As research laboratories on campuses across the US slowed down in March in response to stay-at-home orders, Northwestern’s Recombinant Protein Production Core (rPPC), a Chemistry of Life Processes Institute-affiliated core facility, was running at full speed. In...
Northwestern, Argonne, and partners to launch national resource to unlock the role of metals in human health
Evanston, IL – June 26, 2020: Chemistry of Life Processes Institute (CLP) at Northwestern, the Advanced Photon Source (APS) at Argonne National Laboratory, and several leading research universities, will join forces to launch a first-ever national hub for interdisciplinary, metallomics research and innovation.
The National Institutes of Health (NIH) has awarded Northwestern a five-year, $8.2 million grant to establish the Resource for Quantitative Elemental Mapping for the Life Sciences (QE-Map). The grant is from NIH’s Biomedical Technology Research Resources (P41) program.
QE-Map will enable unprecedented insights into the role of metals and other inorganic (non-living) elements in human health and disease.
The Resource will be directed by Northwestern’s Thomas O’Halloran, the Charles E. and Emma H. Morrison Professor of Chemistry and Professor of Molecular Biosciences in the Weinberg College of Arts & Sciences. The leadership team includes Chris Jacobsen, an Argonne Distinguished Fellow who is also Professor of Physics and Astronomy in the Weinberg College, as well as Professors Hao Zhang and Cheng Sun in the McCormick School of Engineering.
QE-Map will leverage Northwestern’s expertise in the areas of biophotonics, cell biology, inorganic chemistry, and X-ray physics, to pioneer cutting-edge imaging and detection technologies to deepen understanding of the interplay between metals and biological processes.
“Metal fluctuations play a critical regulatory role in a large number of biological processes,” says O’Halloran, the founding Director of CLP and the Director of Northwestern’s Quantitative Bioelement Imaging Center (QBIC). “For example, fluctuations in the availability of zinc or copper can often be a trigger to the cell to change its function or developmental stage. A fluctuation in zinc might signal an egg to ovulate, or a second sperm, not to enter the egg. Too much manganese in the brain can trigger Parkinson’s disease. Pathological iron chemistry in the brain is involved in Alzheimer’s disease, and so on. These findings have generated a tremendous amount of interest across the fields of medicine, biology and physiology.”
Pioneering Testbeds for New Imaging Technologies
The Resource will support 75 faculty research programs, across Northwestern’s Schools of Medicine, Engineering, and College of Arts and Sciences, as well as collaborators from Argonne, Howard Hughes Medical Institute’s Janelia Research Center, Georgia Tech, Johns Hopkins, MIT, UC Berkeley, University of South Carolina, and University of Texas at Austin. Investigators will provide the testbeds for new imaging technologies, tools, software, and quantitative methods for metal analysis and localization. These new approaches will be applied to pioneering research in cardiac disease, fertilization and development, neurodegenerative diseases, and metabolic diseases.
“The ability to map metals and metal dynamics in the brain opens important new avenues in neuroscience research, for neurodevelopmental and neurodegenerative diseases but also for the fundamental understanding of how neurons communicate,” says Yevgenia Kozorovitskiy, Assistant Professor of Neurobiology at Northwestern. “The field has focused on calcium signaling in neurons for a long time, but zinc and other metals serve critical synaptic signaling roles in neurons that remain poorly understood, in addition to their functions as co-factors for important neuronal proteins.”
A new mass spectrometry tool operated by QBIC will enable rapid 2D and 3D imaging of cells in tissue slices. Advances will include development of a completely integrated system with real-time multi-element imaging capabilities, standardized procedures for handling cryogenically preserved biological tissues, and a universal cryo sample mounting system that can move between several different technologies that map and analyze elemental distributions.
Faster and More Sensitive X-ray Imaging
The Resource will also employ large sample format Scanning X-ray Fluorescence Microscopy (SXFM), utilizing one of the nation’s brightest synchrotron radiation sources, the Advanced Photon Source, a U.S. Department of Energy Office of Science user facility located at Argonne National Laboratory. The
SXFM will provide researchers with organ-wide information on metal distribution. Jacobsen, an expert in x-ray microscopy and trace metal quantitation, will lead efforts to increase the speed, cost-effectiveness and imaging sensitivity of SXFM, and standardize approaches for cryogenically preserving biological tissues for universal adoption across platforms.
“We want to push further the boundaries of what can be done with x-ray imaging and apply it to biological systems,” says Jacobsen, a member of Chemistry of Life Processes Institute. “The APS at Argonne is a great way to excite that x-ray florescence with a much higher rate and much higher spatial
resolution than ever could be done in a laboratory system.”
Ultrasonic Detectors that “Hear” the Sound of Color
A third Resource technology, Photo Acoustic Spectroscopy (PAM), is pioneered by Zhang and Sun. PAM deploys a highly novel, modular ultrasonic detector that combines a unique chemical process to image both frozen samples and live tissue at unprecedented resolution. This approach works by scanning a laser across a sample, causing heat and color intensity to increase, and triggering a shockwave that can be detected acoustically. Cheng and Sun will work with collaborators to engineer molecular probes that cater to specific experimental needs. These advances will provide better ways to image time-dependent fluctuations in the concentrations of specific metal ions.
“It’s almost like hearing the sound of a color,” says O’Halloran. “There are disorders of the human brain where sensory inputs get confused between them, but in this case, we’re actually using the absorbance of a photon of a certain wavelength of light, which gives rise to the observation of a color, creating a sound wave that will help us localize an image in the material. By listening to the photo acoustic detectors, we can create a map from the sound pattern. It’s an incredible idea that has never been shown before.”
QE-Map will occupy a unique place among the 40 NIH-funded national resources as the only one advancing technology for studying the role of metals in health and disease.
“We will be collaborating with dozens of biomedical research teams from around country with the goal of understanding the molecular mechanisms at work in a variety of metal-linked diseases, from Wilson disease, Menkes disease, and Alzheimer’s, to Parkinson’s, heart disease, and diabetes,” says O’Halloran. “Each of the investigative teams around the country have a particular question in which they need to know how much metal is in their sample and what is it doing to the sample. We can help answer all those questions.”
This research resource is supported, in part by the National Institutes of Health 1P41GM135018-01 and 1S10OD26786-01. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.
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Lisa La Vallee
Northwestern University received $7 million this year from the National Institute of General Medical Sciences to continue to push the boundaries of precision proteomics through new technologies and approaches to heart disease, cancer, neurological diseases and immuno-disorders, and to expand community engagement. The five-year grant builds upon the success of the National Resource for Translational and Developmental Proteomics (NRTDP), established in 2015 by Northwestern Proteomics, a center affiliated with Chemistry of Life Processes Institute.
“By providing far greater detail with next-generation technology, our national proteomics center is changing the fundamentals of how to read out proteins in basic and clinical research,” says Neil Kelleher, PhD, the Walter and Mary E. Glass Professor of Molecular Biosciences and Faculty Director, Northwestern Proteomics. “This is increasing the efficiency of detection and assignment of function to proteins and their myriad modifications.”
