Center for RNA Biomedicine

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Jay Querido, University of Michigan RNA Faculty Fall 2022

We are thrilled to announce that Jay Brito Querido as agreed to join us as a faculty member in Biological Chemistry, the Center for RNA Biomedicine, and the LSI.

About Dr. Brito Querido:
A native of Cape Verde, Dr. Querido received undergraduate and M.S. degrees at the University of Lisbon. For his Ph.D., Dr. Querido worked with Dr. Yaser Hashem in Strasbourg, France using cryo-EM to study parasite-specific ribosomal proteins. Dr. Querido then moved to Dr. Venki Ramakrishnan’s lab at the MRC Laboratory of Molecular Biology for post-doctoral work, where he has tackled longstanding questions surrounding translation initiation on eukaryotic mRNAs. Most prominently, Dr. Querido determined the structure of a 48S translation initiation complex and suggested a novel mechanism for ribosome recruitment and mRNA scanning (Brito Querido et al., Science 2020).

Future Scientific Plans:
Currently, Dr. Querido is exploring translation initiation on structured mRNAs and the role of the human tumor suppressor protein Pdcd4 in regulating translation. Dr. Querido has exciting plans to continue in this field, with a goal of understanding the many ways in which RNA helicases regulate gene expression in health and disease.

If you would like to reach out to welcome Jay, you may contact him here: jquerido@mrc-lmb.cam.ac.uk

After COVID-19, mRNA vaccines could treat flu, HIV and even cancer

By Justin P. Hicks | jhicks3@mlive.com

Empty syringes wait to be filled with the Pfizer-BioNTech COVID-19 vaccine at the Kalamazoo Expo Center (Joel Bissell | MLive.com)

Vaccines to protect against severe illness and death from COVID-19 started as the key to a return to normal, but they could wind up unlocking much more for the future of health care.

The mRNA vaccine technology used by Pfizer/BioNTech and Moderna for their respective coronavirus vaccines has been heavily touted by doctors and public health officials as a modern miracle of science and a means to revolutionize vaccine development.

“It’s hard to overestimate the impact this will have on human health,” said Nils Walter, a professor of biological chemistry at the University of Michigan who has studied mRNA for about 30 years. “It’s like introducing the iPhone when everyone had a flip phone.”

Beyond its uses for COVID-19, numerous mRNA vaccine candidates are being researched and undergoing clinical trials for the treatment of cancer, including pancreatic cancer, colorectal cancer and melanoma, as well as HIV, influenza, Ebola, Zika, and rabies.

“The same molecule from billions of years ago that gave us life is now coming back to what ails us today in life, which are viral infections and the terrible diseases like cancer,” Walter said. “It’s transformative.”

Vaccines using mRNA technology work by delivering instructions to the cells. In the case of COVID-19, those instructions are to create a protein that mimics the spike protein found in SARS-CoV-2, which triggers an immune response and the development of antibodies to defend against that virus.

Unlike previously used viral vector vaccines, mRNA vaccines don’t introduce live or dead virus into the body as a means of triggering antibody production.

The ingredients of the vaccine are broken down and discarded in a matter of days. The mRNA never enters the nucleus of the cell, and has no interaction with the cell’s DNA, health officials have repeatedly stated.

Dr. Liam Sullivan, an infectious disease specialist for Spectrum Health, expects mRNA technology to “revolutionize vaccine development.”

“This is just the beginning; we’re just scratching the surface here,” he said. “mRNA vaccine technology for treating diseases isn’t going anywhere. If anything, it’s going to get better and better and be used more widespread.”

Previous vaccines like the annual flu shot could take a year to develop, which made it challenging to predict which strains would be around by the next flu cycle. As a result, flu shot effectiveness has varied year to year.

With mRNA vaccines, that timeline can be cutdown 10-fold, Walter said.

