The cell is a complex network of interacting components, or molecules, each of them with its own characteristics and all of them together functioning as a living system. Each of the molecular processes and interactions in the cell bears the risk of becoming dysfunctional, resulting in disease. Biomedical research into processes that power the cell lays the foundation for major therapeutic breakthroughs. However, the minuscule length scales and high speeds at which these intracellular processes take place make it very challenging to observe them directly within a single cell.

Nils Walter’s team at the University of Michigan, Chemistry Department and Center for RNA Biomedicine, has reviewed the latest research on using high-resolution, single molecule fluorescence microscopy tools to study the interactions between molecules in live human cells in real time. The review covers research reported in 85 publications over the last 5 years, aiming to consolidate the developments and disseminate the techniques that can follow multiple molecules at once (“multiplexing”). These techniques are relatively easy to implement, and are becoming increasingly available and affordable.

Red RNA molecules are docking onto green processing bodies containing RNA degrading enzymes.

[Read more…] about Seeing is believing: The cutting edge of watching single molecules inside human cells

Before and after treatment

Over half of our genomes are made of repeating elements within DNA. In rare cases, these repeats can become unstable and grow in size. These repeat “expansions” cause neurodegenerative diseases such as ALS and Dementia as well as learning disorders and autism in Fragile X syndrome. Research to date has focused on how these expanded repeats cause disease, but little attention has been given to the repeats themselves and whether they might have normal functions in genes.

By focusing on the biology of healthy nerve cells, a team from the University of Michigan Department of Neurology found that repeats in the gene that causes Fragile X Syndrome normally regulate how and when proteins are made in neurons. This process may be important for learning and memory in these nerve cells and potentially in people. “The repeats function like a switch, slowing down protein production and then quickly turning things back on,” explains Peter Todd, MD., Ph.D., and Principal Investigator of this research.

[Read more…] about Publication in Nature Neuroscience: Disease-causing Repeats Help Human Neurons Function

The U-M Center for RNA Biomedicine’s fourth annual symposium on March 29 will focus on foundational ribonucleic acid biosciences, from discovery to function.

Recent discoveries in biomedicine have revealed that RNA is critical to most aspects of human health and that its misregulation is responsible for many diseases.

As the messenger molecule that carries the DNA blueprint in human cells, it profoundly impacts all cellular processes, from stem cell differentiation to cancer.

The symposium is free and open to the public. It will feature keynote speakers from across the nation, including:

• Rachel Green of Johns Hopkins University, who will discuss high-resolution ribosome profiling revealing mechanisms of translation elongation regulation.

• Howard Chang of Stanford University, who will focus on genome regulation by long noncoding RNAs.

• Alice Telesnitsky, professor of microbiology and immunology at U-M, who will address HIV-1 RNA fate determination: the ends as a means.

• Kristen Lynch of the University of Pennsylvania, who will share her discoveries in CELF control of RNA processing in human T cells.

• David Bartel of the Massachusetts Institute of Technology, who will host his session on the influence of microRNAs on disease.

The Center for RNA Biomedicine brings U-M faculty together from across campus to pioneer RNA research, translate their discoveries into medical applications and improve human health. RNA biomedicine revelations provide an unprecedented opportunity to invest in advanced studies of RNA as a gateway to precision medicine.

As a Presidential Biosciences Initiative Scientific Research Initiative grantee, the center aims to enrich the university’s intellectual and training environment around RNA biomedicine, promote and develop cross-disciplinary collaborations, and enrich U-M’s intellectual and training environment around RNA biomedicine.

The all-day symposium begins at 8:30 a.m. in the A. Alfred Taubman Biomedical Research Science Building. It is open to U-M faculty, staff, students and anyone interested in the most recent discoveries regarding the many roles of RNA in health and disease.

More information:

• Center for RNA Biomedicine website

• Advance online registration for the symposium

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(Photo by Daryl Marshke, Michigan Photography)

Growing up in Germany, Nils G. Walter formed a positive, but secondhand, impression of the United States.

His father had been a prisoner of war in Texas who often told Walter about the kindness of Americans and T-bone steaks the size of dinner plates.

“There were a lot of positive feelings in my family, and in Germany in general, about America,” said Walter, the Francis S. Collins Collegiate Professor of Chemistry, Biophysics and Biological Chemistry.

Still, it was Walter’s love of chemistry that ultimately led him to move to the United States.

