COVID-19 Faculty Research Projects

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Single Molecule FISH-based Method to Detect SARS-CoV-2 Viral RNA from Patients at Unprecedented Scale and Speed

Long Cai
Professor of Biology and Biological Engineering

Professor Long Cai and his team are developing an innovative fluorescence in situ hybridization (FISH)-based method to directly detect viral RNA without purification and biochemical amplification to significantly improve the scale and speed of detecting COVID-19 infections. They have already published a proof-of-principle method to detect 10,000 mRNA molecules in a multiplexed fashion. For multiplexing patient samples rather than different RNA, the team will use patient-specific barcodes to the probes hybridized to RNA from saliva/nasal swabs/other collection methods. Then all patient samples can be pooled and run in a single automated microscopy experiment. They expect to barcode and detect 10,000 to 100,000 patient samples in a single run that can be completed in less than 24 hours if this project is successful. Professor Cai further anticipates this approach can be used to detect host antibodies in the same highly multiplexed fashion from the same patient samples. In addition, other co-infection pathogens can be detected simultaneously at high sensitivity

Philanthropic goal: $300,000
Suggested minimum gift: $1,000

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For more information, please contact: Noëlle Gervais, Senior Director of Development

 


 

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Boosting the Innate Immune System to Fight SARS-CoV-2

Judith L. Campbell
Professor of Chemistry and Biology

Professor Judith Campbell is exploring how existing cancer therapeutics, which are known to have a stimulatory effect on type 1 immunity, could be repurposed to enhance the immune response to SARS-CoV-2 infection. SARS-CoV-2 evades the innate immune system by suppressing type I immunity. Recent work in the cancer field has shown that inhibition of DNA repair has a profound stimulatory effect on type I immunity. The Campbell lab proposes to explore whether artificially stimulating type I immunity by inhibiting DNA repair pathways using known DNA2 and PARP inhibitors (PARPi) could be used to induce interferons, to limit the efficiency of SARS-CoV-2 infection. PARPi is already a clinically approved drug. Therefore, this approach can be considered as a drug repurposing proposal to fight SARS-CoV-2 with a unique mode of action (preventing progression). Since PARPis are approved compounds, all the earlier compounds made during their development are incorporated into the larger libraries by relevant companies. Such compounds are being screened for preventing infectivity by the Bill and Melinda Gates Foundation, but because of the novel mode of action proposed here, the Gates Foundation screen would not be expected to identify compounds with the activity sought here.

Philanthropic goal: $225,000
Suggested minimum gift: $1,000

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For more information, please contact: Janny Manasse, Senior Director of Development

 


 

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Social Distancing 2.0: Tools for Infection Risk Assessment Based on Combining Location Data with Wearable Sensor Data

Chiara Daraio
Professor of Mechanical Engineering and Applied Physics

Azita Emami
Andrew and Peggy Cherng Professor of Electrical Engineering and Medical Engineering; Investigator, Heritage Medical Research Institute; Executive Officer for Electrical Engineering

Tapio Schneider
Theodore Y. Wu Professor of Environmental Science and Engineering; Jet Propulsion Laboratory Senior Research Scientist

Caltech researchers have imagined a way to achieve targeted social distancing with voluntary participation from only a small fraction of the population that improves automatically with wider participation and added information. They propose a scalable platform that provides users with individualized and predictive measures of infection risk, based on location data from cell phones and monitoring of core body temperature with inexpensive, wearable devices. Social distancing measures, where applied consistently, are successfully inhibiting the spread of COVID-19. However, the blanket restrictions come at an immense economic cost. This platform is aimed at developing optimal social distancing in the least restrictive way possible. It builds on the multidisciplinary expertise of Chiara Dario, who develops new materials for highly accurate temperature sensing; Azita Emami, who designs compact integrated circuits for wearable and implantable medical devices; and Tapio Schneider, who develops risk assessment algorithms and software. The core idea is to use results from network theory to calculate the likelihood of a virus to reach a node (individual) on a graph whose edges (links) are established by users that are in close contact for a brief period. Available location data from cell phones and other mobile devices can be used to establish links between individuals, and statistical algorithms can be used to calculate the likelihood of infection at each node. A first estimate can be calculated from location data alone, paired with knowledge of geographic variations of infection risk. The added information, which augments the platform’s capability, can come from self-reporting of symptoms and from inexpensive, wearable sensors that measure and automatically report core body temperatures. Within 6 months, the researchers propose to prototype this platform, which combines search and automated learning algorithms with accurate wearable temperature sensors. The sensors are millimeter-thin, Band-Aid-like patches that will wirelessly connect to cellphones. The platform will provide individual users with risk assessment tools regarding self-isolation or visiting certain locations. It would learn automatically as the user base grows over time and more data about infections is provided, leading to steadily improving risk assessments.