The grant will enable major upgrades in technology for cell-specific analysis of whole protein molecules — an approach known as top-down proteomics.
Advancing Biomedical Research from SARS-CoV-2 and Cancer to Alzheimer’s
“In the past five years, we’ve been on the warpath to teach people about proteoforms,” said Paul Thomas, PhD, Research Associate Professor, Molecular Biosciences and Managing Director of Northwestern Proteomics. “Proteoforms are the individual modified protein molecules that exist in a biological system that may be responsive to, or causative of, diseases.”
The Center will advance dozens of translational research programs across Northwestern and other academic institutions that will focus on four key areas of research led by Jeannie Camarillo, PhD (Cancer Proteomics), Eleonora Forte, PhD (Immunoproteomics), Steven Patrie, PhD (Neuroproteomics), and John Wilkins, MD (Cardiac Proteomics).
Project collaborators will look at the proteomics of pediatric brain tumors, liver transplant rejection, aging, heart failure, and Alzheimer’s and Parkinson’s disease, to name a few. These efforts, in turn, will drive technology development and applications for NRTDP’s new style of mass spectrometry-based proteomics.
“Despite decades of effort we have only begun to scratch the surface regarding the complex proteoform-level landscape of many disease-modifying proteins involved in neurodegenerative disorders such as Alzheimer’s disease and Parkinson’s disease.” says Patrie, Research Associate Professor of Chemistry and Director of Neuroproteomics. “With greater understanding of the composition and structure of proteins in the brain, as well as, the selectivity of diagnostics/therapeutics for families of proteoforms, the path to effective early diagnostics and disease-modifying therapeutics will undoubtedly become clearer.”
The Center is supported by “an exceptional group of research scholars” says Kelleher. In addition to Kelleher, Thomas, and the heads of the Center’s four research pillars, the leadership team includes:
- Jared Kafader, Director of Instrumentation (incoming)
- Phil Compton, Director of Instrumentation (outgoing)
- Richard LeDuc, Director of Computational Proteomics
- Robert (Vince) Gerbasi, Director of Immunoproteomics (outgoing)
- Ryan Fellers, Director of Software Engineering
- Young Ah Goo, Director of the Proteomics Core
Improved Testing for COVID-19
Proteoform-level analysis allows drug developers to find higher value biomarkers for disease, including COVID-19. Center researchers are working closely with Northwestern Feinberg School of Medicine investigators to understand how the human body generates antibodies to the SARS-CoV-2 proteins.
“We expect that our transplant patients, who all are on immunosuppression to maintain their transplanted organ, will respond differently to COVID-19,” says Feinberg investigator Daniela P Ladner, MD, MPH, Associate Professor of Surgery and Medical Social Sciences. “Our collaboration with the Proteomics Center allows us to examine the antibody repertoire of COVID-19 positive transplant recipients.”
Expanding the Field
To encourage widespread adoption of top-down proteomics, NTDP offers a robust four-day training course for users of the Center’s core facilities located in Chicago and Evanston. The Center also provides tools, materials, tutorials and exportable workflows enabling researchers among multiple disciplines and institutions to routinely access mass spectrometric measurements of their samples and proteins of interest.
“In its next five years, the Center will support over 100 laboratories at Northwestern and beyond, accelerating technology uptake via dissemination in the public and private sectors, and increasing the number of examples where proteoform-resolved biology provides clarity across a range of diseases,” says Kelleher. “We’ve also spun out a new company, Integrated Protein Technologies led by Phil Compton, that will enable the field to continue to flourish and make significant advances in human health and disease.”
Research reported in this publication was supported by the National Institute of General Medical Sciences of the National Institutes of Health under Award Number P41GM108569. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.
Northwestern University chemist Teri Odom has received the 2020 Centenary Prize from the Royal Society of Chemistry.
The prestigious award, given annually to three chemists outside Great Britain, recognizes scientists for high-impact research and exceptional communications skills. The award comes with a £5,000 cash prize, a medal and an invitation to give a series of lectures in the United Kingdom.
Eric Anslyn of the University of Texas at Austin and James Tour of Rice University also received the Centenary Prize this year.
An expert in designing structured nanoscale materials, Odom received the award for her research into multi-scale materials that enable new ways to achieve ultrafast, coherent and directional light emission at the nanoscale.
“I’m very grateful to have received this award, not only to join the impressive ranks of previous recipients but also because of the breadth and inclusiveness of chemistry featured,” Odom said. “The celebration of a broad range of chemistry — that can also be clearly communicated — is pretty special and, at least to me, emphasizes the forward-looking nature of this award.”
Odom is the chair of Northwestern’s chemistry department and the Charles E. and Emma H. Morrison Professor of Chemistry in the Weinberg College of Arts and Sciences. She also is a member of Northwestern’s International Institute for Nanotechnology and the Chemistry of Life Processes Institute.
Odom’s research focuses on designing structured nanoscale materials with extraordinary size- and shape-dependent properties. She has pioneered a suite of multi-scale nanofabrication tools that have resulted in nanoparticle lattice optics that can manipulate light at the nanoscale, plasmon-based nanoscale lasers that exhibit tunable color and anisotropic nanoparticle probes for imaging.
Odom is a member of the American Academy of Arts and Sciences and a fellow of the Royal Society of Chemistry, the American Chemical Society, the Materials Research Society, the American Physical Society and the Optical Society of America. She is currently the editor-in-chief of Nano Letters.
Original story posted by Northwestern Now on June 25, 2020 by Amanda Morris.
On May 28, 2020, 300 investors, venture firms, pharma and biotech industry members and researchers, from across the US, Canada, China, UK and beyond tuned into the second annual Biotech by the Lake Investor Summit hosted by the Chemistry of Life Processes Institute (CLP) at Northwestern University, in partnership with Oppenheimer & Co. and BioCentury, Inc. The virtual conference, held the day before the American Society of Clinical Oncologists’ Annual Meeting, highlighted the latest cancer therapies and technologies pioneered by Northwestern investigators, as well as leading biotech companies, and panel discussions lead by industry insiders about the hottest trends and investment strategies for oncology biotech.
Thomas O’Halloran, PhD, the Founding Director of CLP, opened the program with a welcome and brief history of the Institute which celebrated its 10th anniversary in Silverman Hall this year.
A Launchpad for Drug Development
“The Institute was initiated as my colleagues and I began to realize that some of the most important applications in chemistry need to have a very deep partnership with biology, medicine and engineering,” said O’Halloran, the Charles E. and Emma H. Morrison Professor of Chemistry and Professor of Molecular Biosciences, Weinberg College of Arts & Sciences; Professor of Medicine, Feinberg School of Medicine.
O’Halloran described CLP as an interdisciplinary network of 66 institute investigators across 20 departments that have contributed to the launch of commercially successful drugs in many disease areas. He noted that, since its founding, the Institute has incubated 27 new companies raising $2.3B in total capital and helped to “lower the barriers between the disciplines and facilitate interaction with the investment and pharma communities.”
CLP’s Executive Advisory Board members, said O’Halloran, were “an extraordinary group of alums and professionals across the industry, neighbors, investors throughout the Chicago region who have a deep and abiding interest in promoting transdisciplinary research and facilitating the translation of new discoveries from the bench rapidly out to society.”