Walter’s original plan was to return to Germany after his postdoctoral work. However, his affinity for the United States, and the country’s support for young academics by granting tenure-track positions made him decide to apply mostly to American universities.

Walter was hired for a professorship at U-M in 1999, and has been rising through the ranks since. He is a professor of chemistry and biophysics in LSA, and professor of biological chemistry in the Medical School, and the founding director of the Single Molecule Analysis in Real-Time Center, a university-funded, open-access facility that allows researchers, inside or outside of the university, to use tools that allow them to see single, microscopic molecules, one at a time.

“Being able to see a single molecule is to see the smallest entity that we encounter in daily life,” Walter said. “Our everyday experience is made up of the small single molecules that make up all matter around us.”

Walter first learned about RNA molecules when enzymes built from RNA were a new concept.

Years later, while attending a symposium in Switzerland, Walter met Tom Cech — one of two chemists awarded the 1989 Nobel Prize in chemistry for discovering catalytic properties of RNA, suggesting that RNA could have sparked life on earth. This notion is the center of Walter’s work today.

To both inform his organizational work at the center and to prepare for submitting a funding proposal to U-M’s Biosciences Initiative, Walter spent six weeks at the Chan Zuckerberg Biohub in San Francisco. The Biohub aims to unite pillars of excellence across disciplines to cure all diseases within the next 100 years.

The Center for RNA Biomedicine’s proposal recently was chosen by the Biosciences Initiative for tier-one funding. With this funding, the center will hire five people to evaluate RNA functions in diseases and help all center faculty discover ways to combat these diseases with drugs, or to use RNA molecules themselves as therapeutic drugs.

“Every disease, every physiological state, every developmental aspect of a cell has a relationship to RNA,” Walter said. “Since RNA Enzymes sparked life on earth, there’s a gut feeling that they can do a lot more today. We’ve surely only seen the tip of the iceberg so far.”

Read full article in the The University Record : Professor’s work focuses on molecules key to curing diseases

PDF version

October 29, 2018

University of Michigan Biosciences Initiative video

ANN ARBOR—A new center for the study of concussions, an institute for global change biology, and a facility to advance the new field of cryo-electron tomography are among the University of Michigan projects to be funded in the first round of investments from President Mark Schlissel’s Biosciences Initiative.

Five large projects and four smaller ones, totaling up to $45 million, will be funded this fiscal year through the presidential initiative, which aims to create globally leading biosciences research programs focused on solving critical problems. A key element of the multiyear initiative will be the hiring of 30 tenure-track faculty and a one-time investment of $150 million.

Twenty-eight proposals were submitted for the first round of Biosciences Initiative grant funding. The nine selected projects include researchers from all U-M schools and colleges that work in the biosciences and will provide startup funding to hire up to 14 new faculty members.

“We established the Biosciences Initiative to propel the University of Michigan to the forefront in critical areas of life science research. I am thrilled that our faculty have responded with groundbreaking proposals,” Schlissel said.

“Our first projects leverage U-M’s comprehensive excellence, catalyze hiring in the biosciences and related disciplines, and embrace our mission to conduct research for the benefit of society.”

The five large projects are:

“Michigan Concussion Center,” principal investigator Steven Broglio, School of Kinesiology. Broglio is co-director of one of the largest concussion studies in the nation, jointly funded by the NCAA and the Department of Defense.This proposal calls for the creation of a comprehensive U-M concussion research center through the recruitment of an additional epidemiologist, a neuroscientist and a clinical interventionist. The faculty additions will build on existing U-M expertise in biomechanics, biomarkers, imaging, outcomes, sports analytics and biostatistics. The researchers will use a multidisciplinary approach to answer fundamental questions about concussion prevention, identification, diagnosis, management and outcomes.

“Institute for Global Change Biology,” principal investigator Allen Burton, School for Environment and Sustainability; co-principal investigators Inés Ibáñez, SEAS, Allison Steiner, College of Engineering, and Knute Nadelhoffer, Department of Ecology and Evolutionary Biology. Global change biology seeks to understand the biosphere’s responses to human activities. Human-caused global changes include climate shifts, land-use conversion, release of pollutants and species introductions. The new institute will foster research to understand and forecast the interactive effects of global change drivers on organisms and ecosystems. The new funding serves as a planning grant to launch the program; a larger, more comprehensive application will follow.