Philanthropic goal: $300,000
Suggested minimum gift: $1,000

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For more information, please contact: Laura Grinnell, Senior Director of Development

 


 

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Engineering Synthetic RNAs as Interfering Anti-viral Therapeutics

Michael B. Elowitz
Professor of Biology and Bioengineering; Investigator, Howard Hughes Medical Institute; Executive Officer for Biological Engineering

Bruce A. Hay
Professor of Biology

Professors Michael Elowitz and Bruce Hay are engineering a synthetic therapeutic for SARS-CoV-2 based on defective interfering particles (DIPs), which are naturally occurring parasitic mutant virus variants that interfere with the lifecycle of co-infecting wild-type viruses. Previous work on DIP-based therapeutics has focused on ‘top-down’ identification of naturally occurring DIPs. Recent advances in synthetic biology now enable a complementary bottom-up approach, in which one designs synthetic RNA molecules that can function in a manner analogous to natural DIPs, but provide the advantages of rational design and rapid design-build-test cycles. Professors Elowitz and Hay aim to design and optimize such synthetic DIPs, by focusing on two of the best-characterized molecular features of the coronavirus: sequences that interact with viral packaging components and the RNA dependent RNA polymerase, RdRp. They plan to construct synthetic RNA molecules that interact with these systems but which, like natural DIPs, are incapable of replicating and propagating on their own. These RNAs will interfere with the operation of a wild-type virus in the same cell. The team’s strategy will be to independently optimize replication and packaging modules, combine them into a single synthetic DIP, and characterize its ability to inhibit pre-established or subsequent infections by wild-type virus. These efforts should establish proof of principle for the use of synthetically designed interfering particles as specific inhibitors of viral replication and packaging processes.

Philanthropic goal: $150,000
Suggested minimum gift: $1,000

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For more information, please contact: Noëlle Gervais, Senior Director of Development

 


 

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Flattening the Curve with Tech: Wearable Vital Sign Monitoring

Azita Emami
Andrew and Peggy Cherng Professor of Electrical Engineering and Medical Engineering; Investigator, Heritage Medical Research Institute; Executive Officer for Electrical Engineering

Chiara Daraio
Professor of Mechanical Engineering and Applied Physics

George Alba
Pulmonary & Critical Care, Massachusetts General Hospital; Instructor in Medicine, Harvard Medical School

Professors Azita Emami and Chiara Daraio and their colleague Dr. George Alba (Mass. General Hospital) aim to change how we monitor patients with COVID-19- like symptoms by designing a small wearable device that is administered at the point-of-care (clinics and hospitals), and then allows the patient to be monitored at home. Physicians believe that we are likely observing and admitting too many patients to hospitals because the natural history of COVID-19 is still evolving, which unnecessarily strains the healthcare system. Profs. Emami, Daraio and Dr. Alba have estimated that a 4% decrease in admissions will result in a more than $2 billion cost savings, in addition to freeing up resources for those in need and reducing unnecessary disease exposures. The team aims to build a device that will continuously measure the most important vital signs related to COVID-19: oxygen saturation level, cardiac abnormalities, heart rate, respiration rate, and core body temperature. It will be small and comfortable to wear for at least 7 days with a waterproof adhesive. In addition to the built-in algorithms that process data to alert for abnormal ranges, it will allow patients to indicate distress for immediate attention. GPS can be also added to help locate patients. The goal is to design the sensors and algorithms to achieve very high accuracy to avoid picking up artifacts, generating false positives, or generating false negatives. Prof. Emami’s group is currently working on miniaturized wireless devices to measure blood oxygen level and to detect heart abnormalities using machine learning algorithms. Prof. Daraio’s group has developed highly accurate core body temperature sensors that can be easily deployed on the skin with a small Band-Aid. The temperature sensor will interface with a mm-sized integrated circuit, which will be developed by Prof. Emami’s group to further reduce the size and power requirements. Throughout the project, the Caltech team will work closely with Dr. Alba to evaluate the device, interpret the data, and develop reliable algorithms.