“We can now operate at the same speed as the virus and therefore, viruses can no longer outmaneuver us and the vaccine can be made to specs in very, very short time,” he said. “It’s a totally different ball game.” [Read more…] about After COVID-19, mRNA vaccines could treat flu, HIV and even cancer

Arul Chinnaiyan awarded prestigious Sjöberg Prize for cancer research

Renowned U-M researcher is recognized by Royal Swedish Academy of Sciences for pioneering prostate cancer discovery

Arul M. Chinnaiyan, MD, PhD

ANN ARBOR, Michigan — Arul M. Chinnaiyan, M.D., Ph.D., S.P. Hicks Professor of Pathology and Urology at Michigan Medicine, was awarded the 2022 Sjöberg Prize by the Royal Swedish Academy of Sciences, which also awards Nobel Prizes.

Chinnaiyan is being honored for the discovery of recurrent gene fusions in prostate cancer, a groundbreaking finding initially published in 2005 that has led to a better understanding of how prostate cancer develops and improved methods to detect the disease.

“It is a great honor to be selected for this award and to follow in the footsteps of the luminaries who have received this award in the past,” said Chinnaiyan, director of the Michigan Center for Translational Pathology and a member of the University of Michigan Health Rogel Cancer Center.

This is the sixth time the Sjöberg Prize has been awarded. It was established by businessman Bengt Sjöberg, who was diagnosed with cancer and donated two billion Swedish kronor to promote scientific research primarily focused on cancer, health and the environment. The Royal Swedish Academy selects the laureates and the Sjöberg Foundation provides the financing. Winners receive $1 million, which includes $100,000 personal prize and $900,000 to support their research.

Chinnaiyan’s lab found that a prostate-specific gene called TMPRSS2 fuses with the gene ERG, to drive prostate cancer development. This gene fusion, fueled by the hormone androgen, acts as an “on switch” to trigger prostate cancer. The fusion is an exquisitely specific biomarker of prostate cancer that can be detected in prostate needle biopsies and non-invasively in the urine of men with prostate cancer, which has led to improved methods for screening and diagnosing prostate cancer. It also represents a potential target for treatment, and research is ongoing to develop drugs against this genetic anomaly.

“The Sjöberg Prize is an incredibly well-deserved recognition for Dr. Chinnaiyan,” said Eric R. Fearon, M.D., Ph.D., director of the Rogel Cancer Center. “His gene fusion discovery provided unique insights into recurrent genetic defects fueling development of prostate cancers. The work also showed gene fusions could be at the heart of common cancer types. Moreover, he has translated his basic research findings into a screening test that has significantly improved how prostate cancer, especially aggressive prostate cancer, is detected. His discoveries are making a real difference for people with cancer.”

Former Sjöberg laureates include James P. Allison, Ph.D., who was awarded the Nobel Prize in Medicine in 2018.

An award ceremony will be held in Sweden on June 13, and Chinnaiyan will also deliver the Sjöberg Prize lecture then at the Karolinska Institute.

 

Koutmou and Koutmos results published in the Proceedings of the National Academy of Sciences (PNAS)

Kristin Koutmou, Ph.D.

Markos Koutmos, Ph.D.

A University of Michigan team of biochemists, led by Kristin Koutmou, Ph.D., and Markos Koutmos, Ph.D., Assistant Professors in the Department of Chemistry and Department of Biophysics, is reframing the understanding of the biology of a class of enzymes called Pseudouridine Synthases (Pus enzymes). These enzymes modify many types of RNAs, and the Koutmou and Koutmos Labs’ research brings new insights into the selection principles that guide modification incorporation. Their results are published in the Proceedings of the National Academy of Sciences (PNAS).

This novel understanding of pseudouridine biology could have important therapeutic implications because the dysregulation of Pus enzymes is linked to inherited diseases impacting muscle and brain function, such as progressive mitochondrial myopathy and sideroblastic anemia (MLASA). Furthermore, these enzymes also catalyze pseudouridine incorporation into RNA viral genomes, including that of SARS-CoV-2. As such, Pus enzymes present a potential new target for the development of therapeutics.