At the Forefront of Cancer Research
Three Northwestern faculty members gave presentations on innovations in cancer research. Nathan Gianneschi, PhD, Jacob and Rosaline Cohn Professor of Chemistry, Departments of Chemistry, Materials Science & Engineering, Biomedical Engineering and Pharmacology, discussed his work using protein-like polymers (PLP) as an effective delivery platform for peptide-based therapeutics. Josh Leonard, PhD, Associate Professor of Chemical and Biological Engineering; Charles Deering McCormick Professor of Teaching Excellence, presented his work developing new tools for engineering cell therapies through synthetic biology. Daniela Matei, MD, Diana, Princess of Wales Professor of Cancer Research; Professor of Medicine (Hematology and Oncology) and Obstetrics and Gynecology, Feinberg School of Medicine, provided an overview of her pioneering research into the significance of transglutaminase (TG2) and fibronectin (FN) protein complex, in cancer metastasis.
“We’re trying to find chemicals that would block a complex of two proteins which we believe are important in metastasis in ovarian cancer,” said Matei. “People have never looked at it from this standpoint.”
Hottest Trends in Cancer Therapeutics and Technologies
The program then segued into a panel discussion about the hottest trends in cancer therapeutics and technologies led by Simone Fishburn, PhD, VP & Editor-in-Chief of BioCentury. Panelists included Andrew Chan, MD, PhD, Senior VP of Research Biology at Genentech, Neil Kelleher, PhD, the Faculty Director of Northwestern Proteomics, Elizabeth McNally, MD, PhD, Director, Center for Genetic Medicine; Elizabeth J. Ward Professor of Genetic Medicine in the Feinberg School of Medicine, and Nicholas Saccomano, PhD, CSO-SVP, Pfizer Boulder Research and Development. Chan is the chair of of CLP’s Executive Advisory Board.
Panelists touched upon topics ranging from immune checkpoint inhibitor (ICI) development, the future of small molecule kinase inhibitors, to the applications of revolutionary gene editing approaches and proteomics in oncology.
“There’s been a lot of advances in biology and technologies to advance the field of cancer immunotherapy. One of the recent advances is tiragolumab, a novel cancer immunotherapy designed by Genentech/Roche, that binds to TIGIT, an immune checkpoint protein expressed on immune cells,” said Chan, a member of CLP’s Executive Advisory Board. “The impact of the first wave of cancer immunotherapy with PD1/PD-L1 has revolutionized the treatment of melanoma, renal cell, lung and made inroads in breast metastatic cancers.” Chan noted that the company is embarking on multiple phase 3 clinical programs that are “just the tip of the iceberg.”
Breakthroughs in the Pipeline
Three senior biopharma executives provided updates on their companies’ lead cancer therapies. Barbara Klencke, MD, Chief Development Officer, Sierra Oncology (SRRA) described the clinical stage drug development of momelotinib, a potent, selective and orally bioavailable JAK1, JAK2 & ACVR1 inhibitor, for the treatment of myelofibrosis. Mani Mohindru, PhD, CEO, CereXis and a member of CLP’s Executive Advisory Board, discussed the biotech company’s progress on promising treatments for rare brain tumors, such as Neurofibromatosis 2 (NF2). Jonathan Zalevsky, PhD, Chief Research and Development Officer, Nektar (NKTR), detailed the company’s diverse pipeline, including its lead candidate bempeg, a CD122-preferential interleukin-2 (IL-2) pathway agonist which, in combination with nivolumab, is currently in pivotal Ph3 trials in adjuvant treatment of melanoma and invasive bladder cancer.
Investing in Chicago’s Life Sciences Ecosystem
The program wrapped up with a panel discussion on financing and investing in oncology biotech led by Jay Olson, CFA, Research Analyst with Oppenheimer & Co. Olson provided analysis on trends in FDA approvals, IPOs, and M&A activity. Vanessa Bhark, Senior Associate, Frazier Healthcare Partners, Maha Katabi, PhD, CFA, General Partner, Sofinnova Investments, Michael Margolis, RPh, Managing Director, Oppenheimer & Co, and Alex Munns, Assistant Portfolio Manager, Senior Analyst Driehaus Capital, participated in the discussion.
“We have fantastic academic centers in Chicago and a growing sense of the financial capabilities of some of the groups, including ours here in Chicago,” said Munns. “I’m excited to continue to build Chicago into a thriving ecosystem in the life sciences that will make it look more on par with what our colleagues and friends in Boston, San Francisco and New York are doing.”
Click below to view the event recording:
Read Oppenheimer’s detailed report: “Stars Align at CLP Biotech Summit—Highlights from Our 2nd Annual Event.”
Scientists from Northwestern Medicine and the University of Belgrade have pinpointed the electrophysiological mechanism behind upper motor neuron (UMN) disease, unlocking the door to potential treatments for amyotrophic lateral sclerosis (ALS) and other neurodegenerative diseases, such as Hereditary Spastic Paraplegia and Primary Lateral Sclerosis.
The study, published in Frontiers in Molecular Neuroscience on May 19, 2020, reveals the molecular underpinnings of electrical signals from potassium and sodium ion channels within the neuron’s cell membrane.
Maintaining stability is the primary goal of healthy UNMs. Without it, cells begin to degenerate. Like the game of telephone, when UMNs process signals from neighboring neurons incorrectly, the message fails to reach the motor neurons in the spine, which instruct muscles to move.
“Voltage-gated ion channels, as a family, are involved in many neurodegenerative diseases, but their function, modulation, and expression profile are very complicated,” said senior study author Hande Ozdinler, associate professor of neurology at Northwestern University Feinberg School of Medicine.
To identify the precise areas within the ion channels where the dysfunction began, the investigators, led by Dr. Marco Martina, associate professor of physiology and of psychiatry and behavioral sciences at Feinberg, recorded the electrical signals of in vivo cells in the earliest stage of ALS to measure the neuron’s reaction to external stimuli. The team also looked at the genes of the diseased UMNs’ ion channels to measure the changes in the structure of the ion and its subunits to determine whether the cause of degeneration was intrinsic.
The data revealed that early in the disease UMNs were unable to maintain the balance of excitation and inhibition within the cortical circuitry and their behavior was due to dynamic changes in key ion channels and their subunits.
“We all knew ion channels were important, but we did not know which ion channel or which subunit was pivotal for shifting balance from health to disease in UMNs,” said Ozdinler, a member of the Chemistry of Life Processes Institute. “When we received the exon microarray results, it was obvious that the ion channels were perturbed very early in the disease, potentially initiating the first wave of vulnerability.”
By identifying the molecular underpinnings of the early stages of neurodegeneration, the study also identified potential targets for future treatment strategies.
“There are already drugs out there for some of those ion channels and subunits, but we never thought that we could use them for ALS because we did not know the mechanism,” said Ozdinler. “This is the information we needed to move forward. “Now, we may begin to investigate whether we can utilize some of these drugs, already approved by the FDA, for motor neuron diseases.”
