Wearing blue surgical gowns and white respirator hoods, research scientist Pradeep Uchil and post-doctoral fellow Irfan Ullah carry an anesthetized mouse to the lab’s imaging unit. Two days ago, the mouse was infected with a SARS-CoV-2 virus engineered to produce a bioluminescent protein. After an injection of a bioluminescence substrate, a blue glow starts to emanate from within the mouse’s nasal cavity and chest, visible to the imaging unit’s camera and Uchil’s eyes.
“We were never able to see this kind of signal with retrovirus infections.” Uchil is a research scientist at the Yale School of Medicine whose work focuses on the in vivo imaging of retroviral infections. Normally, the mouse would have to be sacrificed and “opened up” for viral bioluminescent signals from internal tissues to be imaged directly.
Most of us, after we flush the toilet, don’t think twice about our body waste. To us, it’s garbage. To epidemiologists, however, wastewater can provide valuable information about public health and help save lives.
History of Wastewater-Based Epidemiology
Wastewater-based epidemiology (WBE) is the analysis of wastewater to monitor public health. The term first emerged in 2001, when a study proposed the idea of analyzing wastewater in sewage-treatment facilities to determine the collective usage of illegal drugs within a community. At the time, this idea to bridge environmental and social sciences seemed radical, but there were clear advantages. Monitoring wastewater is a nonintrusive and relatively inexpensive way to obtain real-time data that accurately reflects community-wide drug usage while ensuring the anonymity of individuals.
The Delta Variant poses a unique challenge to global health. We’ve compiled answers to some of the most common questions about Delta and other SARS-CoV-2 variants.
What is a variant?
A variant is a form of a virus that is genetically distinct from the original form.
“All organisms have mutation rates,” says Luis A Haddock, a graduate student at University of Wisconsin – Madison. “Unfortunately for us, viruses have one of the highest mutation rates of everything that currently exists. And even more unfortunately, RNA viruses have the highest mutation rates even among viruses.”
Luis works in the Friedrich Lab at UW-Madison, which has been sequencing SARS-CoV-2 genomes from positive test samples since the beginning of the pandemic. SARS-CoV-2 is constantly evolving, and sequencing can help us follow it through time and space. Most of the variants don’t behave any differently. A single nucleotide substitution might not even change the amino acid sequence of an encoded protein. However, occasionally a mutation will alter the structure or function of a protein.
Inflammation, a process that was meant to defend our body from infection, has been found to contribute to a wide range of diseases, such as chronic inflammation, neurodegenerative disorders—and more recently, COVID-19. The development of new tools and methods to measure inflammation is crucial to help researchers understand these diseases.
Cytokines—small signaling molecules that regulate inflammation and immunity—have recently become the focus of inflammation research due to their role in causing severe COVID-19 symptoms. In these severe cases, the patient’s immune system responds to the infection with uncontrolled cytokine release and immune cell activation, called the “cytokine storm”. Although the cytokine storm can be treated using established drugs, more research is needed to understand what causes this severe immune response and why only some patients develop it.
Every time a genome is replicated, there’s a chance that an error will be introduced. This is true for all life forms. On a small scale, these mutations can lead to genetic diseases or cancers. On a much larger scale, random mutations are an important tool of evolution.
During the COVID-19 pandemic, the SARS-CoV-2 virus has picked up many mutations as it spread around the world. Most of these mutations have been inconsequential – the virus didn’t change in any significant way. Others have given rise to variants such as B.1.1.7 and B.1.351, which present complications for public health efforts. By studying the evolution of the virus, we can monitor how it’s spreading and predict the characteristics of variants as they are detected.
A year after COVID-19 was declared a pandemic, collaborative efforts among pharma/biotech and academic researchers have led to remarkable progress in vaccine development. These efforts include novel mRNA vaccine technology, as well as more conventional approaches using adenoviral vectors. While vaccine deployment understandably has captured the spotlight in the fight against COVID-19, there remains an urgent need to develop therapeutic agents directed against SARS-CoV-2.
In the March 12 issue of Science, an editorial by Dr. Francis Collins, director of the U.S. National Institutes of Health (NIH), examines lessons learned over the past 12 months (1). Collins points out that many clinical trials of potential therapeutics were not designed to suit a public health emergency. Some were poorly designed or underpowered, yet they received considerable publicity—as was the case with hydroxychloroquine. Collins advises developing antiviral agents targeted at all major known classes of pathogens, to head off the next potential pandemic before it becomes one. A news feature in the same issue discusses the current state of coronavirus drug development (2).
The present crop of drug candidates is remarkably diverse, including repurposed drugs that were originally developed to treat diseases quite different from COVID-19. Typically, however, the mainstream candidates belong to two broad classes: small-molecule antiviral agents and large-molecule monoclonal antibodies (mAbs).
Small- and medium-sized companies are critical to the Spanish economy. During 2020 the COVID-19 pandemic made business difficult for many of these companies, yet they have demonstrated strength and resourcefulness and have led the pandemic recovery in Spain in many ways. Recently, Promega Biotech Ibérica was recognized with a Madrid Community SME (small- and medium-sized business) Award along with 15 other companies. The awards were presented by Manuel Giménez, Minister of Economy, Employment and Competitiveness of the Madrid Region, Andres Navarro delegate director of La Razón, and Francisco Marhuenda, director of La Razón. As part of the award, Promega Biotech Ibérica General Manager, Gijs Jochems, was interviewed about the award and Promega’s work in the region.