“Expanding Natural Products Drug Discovery at the University of Michigan,” principal investigator David Sherman, Life Sciences Institute and College of Pharmacy; co-principal investigator Ashootosh Tripathi, LSI and College of Pharmacy. Sherman has created a unique natural products discovery program based on the collection of about 5,000 microbial strains—gathered at far-flung locations from tropical coral reefs to Himalayan mountaintops—and the integration of some 40,000 microbial extracts into a high-throughput screening laboratory available to all U-M investigators. The new funding will enable recruitment of three new faculty and create a natural products discovery core laboratory to identify bioactivemetabolites. This initiative will also provide the synthetic biology and microbial engineering needed to optimize active compounds as discovery tools and for potential drug development.

“From Cells to Atoms—The Future of Cryo-Electron Microscopy at the University of Michigan,” principal investigators Janet Smith, Melanie Ohi and Michael Cianfrocco of the Life Sciences Institute and the Medical School. Cryo-electron microscopy, which uses electrons to visualize frozen samples, is quickly becoming the go-to technique for structural biologists, and U-M was an early adopter of the technology. The new funding will enable the university to become an international leader in the field and a premiere destination for cryo-EM education. Among other things, the funding will help U-M researchers expand their ability to visualize molecular machines inside intact cells using a developing approach called cryo-electron tomography.

“RNA Biomedicine: An Engine for Synergy, Excellence and Global Leadership at Michigan,”principal investigator Nils Walter, professor of chemistry, biophysics and biological chemistry; co-principal investigator Mats Ljungman, Medical School. Recent discoveries in biomedicine have revealed that ribonucleic acid, or RNA, is critical to most aspects of human health and that its misregulation is responsible for many diseases. This project seeks to rapidly expand U-M’s nascent Center for RNA Biomedicine through the hiring of five faculty members, the creation of three core laboratories, and the funding of pilot and fellowship programs. “We envision that these investments will propel U-M to the forefront of RNA biosciences in the nation,” according to the project proposal.

Exploratory Funding grants of $100,000 were awarded to:

• “The role of tissue barriers in health and disease,” principal investigator David Antonetti, Medical School.
• “Applying an innovation framework to improve health in rural populations,” principal investigator Christopher Friese, School of Nursing.
• “Enabling single-cell and locus-specific chromatin proteomics at U-M,” principal investigator Sundeep Kalantry, Medical School.
• “Establishing the U-M re-targeting discovery platform,” principal investigator Jonathan Sexton, Medical School.

In addition to the roughly $45 million in funding provided to the nine projects through the presidential initiative, $6.7 million will be contributed by the researchers’ home departments, schools, colleges, institutes and centers.

“I’m really pleased by the amazing breadth of science and the transdisciplinary nature of the funded proposals,” said Roger Cone, vice provost and director of the Biosciences Initiative, director of the Life Sciences Institute, and chair of the 16-member Biosciences Initiative Coordinating Committee that reviewed and ranked the proposals.

“In this round alone, we were able to fund proposals serving investigators in every U-M school and college in the biosciences. These new programs address critical problems of incredible diversity, from measuring global biological change to improving rural health care delivery to developing the technology for high-resolution imaging of molecules inside living cells.”

The evaluation process for the large proposals included three independent levels of review. Sixteen letters of intent were submitted, and the Biosciences Initiative Coordinating Committee requested full proposals from nine of them.

Two to three external content reviewers from around the nation provided feedback on each proposal. In addition, a Biosciences Initiative Council composed of Tachi Yamada, formerly of the Bill & Melinda Gates Foundation; Jack Dixon of the University of California, San Diego; and Gail Mandel of the Oregon Health & Science University reviewed the nine full proposals.

Based on composite scores and recommendations from the council, the Biosciences Initiative Coordinating Committee then provided funding recommendations to the president and provost.

Biosciences Initiative research grants will be awarded annually through fiscal year 2022, and all Ann Arbor campus faculty are eligible to participate. Letters of intent are due in April 2019.

More information:

• Bioscience Initiative
• Biosciences Initiative Coordinating Committee

Read Full Story Here

October 29, 2018

ANN ARBOR, Mich. – A new center for the study of concussions, an institute for global change biology and a facility to advance the new field of cryo-electron tomography are among the University of Michigan projects to be funded in the first round of investments from President Mark Schlissel’s Biosciences Initiative.

