THE CENTER FOR MOLECULAR BIOLOGY OF RNA
One of the largest communities of RNA scientists in the world is at the University of California at Santa Cruz —biologists, geneticists, engineers, and computer scientists — and their work is defining the future of this field.
THE CENTER FOR MOLECULAR BIOLOGY OF RNA Scientists in the UC Santa Cruz Center for Molecular Biology of RNA are pushing the boundaries of the central dogma of molecular biology — the theory that explains how genetic information flows from DNA to RNA to produce proteins and regulate other functions in living cells. Many in the field of RNA biology, including scientists on our campus, believe that life emerged from an RNA world in which RNA, instead of DNA, carried the genetic information and RNA, instead of proteins, catalyzed the biochemical reactions of life. In the course of molecular evolution, biologicial activity expanded to include DNA and proteins. For the past three decades, UC Santa Cruz researchers have been at the forefront of challenging conventional wisdom with innovative ideas and creative approaches. With this alternative perspective, our scientists are driving a revolution in how we understand the complex functions of DNA, RNA, and proteins. Our RNA scientists were the first to deternine the molecular structure of the ribosome, the macromolecular machine composed of RNA and proteins that is the engine of protein synthesis within our cells. The rich science of RNA is transforming how we understand life itself, and especially how disease is diagnosed, treated, and prevented — science the world witnessed in the rapid development of the revolutionary messenger RNA vaccines for the COVID-19 virus. The UC Santa Cruz Center for Molecular Biology of RNA has helped to drive these discoveries, with award-winning and prestigious faculty, students, and postdoctoral scientists working to develop novel RNA platforms for early cancer diagnosis, explore the potential for RNA-based therapeutics to treat cancer and rare inherited diseases in children, and understand the function of long non-coding RNAs, as well as the structural and mechanistic underpinnings of RNA in biological systems. This is just the beginning of what RNA research at UC Santa Cruz will mean for the world.
OPPOSITE
Key components of a nanopore DNA sequencer. A processive enzyme (green) binds to a DNA strand (pink) and regulates the speed and distance at which the DNA progresses through a protein nanopore sensor (blue). DNA bases are sequentially read by ions flowing through the nanopore driven by an applied voltage. Scientists at UC Santa Cruz invented and helped pioneer this technology.
INSPIRING GROUNDBREAKING SCIENCE FOR 30 YEARS Since 1992, with the founding of the Center for Molecular Biology of RNA with a grant from the Markey Trust, faculty and students at UC Santa Cruz have made landmark contributions to the field of RNA research. Under the leadership of distinguished faculty, such as Harry Noller, Carol Greider, and David Haussler, the university has attracted dozens of promising early-career researchers in diverse fields who have already made significant contributions to RNA discoveries, both basic and applied. One of the largest communities of RNA scientists in the world is at UCSC — biologists, geneticists, engineers, computer scientists — and their work is defining the future of this field. The center now encompasses 20 RNA faculty laboratories across the departments of Molecular, Cell and Developmental Biology;
Chemistry and Biochemistry; Biomedical Engineering; and Computer Science and Engineering. This powerful interdisciplinary research community is poised to solve some of the most challenging scientific problems, such as unraveling the relationship between RNA structure and its biological functions, and developing computational tools to harvest biomedical information from the vast databases of genomic sequences. Research ranges from foundational science on RNA structure to tool building, and to methods for reshaping proteins to detect or treat specific diseases. Our RNA scientists inspire probing questions and novel collaborations, attracting resources, talented students and postdocs, entrepreneurs, and global partnerships. We are in the early stages of this work. Discoveries are made every day — the field
“As the science of RNA biology continues to explode, the Center for Molecular Biology of RNA at UCSC is poised to play a major role in solving the mysteries of this ancient molecule, and forging exciting new approaches to the understanding, diagnosis, and treatment of human disease.” — Harry Noller, Professor Emeritus of Molecular, Cell and Developmental Biology; Robert L. Sinsheimer Professor of Molecular Biology; Director, Center for Molecular Biology of RNA (pictured on opposite page)
RNA CENTER HIGHLIGHTS
is exploding and attracting interest among many early-career scientists, public and private funders, and biotech companies. This is, in part, due to the deployment of exciting new computational tools and methods that were undreamed of only a few years ago, some of which were invented at UCSC. While much progress has been made, there is still so much that we don't know. Ongoing genomics discoveries are consistently pointing to the centrality of RNA in every function of life. Scientists continue to discover new functions for these molecules and even find entirely new classes of RNA. But central questions remain open. For example, we know that only 10 percent of the RNA in our cells is involved in making proteins, and the biological function of the other 90 percent is still largely a mystery. We already know that the emergence of certain cancers is linked to disruption of the functions of some of these mysterious RNAs. RNA faculty at UCSC are working to solve these mysteries, which will lead rapidly to concrete improvements in human health care, and will, in turn, lead to new and deeper questions. This is the dawn of a transformational era in RNA science.