Pavle R. Andjus, a faculty member of Biology University of Belgrade in Serbia, is a co-author of the study.
“At the end of the day it was persistence and friendship that allowed us to make this discovery happen,” said Ozdinler. “I think if we team up and walk extra mile there isn’t any discovery we cannot make.”
This work was funded by NIA-RO1AG061708, Les Turner ALS Foundation, National Institutes of Health (NIH) grant NS066675, Amyotrophic Lateral Sclerosis Association Milton Safenowitz Postdoctoral Fellowship, and European Commission H2020 MSCA RISE grant 778405.
by Lisa La Vallee
Northwestern University synthetic biologists have received funding to develop an easy-to-use, quick-screen technology that can test for infectious diseases, including COVID-19, in the human body or within the environment.
Similar to a pregnancy test, the tool uses one sample to provide an easy-to-read negative or positive result. By simplifying testing, the researchers could put diagnostics into the hands of people everywhere — without the need for expensive laboratories or expertise. This could provide the large-scale testing required for ending stay-at-home orders, reopening the economy or preparing for a predicted virus resurgence in the fall.
The team is working to develop and optimize the test so that it will be a single step, taking less than an hour to provide a result and less than a dollar to manufacture.
On Friday, the project received a rapid response research (RAPID) grant from the National Science Foundation (NSF), which has called for immediate proposals that have potential to address the spread of novel coronavirus (COVID-19). The grant provides $200,000 over one year.
“The current COVID-19 pandemic highlights the limitations of laboratory-based testing,” said Northwestern’s Julius Lucks, the principal investigator on the project. “Those tests have not scaled with the sudden and dramatic increase of needed volume. They require too much equipment, time, expertise and infrastructure, which have resulted in major logistical challenges and, ultimately, inadequate testing. It’s become clear that we need to dramatically increase the scale of testing to safely restart the economy, to provide critical information if the virus resurges and to provide monitoring to prevent this in the future.”
Lucks devised the project with fellow Northwestern Center for Synthetic Biology (CSB) members Michael Jewett, Joshua Leonard and Niall Mangan. Jewett and Leonard are professors of chemical and biological engineering in Northwestern’s McCormick School of Engineering; Mangan is an assistant professor of engineering sciences and applied mathematics in McCormick. They have partnered with Khalid Alam, a former postdoctoral fellow in Lucks’ laboratory and CEO of Stemloop, Inc., which spun out of the CSB to commercialize rapid, field-deployable synthetic biology diagnostics technologies.
“Over the past few years, we have pioneered the use of cell-free systems as easy-to-use, point-of-need diagnostics,” said Jewett, director of the CSB. “These field-deployable systems can sense a variety of contaminants relevant to public health, including lead, fluoride and atrazine. We are trying to use that know-how to help address gaps in COVID-19 testing.”
The test works by combining gene-editing tool CRISPR, custom genetic circuits and cell-free synthetic biology in order to detect the virus and signal its presence. The team envisions that the final product could test patients’ samples from a nasal swab or saliva sample as well as water and surfaces in the surrounding environment.
“As far as we know, this is the first diagnostic tool to confront environmental monitoring,” Lucks said. “We could use this technology to monitor the presence of the virus on surfaces or even in the water. Recent research suggests that monitoring wastewater might provide clues about viral spread. Given the broad-scale need, we also plan to aim for clinical applications.”
After the test is developed in the laboratory, Stemloop will quickly transition the technology for manufacturing, deployment and distribution. The researchers aim to have the test ready for the novel coronavirus’ predicted resurgence in the fall. The tool, however, also can be rapidly reprogrammed to detect new emerging pathogens for future pandemics.
Lucks, Jewett and Leonard are members of Northwestern’s Chemistry of Life Processes Institute. Jewett and Leonard are members of the Robert H. Lurie Comprehensive Cancer Center of Northwestern University. Alam is an entrepreneur in Argonne National Laboratory’s Chain Reaction Innovations program.
Editor’s note: Lucks and Jewett have financial interests in Stemloop Inc.
Original story posted by Northwestern Now on April 20, 2020 by Amanda Morris.
Northwestern Professor Daniel Batlle, Earle, del Greco, Levin Professor of Nephrology/Hypertension in the Feinberg School of Medicine, is working on using shorter forms of Angiotensin-converting enzyme (ACE2) as a therapy for kidney diseases. The devastation of COVID-19 has pushed many researchers to think of ways to treat patients by borrowing therapies and ideas from similar viruses like SARS-CoV (2002-2004) and Ebola. ACE2 has been demonstrated to be the main receptor for the spike protein in SARS-CoV and recently SARS-CoV-2. The soluble, i.e. shorter, ACE2 molecule developed by Batlle and Wysocki could be used as a competitive interceptor of SARS-CoV-2, thereby preventing infection (Main Image).
In Figure 2, radiolabeled ACE2 is used to compare distribution of a soluble short ACE2 (left) and full size soluble native ACE 2 (right). Chemistry of Life Processes Institute’s Center for Advance Molecular Imaging provides state-of-the-art Single Photon Emission Computed Tomography (SPECT) imaging to visualize differences in the two ACE2 molecules. Although Figure 2 is a 2D presentation of the data, SPECT provides quantitative, in vivo, noninvasive, 3D data.
Soluble Angiotensin-Converting Enzyme 2: A Potential Approach for Coronavirus Infection Therapy? Daniel Batlle, Jan Wysocki, Karla Satchell Clin Sci (Lond) 2020 Mar 13;134(5):543-545. doi: 10.1042/CS20200163. PMID: 32167153 DOI: 10.1042/CS20200163
When it comes to fighting a fast-spreading pandemic, speed is critical.
Researchers at Northwestern and Cornell Universities have developed a new platform that could produce new therapies more than 10 times faster than current methods. The secret behind the platform’s unmatched speed is an unlikely tool: bacteria.
After taking the molecular machinery out of bacteria, the researchers then use that machinery to make a product, such as therapeutics, in a safe, inexpensive and rapid manner. The idea is akin to opening the hood of a car and removing the engine, which allows researchers to use the engine for different purposes, free from the constraints of the car.
Through their startup company, SwiftScale Biologics, the Northwestern and Cornell researchers are working to mass produce a promising antibody therapy developed by an outside biotherapeutics company. The antibody binds to the part of the coronavirus that infects the host cells, stopping it in its tracks.
“Everything is moving so incredibly fast, and this is an urgent problem,” said Northwestern’s Michael Jewett. “We believe that cell-free biomanufacturing can cut production times of antiviral medicines to the timescale of just a few months rather than closer to a year. This could help us address the current outbreak.”
Jewett is a professor of chemical and biological engineering in the McCormick School of Engineering and director of Northwestern’s Center for Synthetic Biology. He co-founded SwiftScale Biologics with Matthew DeLisa, the William L. Lewis Professor of Engineering at Cornell and director of the Cornell Institute of Biotechnology, and David Mace from 8VC.
The team had been using the synthetic biology-based platform to mass manufacture potential protein therapeutics for cancer. But it quickly pivoted to leverage the technology to help address the novel coronavirus (COVID-19) pandemic, for which no reliable treatment yet exists.
