Marcelo Finger, a computer scientist at the Institute of Mathematics and Statistics of the University of São Paulo (IME-USP), believed his expertise in computational linguistics could be useful in identifying patients with respiratory failure, one of the main symptoms of severe COVID-19 disease. “The methods we use to process text can also be used to process voice data. Instead of converting words, we would convert sounds into numbers. I wondered whether voice analysis could be used to identify people with shortness of breath,” he explains. Ester Sabino, of the Institute of Tropical Medicine at the School of Medicine at USP, was enthusiastic when she learned about the idea from one of his students, and started collaborating with Finger. “She saw potential for using this approach to triage patients.” In a project recently approved by FAPESP, the researcher will collect hundreds of voice samples from people with COVID-19 and from healthy individuals to identify vocal differences between the two groups caused by differing oxygen saturation and respiratory rates. This will be used to create an automated classification tool powered by artificial intelligence, signal processing, and machine learning. Medical students are currently working to capture sound recordings from patients, while healthy patients are providing recordings over the internet. A software system will also be developed for triage in a healthcare setting. “Our idea is to create a phone-based service. Patients call in, record their voice, and the tool analyzes the recording for signs of respiratory failure. A health professional then decides whether admission is needed.” Finger estimates the first version of the system will be available within one year.
The initiative is one of the 210 COVID-19 research projects receiving grant funding from FAPESP (see the Data section). Of these, 144 were existing projects that were repurposed to include the disease as a research target. Early in the pandemic, the Foundation invited researchers with projects already approved via the Thematic Project, Young Investigator Award, and Research, Innovation, and Dissemination Centers (RIDC) grant schemes to join the effort against the pandemic, with many of them submitting project proposals. The other 66 were selected in calls for proposals specially organized in response to the pandemic. These received regular research grants as well as grants within the Research for Innovation in Small Businesses (RISB, or PIPE in the Portuguese acronym) program, in partnership with the Brazilian Funding Authority for Studies and Projects (FINEP). Funding awarded to companies is primarily intended for the development of equipment, such as low-cost ventilators and electrical impedance tomographs used to monitor patients on ventilators.
Life sciences are the most prevalent field of research. Reinaldo Salomão, an infectious disease specialist at the São Paulo School of Medicine at the Federal University of São Paulo (EPM-UNIFESP), is leading a project that will monitor 100 COVID-19 patients treated at Hospital São Paulo. The principal goal of the project will be to identify biomarkers that can predict the progression of the disease. Salomão notes that COVID-19 has a particularly long progression. “While many patients are discharged immediately, others will need to initiate oxygen therapy a week after hospitalization. Yet others will require admission to an ICU (Intensive Care Unit) after several days have elapsed. Often, the length of disease progression appears to be different for patients who survive and for those who don’t. The study will attempt to determine whether there are any patterns in patient responses that correlate with different outcomes,” he says. The researchers will collect peripheral blood samples from patients on admission, on discharge, and 30 days after discharge, to understand the evolution of the disease. The population of lymphocytes is one of his main parameters of interest. “Low white blood cell counts are one of the signs of poor patient progression,” explains Salomão. Inflammatory mediators produced by the immune system, which cause exacerbated reactions similar to those seen in sepsis, are another telltale sign of disease severity. The initiative is a spinoff from a Thematic Project led by Salomão that is studying the onset of sepsis and strategies against this highly lethal disease. “We were able to quickly put together a proposal because we were already doing research on the body’s response to infection in sepsis,” he says.