Breakthrough Prize In 2017, Center for Molecular Biology of RNA Founder and Director Harry Noller was selected for the highly competitive and prestigious Breakthrough Prize for his transformative discovery of the centrality of RNA in forming the active centers of the ribosome—the fundamental machinery of protein synthesis in all cells—thereby connecting modern biology to the origin of life and also explaining how many natural antibiotics disrupt protein synthesis. This groundbreaking work at UCSC powered the formation of the RNA Center, attracting extraordinary talent to join Noller in building a powerhouse research enterprise here. Nobel Prize In 2020, Dr. Carol Greider, winner of the 2009 Nobel Prize in Medicine, joined the UCSC biology faculty. Greider was attracted to UC Santa Cruz by both the RNA Center’s scientific strengths and the university’s core commitments to expanding opportunities for historically underrepresented populations and women in science. Global Impact Ranked among the top computer scientists in the world, David Haussler pioneered the use of hidden Markov models, stochastic contextfree grammars, and the discriminative kernel method for analyzing RNA, DNA, and protein sequences. As a collaborator on the international Human Genome Project, Haussler’s team at UC Santa Cruz posted the first publicly available computational assembly of the human genome sequence on the Internet on July 7, 2000. Following this, Haussler and his team developed the UCSC Genome Browser, a web-based tool that is used extensively around the world and is essential for biomedical research and serves as the platform for several large-scale genomics projects. Haussler’s work has accelerated the understanding of cancer, human development, evolution, and neuroscience.
A BOLD RESEARCH AGENDA The range and depth of disciplinary expertise at the center opens the way for faculty to take on some of the most challenging problems of RNA research. Linking experimental with computational science. At UC Santa Cruz, there has long been a fruitful connection between experimental and computational research. Our computational biologists have led the international effort to assemble the human genome and have established the Santa Cruz Genome Browser, which is used globally to exploit the unprecedented explosion of sequence information in the human genome databases. Others are developing powerful computational methods to understand cancer and other diseases, and potentially to treat defects in the immune system. The lines between the two methods of discovery are increasingly blurring, with many examples of faculty blending experimental work with computational methods to more rapidly and thoroughly understand RNA processes. Disease diagnosis and treatment. Center faculty are focusing on a range of diseases and conditions. • Most human viral diseases are caused by RNA viruses—COVID, influenza, polio, rabies, the common cold, HIV/AIDS, and countless other diseases. The discovery of messenger RNA (mRNA) vaccines will
almost certainly enhance prevention and treatment of all these viral diseases. • Cancer is the focus for a number of earlycareer researchers. For example, UCSC scientists have developed blood tests that have the potential to detect cancers at early stages, even revealing its location in the body. Computational tools are helping scientists understand how defects in RNA impact cancer growth. Others are working on developing medications based on RNA sequences to treat RNA-based diseases. Pediatric cancers, including rare ones, are the target of much work based at UCSC’s Treehouse Childhood Cancer Initiative. • Other researchers are working to understand neurodegenerative disorders, such as Alzheimer’s disease, as well as disruptions of the immune system caused by RNA “splicing mistakes.” Further, the center faculty and research questions also intersect with the university’s other research strengths, such as those in genomics and in other areas of biology, chemistry, and computer and biomedical engineering. This work also intersects with fundamental questions of ethics, identity, and social justice—areas where UC Santa Cruz has been a pioneer and leader. We expect these interconnections to grow deeper as this work continues. There are no limits to the power of collaboration.
RNA INNOVATION AND THE BIOMEDICAL MARKETPLACE Researchers are just beginning to glimpse the potential of this research for its importance to human health. UC Santa Cruz foresees this powerful research contributing to the future economic prosperity of California and the Santa Cruz region by creating new opportunities in the biomedical marketplace. To catalyze this process, UC Santa Cruz recently created the RNA Therapeutic Discovery Initiative that will leverage the power of its RNA faculty’s research for the understanding and treatment of rare diseases. This initiative will support projects that seek to understand why and how RNA instructions sometimes make errors that lead to disease; it will accelerate discovery of drugs that will correct these errors or treat diseases; and it will stimulate the use of RNA therapeutics in the practice of precision medicine. UCSC is also educating students to be future innovation leaders in this field, and many are already pursuing careers in the biotech industry. The UCSC RNA curriculum gives aspiring industry leaders a multidisciplinary technical background necessary to pursue careers in start-ups or in companies that will safely and rapidly propel lab research into new tools and treatments for the world.