Since RNAs are central to the protein synthesis machinery, its chemical modifications can alter how fast and/or how accurately proteins are made. These modifications can have many consequences for cellular health, overall cellular adaptation, and cellular regulation. [Read more…] about Koutmou and Koutmos results published in the Proceedings of the National Academy of Sciences (PNAS)

Being and belonging: science and community

The scientific journey of Bambarendage (Pini) Perera, Ph.D., Research Assistant Professor of Environmental Health Sciences, School of Public Health

Diet, exercise, or environmental exposures have an impact on how our genes are activated or silenced. These factors do not permanently affect our DNA, but they can interfere with our gene expression by acting upon RNA regulation mechanisms. These phenomena comprise “epigenetics,” a field of research that fascinates Bambarendage Pinithi (Pini) Perera, Ph.D., Research Assistant Professor in the department of Environmental Health Sciences of the School of Public Health, and a new member of the Center for RNA Biomedicine. Through epigenetics research, she sees the opportunity to contribute to society, and to scientifically inform the public and stakeholders about the benefits and risks of environmental exposures.

Dr. Perera is particularly interested in embryonic development and the effect of environmental exposures during pregnancy. In this context, she studies the consequences of toxic exposures on imprinted genes—these are normal monoallelic genes, meaning that only one of the two parents’ genes is activated—and RNA regulation processes.

[Read more…] about Being and belonging: science and community

CRISPR to KLIPP cancer

While most efforts involving CRISPR are focused on genome editing, the CRISPR machinery could also be used as a molecular weapon to slice up chromosomes of cancer cells. Research has shown that chromosomes may undergo a “catastrophic” event early in the process of carcinogenesis causing multiple breakages. While many cells die in such events, some of them repair the damaged chromosomes in ways that give them the power to multiply faster and to form tumors. Such chromosome rearrangements bring into close proximity pieces of chromosomes that are normally far apart. The formation of chromosome rearrangements is unique to cancer cells and is observed across all forms of cancer. “This is our Achilles’ heel, right there,” said Dr. Ljungman, Professor of Radiation Oncology and co-director of the Center for RNA Biomedicine, “and we could use CRISPR to specifically target these chromosome rearrangement junctions and cut tumor DNA strands similarly to what is done with radiation therapy, but without affecting normal cells.”

This article is reprinted from RNA Translated 2021. Photo: KLIPP team, Summer 2021. From left to right: Mats Ljungman, Radhika Suhas Hulbatte, Huibin Yang, Lauren Hertzer, and Natalie Gratsch. Photo: Elisabeth Paymal

[Read more…] about CRISPR to KLIPP cancer

Dr. Rajesh Rao receives a Career Advancement Award from Research to Prevent Blindness (RPB).

Congratulations to Dr. Rajesh Rao for receiving a Career Advancement Award from Research to Prevent Blindness (RPB). The Career Advancement Award assists outstanding early-career vision scientists in pursuit of ongoing research of unusual significance and promise. This one-time award is available to candidates who have already received their first NIH R01 and are collecting new data to apply for a second R01.

See also: “Sustaining Independent Careers in Vision Research: Demographics and Success in Second R01 Attainment Among Clinician–Scientists from 1985 to 2019,” Elaine A. Liu; Sophia Y. Wang; Rajesh C. Rao, Translational Vision Science & Technology, November 2020, Vol.9, 32. doi:https://doi.org/10.1167/tvst.9.12.32

A publication by Dr. Barmada and his team is “Editor’s pick” of the Journal of Biological Chemistry

Dr. Sami BarmadaSami Barmada, M.D., Ph.D., Department of Neurology and member of the Center for RNA Biomedicine, with Nathaniel Safren, Ph.D., from Northwestern University, and other UM colleagues, was awarded “Editor’s pick” by the Journal of Biological Chemistry (JBC). This recognition signals “a top-rated paper published in JBC across the field of biological chemistry, as determined by JBC’s Associate Editors, Editorial Board Members and other referees.”

In this article, Barmada and his team are interested in autophagy activity, a pathway responsible for mediating the breakdown of cellular proteins and organelles. Autophagy can be compared to a cellular cleaning service, and its dysfunction is associated with many diseases including cancers and neurodegenerative diseases.

