Human lung cells (blue) infected with SARS-CoV-2 (red). Courtesy of Hekman, et al. Credit: Courtesy of Hekman, et al.
Multipronged BU research team finds 18 FDA-approved drugs that could halt coronavirus infection earlier.
What if scientists knew exactly what impact the SARS-CoV-2 virus had inside our lung cells, within the first few hours of being infected? Could they use that information to find drugs that would disrupt the virus replication process before it ever gets fully underway? The discovery that several existing FDA-approved drugsincluding some originally designed to fight cancercan stop coronavirus in its tracks indicates the answer is a resounding yes.
A team of Boston University researchershailing from BUs National Emerging Infectious Diseases Laboratories (NEIDL), the Center for Regenerative Medicine (CReM) at BUs Medical Campus, and BUs Center for Network Systems Biology (CNSB)embarked on a months-long, collaborative and interdisciplinary quest, combining multiple areas of expertise in virology, stem cellderived lung tissue engineering, and deep molecular sequencing to begin answering those questions. They simultaneously infected tens of thousands of human lung cells with the SARS-CoV-2 virus, and then tracked precisely what happens in all of those cells during the first few moments after infection. As if that was not complicated enough, the team had to cool their entire high-containment research facility inside the NEIDL to a brisk 61 degrees Fahrenheit.
The result of that challenging and massive undertaking? The BU team has revealed the most comprehensive map to date of all the molecular activities that are triggered inside lung cells at the onset of coronavirus infection. They also discovered there are at least 18 existing, FDA-approved drugs that could potentially be repurposed to combat COVID-19 infections shortly after a person becomes infected. Experimentally, five of those drugs reduced coronavirus spread in human lung cells by more than 90 percent. Their findings were recently published in Molecular Cell.
Now, academic and industry collaborators from around the world are in contact with the team about next steps to move their findings from bench to bedside, the researchers say. (Although COVID-19 vaccines are starting to be rolled out, its expected to take the better part of a year for enough people to be vaccinated to create herd immunity. And there are no guarantees that the current vaccine formulations will be as effective against future SARS-CoV-2 strains that could emerge over time.) More effective and well-timed therapeutic interventions could help reduce the overall number of deaths related to COVID-19 infections.
What makes this research unusual is that we looked at very early time points [of infection], at just one hour after the virus infects lung cells. It was scary to see that the virus already starts to damage the cells so early during infection, says Elke Mhlberger, one of the studys senior investigators and a virologist at BUs NEIDL. She typically works with some of the worlds most lethal viruses like Ebola and Marburg.
The most striking aspect is how many molecular pathways are impacted by the virus, says Andrew Emili, another of the studys senior investigators, and the director of BUs CNSB, which specializes in proteomics and deep sequencing of molecular interactions. The virus does wholesale remodeling of the lung cellsits amazing the degree to which the virus commandeers the cells it infects.
Viruses cant replicate themselves because they lack the molecular machinery for manufacturing proteinsthats why they rely on infecting cells to hijack the cells internal machinery and use it to spread their own genetic material. When SARS-CoV-2 takes over, it completely changes the cells metabolic processes, Emili says, and even damages the cells nuclear membranes within three to six hours after infection, which the team found surprising. In contrast, cells infected with the deadly Ebola virus dont show any obvious structural changes at these early time points of infection, and even at late stages of infection, the nuclear membrane is still intact, Mhlberger says.
The nuclear membrane surrounds the nucleus, which holds the majority of a cells genetic information and controls and regulates normal cellular functions. With the cell nucleus compromised by SARS-CoV-2, things rapidly take a bad turn for the entire cell. Under siege, the cellswhich normally play a role in maintaining the essential gas exchange of oxygen and carbon dioxide that occurs when we breathedie. As the cells die, they also emit distress signals that boost inflammation, triggering a cascade of biological activity that speeds up cell death and can eventually lead to pneumonia, acute respiratory distress, and lung failure.
