should think the vaccine-development process is simple,” Maquat says.

Epidemiologists now know new infectious pathogens are imminent, given the increase in international travel, including to and from places where humans and animals are in close contact. Bats, in particular, are reservoirs for viruses. Many bat species are able to live with viruses without experiencing ill effects, given bats’ unusual physiology. If such bat viruses mutate so they become capable of infecting humans, however, there will be new diseases.

“It is just a matter of when this will happen again and what the virus will be,” Maquat says. “The hope is that we will be ready and able to develop vaccines against these new viruses with the new pipelines that have been put in place for COVID-19.”