“Since the COVID-19 outbreak, we have dedicated nearly all of our resources to producing an antiviral therapy to fight it,” Jewett said. “Specifically, we are designing simplified antibody-based drugs that can be produced in bacteria rather than mammalian cells, which are far slower and more expensive to scale. In this way, we believe that we will be able to get a COVID-19 treatment into the clinic and ultimately to affected patients worldwide more quickly while increasing access.”
The SwiftScale Biologics team is currently engineering bacterial strains with increased production levels of previously discovered SARS-CoV antibodies as a test case. Next week, the team will test the bacterial strains to produce antibodies for COVID-19. This material will be used for animal studies to confirm the drug’s safety before entering human clinical trials, potentially as soon as this summer.
Jewett is a member of Northwestern’s Chemistry of Life Processes Institute and the Robert H. Lurie Comprehensive Cancer Center of Northwestern University.
Editor’s note: Jewett has financial interests in SwiftScale Biologics. Northwestern University has financial interests (equities, royalties) in SwiftScale Biologics.
Original story appeared in Northwestern Now on April 2, 2020 by Amanda Morris.
AIMBE’s College of Fellows comprises the top 2 percent of medical and biological engineers in the country. Fellows are recognized for their notable contributions advancing the fields of medical and biological engineering through research, practice, or education.
Jewett and Gianneschi are among 156 engineers who make up the College of Fellows Class of 2020. They were formally inducted remotely on March 30.
Jewett, Walter P. Murphy Professor of Chemical and Biological Engineering, is an expert on cell-free synthetic biology, protein synthesis, therapeutics, glycosylation, and engineered ribosomes. He is developing cell-free biology as an enabling technology for biomanufacturing lifesaving therapeutics, sustainable chemicals, and novel materials, both quickly and on-demand.
The director of Northwestern’s Center for Synthetic Biology, Jewett was elected to AIMBE for “outstanding contributions to develop cell-free synthetic biology and repurpose translation for on-demand biomanufacturing, portable diagnostics, and education kits.”
Jewett recently introduced a system that can rapidly create cell-free ribosomes in a test tube, then select the ribosome that can perform a certain function. The platform could help enable new manufacturing approaches to sustainable materials and targeted therapies.
Gianneschi, the Jacob and Rosalind Cohn Professor of Chemistry in the Weinberg College of Arts and Sciences and professor of materials science and engineering and biomedical engineering at the McCormick School of Engineering, studies how nanomaterials interact with cells, tissues, and biomolecules, with an interest in synthetic materials programmed with biopolymers as delivery systems. His research group also develops responsive materials and “smart” nanoparticles as well as new techniques for the discovery of functional nanomaterials and bionanomaterials through library screening methodologies.
He was recognized by AIMBE for “pioneering and creative contributions to nanomedicine through the invention of bioresponsive phase-change materials for selective tissue targeting.”
Last year, Gianneschi developed a new drug-delivery system that disguises chemotherapeutics as fat in order to penetrate and destroy tumors. The system tricks tumors into inviting in the chemotherapeutic, which then activates the targeted drug and immediately suppresses tumor growth.
Original story appeared in Northwestern Engineering News on March 30, 2020 by Alex Gerage.
Michael Jewett and Nathan Gianneschi are both members of the Chemistry of Life Processes Institute. Jewett is also co-director of CLP’s Recombinant Protein Production Core.
A new potential drug target has been identified in SARS CoV-2 — the virus that causes COVID-19 — by scientists who say multiple drugs will likely be needed to respond to the pandemic.
Scientists from Northwestern University Feinberg School of Medicine have mapped the atomic structure of two critical proteins in a complex, nsp10/16. These proteins modify the genetic material of the virus to make it look more like the host (human) cell RNA.
This allows the virus to hide from the cells, giving it time to multiply. If a drug can be developed to inhibit nsp10/nsp16, the immune system should be able to detect the virus and eradicate it faster.
“This is a really beautiful target, because it’s a protein absolutely essential for the virus to replicate,” said lead investigator Karla Satchell.
Satchell is a professor of microbiology-immunology at Northwestern and director of Center for Structural Genomics of Infectious Diseases (CSGID), an international consortium of scientists who are investigating the structure of the virus to aid drug development.
Satchell’s team is sending the new protein to Purdue University, the drug-discovery site of the center, to be screened for novel inhibitors that could be developed as new drugs.
The nsp10/nsp16 protein is called an RNA methyltransferase or MTase. It is comprised of two proteins bound together, which makes it more difficult to work with. The association of the two pieces together is required to make a functional protein, according to prior research on SARS.
The structure of nsp10/16 was released to the scientific community March 18 on the RSCB Protein Data Bank.
This is the fourth protein structure of a potential drug target of SARS-CoV-2 determined by the CSGID team of scientists.
“We need multiple drugs to treat this virus, because this disease is likely to be with us for a long time,” Satchell said. “It’s not good enough for us to develop a single drug. If COVID-19 develops a resistance to one drug, then we need others.”
The center is racing to release more structures for drug development. The center’s goal is to determine structures of all of the proteins that are potential drug targets. The team also is collaborating to provide proteins to investigators for design of improved vaccines.
Data for this structure was collected at the Northwestern managed Life Sciences Collaborative Access Team beamline at the Advanced Photon Source at Argonne National Labs. The LS-CAT staff worked quickly with APS and Satchell to provide rapid access to the beamline over a weekend specifically to collect data for this project.
“The center has shown a great ability to bring structure biology to the scientific community at an unprecedented rate,” Satchell said. But their work has become more challenging because so many universities have reduced activities and some labs have shut down entirely.
“Our ability to do experiments is abating,” Satchell said. Still, the center will continue to release new structures until they reach their goal, she said.
Structures of three other proteins important for the replication of the virus have also been released: the nsp15 endonuclease, nsp3 ADP ribose phosphate and nsp9 replicase. These structures were determined by the center scientists at University of Chicago headed by professor Andrzej Joachimiak, Distinguished Fellow of Argonne, who also is an adjunct professor at Northwestern. All work conducted by both the University of Chicago and Northwestern teams was designed by the bioinformatic team of Adam Godzik at the University of California at Riverside, based on research conducted in SARS.
The CSGID is supported by a contract from the National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health, in part to serve as a response site to conduct structure biology research in the event of an unexpected infectious disease outbreak. NIAID has been working closely with the Center since early January to coordinate center activities with other research supported by NIAID to enable drug discovery.
This study has been funded by contract HHSN272201700060C from the National Institute of Allergy and Infectious Diseases, part of the NIH.
The original story was published in Northwestern Now on March 27, 2020 by Marla Paul.
Purification of the protein targets identified by Satchell and team was conducted by Chemistry of Life Processes Institute’s Recombinant Protein Production Core. The rPPC provides quality controlled recombinant proteins for Northwestern researchers as well as academic and industry researchers outside of the University, including CSGID scientists.