Five large projects and four smaller ones, totaling up to $45 million, will be funded this fiscal year through the presidential initiative, which aims to create globally leading biosciences research programs focused on solving critical problems. A key element of the multiyear initiative will be the hiring of 30 tenure-track faculty and a one-time investment of $150 million.

Twenty-eight proposals were submitted for the first round of Biosciences Initiative grant funding. The nine selected projects include researchers from all U-M schools and colleges that work in the biosciences and will provide startup funding to hire up to 14 new faculty members.

The five large projects are:

•  The Michigan Concussion Center principal investigator Steven Broglio, School of Kinesiology. Broglio is co-director of one of the largest concussion studies in the nation, jointly funded by the NCAA and the Department of Defense.

This proposal calls for the creation of a comprehensive U-M concussion research center through the recruitment of an additional epidemiologist, a neuroscientist and a clinical interventionist. The faculty additions will build on existing U-M expertise in biomechanics, biomarkers, imaging, outcomes, sports analytics and biostatistics. The researchers will use a multidisciplinary approach to answer fundamental questions about concussion prevention, identification, diagnosis, management and outcomes.

•  The Institute for Global Change Biology principal investigator Allen Burton, School for Environment and Sustainability; co-principal investigators Inés Ibáñez, SEAS; Allison Steiner, College of Engineering; and Knute Nadelhoffer, Department of Ecology and Evolutionary Biology.

Global change biology seeks to understand the biosphere’s responses to human activities. Human-caused global changes include climate shifts, land-use conversion, release of pollutants and species introductions. The new institute will foster research to understand and forecast the interactive effects of global change drivers on organisms and ecosystems. The new funding serves as a planning grant to launch the program; a larger, more comprehensive application will follow.

•  “Expanding Natural Products Drug Discovery at the University of Michigan,” principal investigator David Sherman, Life Sciences Institute and College of Pharmacy; co-principal investigator Ashootosh Tripathi, LSI and College of Pharmacy.

Sherman has created a unique natural products discovery program based on the collection of about 5,000 microbial strains—gathered at far-flung locations from tropical coral reefs to Himalayan mountaintops—and the integration of some 40,000 microbial extracts into a high-throughput screening laboratory available to all U-M investigators. The new funding will enable recruitment of three new faculty members and create a natural products discovery core laboratory to identify bioactive metabolites. This initiative will also provide the synthetic biology and microbial engineering needed to optimize active compounds as discovery tools and for potential drug development.

•  “From Cells to Atoms—The Future of Cryo-Electron Microscopy at the University of Michigan,” principal investigators Janet Smith, Melanie Ohi and Michael Cianfrocco, of the Life Sciences Institute and the Medical School.

Cryo-electron microscopy, which uses electrons to visualize frozen samples, is quickly becoming the go-to technique for structural biologists, and U-M was an early adopter of the technology. The new funding will enable the university to become an international leader in the field and a premiere destination for cryo-EM education. Among other things, the funding will help U-M researchers expand their ability to visualize molecular machines inside intact cells using a developing approach called cryo-electron tomography.

•  “RNA Biomedicine: An Engine for Synergy, Excellence and Global Leadership at Michigan,” principal investigator Nils Walter, professor of chemistry, biophysics and biological chemistry; co-principal investigator Mats Ljungman, Medical School.

Recent discoveries in biomedicine have revealed that ribonucleic acid, or RNA, is critical to most aspects of human health and that its misregulation is responsible for many diseases. This project seeks to rapidly expand U-M’s nascent Center for RNA Biomedicine through the hiring of five faculty members, the creation of three core laboratories and the funding of pilot and fellowship programs. “We envision that these investments will propel U-M to the forefront of RNA biosciences in the nation,” according to the project proposal.

Exploratory funding grants of $100,000 were awarded to:

•    “The role of tissue barriers in health and disease,” principal investigator David Antonetti, Medical School.

•    “Applying an innovation framework to improve health in rural populations,” principal investigator Christopher Friese, School of Nursing.

•    “Enabling single-cell and locus-specific chromatin proteomics at U-M,” principal investigator Sundeep Kalantry, Medical School.

•    “Establishing the U-M re-targeting discovery platform,” principal investigator Jonathan Sexton, Medical School.

In addition to the roughly $45 million in funding provided to the nine projects through the presidential initiative, $6.7 million will be contributed by the researchers’ home departments, schools, colleges, institutes and centers.

Read Full Story Here