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Presidential Biosciences Initiative grantee Nils Walter talks RNA research and curing disease.
Read full article in the The University Record : Professor’s work focuses on molecules key to curing diseases
As Phillip Sharp, Tyler Jacks and Susan Hockfield of MIT posit in a 2016 report : “The life sciences are in the midst of a revolution… The Convergence Revolution promises to enhance quality of life worldwide … as a result of the sharing of methods and ideas by chemists, physicists, computer scientists, engineers, mathematicians, and life scientists across multiple fields and industries. It is the integration of insights and approaches from historically distinct scientific and technological disciplines.” Perhaps nowhere is this both more apparent and more needed than in taking advantage of the rapid expansion of the RNA biosciences universe and the resulting opportunities for translating discoveries into precision medicines . Converging technological advances, ranging from single-cell RNA sequencing to single-molecule particle tracking at super-resolution, are laying the foundation for reaching an entirely new level of insight into cellular physiology that eluded us just a few years ago . Beyond the emerging catalogues of cellular contents, mechanistic studies of the diverse modes of action of RNAs and their interaction partners are handing us the keys for accelerating progress toward shaping our own destiny. The better we understand the scope and limitations of these new tools, the better we will be equipped to wield them effectively.
Read full editorial in the journal Methods : Convergence of science and technology: fluorescent resolution of single RNA molecules
October 29, 2018
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.
Read full article in Michigan News here : U-M Biosciences Initiative invests $45M in ‘groundbreaking’ research
Mutated DNA strands — even those with only a change in a single nucleobase — can be the cause of serious health problems. Quantifying these mutant DNA strands is particularly challenging when they are present in low concentrations in a patient’s urine or blood samples and must be detected against a large background concentration of wild-type DNA. Now, writing in the Journal of the American Chemical Society, Nils Walter and co-workers report the development of an amplification-free method that they call single-molecule recognition through equilibrium Poisson sampling (SiMREPS).
“We were seeking a powerful tool to detect mutations that are cancer causing, or that make cancer harder to treat,” explains Walter. “One such mutation is found in the epidermal growth factor receptor (EGFR), where a cytosine-to-thymine mutation in the DNA results in substitution of a threonine with a methionine in the protein. The ultimate result of this change is that certain classes of tyrosine kinase inhibitor (TKI) drugs no longer work.”
Read full research highlight in the journal Nature Reviews Materials : Signals from single molecules
“Modern techniques like RNA sequencing run into the challenge that low-expressed RNAs are difficult to detect, but often they are more important than the abundant ones,” observes Dr. Walter. “We need tools to look at them.” In a recent study, Dr. Walter and colleagues developed fluorescence-based tools to examine the subcellular location, integrity, and activity of microRNA at single-molecule resolution. “We can localize single microRNA molecules in cells, track them, measure their diffusion constants, and ask how quickly they move between sub-compartments,” asserts Dr. Walter
Full text in pdf format.
Francesca Storici and Ailone E. Tichon
Small RNAs generated at DNA break sites are implicated in mammalian DNA repair. Now, a study shows that following the formation of DNA double-strand breaks, bidirectional transcription events adjacent to the break generate small RNAs that trigger the DNA damage response by local RNA:RNA interactions.
Maintenance of DNA integrity is crucial for a cell to have a healthy life and for transmission of accurate genetic information to its progeny. Exogenous agents, including radiation or chemicals, as well as endogenous sources, such as reactive oxygen species or defects in DNA metabolism, pose threats to genome stability. Among the most dangerous DNA lesions are DNA double-strand breaks (DSBs), which if not properly and timely sealed can become sites of mutations or chromosomal rearrangements — well-known hallmarks of cancer and other genetic disorders1. The process of DSB repair is one of the most extensively studied mechanisms of DNA repair, yet much remains to be understood about its players and dynamics.
The DNA damage response (DDR) is a complex network of cellular pathways that detect DNA lesions and organize a response signal cascade to repair the DNA. In this issue of Nature Cell Biology, Michelini et al.2 uncover an aspect of the DDR in which RNAs are the directors. The study shows that sequencespecific RNA:RNA interactions orchestrate the DDR in response to DSBs.
Full text in pdf format.
News and Views pice in reference to the Walter Lab NCB paper (ref. 164 at https://sites.lsa.umich.edu/walter-lab/publications)
Dynamic DNA nanotechnology enables the design of DNA-based nanomachines, such as molecular motors or nanorobots. However, most DNA nanomachines operate on a slow timescale, ranging from minutes to hours. Now, Nils Walter and colleagues, writing in Nature Nanotechnology, have made a single-stranded DNA walker that moves by performing cartwheels and at considerably faster speeds than previously reported DNA walkers.
Read full research highlight in the journal Nature Reviews Materials : Head over heels
Finding by Rice, Michigan chemists could point way to new antibiotics
HOUSTON — (May 21, 2018) — In a discovery that points to potential new antibiotic medicines, scientists from Rice University and the University of Michigan have deciphered the workings of a common but little-understood bacterial switch that cuts off protein production before it begins.