Philanthropic goal: $150,000
Suggested minimum gift: $1,000

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For more information, please contact: Laura Grinnell, Senior Director of Development

 


 

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Uncovering the Mechanisms of SARS-CoV-2 Biosynthesis and Immune Evasion

Mitchell Guttman
Professor of Biology; Investigator, Heritage Medical Research Institute

Professor Mitch Guttman and his team are experts in RNA biology and have developed numerous cutting-edge genomic and proteomic approaches for studying RNA interactions using Mass Spectrometry and high-throughput sequencing. Using these methods, Professor Guttman aims to uncover the host proteins and messenger RNAs (mRNAs) that interact with the SARS-CoV-2 RNA. The team will use this information to understand how the virus hijacks the host cell machinery to produce its critical proteins and evade host cell immune responses to replicate and propagate. One viral mechanism used to enable translation by the host cell is to hijack the 5’-cap structure of host mRNAs to trick the host cell machinery into recognizing and translating viral proteins. This “cap-snatching” mechanism has also been proposed as a mechanism for driving the selective downregulation of host mRNAs encoding critical immune proteins. Yet, the interactions between the SARS-CoV-2 viral RNAs and host mRNAs have not been explored and it is therefore unclear if this is a mechanism utilized by SARS-CoV-2. The team anticipates that knowledge gained in this project will advance scientists’ ability to define new anti-viral therapeutic strategies that could be effective in targeting this virus.

Philanthropic goal: $150,000
Suggested minimum gift: $1,000

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For more information, please contact: Noëlle Gervais, Senior Director of Development

 


 

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Characterizing the Role of ORF6 in COVID-19

André Hoelz
Faculty Scholar, Howard Hughes Medical Institute; Investigator, Heritage Medical Research Institute; Professor of Chemistry

Professor Andre Hoelz, a leading expert in establishing the structure-function of the Nuclear Pore Complex (NPC), is investing how the SARS-CoV-2 peptide ORF6 interacts with the NPC to hijack host cells and facilitate its own survival. Previous work on the closely related SARS-CoV-1 virus that caused SARS showed that one of its components, a peptide called ORF6, contributes to the attenuation of the host cell’s immune response by targeting the nuclear transport factor karyopherin-a2. ORF6 is also present in SARS-CoV-2 and preliminary data from the UCSF COVID- 19 initiative show that it binds to components of the NPC called Rae1 and Nup98. Both findings suggest that ORF6 interferes with normal intracellular transport between the cytoplasm and nucleus, thereby contributing to SARS-CoV-2’s hijacking of host cells, and thus representing a promising therapeutic target. As a first step toward developing novel COVID-19 therapies, the Hoelz lab is elucidating the molecular details of the interactions between SARS-CoV ORF6 and its cellular binding partners Rae1, Nup98 and karyopherin-a2 through biochemical and structural studies.

Preliminary data obtained by the Hoelz lab in the past two weeks supports the hypothesis that SARS-CoV-2 ORF6 forms an octameric plug in the central transport channel of the octameric NPC. Because each NPC contains 48 copies of Rae1•Nup98, multiple SARS-CoV2 ORF6 octamers could form a stack in the central transport channel. Such ORF6 octamer stacks could not only block mRNA export by competing with mRNA binding to Rae1 but also physically block the central transport channel by holding on to numerous Rae1 molecules with their ‘sticky’ C-terminal regions. Moreover, karyopherin-alpha isoforms are known to bind to phenylalanine-glycine (FG) repeats in the central transport channel and their trapping by ORF6 could further exacerbate NPC blockage. The SARS-CoV2 ORF6 homo-octamer thus represent another high-priority target for structure determination, in addition to the complex structures between SARS-CoV- 2 ORF6 and Rae1•Nup98 and various karyopherins.