ANGELA BROOKS Professor, Biomolecular Engineering
Mining Genomic Data for Improved Cancer Treatment Driving the capacities of computer science to provide amazing research tools is the mission of Angela Brooks and her lab team. “Our work focuses on mining cancer genomes — which are really large databases — to understand just how mutations in DNA may be disrupting the way RNA is produced and works,” Brooks says. She and her team have developed a range of analytic tools to search genomic data for important patterns in RNA production, and she has published these tools to make them widely available to the cancer and RNA research community. These tools are essential for researchers working with such vast data sets, allowing them to rapidly and reliably answer a range of research questions. “Our goal ultimately is to develop important tools that will find new ways to treat cancer, and potentially other conditions that affect human health,” Brooks says.
F A C U LT Y I M PA C T
MARK AKESON Professor Emeritus, Biomedical Engineering
Nanopore RNA Sequencing Mark Akeson is a trailblazer in developing nanoscale tools to analyze individual biological molecules. One of his most important contributions is the co-invention of nanopore DNA sequencing, a concept pioneered at UC Santa Cruz. It works by monitoring changes to an electrical current as nucleic acids pass through a protein nanopore, which generates an ionic current signal that is decoded to give the nucleotide (A,C,G,T) strand sequence. He is now focused on nanopore direct RNA sequencing. “Nanopore RNA sequencing is the new frontier, and our worldrenowned Center for Molecular Biology of RNA is the ideal environment to advance this technology for basic science and medical applications,” Akeson says. UCSC's nanopore technology patents have been licensed and commercialized by Oxford Nanopore Technologies (U.K.), and are now widely used around the world, including at remote sites such as the Arctic, rural West Africa, and the International Space Station.
EDUCATING RNA RESEARCH LEADERS OF THE FUTURE UC Santa Cruz’s strength in this field has long attracted diverse student talent, at both the graduate and undergraduate level. Many UCSC Ph.D. graduates—in biology, engineering, and computer science—have gone on to already-stellar careers in RNA research at universities and research programs around the world. The reputation of the program attracts amazing student talent each year. Coursework across all departments involved at the center is continually evolving to reflect the pace of new RNA discoveries and technologies. The center also engages dozens of undergraduates who participate in the research as valued members of the team, often publishing their first research papers—a unique training experience. Further, we already see opportunities to translate this work to the biomedical market, and students will be well prepared with the technical background to pursue careers in start-ups or in biotech companies to extend these technologies safely and rapidly into wide use. We can easily foresee this research contributing to the future economic prosperity of the region and the state.
OLENA MOROZOVA VASKE Associate Professor, Molecular, Cell and Developmental Biology; Colligan Presidential Chair in Pediatric Genomics
Understanding Childhood Cancers Seeing the urgency of saving children from cancer has driven Olena Vaske’s research since she was a graduate student, and she has been a world leader in using new technologies and mining genomic data to make a difference. As a member of the Center for Molecular Biology of RNA, she has collaborated with many other researchers, developing new computational tools to identify less toxic, effective treatments for the youngest cancer patients. She founded the Treehouse Childhood Cancer Initiative at UC Santa Cruz in 2016 to increase the number of pediatric cancer patients that benefit from the genomic characterization of their tumors and to facilitate sharing of data on rare childhood cancers across many labs and hospitals, with the goal of accelerating progress and saving more kids. “The great advances in information technology and life sciences in the last decades have given us a new opportunity to save our children from the scourge of cancer,” wrote Vaske and her UCSC colleague David Haussler in a 2019 article in Science.