I couldnt have predicted a lot of these pathways, most of them were news to me, says Andrew Wilson, one of the studys senior authors, a CReM scientist, and a pulmonologist at Boston Medical Center (BMC), BUs teaching hospital. At BMC, Bostons safety net hospital, Wilson has been on the front lines of the COVID-19 pandemic since March 2020, trying to treat and save the sickest patients in the hospitals ICU. Thats why our [experimental] model is so valuable.
Science is the answerif we use science to ask the lung cells what goes wrong when they are infected with coronavirus, the cells will tell us. Darrell Kotton
The team leveraged the CReMs organoid expertise to grow human lung air sac cells, the type of cell that lines the inside of lungs. Air sac cells are usually difficult to grow and maintain in traditional culture and difficult to extract directly from patients for research purposes. Thats why much coronavirus research to date by other labs has relied on the use of more readily available cell types, like kidney cells from monkeys. The problem with that is kidney cells from monkeys dont react the same way to coronavirus infection as lung cells from humans do, making them a poor model for studying the viruswhatever is learned from them doesnt easily translate into clinically relevant findings for treating human patients.
Our organoids, developed by our CReM faculty, are engineered from stem cellstheyre not identical to the living, breathing cells inside our bodies, but they are the closest thing to it, says Darrell Kotton, one of the studys senior authors. He is a director of the CReM and a pulmonologist at BMC, where he has worked alongside Wilson in the ICU treating COVID-19 patients. The two of them often collaborated with Mhlberger, Emili, and other members of their research team via Zoom calls that they managed to join during brief moments of calm in the ICU.
In another recent study using the CReMs engineered human lung cells, the research team confirmed that existing drugs remdesivir and camostat are effective in combating the virus, though neither is a perfect fix for controlling the inflammation that COVID-19 causes. Remdesivir, a broad-use antiviral, has already been used clinically in coronavirus patients. But based on the new studys findings that the virus does serious damage to cells within hours, setting off inflammation, the researchers say theres likely not much that antiviral drugs like remdesivir can do once an infection has advanced to the point where someone would need to be put on a ventilator in the ICU. [Giving remdesivir] cant save lives if the disease has already progressed, Emili says.
Seeing how masterfully SARS-CoV-2 commandeers human cells and subverts them to do the manufacturing work of replicating the viral genome, it reminded the researchers of another deadly invader.
I was surprised that there are so many similarities between cancer cells and SARS-CoV-2-infected cells, Mhlberger says. The team screened a number of cancer drugs as part of their study and found that several of them are able to block SARS-CoV-2 from multiplying. Like viruses, cancer cells want to replicate their own genomes, dividing over and over again. To do that, they need to produce a lot of pyrimidine, a basic building block for genetic material. Interrupting the production of pyrimidineusing a cancer drug designed for that purposealso blocks the SARS-CoV-2 genome from being built. But Mhlberger cautions that cancer drugs typically have a lot of side effects. Do we really want to use that heavy stuff against a virus? she says. More studies will be needed to weigh the pros and cons of such an approach.
The findings of their latest study took the four senior investigators and scientists, postdoctoral fellows, and graduate students from their laboratories almost four months, working nearly around the clock, to complete the research. Of critical importance to the teams leaders was making sure that the experimental setup had rock-solid foundations in mimicking whats actually happening when the SARS-CoV-2 virus infects people.
Science is the answerif we use science to ask the lung cells what goes wrong when they are infected with coronavirus, the cells will tell us, Kotton says. Objective scientific data gives us hints at what to do and has lessons to teach us. It can reveal a path out of this pandemic.
Hes particularly excited about the outreach the team has received from collaborators around the world. People with expertise in supercomputers and machine learning are excited about using those tools and the datasets from our publication to identify the most promising drug targets [for treating COVID-19], he says.