Philanthropic goal: $350,000
Suggested minimum gift: $1,000

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For more information, please contact: Janny Manasse, Senior Director of Development

 


 

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New Method for High-Quality RNA Extraction to Enable Global Distributed COVID-19 Diagnostics

Rustem F. Ismagilov
Ethel Wilson Bowles and Robert Bowles Professor of Chemistry and Chemical Engineering; Director of the Jacobs Institute for Molecular Engineering for Medicine

Professor Rustem Ismagilov is exploring how to overcome a major impediment to rapid, inexpensive, point-of-care testing – efficient RNA extraction that does not require a centrifuge – by exploiting RNA purification strategies recently developed by his lab. Up to half of all people infected with COVID-19 are asymptomatic, rendering screening and containment strategies based solely on clinical presentation impossible. There is therefore an urgent need for a universally accessible, rapid diagnostic with accurate, reliable results that can be deployed at an unprecedented global scale. This diagnostic must be inexpensive, sensitive, robust to user error, scalable, and capable of operating with high accuracy in limited resource settings (LRS). Antibody-based tests cannot meet this demand because they fail to detect early infections when viral shedding is greatest. Only RNA-based assays can fill this need, yet the diagnostics field has struggled for decades to make these complex tests compatible with point-of-contact settings. The RNA extraction step is the key bottleneck. This step must be greatly simplified and parallelized while maintaining (or exceeding) the performance achieved by trained personnel in high-complexity clinical laboratories. The Ismagilov lab aims to solve this challenge using its recently developed in-house technologies that improve RNA extraction quality while reducing equipment requirements. They plan to demonstrate that they can greatly improve the purity, yield, and concentration of extracted SARS-CoV-2 RNA without the need for centrifugation – the aspect of the process that most limits its wide scale deployment. The team already has preliminary data showing the feasibility of its approach for efficiently extracting SARS-CoV-2 RNA. Their goal is to provide a scalable, inexpensive, high- performance SARS-CoV-2 RNA sample-preparation technology that can be used for SARS-CoV-2 testing outside clinical labs at a global scale.

Philanthropic goal: $250,000
Suggested minimum gift: $1,000

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For more information, please contact: Janny Manasse, Senior Director of Development

 


 

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Developing a Breathalyzer Device that can Detect the State of COVID-19 Disease Early Through Infrared Spectroscopy

Axel Scherer
Bernard Neches Professor of Electrical Engineering, Applied Physics and Physics

The Scherer group is working on is a breath analyzer that uses high-resolution infrared (IR) spectroscopy to uniquely identify specific molecules, whose relative levels are associated with infection. Target molecules to detect for COVID-19-related illnesses include ketones, aldehydes, esters, short-chain fatty acids, acetic acid, and other organic acids. The device will analyze the relative concentrations of the target molecules. Signatures from healthy subjects can be compared with those from patients with lower respiratory infections for early detection of disease. The Scherer group has built an inexpensive mid-IR spectrometer by leveraging the low cost of modern thermal imaging cameras. They also use a novel sample collection system that collects gases onto an IR- transparent silicon sample collector/holder with a built-in heater that enables the rapid deconvolution of complex samples to analyze constituents. The next step is to build 50 prototypes and enough sample holders to bring this instrument into clinical use and start the FDA clearance process under the emergency use authorization format. Prof. Scherer has already identified clinical partners for testing this breathalyzer system.