Although autophagy plays an important role in cellular biology, to this day, methods to accurately measure its activity are limited and somewhat unreliable. The Barmada team developed a novel biochemical technique that uses protein fluorescent tags inserted into the genome via CRISPR Cas9. This method enables accurate and sensitive assessments of autophagy in living cells by optical pulse labeling, a noninvasive approach that can be used in living cells

“Autophagy has received a great deal of attention because of its therapeutic implications for neurodegenerative and other age-related conditions,” says lead author Dr. Barmada. “Even so, our ability to accurately track autophagy activity or flux has been severely limited by the available tools. Here, we leveraged CRISPR/Cas9 to label an autophagy-related protein in human cells, allowing us for the first time to actually see autophagy in action, and measure flux in a quantitative and reliable fashion.” [Read more…] about A publication by Dr. Barmada and his team is “Editor’s pick” of the Journal of Biological Chemistry

Unveiling the hidden cellular logistics of memory storage in neurons

Exploring the mechanisms involved in sleep-dependent memory storage, a team of University of Michigan (U-M) cellular biologists found that RNAs associated with an understudied cell compartment in hippocampal neurons vary greatly between sleeping and sleep-deprived mice after learning.

Sara Aton, Associate Professor in the Department of Molecular, Cellular, and Developmental Biology, and James Delorme, a recent U-M neuroscience graduate student, hypothesized that both a learning event and subsequent sleep (or sleep loss) would impact mRNA translation. Most prior work on the effects of sleep on mRNAs have focused on transcripts in the neuronal cytosol. However, Drs. Aton and Delorme found that after learning, major changes in RNAs are instead present —almost exclusively— on ribosomes associated with neuronal cell membranes. These results have been published in the Proceedings of the National Academy of Sciences, in November 30, 2021.*

In this representation, the red background is the cytosol, and ribosomes are in light green. tRNAs are the purplish blue blobs. Some tRNAs are in the cytosol and others are bound to the green ribosomes. The mRNAs are represented in yellow. The thin purple strand coming out the other side of the ribosomes (and into the ER lumen) is the protein. The big thick black lines in the bottom left corner represents the lipid bilayer of the ER membrane. (Image credit: Sara Aton)

[Read more…] about Unveiling the hidden cellular logistics of memory storage in neurons

Amanda Garner, Ph.D., is nominated the ACS Division of Medicinal Chemistry 2022 David W. Robertson Award for Excellence in Medicinal Chemistry!

Congratulations to Amanda Garner, Ph.D., for receiving the ACS Division of Medicinal Chemistry 2022 David W. Robertson Award for Excellence in Medicinal Chemistry!
The David W. Robertson Award for Excellence in Medicinal Chemistry, awarded in even-numbered years, is intended to recognize seminal contributions by young scientists to medicinal chemistry. The nominee must have had a primary role in the discovery of a novel therapeutic agent(s), target(s), theoretical concept(s) in medicinal chemistry or drug discovery, and/or made a significant scientific discovery that enhances the field of medicinal chemistry.

Amanda Garner is Associate Professor, Medicinal Chemistry, College of Pharmacy, and former Member of our Executive Committee.

Chase Weidmann, Ph.D., receives a K22 grant from NCI

Congratulations to Chase Weidmann, Ph.D., for receiving a K22 grant from NCI for “Unraveling the MALAT1 lncRNA-protein interaction networks that drive lung cancer metastasis”

This project’s goal is to integrate cutting-edge sequencing and quantitative proteomics technologies with cell-based functional approaches to understand how RNA-protein interaction networks of MALAT1 promote metastatic activity in human lung cancers.

Chase Weidmann is our second RNA Faculty Scholar hire and is an Assistant Professor in the department of Biological Chemistry at the Medical School.

Weidmann page
Read about Weidmann’s journey into science: “Exploring unknown territories”
Read his scientific feature
Watch his introduction video

U-M study sheds light on how bacteria control their detoxification

By Morgan Sherburne, Michigan News

Bacteria need to constantly adapt to compete against other species for nutrient sources and to survive against threats such as antibiotics and toxins. In an effort to understand how bacteria control and regulate this adaptation, University of Michigan researchers from the Center for RNA Biomedicine are examining how RNA polymerase—the enzyme that transcribes genetic information from DNA onto RNA—slows during transcription in a process called transcriptional pausing.

They found that a protein called N-utilizing substance A, or NusA, in concert with another control element called a riboswitch, fine-tunes the transcription speed in order to regulate gene expression. Gene expression is the process by which genetic information is converted into the building blocks of the bacterium.