Kotton says the theme thats become obvious among COVID-19 clinicians and scientists is understanding that timing is key. Once a patient is on a ventilator in the ICU, we feel limited in what we can do for their body, he says. Timing is everything, its crucial to identify early windows of opportunity for intervention. You can keep guessing and hope we get luckyor you [do the research] to actually understand the infection from its inception, and take the guesswork out of drug development.
Reference: Actionable Cytopathogenic Host Responses of Human Alveolar Type 2 Cells to SARS-CoV-2 by Ryan M. Hekman, Adam J. Hume, Raghuveera Kumar Goel, Kristine M. Abo, Jessie Huang, Benjamin C. Blum, Rhiannon B. Werder, Ellen L. Suder, Indranil Paul, Sadhna Phanse, Ahmed Youssef, Konstantinos D. Alysandratos, Dzmitry Padhorny, Sandeep Ojha, Alexandra Mora-Martin, Dmitry Kretov, Peter E.A. Ash, Mamta Verma, Jian Zhao, J.J. Patten, Carlos Villacorta-Martin, Dante Bolzan, Carlos Perea-Resa, Esther Bullitt, Anne Hinds, Andrew Tilston-Lunel, Xaralabos Varelas, Shaghayegh Farhangmehr Ulrich Braunschweig, Julian H. Kwan, Mark McComb, Avik Basu, Mohsan Saeed, Valentina Perissi, Eric J. Burks, Matthew D. Layne, John H. Connor, Robert Davey, Ji-Xin Cheng, Benjamin L. Wolozin, Benjamin J. Blencowe, Stefan Wuchty, Shawn M. Lyons, Dima Kozakov, Daniel Cifuentes, Michael Blower, Darrell N. Kotton, Andrew A. Wilson, Elke Mhlberger and Andrew Emili, 18 November 2020, Molecular Cell.DOI: 10.1016/j.molcel.2020.11.028
This research was funded by the National Institutes of Health, the Australian National Health and Medical Research Council, the Pulmonary Fibrosis Foundation, the Massachusetts Consortium on Pathogen Readiness, the C3.ai Digital Transformation Institute, the Canadian Institutes of Health Research, and Fast Grants.
The rest is here:
How Coronavirus Damages Lung Cells Within Mere Hours And What Drugs Could Halt COVID-19 Infection - SciTechDaily
- Heres How Fasting Benefits Your Mental and Physical Wellbeing - News18 - October 4th, 2022
- Asymmetrex Gives First Cell Culture Core Facility Introduction to Online Rapid Stem Cell Counting in the Institute for Applied Life Sciences at... - September 25th, 2022
- Asymmetrex's Introduction of Online Calculators for Determination of the Dosage of Therapeutic Stem Cells Announced as a Reformation in Stem Cell... - September 16th, 2022
- UMass Dartmouth awarded $750000 Massachusetts Life Science grant to diversify the field - New Bedford Guide - September 16th, 2022
- ALS Thought Leaders Weigh in Ahead of Second Amylyx Adcomm - BioSpace - September 8th, 2022
- Scientists convert kidney to universal O blood type - Freethink - August 30th, 2022
- Case Study: SARS-CoV-2 Virus Infecting the Inner Ear - Victoria News - August 14th, 2022
- Evidence Is Growing That LSD Improves Learning and Memory - Futurism - August 14th, 2022
- Rice University: Rice, Baylor developing implants to heal heart attack injuries | India Education | Latest Education News | Global Educational News |... - August 14th, 2022
- Iconic everyday inventions and the women behind them - YourStory - August 14th, 2022
- Head to Head Analysis: VolitionRx (NYSE:VNRX) vs. Intellia Therapeutics (NASDAQ:NTLA) - Defense World - August 14th, 2022
- Man who saved life as stem cell donor urges others to help his friend find a match after five-year search - Lancashire Evening Post - August 5th, 2022
- The 3D Cell Culture Market is expected to reach a value of USD 3721.86 Million by 2027, at a CAGR of 13.4% (2021 2027) - Digital Journal - August 5th, 2022