According to rPPC Managing Director Sergii Pshenychnyi, rPPC produced two SARS-CoV-2 proteins, SARS-CoV-2 papain-like protease (PLpro) and chymotrypsin-like protease (3CLpro) for CSGID and sent them to Purdue University for the purpose of testing possible drugs that inhibit the proteases central to the function of the virus.
“Data suggests that some of the compounds that made it through early stage clinical trials may be working,” says Pshenychnyl. “The process, however, will take months (possibly a year) of subsequent drug development.”
Pshenychnyl is also working with Daniel Batlle Group (FSM, Nephrology and Hypertension Department) to purify the human angiotensin-converting enzyme 2 (hACE2). SARS-CoV-2 enters the human body by binding to hACE2. He is also working on another project for Pablo Penaloza (Department of Microbiology and Immunology), producing receptor binding domain of SARS-CoV-2, Wuhan-Hu-1 Spike Glycoprotein in HEK293 cells. Both will be used to perform critical vaccine studies.
Northwestern University researchers have mapped a group of proteins that play a critical role in both gene expression and repairing damaged DNA. By understanding this protein complex, called SWI/SNF, researchers hope to better understand how cancer arises.
SWI/SNF regulates the structure of chromatin, which comprises genetic material in a cell’s nucleus and often mutates as cancer develops.
“Mutations of this essential complex have been found in more than 20 percent of all human cancers associated with a wide range of tissue types,” said Northwestern’s Yuan He, who led the study. “Understanding the molecular mechanism of the SWI/SNF complex in regulating chromatin structure and gene transcription is thereby essential for a complete understanding of how chromatin structure alterations lead to cancer.”
To determine the unique structure, the He lab used cryogenic electron microscopy (cryo-EM), a powerful technique capable of revealing the 3D shape of large protein complexes. The technique involves flash-freezing proteins at a speed where water molecules don’t have time to re-organize to form crystalline ice. These protein complexes are then directly imaged by an electron microscope, and their 3D shape can then be reconstructed in 3D using a supercomputing cluster. Before cryo-EM, researchers mainly used X-ray crystallography, which is incapable of capturing high-resolution images of important complexes such as this.
This landmark study is the first time that researchers have used cryo-EM to determine the SWI/SNF structure bound to a nucleosome, at near-atomic resolution. “cryo-EM is a revolutionary technique,” said Carole LaBonne, chair of the Department of Molecular Biosciences. “It is taking over in the critical field of structural biology. Every major research university is making major investments in this field because it is clear that it holds the key to unraveling many unanswered questions in biomedical science.”
Professor Yuan He explained that the structure will allow researchers to map and rationalize cancer-related mutations in the human SWI/SNF complex.
He added that the study will provide the molecular platform for better understanding the important functions of SWI/SNF in both healthy and cancerous states, as well as for developing potential therapeutic strategies for human malignancies.
“Our study gives insight into how the complex suppresses tumor development,” He said. “And it could contribute to developing therapeutics for cancers harboring mutations in genes encoding the SWI/SNF complex.”
The study, “Cryo-EM structure of SWI/SNF complex bound to a nucleosome,” was supported by a Cornew Innovation Award from the Chemistry of Life Processes Institute at Northwestern University, the American Cancer Society (award number IRG-15-173-21) and the National Institutes of Health (award number R01GM135651, P01CA092584, U54CA193419 and 5T32 GM008382).
The original story was published in Northwestern Now on March 11, 2020 by Rebecca Lindell.
Yuan He is a member of the Chemistry of Life Processes Institute.
As a child growing up in a large family in rural Iran, Nayereh Ghoreishi-Haack, Assistant Director, Developmental Therapeutics Core, Chemistry of Life Processes (CLP) at Northwestern University, spent her days exploring the abundant orchards, bogs and farms that dotted the countryside near her home. Little did she guess that someday her childhood pastime would transport her from the family orchards to the labs of major US-based pharmaceutical companies, small biotech firms, and a world-renown research university.
“As a nature lover, I was fascinated by life and how our biological systems work in other beings, as well as in our bodies.”
Due to the political situation in Iran at the time, Ghoreishi-Haack immigrated to US in the late 80s.
Ghoreishi-Haack earned her BS in Zoology at University of Alabama in Huntsville.
“Just by luck, I was near graduation from college and visiting my sister in Chicago during Christmas,” said Ghoreishi-Haack. “I didn’t even have a CV, but I saw these ads in the Chicago Tribune for a research scientist posted by GD Searle.”
She applied for the position and, to her surprise, got the job. While at Searle, she earned her MS in Molecular and Cellular Biology from Northeastern Illinois University.
“At first, I was very naïve. I had no idea what it meant to be a pharmacologist,” Ghoreishi-Haack said. “Eventually, I learned how critical research was in fighting diseases and drug development. That’s when I got hooked.”
While at Searle, Ghoreishi-Haack witnessed the blockbusting success of Celebrex (celecoxib), a cyclo-oxygenase-2 inhibitor for arthritis and pain that became one of the most prescribed drugs in the US at the time.
“It was fascinating to see the process of bringing a new drug from the laboratory bench to market,” she said.
Ghoreishi-Haack worked for Searle for 12 years, then moved to the Integrative Pharmacology Department at Abbott Labs. There, she evaluated compounds for their efficacy from various cancer projects and against glioblastoma. Subsequent career moves included senior pharmacologist and senior research manager at AbbVie, Naurex Inc., and Apitnyx Inc., where she performed pre-clinical testing of potential new drugs in various therapeutic areas including inflammatory pain, neuropathic pain, and neurodegenerative diseases.
At Northwestern, Ghoreishi-Haack works closely with investigators across disciplines, and oversees efforts to evaluate preclinical models and lead compounds for potential new therapies for cancer and other diseases.
“Usually researchers move from academia to industry,” says Ghoreishi-Haack. “I’ve done the reverse because I knew I could have a greater impact working at CLP. Having all the cores nearby, and access to their resources and instruments, makes the Institute like a biotech: generating vast amount of data and capable of producing numerous INDs (investigational new drugs).”
by Lisa La Vallee
One of the hallmarks of cancer is cell immortality. A Northwestern University organic chemist and his team now have developed a promising molecular tool that targets and inhibits one of cell immortality’s underlying gears: the enzyme telomerase.
This enzyme is found overexpressed in approximately 90% of human cancer cells and has become an important subject of study for cancer researchers. Normal cells have the gene for telomerase, but it typically is not expressed.
“Telomerase is the primary enzyme that allows cancer cells to live forever,” said Karl A. Scheidt, who led the research. “We want to short-circuit this immortality. Now we have designed a first-of-its-kind small molecule that irreversibly binds to telomerase, shutting down its activity. This mechanism offers a new pathway for treating cancer and understanding cellular aging.”
Scheidt is a professor of chemistry in the Weinberg College of Arts and Sciences and a professor of pharmacology at Northwestern University Feinberg School of Medicine.
The big idea for the small molecule design came from nature. A decade ago, Scheidt was intrigued by the biological activity of chrolactomycin, which is produced by bacteria and has been shown to inhibit telomerase.
Scheidt and his team used chrolactomycin as a starting point in the design of their small molecules. They produced more than 200 compounds over the years, and the compound they call NU-1 was the most effective of those tested. Its synthesis is very efficient, taking fewer than five steps.