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Three separate COVID-19 projects have been proposed by researchers linked to a Thematic Project led by Paulo Roberto Bueno, of the Araraquara Institute of Chemistry at São Paulo State University (UNESP), which is developing biosensors to detect diseases. One of these projects, led by Bueno himself, will attempt to develop an electrochemical platform for detecting SARS-CoV-2 without the need for reagents. This technology has previously been used successfully to diagnose other infectious diseases and even some types of cancer, in a collaboration with the University of Oxford. Antibodies, proteins or other biomarkers are detected in a blood sample using microscopic electrodes—a change in the electric signal through the electrode surface indicates the presence of the target antigen. “We have already developed a proof of concept for dengue. We will now change the receptor molecule on the surface of the sensor to detect infection by SARS-CoV-2,” says Bueno. The first results from the project are expected within 8 to 12 months. The second project, which is investigating the use of peptides to inactivate the novel coronavirus, is being led by Eduardo Maffud Cilli, the current director of the Institute of Chemistry, in a collaboration with researchers at UNESP in São José do Rio Preto. The project is building on previous research which found that certain peptides are effective in neutralizing the hepatitis C and Zika viruses by preventing their replication in cells. “We have already started in vitro testing for SARS-CoV-2 with peptides that have previously shown virucidal action,” says Cilli. The third project, led by chemical engineer Ronaldo Censi Faria of the Federal University of São Carlos (UFSCar), will attempt to develop a simple and low-cost disposable device for detecting RNA sequences from SARS-CoV-2.
Geneticist Maria Rita Passos-Bueno, of the Biosciences Institute at USP (IB-USP), was in Italy in February when the epidemic broke out in the country’s northern provinces. “I wanted to take a test as soon as I arrived, but found out there were none available,” she recalls. This sparked her interest in developing a lower-cost test using an alternative technology to the gold-standard essay, RT-qPCR. “In Brazil, dependence on imported supplies has been one of the biggest constraints on testing for COVID-19,” says Passos-Bueno. The way around this has been to use a method, called RT-LAMP, that does not require sophisticated equipment and can be performed on saliva swabs in locations with limited infrastructure. The enzymes needed for the test have been obtained through a collaboration with Shaker Farah, of the USP Institute of Chemistry. The researchers hope the test will be validated within the following weeks. For Farah, the technology could find applications in diagnosing other infectious diseases, including veterinary and plant diseases. The project, led by geneticist Mayana Zatz, is being developed at the Human Genome and Stem Cell Research Center, a FAPESP-funded RIDC.
Several other projects are developing drugs against the disease. Nícolas Hoch, a pharmaceutical engineer at the USP Institute of Chemistry, has received funding from FAPESP since 2019 within the Young Investigator Award grant scheme, to develop a project that is investigating the proteins involved in signaling damage to DNA. A protein modification he studies, called ADP-ribosylation, has a role in the immune response. “When cells are infected by SARS-CoV-2, several proteins of both the human host and the virus are modified with ADP-ribose and this helps to prevent viral replication. However, the virus encodes an enzyme that blocks this signaling—a function essential for virus spread. This led to the idea of finding an inhibitor for this enzyme,” he says. He submitted a project proposal to identify compounds, preferably already approved for other uses, that can be used against COVID-19. Using computational methods, he identified 79 potential candidates, out of a list of 6,000 molecules, to be tested in biochemical and cellular assays. This will narrow the list to five compounds that can be tested on cells infected with the virus. Hoch is collaborating with colleagues at the USP Institute of Chemistry, including Deborah Shechtman, Flávia Meotti, and Alexandre Bruni Cardoso, and has established other collaborations with research groups in the US and Europe to develop the project.
Parasitologist Fabio Trindade Maranhão Costa, from the Biology Institute at the University of Campinas (IB-UNICAMP), is prospecting for promising drug candidates against COVID-19, drawing on the expertise he developed during a Thematic Project he led to identify molecular targets for therapies against malaria. His group is virtually screening more than 1 million drugs and chemical compounds for their potential to inhibit protein interactions that enable the virus to enter the host cell. Costa is conducting bench tests with these drugs and supplying the resulting data to his colleague, Carolina Horta Andrade, at the School of Pharmacy at the Federal University of Goiás (UFG), who then uses artificial intelligence to find useful molecules against COVID-19. “It’s a dynamic process. The phenotype results help to train the drug activity prediction algorithm that Andrade is developing,” he explains. Although the current focus is on approved compounds, Costa is also looking to explore untested molecules which could lead to new drugs in the long term. “I don’t believe we’ll find a silver bullet against COVID-19 in the immediate future. It is more likely that a combination of drugs will be found to produce some effect in stopping viral progression in patients at different stages of the disease.” The project is also collaborating with virologists José Modena, of IB-UNICAMP, and Rafael Elias of the National Biosciences Laboratory (LNBio).
144 FAPESP-funded projects have incorporated COVID-19 as a research interest
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