- Flow Cytometry Market is expected to reach a value of USD 11467.80 Million by 2027, at a CAGR of 8.88% over the forecast period (2021 2027) - Digital... - July 27th, 2022
- Stem Cells Market Competitive Insights And Global Outlook 2022 To 2027 Vcanbio, Boyalife, Beikebiotech, Thermo Fisher Scientific (Massachusetts, US),... - July 11th, 2022
- Seven UMass Amherst Faculty Members Receive NSF CAREER Awards in 2021-22 Academic Year - UMass News and Media Relations - July 11th, 2022
- BrainStorm Strengthens Executive Team with Key Appointments in R&D and Legal - GuruFocus.com - June 22nd, 2022
- Asymmetrex Presents New Developments in its Rapid Stem Cell Counting Technology at the ARMI|BioFabUSA Meeting in the Millyard on Regenerative Medicine... - June 13th, 2022
- Investigators Seek to Push Combination Therapy to the Front-line Treatment of aGVHD - OncLive - June 4th, 2022
- Stem Cells Market 2022 Industry Analysis, Segmentation, Share, Size, Opportunities and Forecast to 2027 The Greater Binghamton Business Journal - The... - June 4th, 2022
- Sheldon Krimsky, Who Warned of Profit Motive in Science, Dies at 80 - The New York Times - May 15th, 2022
- We met during cancer treatments, fell in love and got married - New York Post - May 15th, 2022
- Ticking time bombs of DNA mutation may dictate when animals die - Livescience.com - May 2nd, 2022
- Sen. Orrin Hatch's legacy tracks the GOP's evolution on health - Wisconsin Public Radio - May 2nd, 2022
- Emerging interactions between skin stem cells and their ... - April 6th, 2022
- Priothera Receives R&D Innovation Loan from Bpifrance - PR Newswire - April 6th, 2022
- What is Regeneration? review: A dive into the science of regrowth - New Scientist - April 6th, 2022
- 5 FDA decisions to watch in the second quarter - BioPharma Dive - April 6th, 2022
- Takeda and the New York Academy of Sciences Announce 2022 Innovators in Science Award Winners - The New York Academy of Sciences - April 6th, 2022
- MorphoSys and Incyte Announce Swissmedic Temporary Approval of Minjuvi(R) (tafasitamab) in Combination with Lenalidomide for the Treatment of Adults... - March 25th, 2022
- January 2022: 2021 Papers of the year - Environmental Factor Newsletter - January 5th, 2022
- Liso-Cel Outperforms Standard Therapy in Improving QoL in Relapsed/Refractory LBCL - www.oncnursingnews.com/ - January 5th, 2022
- Stem cells: Sources, types, and uses - Medical News Today - December 24th, 2021
- cGVHD Paradigm Gains Systemic Options Beyond Steroids, But Real-World Data Are Required - OncLive - October 28th, 2021
- Asymmetrex Will Present a New Test for Therapeutic Stem Cell Potency at the ISSCR 2021 Annual Meeting - PRNewswire - June 23rd, 2021
- Infertility: Men account for at least half of cases. So why have women shouldered the blame? - The Irish Times - June 23rd, 2021
- On systemic sources of early life stress, and empathetic responses - MIT News - June 6th, 2021
- Orchard Therapeutics Outlines Comprehensive Presence at 2021 WORLDSymposium - GlobeNewswire - February 1st, 2021
- NurOwn May Be Given to Early ALS Patients in US Who Finished Phase... - ALS News Today - December 20th, 2020
- Be Biopharma debuts with $52M to advance engineered B-cell therapies - FierceBiotech - October 24th, 2020
- Targeted Therapy for Non-Hodgkin Lymphoma: Current Progress and Future Plans - Cancer Therapy Advisor - September 5th, 2020
- Massachusetts Eye and Ear Enters Licensing Agreement with Biogen to Develop Treatment for Inherited Retinal Disorder - Newswise - July 2nd, 2020