“NU-1 inhibits telomerase unlike anything that came before it,” Scheidt said. “It does this by forming a covalent bond. Another advantage of NU-1 is that its molecular structure should enable scientists to add cargo, such as a therapeutic.”
The study was published last week by the journal ACS Chemical Biology.
All human cells have telomeres, short DNA sequences that cap the ends of each strand of DNA. Their job is to protect our chromosomes and DNA. When a cell divides, the telomeres get shorter until they can no longer do their job. Natural cell death follows.
In contrast, cancer cells, with their heightened telomerase activity, become immortal by reversing the normal telomere shortening process. The enzyme telomerase copies telomeres over and over again, lengthening the telomeres. The result is unlimited cell division and immortality. The famous HeLa cells, isolated from the cervical cancer tissue of Henrietta Lacks in the 1950s, are still dividing.
Telomerase has been a target for cancer therapeutics research for decades. In 2009, three scientists received the Nobel Prize in Physiology or Medicine for their earlier research into telomeres and telomerase.
After developing their new compounds, Scheidt and his team initiated collaborations with Professor Stephen Kron at the University of Chicago and Scott Cohen at the Children’s Medical Research Institute in Sydney to investigate the extra-telomeric role of telomerase inhibition.
The studies focused on how the new compounds interact with telomerase on a molecular level and how telomerase inhibition sensitizes cells to chemotherapies and irradiation. From this work, NU-1 rose to the top.
“By publishing this study, we are test driving this exquisite tool to see what it can do and to learn more about telomerase,” Scheidt said. “We also are continuing to make it better.”
The research was done in human cells. The next steps, Scheidt said, are to make more potent compounds and investigate them in animal models.
The study was supported by the Chicago Cancer Baseball Charities at the Lurie Cancer Center of Northwestern University, the National Institute of General Medical Sciences (training grant GM105538) and the National Institutes of Health (grant R01 CA217182).
The paper is titled “Targeted Covalent Inhibition of Telomerase.” Scheidt is the corresponding author; Rick C. Betori, who recently received his Ph.D., is the first author; and Kron and Cohen are co-authors.
Northwestern has filed a provisional patent for NU-1 and related analogs.
Scheidt also is director of Northwestern’s Center for Molecular Innovation and Drug Discovery; the executive director of NewCures, Northwestern’s biomedical accelerator; a member of the Robert H. Lurie Comprehensive Cancer Center of Northwestern University; and a member of the Chemistry of Life Processes Institute.
The original story was published on March 3, 2020 in Northwestern Now by Megan Fellman.
Main image: The ends of chromosomes are protected by specific DNA sequences called telomeres, visualized here in red. Credit: National Institutes of Health
Karl Scheidt is a member of the Chemistry of Life Processes Institute.
Northwestern Proteomics, a Chemistry of Life Processes Institute-affiliated center, together with an interdisciplinary team of Northwestern mathematicians, experimentalists, biomedical engineers, and biochemists, recently published two academic papers announcing a new, game-changing technique for characterizing and identifying proteins with extreme precision.
For the first time, using the commercially available Orbitrap mass analyzer system, researchers successfully integrated two mass spectrometry (MS) approaches: native or top-down MS and, an even more pioneering technique, individual ion mass spectrometry (I2MS), both pioneered by the Kelleher Research Group. The powerful and new approach, two-and-a half years in the making, will help illuminate complex questions within fundamental biology and transform understanding of disease and infection and to accelerate the design of new therapies.
“If you want to know the distribution of molecules that are in a sample, you can now know that within an hour,” says Neil Kelleher, Walter and Mary E. Glass Professor of Molecular Biosciences and Faculty Director, Northwestern Proteomics, who led the research. Kelleher is a pioneer in the fields of native and top-down mass spectrometry. “We’ve been able to fragment a protein, read out the fragments as individual ions, and determine their charge. With that information, we then calculate their mass and resolve the protein components.”
Traditional MS measurements collect averaged data from a mixed population of multiple ions. Mass spectrometers work by measuring the mass-to-charge ratio of each item. I2MS facilitates the accurate detection of each ion and their individual charges to reveal their precise mass.
In a paper published today (March 2) in Nature Methods, first author Jared Otto Kafader, senior research associate in the Kelleher Research Group, and collaborators, detail the process for developing the I2MS method.
“We created a mass spectrum platform and applied it to a huge range of intact proteins – everything from small proteins to antibodies to virus-like particles and demonstrated that we can deconvolute masses and obtain actual mass assignments,” says Kafader.
The breakthrough has major implications for the biopharmaceutical industry and biomedical research writ large according to Kelleher, a member of the Chemistry of Life Processes Institute.
“Antibody-based drugs are comprised of a complex mixture of large molecules that are often based on proteins, or virus particles, that reach well into the megadalton range,” says Kelleher. “Now, you can get the size distribution and exact characterization of the proteins in that mixture. Instead of having some blurry view of what you’re injecting in the body as a drug, this technology allows you to get down to the molecular level and be very precise in doing so. In the old way, there would be no data.”
In a second paper published in the Journal of Proteome Research, researchers used I2MS to detect fragment ions resulting from top-down analysis, a significant leap forward in current capabilities for protein characterization. Fragment ions are crucial for characterizing a protein’s sequence and post-translational modifications. The fragments detected with I2MS were complementary with those from traditional analysis, greatly enhancing the combined level of detail for characterizing a protein.
“Whereas the first approach maps the protein universe, the second approach provides super-detailed characterization of each protein through single particle/ion counting,” says Kelleher, a member of the Chemistry of Life Processes Institute.
The new technology promises to aid understanding of disease and infection and accelerate the design of vaccines for deadly viruses, such as the coronavirus.
“This technology enables researchers to weigh the whole virus and get a mass distribution, virus particle by virus particle, and determine the difference in mass of different strains of a constantly mutating virus,” says Kelleher. “The approach will allow epidemiologists to know the efficacy of different vaccines, irrespective of how complicated the sample is. Most approaches take a long time to accomplish that. With our approach, you can do it in a matter of minutes.”
The research was supported by National Institute of General Medical Sciences, National Institutes of Health (grant P41 GM108569), and Thermo Fisher Scientific and the Sherman Fairchild Foundation.
by Lisa La Vallee
Main image: (Left-right): Jack McGee, Chemical and Biological Engineering graduate student, Professor Neil Kelleher, and Jared Otto Kafader, senior research associate, in the Kelleher Research Group.
Many people consult their friends and neighbors before making a big decision. It turns out that cells also are consulting their neighbors in the human body.
Scientists and physicians have long known that immune cells migrate to the site of an infection, which individuals experience as inflammation — swelling, redness and pain. Now, Northwestern University and University of Washington researchers have uncovered new evidence that this gathering is not just a consequence of immune activation. Immune cells count their neighbors before deciding whether or not the immune system should kick into high gear.
Understanding how to influence inflammation and activate an immune response could lead to new therapies to treat chronic autoimmune diseases or to mobilize the immune system to help fight cancer.