The researchers say their work, published in the Proceedings of the National Academy of Sciences, expands our general understanding of the transcription process in bacteria, and could provide a target for developing new antibiotics.

READ MORE

Reference: “Dynamic competition between a ligand and transcription factor NusA governs riboswitch-mediated transcription regulation,” Adrien Chauvier, Pujan Ajmera, Rajeev Yadav, and  Nils G. Walter, Proceedings of the National Academy of Sciences, November 23, 2021 118 (47) e2109026118; https://doi.org/10.1073/pnas.2109026118

M-RNA therapeutics at the University of Michigan

An initiative to make the University of Michigan a world leader in RNA therapeutics,
spearheaded by the Center for RNA Biomedicine and the Biointerfaces Institute

 

Fueled by the COVID-19 mRNA vaccine success and the recent Nobel Prize in Chemistry for the discovery and elucidation of the bacterial CRISPR systems that can be harnessed for genome editing, RNA therapeutics has garnered considerable interest from academia, the pharmaceutical industry, and the public at large. To capitalize on this great momentum, the Center for RNA Biomedicine and the Biointerfaces Institute plan to leverage the strength of University of Michigan (U-M) research in RNA biomedicine and nanoparticle sciences to build a world-class resource that will convert U-M foundational research innovations into RNA-based clinical treatments.

 

 

Together, we envision establishing a pipeline of RNA therapeutics reaching from the research lab to the clinic in five to ten years. Our therapies will include mRNA for vaccines against a multitude of diseases, antisense oligonucleotides (ASOs) for the suppression of undesired genes, and CRISPR for genome editing of defective genes and for precision targeting of cancer cells. M-RNA Therapeutics will also offer these technologies for laboratory research such as gene knockouts and screens.

(Reprinted from RNA Translated 2021)

[Read more…] about M-RNA therapeutics at the University of Michigan

Redefining long non-coding RNAs (lncRNAs) to study transposons in plants

Long non-coding RNAs (lncRNAs) constitute the new frontier of investigation for molecular biologists. However, lncRNA is inconsistently defined, which fails the research community in several ways. In a scientific review [2], Professor Andrzej Wierzbicki from the University of Michigan, Department of Molecular, Cellular and Developmental Biology, and collaborators challenge the contemporary ways of understanding lncRNAs and propose a definition that is based on function and biogenesis. “Here we propose a definition that is clear and specific,” said Wierzbicki, “and we hope that this operational definition will be widely adopted.”

The authors propose the following definition: “a lncRNA is an RNA that has a function independent of its protein-coding potential and that is produced by a mechanism other than molecular ruler-based dicing or trimming.”

Photo: Arabidopsis thaliana (juvenile, flowering and fruiting). For geneticists, Arabidopsis thaliana, a common plant from the mustard (Brassicaceae) family, is considered the equivalent of the fruit fly (Drosophilia melanogaster). This plant can easily be used as a model system for identifying genes and determining their functions. Arabidopsis thaliana is the first plant for which a complete genome sequence was established in 2000. [1]

[Read more…] about Redefining long non-coding RNAs (lncRNAs) to study transposons in plants

Introducing Chase Weidmann, Ph.D., U-M RNA Faculty Scholar

Introducing Chase Weidmann, Ph.D.,
Assistant Professor in the Department of Biological Chemistry
and RNA Scholar Faculty of the Center for RNA Biomedicine.

Exploring unknown territories

Chase Weidmann had three goals for a career: do something “cool,” improve the lives of other people, and, of course, be able to support himself.

Weidmann found the “cool” in high school science classes and he quickly realized that biology and `biotechnology offer vast uncharted territories to explore. One such uncharted area was the academic system itself, as he sometimes struggled to navigate his way through college. Still, he was very glad to find that stipends and resources would enable him to continue exploring in graduate school. He pursued his doctoral research at the University of Michigan (U-M) where now, a decade later, he is joining the RNA faculty community as an Assistant Professor in the Department of Biological Chemistry and as the second hired RNA Scholar Faculty of the Center for RNA Biomedicine.

[Read more…] about Exploring unknown territories

Refer your colleagues to join the U-M Center for RNA Biomedicine.