- Startup targets glioblastoma tumors with CAR-T therapy - FierceBiotech - May 28th, 2020
- Infrared Laser Treatment of TBI, PTSD, and Depression: An Expert Perspective - Psychiatry Advisor - April 3rd, 2020
- 10 Of The Biggest World Revelations In The 21st Century - World Atlas - February 29th, 2020
- Where Are They Now? Top 3 Biotech Startups From NextGen Bio Class of 2018 - BioSpace - January 10th, 2020
- Firm adds a new wrinkle to anti-aging products - Williamson Daily News - January 5th, 2020
- Top Emerging Technologies of the Year - Technowize - December 29th, 2019
- New Podcast Sponsored by Asymmetrex Increases Awareness to the Need for Stem Cell Dose in Stem Cell Treatments - PR Web - November 9th, 2019
- Exercise found to block chronic inflammation in mice - Harvard Gazette - November 9th, 2019
- Arkuda bags $44M to target progranulin and head off inherited dementia - FierceBiotech - November 9th, 2019
- New study reveals why breast cancer spreads to the brain - USC News - October 23rd, 2019
- Comparison of Merus N.V. (MRUS) and Sage Therapeutics Inc. (NASDAQ:SAGE) - MS Wkly - October 23rd, 2019
- Reviewing Cellectis S.A. (CLLS)'s and Magenta Therapeutics Inc. (NASDAQ:MGTA)'s results - MS Wkly - October 23rd, 2019
- Massachusetts Stem Cells | Stem Cell TV - September 10th, 2019
- Chronic variable stress activates hematopoietic stem cells ... - April 12th, 2019
- Boston, MA, Stem Cell Transplant, Weston, Nantucket ... - January 10th, 2019
- Cloning/Embryonic Stem Cells - National Human Genome ... - July 5th, 2018
- Alternate Methods for Preparing Pluripotent Stem Cells ... - September 25th, 2017
- Doubts raised about CRISPR gene-editing study in human embryos - Nature.com - September 2nd, 2017
- For Lowell native, stem cell match becomes a match as friends - Lowell Sun - September 2nd, 2017
- Lymphoma Patient's Brain Tumor Disappeared After She Received JCAR017, Study Reports - Lymphoma News Today - September 2nd, 2017
- Asymmetrex Introduces New Contract Service For Producing ... - PR Web (press release) - August 29th, 2017
- ORGANOID - Science Magazine - August 27th, 2017
- Current humanized mice not good models for studying stem cell transplants, say researchers - Scope (blog) - August 27th, 2017
- Mouse Model of Human Immune System Inadequate for Stem Cell ... - Technology Networks - August 27th, 2017
- CRISPR fixes disease gene in viable human embryos - Nature.com - August 6th, 2017
- X4 joins hands with Yale on rare disease program - FierceBiotech - August 6th, 2017
- TGF-1: ALS Astrocytes' Secret Sauce? - ALS Research Forum - August 6th, 2017
- From Stem Cells to Human Development - September 2016 ... - December 4th, 2016
- Stem cell controversy - Wikipedia - December 1st, 2016
- What Are Stem Cells? - Massachusetts General Hospital ... - November 22nd, 2016
- New England Cord Blood Bank - Cord Blood and Cord Tissue ... - November 22nd, 2016
- Stem-cell-based therapy promising for treatment of breast ... - September 26th, 2016
- Stem Cell FAQ - Massachusetts General Hospital, Boston, MA - July 27th, 2016
- Stem Cell Facts - University of Massachusetts Medical School - July 27th, 2016
- Scientists engineer toxin-secreting stem cells to treat ... - October 19th, 2015
- Cloning/Embryonic Stem Cells - Genome.gov - October 19th, 2015
- Biomedical engineer developing nanomaterial for healing broken bones - March 18th, 2015
- Researchers identify a vital protein that can determine head and brain development - March 13th, 2015