According to Gijs Jochems, General Manager of Promega Biotech Ibérica, while Promega Corporation is an American multinational company, it remains privately held, which offers a great deal of flexibility to the subsidiaries to adapt to local needs. It also allows the company to place increased emphasis on employee well-being (critical during the pandemic), reinvest profits in research and development, and work to mitigate the impact of company activities on the environment. All these business practices reflect a long-term vision of sustainable business growth.
A worldwide pandemic requires scientific research to understand the viral pathogen. The focused efforts of global scientists are even more necessary in the face of a novel coronavirus like SARS-CoV-2, the causative agent of COVID-19. However, because SARS-CoV-2 causes human disease, research efforts are restricted by the need for physical laboratories that are equipped to handle the required level of containment and personnel trained to handle pathogens in these facilities. But what if we could bypass the restrictive facility requirements by engineering a synthetic, replication-defective version of SARS-CoV-2 that more researchers could use to study the pandemic coronavirus, expanding the capacity to test and develop methods to attenuate its devastating effect on humans?
The challenge is to develop a derivative of SARS-CoV-2 that reflects how it behaves in the cell but is compromised such that it is unable to infect cells more than a single time. That is, the virus can get into a cell or be introduced into cells and replicate but is unable to produce infectious virus would offer a pathway to expand research capacity without the use of special laboratory facilities. This replication-defective SARS-CoV-2 could be created to encode as much or as little of the genome needed to examine its lifecycle without becoming a fully infectious virus. In fact, this replication-defective version of SARS-CoV-2 could include additional genetic elements that could be used to control its expression, track the virus in cells and measure the level of its replication. This task has been undertaken by Dr. Bill Sudgen’s group at the University of Wisconsin–Madison McArdle Laboratory for Cancer Research, explained by graduate student Rebecca Hutcheson during her presentation “Making the Virus Causing COVID-19 Safe for Research”.
The past year has been a challenge. Amidst the pandemic, we’re thankful for the tireless work of our dedicated employees. With their support, we have continuously stayed engaged and prepared during all stages of the COVID-19 pandemic so that we can serve our customers at the highest levels.
How We Got Here
The persistent work by our teams has made a great impact on the support we can provide for scientists and our community during the pandemic. From scaling up manufacturing to investing in new automation, every effort has helped.
Promega has a long history of manufacturing reagents, assays, and benchtop instruments for both researching and testing viruses. When the pandemic began in 2020, we responded quickly and efficiently to unprecedented demands. In the past year, we experienced an approximately 10-fold increase in demand for finished catalog and custom products for COVID-19 testing. In response to these demands, we increased production lines. One year ago, we ran one shift five days per week. Currently, we run three shifts seven days per week. This change has allowed 50 different Promega products to support SARS-CoV-2 testing globally in hospitals, clinical diagnostic laboratories, and molecular diagnostic manufacturers. Additionally, our clinical diagnostics materials make up about 2/3 of COVID-19 PCR tests on the global market today. Since January 2020, Promega has supplied enough reagents to enable testing an estimated 700 million samples for SARS-CoV-2 worldwide.
Developments and Advances
Promega products are used in viral and vaccine research. This year, our technologies have been leveraged for virtually every step of pandemic response from understanding SARS-CoV-2 to testing to research studies looking at vaccine response.
We are extremely grateful for our employees. In the past year, we hired over 100 people and still have positions open today. While welcoming newcomers, this challenging year also reinforced the importance of our collaborative culture. Relationships at Promega have been built over multiple years. The long history of our teams allows us to stay coordinated while prioritizing product distribution to customers across the globe. It also leads to effective communication with colleagues and vendors. Those leading our manufacturing operations team, for example, have an average tenure of 15 years. Their history in collaborating through challenging situations helps them quickly focus where needed most.
Our 600 on-site employees support product manufacturing, quality, and R&D. They do it all while remaining COVID-conscious by social distancing, wearing masks, working split shifts, and restricting movement between buildings. While we continue to practice physical safety precautions, we also prioritize our employees’ mental health and wellness. Promega provides a variety of wellness resources including phone and video mental health sessions, virtual fitness and nutrition classes, and stress and anxiety tools.
What’s to Come
While we acknowledge that the COVID-19 is not over, we are proud of the support we have been able to provide to customers working both on pandemic research and critical research not related to COVID-19. Our policies of long-term planning and investing in the future has allowed us to respond quickly and creatively and learn from the experience.
When you look at our top 10 most viewed blog posts of 2020, there’s no surprise that all relate to COVID-19. We have come a long way since the beginning of the year, thanks to tireless scientists and researchers around the globe. They have led the way in COVID-19 research, treatment, and testing. Let’s take a closer look at this top 10 list:
10. Tips to Maintain Physical Distance in the Lab
The spread of COVID-19 forced us to adapt and adjust to new ways in life, in work, and for this blog post, in the lab. In response to the pandemic, some labs shut down completely. Others have stayed open, especially those involving coronavirus research. This post provides 10 helpful distancing tips for researchers to stay safe and productive while working in the lab.
9. Investigation of Remdesivir as a Possible Treatment for SARS-2-CoV (2019 nCoV)
Scientists have worked hard to determine possible treatment for COVID-19. This blog post focuses on Remdesivir (RDV or GS-5734), an encouraging treatment used for the first case in the United States. It provides an in-depth look at numerous studies and clinical trials on Remdesivir as treatment for COVID-19. One key finding is that RDV needed to be administered either before or shortly after infection to limit lung damage.
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