When you join the University of Michigan Center for RNA Biomedicine, you join an RNA research community of over 150 faculty and their labs, across seven Schools and Colleges. This is a great opportunity to network, learn about each other’s expertise and research, and collaborate on innovative grant proposals. Membership in the Center for RNA Biomedicine is free and open to all University of Michigan affiliates (faculty, students, post-docs, lab technicians and staff) whose work involves RNA science.

 

BECOME A MEMBER

[Read more…] about Refer your colleagues to join the U-M Center for RNA Biomedicine.

First step first: understanding normal processes before tackling pathologies

Photo: Adrien Chauvier, Ph.D., in the Nils Walter’s lab (Credit: Laura Penabad-Peña)

 

Dr. Adrien Chauvier’s journey has taken him around the world, from the Amazon rainforest to Michigan snowy winters, and his passion for science has never left him. He is now a postdoctoral fellow in Nils Walter’s lab, in the Department of Chemistry of the University of Michigan.

Dr. Chauvier grew up in the equatorial forests of French Guiana, north of Brazil. French Guiana is an important biodiversity hotspot and is also the largest French territory outside the metropole.

His father owned a large plant nursery and he is the one who instilled a deep interest for the natural world into him. ” I always wanted to go outside with my dad. I was very curious. We would take care of the plants and the soil together. It was no surprise that growing-up, I wanted to pursue a career in Science and especially in the biological field (…),” he fondly recalled. [Read more…] about First step first: understanding normal processes before tackling pathologies

How sleep loss sabotages new memory storage in the hippocampus

While some students may think it’s a good idea to pull an all-nighter before an exam, conventional wisdom may be correct: a good night’s sleep may actually be more helpful, according to University of Michigan research.

U-M scientists Sara Aton and James Delorme found when mice are sleep deprived, there is an increase in activity in inhibitory neurons in the hippocampus, an area of the brain essential for navigation, as well as for processing and storing new memories.

“Because these neurons limit activity in their neighbors, this physiological response makes it impossible to muster normal neuronal activity in the hippocampal structure,” said Sara Aton, an associate professor in the U-M Department of Molecular, Cellular and Developmental Biology and a member of the U-M Center for RNA Biomedicine executive committee. “I always tell my students that an overnighter is not helping them prepare for an exam.”

The researchers’ results are published in the Proceedings of the National Academy of Sciences, and their findings could have implications for human performance and learning strategies.

 

Image: Somatostatin-expressing interneurons in the mouse dentate gyrus, labeled with Brainbow 3.0 (which labels each neuron a distinct color). cFos (labeled green) is present in the nuclei of surrounding pyramidal cells which are active during sleep. Image by Frank Raven

[Read more…] about How sleep loss sabotages new memory storage in the hippocampus

An often overlooked cause of genetic disease

by Elisabeth Paymal

Often overlooked because they might not alter the amino acid production, splicing defects can play an important role in rare genetic pituitary gland diseases.

Several clinical endocrinologists and bioinformaticians, led by Sally Camper and Jacob Kitzman, Professors of Human Genetics at the University of Michigan Medical School (UMMS), came together to further investigate splicing defects and their roles in rare genetic hormonal diseases. Cathy Smith, a PhD student, established a catalog of predicted variants that could either be tolerated or disease causing.

The pituitary gland is a very important center for hormonal activity. It produces several different hormones which control growth and the functions of other endocrine glands. Specific to the pituitary gland is POU1F1 (also known as PIT1), a transcription factor critical for the development of three of the hormone-producing cell types: growth hormone, prolactin, and thyroid stimulating hormone. Most of the time, a mutation in POU1F1 is recessive, but there are some cases when the variants have a dominant effect. Either genetic cause usually results in multiple hormone deficiencies.

Figures: POU1F1 acts as a dimer and binds to its own gene and the growth hormone to activate transcription (figure 1). The patient variants shift splicing to producing the repressor isoform, which can block the action of the alpha isoform produced from the normal gene copy of POU1F1 (figure 2). This results in less POU1F1 transcription, fewer hormone producing cells, and less growth hormone.

[Read more…] about An often overlooked cause of genetic disease