“This is a previously unrecognized aspect of immune function,” said Northwestern’s Joshua Leonard, a member of the Chemistry of Life Processes Institute, who co-led the study. “The cells make a coordinated decision. They don’t uniformly activate but instead collectively decide how many cells will activate, so that together, the system can fend off a threat without dangerously overreacting.”
“A key part of this work relied on the development of new computational models to interpret our experiments and elucidate how cells perform calculations to make coherent decisions,” said University of Washington’s Neda Bagheri, who co-led the work with Leonard.
The research was published today (Feb. 13) in the journal Nature Communications.
Leonard is an associate professor of chemical and biological engineering at Northwestern’s McCormick School of Engineering and a member of Northwestern’s Center for Synthetic Biology. Bagheri is an associate adjunct professor of chemical and biological engineering at McCormick and an assistant professor of chemical engineering and biology and a Distinguished Washington Research Foundation Investigator at the University of Washington. The paper’s first author is Joseph Muldoon, a graduate student in Northwestern’s Interdisciplinary Biological Sciences Graduate Program, who is co-advised by Leonard and Bagheri.
The body’s immune system is constantly working to maintain a delicate balance. When a threat is introduced, the system needs to respond strongly enough to fight off infection or disease but not so strongly that it causes harm.
“When it comes to immune responses, it’s the difference between life and death,” Leonard said. “If your body over-responds to a bacterial infection, then you could die from septic shock. If your body doesn’t respond enough, then you could die from rampant infection. Staying healthy requires the body to strike a balance between these extremes.”
Original story published in Northwestern Now by Amanda Morris.
Josh Leonard is a member of the Chemistry of Life Processes Institute. The CLP Cornew Award was awarded to both Leonard and Neda Bagheri, a former member of the Institute.
Northwestern University researchers have, for the first time, determined the 3D atomic structure of a key complex in paramyxoviruses, a family of viruses that includes mumps, human parainfluenza and respiratory syncytial virus (RSV).
This information could help others design and develop antiviral drugs for these viruses as well as for coronavirus, which functions similarly to paramyxoviruses.
“This takes some of the guesswork out of designing drugs,” said Northwestern’s Robert Lamb, who co-led the study. “Traditionally, you have to develop drugs randomly and hope you hit a target, but it doesn’t happen very often.”
To find the unique structure, researchers used cryogenic electron microscopy (cryo-EM). The relatively new technique enables researchers to peer inside molecules to determine the 3D shape of proteins, which are often thousands of times smaller than the width of a human hair. Before cryo-EM, researchers mainly used X-ray crystallography, which is incapable of capturing high-resolution images of this enzyme. Called a polymerase, the enzyme assembles RNA molecules.
“Crystallography only works for very orderly and organized proteins,” said Northwestern’s Yuan He, who co-led the study. “Virus polymerase complexes are too big to be crystallized and don’t have uniformity.”
The study will be published online this week in the Proceedings of the National Academy of Sciences.
Lamb is the Kenneth F. Burgess Professor of Molecular Biosciences in Northwestern’s Weinberg College of Arts and Sciences and an investigator of the Howard Hughes Medical Institute. Yuan He is an assistant professor of molecular biosciences in Weinberg.
Although the first documented case of mumps occurred in the 5th century and measles in the 9th century, researchers did not have the equipment to characterize their atomic structures until relatively recently. A trio of biophysicists received the 2017 Nobel Prize in Chemistry for developing cryo-EM, which ultimately opened the door for Lamb and He.
Cryo-EM works by blasting a stream of electrons at a flash-frozen sample to take many 2D images. For this study, He and his team captured hundreds of thousands of images of one sample of human parainfluenza virus 5 polymerase. The team then used computational algorithms to reconstruct a 3D image.
The resulting image was an irregular, round-shaped globule with a long tail made of four phosphoproteins (or proteins containing phosphorous). The structure contains more than 2,000 amino acids and five proteins.
“Part of the image was expected,” Lamb said. “But part of it was a surprise. Two of the proteins are completely new. They have never been seen before.”
Another surprise: the team found that this virus uses the same protein to switch between genome replication and transcription.
“This machinery has a dual-function,” He said. “It gets both jobs done with one enzyme. The virus’s genome is so small, and this gives it economy of scale.”
Original story published in Northwestern Now by Amanda Morris.
This work was partially supported by the Chemistry of Life Processes Institute’s Cornew Innovation Award.
Did you know that women comprise a mere 24 percent of the science, technology, engineering and math (STEM) workforce? Were you also aware that the National Institutes of Health NIH gives first-time male principal investigator scientists considerably more funding than women, even at the nation’s top research institutions? Women are also less likely to be hired and promoted to manager: For every 100 men promoted and hired to manager, only 72 women are promoted and hired. Men hold 62 percent of manager-level positions, while women hold just 38 percent. The number of women decreases at every subsequent level.*
In honor of the University’s year-long celebration of ‘150 Years of Women at Northwestern, Chemistry of Life Processes Institute will host the second of three ‘CLP Spills the Tea‘ events on March 11 at 4:00 p.m. in Evanston. The discussion will include four prominent women in science from diverse backgrounds who will address issues of gender disparity in the workplace and share insights on how to thrive in male-dominated science fields, from higher education and biotech to national laboratories and beyond. Tea, coffee and cookies will be served.
Lindsay Chase-Lansdale, PhD, Frances Willard Professor of Human Development and Social Policy, Vice Provost for Academics, Northwestern University
Margarita Chavez, JD, Managing Director, AbbVie Ventures
Lydia Finney, PhD, CDP, Diversity and Inclusion Partner and Physicist, Leadership Institute, Argonne National Laboratory
Kapila Viges, Director, Strategy Insights and Planning, Oncology Group, ZS Associates
Teresa K. Woodruff, PhD, Thomas J. Watkins Professor of Obstetrics and Gynecology and Dean, The Graduate School, Northwestern University
The program will be held in Cohen Commons, Northwestern University, Room L482, fourth floor north, in the Technological Institute, 2145 Sheridan Road, Evanston, IL.
* Source: LeanIn.org
Working across disciplines, several Chemistry of Life Processes Institute faculty members are accelerating the time it takes to bring new cancer therapies and diagnostic tools from the lab into clinics. In honor of World Cancer Day, here are just a few examples of our progress:
CLP startup Actuate Therapeutics has developed an exciting new treatment, currently in clinic trials, for advanced and drug-resistant cancers, including glioblastoma, melanoma, pancreatic, appendix, breast and ovarian, and select inflammatory diseases.
Among other cancer therapies, CLP spinout Monopar Therapeutics is developing new & powerful therapies currently in clinical trials for oropharyngeal cancer, pancreatic, ovarian, and metastatic breast cancer.
CLP member Nathan Gianneschi and first author Cassandra Callmann have developed a new way to deliver chemo into cancer cells with much fewer side effects and astonishing results.
In the face of great doubt, CLP member Vadim Backman and collaborators developed partial wave spectroscopy (PWS) nanocytology, a new diagnostic technology that not only views cells at these elusive length scales but also uncovers shrouded cancer malignancies in their earliest stages. #WorldCancerDay