Philanthropic goal: $250,000
Suggested minimum gift: $1,000

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For more information, please contact: Robin Gibbin, Senior Director of Development

 


 

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High-density Cell/Virus Culturing Technology for Vaccine Production

Yu-Chong Tai
Anna L. Rosen Professor of Electrical Engineering and Medical Engineering; Andrew and Peggy Cherng Medical Engineering Leadership Chair; Executive Officer for Medical Engineering

Professor Yu-Chong Tai and his group are developing a high-density cell/virus culturing technology to rapidly meet global demand for vaccines and overcomes existing bottlenecks. Conventionally, virus specimens (i.e., inactivated virus, attenuated virus, or a virus segment) for vaccination are produced using fertilized chicken eggs; one or two eggs are required per vaccine, and roughly two months are needed for each batch of eggs. Approximately 3.6 billion vaccine doses are needed to vaccinate 60% of the world’s population to reach “community immunity.” This helps explain why candidate vaccines may be in clinical trials within a few months, but will take more than a year to be widely available. Prof. Tai and his group are designing a better system to produce vaccine rapidly and at needed scale. Instead of eggs, cells are grown and then infected with viruses, and then the cells reproduce with the viral infection intact. This novel method of reproducing the virus is, in theory, much more efficient than using eggs, as long as large enough numbers of cells may be grown and reproduced. This is exactly what Prof. Tai’s new technology can achieve. In 2018, the Tai lab demonstrated a new MEMS bioreactor device that could grow cells with 100- times higher cell density than state-of-the-art cell bioreactors. In 2019, the technology was transferred to the City of Hope (with collaborator, Dr. Yuman Fong) and a 1000-times higher cell density (~108 cells/cm3) was demonstrated there using only half the normal cell-culturing time. In early 2020, AAVs (adeno-associated viruses) were produced with equally high efficiency (compared to other bioreactors) using this technology. These numbers indicate the possibility of producing an enormous number of vaccines in as short as 6 months (rather than 12-18 months) and at 10% of the typical cost. To reach this goal, the engineering work required includes production of the MEMs devices and access to a qualified culturing facility with appropriate biosafety level controls. If granted resources, the Tai lab plans to demonstrate small-scale production of coronavirus for vaccine purposes using its technology.

Philanthropic goal: $100,000
Suggested minimum gift: $1,000

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For more information, please contact: Robin Gibbin, Senior Director of Development

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Developing a screening platform to identify therapeutics targeting SARS- CoV-2’s main protease Mpro

Jost G. Vielmetter
Director of Caltech Protein Expression Center

Dr. Vielmetter aims to develop a new screening platform that leverages the expertise of Caltech’s protein expression facility to identify small molecule therapeutics targeting Mpro, the main protease of SARS-CoV-2, and a key component of the viral life cycle.

A current approach to accelerate drug development for COVID-19 is to screen existing drugs for their potential to be repurposed as SARS-CoV-2-specific antiviral agents. One attractive drug target is the SARS-CoV-2 Mpro (or 3CLpro) protease, which is required for generating mature viral proteins in the cell, and which has no human protease analog, making it less likely that inhibitors will show toxic side effects. Existing inhibitors of these types of viral proteases from human enteroviruses and feline peritonitis viruses show no significant toxicity in humans or cats, further reinforcing the potential value of this approach. To identify inhibitors against Mpro, Dr. Vielmetter aims to create a screening platform that takes advantage of Caltech’s assay automation core including its automated liquid handling robots, high throughput SPR-32 (Surface Plasmon Resonance) instrument, and its expertise expressing proteins that are essential assay reagents for the proposed platform. The core idea is to screen libraries of compounds against a construct that contains a well-characterized Mpro substrate, the octapeptide AVLQSGFR. A negative control reference protein will also be produced using the same protocols. An SPR-32 readout (i.e., decreases in signals) will enable the researchers to identify inhibitors. This assay platform will allow the group to screen approximately 3840 compounds in about 15-20 hours. In this manner, the group could provide a chemical compound screening hub that can serve to test chemical compound libraries including those already at Caltech, or brought to the group by Caltech researchers or external chemistry labs working on COVID-19 initiatives. Dr. Vielmetter has decades of experience building automated screening platforms and his expertise together with the recent acquisition of a high throughput SPR instrument (the first of its kind in the U.S.) position his lab uniquely to carry out the proposed viral protease inhibitor screening project. This screening approach is unique and different from typical protease screens and it has a high likelihood of success as protease SPR assays have been demonstrated to work well in the past.

Philanthropic goal: $100,000
Suggested minimum gift: $1,000

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For more information, please contact: Noëlle Gervais, Senior Director of Development