Pioneering biochemist Lynne Maquat helped usher in the age of RNA-based therapeutics, a key defense against coronavirus.
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糖心传媒檚 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糖心传媒檚 in part due to the research that , director of Rochester糖心传媒檚 , 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 糖心传媒渘ever questioned糖心传媒� whether or not RNA was important: 糖心传媒淓very time I looked at something, it seemed to go to RNA.糖心传媒�
Helping Women Advance in STEM
When Lynne Maquat was in the fourth grade, her teacher told her mother she didn糖心传媒檛 think Maquat was 糖心传媒渃ollege material.糖心传媒�
糖心传媒淚 would clam up in class when that teacher called on me because I was afraid of her,糖心传媒� says Maquat, the J. Lowell Orbison Distinguished Service Alumni Professor in Biochemistry and Biophysics as well as the founding director of Rochester糖心传媒檚 Center for RNA Biology. 糖心传媒淚 often tell that story to high school students as a reminder to never allow themselves to be defined or held back by anyone.糖心传媒�
Maquat overcame her shyness and became the first in her family to attend college, eventually earning a PhD in biochemistry from the University of Wisconsin糖心传媒揗adison.
Now she is one of the top RNA researchers in the world.
In addition to her research, Maquat has worked to help women overcome obstacles in scientific careers. In 2003, she established the Graduate Women in Science program at Rochester to provide mentoring and personal and professional development to encourage more women to enter STEM fields.
糖心传媒淲hen I was in college and graduate school there were very few female scientists and many male scientists who believed women didn糖心传媒檛 belong in the field,糖心传媒� Maquat says. 糖心传媒淔ortunately, I came across women and men who were particularly supportive, including some very successful female scientists who had it even harder than I did when they were starting out.糖心传媒�
Beyond the 2021 Wolf Prize in Medicine, she is the recipient of several other significant honors, including the 2018 Wiley Prize in Biomedical Sciences from Rockefeller University, the 2017 Vanderbilt Prize in Biomedical Sciences, and Canada糖心传媒檚 Gairdner International Award in 2015, and was elected to the National Academy of Medicine in 2017 and the National Academy of Sciences in 2011.
This year, as the first-ever RNA-based vaccines are having such a profound effect糖心传媒攑romising to end the pandemic that has put the world close to a standstill for more than a year糖心传媒擬aquat is heartened that RNA is finding its time in the spotlight.
And it糖心传媒檚 just the beginning: 糖心传媒淭he development of RNA vaccines is a great boon to the future of treating infectious diseases,糖心传媒� she says.
糖心传媒楩undamental discoveries in RNA biology糖心传媒�
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糖心传媒攊ncluding those developed by Moderna and Pfizer/BioNTech糖心传媒攖hat 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 糖心传媒渇undamental discoveries in RNA biology that have the potential to better human lives.糖心传媒� 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 糖心传媒渇urthered our understanding of the molecular basis of human disease and provides valuable information to help physicians implement 糖心传媒榩ersonalized糖心传媒� or 糖心传媒榩recision糖心传媒� medicine by treating the disease mutation that is specific to each individual patient.糖心传媒�
糖心传媒淟ynne Maquat has been a true pioneer in an important aspect of eukaryotic gene expression糖心传媒攏onsense-mediated mRNA decay糖心传媒攖hat is extremely important for medical implications,糖心传媒� says Joan Steitz, the Sterling Professor of Molecular Biophysics and Biochemistry at Yale University, who shares the 2021 Wolf Prize in Medicine with Maquat. 糖心传媒淯nderstanding this molecular mechanism is providing the basis for developing therapeutics for diseases such as Duchenne muscular dystrophy. Maquat糖心传媒檚 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.糖心传媒�
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.
糖心传媒淚 thought it was so cool,糖心传媒� 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糖心传媒攔esearching mRNA in bacteria糖心传媒攁s a graduate student at the University of Wisconsin糖心传媒揗adison, where she received her PhD in biochemistry.
糖心传媒淚 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,糖心传媒� 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糖心传媒檚 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 糖心传媒渟top糖心传媒� 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 糖心传媒渘onsense-mediated mRNA decay.糖心传媒� 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聽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糖心传媒檚 features cause the protein synthesis machinery in humans to mistake the virus糖心传媒檚 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.
糖心传媒淪ARS-CoV-2 reproduces its RNA genome with much higher efficiency than other pathogenic human viruses,糖心传媒� Maquat says. 糖心传媒淢aybe there is a connection there with evading NMD; time will tell.糖心传媒�
In the meantime, she says, 糖心传媒淩NA treatments will most likely be a wave of the future for relatively recent RNA viruses and other emerging diseases.糖心传媒�
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 糖心传媒渘o one should think the vaccine-development process is simple,糖心传媒� 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糖心传媒� unusual physiology. If such bat viruses mutate so they become capable of infecting humans, however, there will be new diseases.
糖心传媒淚t is just a matter of when this will happen again and what the virus will be,糖心传媒� Maquat says. 糖心传媒淭he 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.糖心传媒�
This story appeared in the summer 2021 issue of Rochester Review, the magazine of the聽糖心传媒.