F A C U LT Y I M PA C T
JEREMY SANFORD Professor of Molecular, Cell and Developmental Biology
MICHAEL STONE Professor of Chemistry and Biochemistry
RNA-Based Disease Mechanisms and RNA Therapeutics Treatments for RNA-based genetic disorders represent a huge unmet need in medicine. Jeremy Sanford and Michael Stone and their research groups have teamed up to tackle inherited disease defined by defective RNA processing. They are looking at ways mutations corrupt the genetic instructions that are stored in our genes and how, in many cases, these changes to our DNA code impact the structure and function of RNA. By exploiting the chemical language of RNA, their work is leading directly to drug design and can ultimately ease the suffering of those impacted by RNAbased diseases. “If successful, this work is broader than a single federal grant mechanism. We need funding to be flexible and agile enough to respond to a broad array of diseases.” — Jeremy Sanford
“We’ve built a platform to rapidly discover antisense oligonucleotides and determine their mechanisms of action. Our goal is to create an open access resource for rare disease patients, where we can rapidly assess the impact of mutations on splicing, develop splicecorrecting drugs, and assess the function of the rescued RNA transcript.” — Michael Stone
DANIEL KIM Assistant Professor, Biomedical Engineering Research Scholar, American Cancer Society
RNA and Early Detection of Cancer Detecting cancer at a very early stage with a simple, fast, and non-invasive blood test: This long-sought goal in cancer diagnosis is now taking a giant step forward through the work of Daniel Kim and his colleagues at UC Santa Cruz. Using the latest genomic technologies, some of them developed at UC Santa Cruz, Kim is seeking to develop a “liquid biopsy” to identify cancer at its earliest stages. While existing blood tests use DNA to detect when cancer is present, these DNA tests miss the majority of early stage cancers. By focusing on molecules of RNA in the blood, Kim is tracing early stage cancer to its source. “We have identified RNA signatures of early molecular changes that occur during lung and pancreatic cancer formation,” Kim says. “I believe that RNA is the key to detecting cancer at the earliest stages through a blood test.” Kim sees the impact going beyond cancer to diagnose many other conditions. “All of the cells in our different organ systems release RNA into the blood. Using our RNA liquid biopsy platform, we can get a snapshot of the health of every organ system in the body. This new approach will be beneficial for diagnosing and understanding many different types of diseases, including neurodegenerative and cardiovascular diseases.”
F A C U LT Y I M PA C T
SUSAN CARPENTER Professor, Molecular, Cell and Developmental Biology
Protecting Our Bodies from Infection and Inflammatory Diseases One of the many puzzles of RNA science today is finding what most of it is for: Some RNAs produce proteins in cells, but only a small percentage of RNA seems to be involved in this. What the rest of the RNA is doing remains a mystery. Susan Carpenter and her team seek to untangle this problem, focusing on the molecular mechanisms that control the human immune system and protect us from infections and inflammatory conditions, such as rheumatoid arthritis. Her lab deploys the full range of molecular biology tools to answer these questions, including RNA sequencing, CRISPR technology, and fluorescent microscopy. Carpenter is finding evidence that this mystery RNA is playing a powerful role in how our cells fight inflammation. “Understanding what most of this RNA is doing within these cells will bring new insights into human disease and help us to find new targets for therapeutic intervention,” Carpenter says. “We are just scratching the surface right now. The more resources we can get, the faster we can find answers to some of our most pressing questions.”
SUPPORTING TRANSFORMATIONAL RNA SCIENCE UC Santa Cruz is seeking visionary philanthropic partners to accelerate this research at a crucial moment. We believe RNA research has tremendous momentum as a high global research priority. Investing in facilities, faculty, students, and postdoctoral researchers can give UC Santa Cruz a competitive edge in securing higher levels of federal, state, and industry research funding, greatly leveraging the impact of philanthropic gifts. With our past achievements and with targeted investment for the future, UCSC will be a solutions-oriented global leader in RNA science and its myriad applications. An investment today will have long-lasting, era-defining impact on improving health and well-being, solving environmental challenges, and shaping economic opportunities.
We are seeking support for a range of opportunities: Shared key research resources, including the UCSC Biomolecular Cryo-Electron Microscopy Facility, a shared CRISPR facility, a proposed RNA mass spectrometry facility, and an interdisciplinary RNA computational facility. Endowed chairs to attract and retain the best faculty leaders, at both the senior and junior level, at UC Santa Cruz. Fellowships for postdoctoral researchers and graduate students, who are the central players in RNA research and who will be the future leaders in the field. Research funding for the RNA Therapeutic Discovery Initiative, offering seed money and other support for applied translational research into RNA diseases. Annual international RNA research conferences to be held in Santa Cruz, for collaborative visits from RNA scientists from throughout the world to share findings and increase connections.
TO LEARN MORE: PRIYA MEHTA, ASSOCIATE VICE CHANCELLOR FOR DE VELOPMENT, PMEHTA7@UCSC.EDU
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