Many gram-positive bacteria use T-box riboswitches to regulate production of proteins that utilize amino acids, the basic building blocks of all proteins. A study in Nature Communications describes how one of these switches, a glycine regulator in Bacillus subtilis, flips and locks into the “on” position via a snap-lock mechanism. Engaging the lock increases production of proteins that utilize glycine, the simplest amino acid. Researchers also detailed the switch’s “off” position: A single glycine at the tip of the locking arm blocks protein production.
Read full text here: Study finds snap-lock mechanism in bacterial riboswitch
A molecular motor flips end over end to cover 300 nanometres a minute.
An acrobatic DNA segment that cartwheels across a surface is one of the fastest ‘walking’ molecules yet designed.
Researchers seeking to design nanorobots have synthesized DNA molecules that move autonomously. But most of these ‘walkers’ require several minutes to take a single step.
Nils Walter at the University of Michigan in Ann Arbor and his colleagues built a DNA walker that moves along a grid of ‘footholds’, which are made of complementary DNA building blocks called nucleotides. Each end of the walker has sequences of nucleotides that it uses to attach itself to the grid. Then it flips end over end to attach itself to another foothold.
The molecule can flip as many as 43 times per minute, covering a distance of 300 nanometres. This is an order of magnitude faster than the pace of other types of DNA walker.
Read full research highlight in the journal Nature : Gymnastic feats help DNA ‘walker’ set speed record
Researchers build a one-wheeled vehicle out of DNA rings
Scientists have used nanostructures to construct a tiny machine that constitutes a rotatory motor and can move in a specific direction. The researchers used circular structures from DNA.
Together with colleagues from the USA, scientists from the University of Bonn and the research institute Caesar in Bonn have used nanostructures to construct a tiny machine that constitutes a rotatory motor and can move in a specific direction. The researchers used circular structures from DNA. The results will now be presented in the journal Nature Nanotechnology.
Read full text here: Tiny nanomachine successfully completes test drive
When it comes to matching simplicity with staggering creative potential, DNA may hold the prize. Built from an alphabet of just four nucleic acids, DNA provides the floorplan from which all earthly life is constructed.
But DNA’s remarkable versatility doesn’t end there. Researchers have managed to coax segments of DNA into performing a host of useful tricks. DNA sequences can form logical circuits for nanoelectronic applications. They have been used to perform sophisticated mathematical computations, like finding the optimal path between multiple cities. And DNA is the basis for a new breed of tiny robots and nanomachines. Measuring thousands of times smaller than a bacterium, such devices can carry out a multitude of tasks.
In new research, Hao Yan of Arizona State University and his colleagues describe an innovative DNA walker, capable of rapidly traversing a prepared track. Rather than slow, tentative steps across a surface, the DNA acrobat cartwheels head over heels, covering ground 10- to 100-fold faster than previous devices.
“It is exciting to see that DNA walkers can increase their speed significantly by optimizing DNA strand length and sequences, the collaborative effort really made this happen,” Yan said.
Yan is the Milton D. Glick Distinguished Professor of Chemistry and Biochemistry at ASU and director of the Biodesign Center for Molecular Design and Biomimetics.
The study was led by Nils G. Walter, Francis S. Collins Collegiate Professor of Chemistry, Biophysics & Biological Chemistry, founding director of the Single Molecule Analysis in Real-Time (SMART) Center and founding co-director of the Center for RNA Biomedicine at the University of Michigan, and his team, along with collaborators from the Wyss Institute, the Dana Farber Cancer Institute and the Department of Biological Chemistry at Harvard (all in Boston, Massachusetts).
“The trick was to make the walker go head over heels, which is so much faster than the hopping used before—just as you would see in a kung fu action movie where the hero speeds up by cartwheeling to catch the villain,” says Walter.
The improvements in speed and locomotion displayed by the new walker should encourage further innovations in the field of DNA nanotechnology.
The group’s findings appear in the advanced online issue of the journal Nature Nanotechnology.
Read full text here: Building Motors to Drive Nanorobots
Read full text here: Building Motors to Drive Nanorobots
View in pdf format or read full text here: Technology promises to provide early detection of treatment-resistant cancer mutations
Read full article in BioTechniques. : ‘DNA Robots Inspired by Swarm Behavior.”
Read full article in Michigan News : ‘Detective’ iSHiRLoC investigates role of RNA, could help researchers study genesis of cancer.
Read full article in U-M Record : Second Annual Symposium of Center for RNA Biomedicine.
Read full article in The Detroit News : New UM center to take medicine to personalized level.
A collaborative project with Rice University to test ‘T box’ riboswitch wins NIH grant!
A video highlight of Nils’s presentation at T&T Seminar is now available online here.
Congratulations to Dr. Paul Lund for successfully defending his thesis entitled ”Interactions between the translation machinery and a translational preQ1 riboswitch”!
Congratulations to Dr. Matthew Kahlscheuer for successfully defending his thesis entitled ”Characterization of pre-mRNA Dynamics and Structure throughout Spliceosome Assembly and Catalysis”!
Nils is quoted in Nature News – “March of the Machines”. Highlight on “The University Record- University of Michigan” and full News in pdf format