Since the novel coronavirus was identified in China in December 2019, its rapid spread has turned into a global pandemic. The highly contagious COVID-19 has ripped through communities and challenged medical resources, particularly in epicenters like New York City, where, as of April 1, the reported cases of those infected with COVID-19 have soared to surpass 45,000 in the five boroughs alone.

The surge in positive cases have summoned clinical communities to the front lines of the pandemic. And while governments—state and federal—have ordered residents to shelter-in-place, to social distance or self-quarantine, the scientific community has mobilized and converged its diverse areas of expertise to problem-solve a cure for the virus in real time. 

Dr. Andrea Califano is applying his computational methods to study COVID-19.

Researchers from the Herbert Irving Comprehensive Cancer Center (HICCC) at NewYork-Presbyterian/Columbia are swiftly transforming their discoveries and innovation in cancer to address COVID-19. HICCC members, whose expertise range from computational biology and bioinformatics to molecular biology, genomics, and pathology, are leveraging tools and technologies developed and validated for cancer to study COVID-19.

“Recognizing the enormous impact that COVID-19 already has and will continue to have on our global society, we have rapidly reorganized our cancer center to refocus some of our research efforts on COVID-19,” says Anil K. Rustgi, MD, director of the Herbert Irving Comprehensive Cancer Center. “Our members come from six different schools and more than 35 departments across Columbia University. Their expertise across disciplines provides expanded perspectives in the war against this virus.”

There has been an incredible outpouring of rapid response by academic researchers to aid in a cure or uncover the fundamental biology driving the novel coronavirus.

“This is an unprecedented time in history, when scientists from all fields who are not necessarily experts in virology are forming teams with exceptional complementary talent to address one of the greatest challenges our society has every faced,” says Andrea Califano, Dr, who co-leads the Precision Oncology and System Biology research program at the HICCC and chair of Columbia’s Department of Systems Biology. “The current situation creates a unique and unprecedented commitment to a shared goal without institutional, geographic, or expertise boundaries.”

“Our members come from six different schools and more than 35 departments across Columbia University. Their expertise across disciplines provides expanded perspectives in the war against this virus.”

Anil K. Rustgi, MD  

 

Many scientists at CUIMC are in the research foreground of the pandemic, including cancer researchers at the HICCC. Several projects are just getting off the ground or are still being formulated, but the researchers are working on an aggressive timeline to meet the pressing needs to overcome this global crisis.

“This is an opportunity for us to show our value as scientists to society in a very clear and concrete way,” says Alejandro Chavez, MD, PhD, a member of the HICCC’s Precision Oncology and Systems Biology program and assistant professor of pathology and cell biology at Columbia. “It has been a terrible time for all of us but also it’s been a joyous time seeing how people are coming together, especially the scientific community. The level of mobilization is unprecedented. There is such a dissemination of ideas right now.”

Below is a sample of COVID-19 research currently underway at the HICCC.

CRISPR-based Therapeutics

Coronavirus genomes are comprised of single-stranded RNA, and the novel coronavirus, SARS-CoV-2 that leads to COVID-19, is part of a family of viruses that include SARS and MERS—two devastating infectious diseases that surfaced in the last 20 years. Xuebing Wu, PhD, a member of the HICCC's Precision Oncology and Systems Biology research program, is an expert in RNA research and studies RNA-centric gene regulation in mammalian cells. He is currently working on developing a CRISPR-based approach for killing the SARS-CoV-2 virus, and potentially also the infected surrounding cells.

CRISPR is a natural bacterial immune system that scientists have begun to use as a revolutionary tool to alter genomes. Dr. Wu and his collaborators have already developed a similar CRISPR-based technique to eliminate cancer cells, and intend to apply this method to target COVID-19. The hope is that this research can aid in the speedier development of a therapeutic, not just for this novel strain but for future variants of SARs-CoV-2. Dr. Wu, who holds appointments in the departments of medicine and systems biology, and is working on this project with infectious disease expert Dr. Ian Lipkin and the Center for Infection and Immunity at Columbia.

Data-driven Solutions

Barry Honig, PhD, also a member of the HICCC’s Precision Oncology and Systems Biology research program and a professor of systems biology, and Sagi Shapira, PhD, an assistant professor of systems biology, have developed a computational method, termed P-HIPSTer, that leverages the supercomputing infrastructure at CUIMC to identify key interactions between all human infecting viruses and the cells that they infect (the work was recently published in Cell). The pair are now applying the same method to uncover how SARS-CoV-2 causes disease differently from other coronaviruses. They have already made interesting observations about how the virus manipulates the immune system and have some hints as to why the disease progresses the way it does. They are also using the information to identify FDA-approved drugs that may be repurposed and immediately deployed, and are investigating vaccine design.

Andrea Califano, Dr, who co-leads the HICCC’s Precision Oncology and Systems Biology research program, is a pioneer in the field of system biology and founding chair of Columbia’s Department of Systems Biology. He has developed sophisticated algorithms to identify key master regulator proteins in tumors and enable the prioritization of FDA-approved drugs that could treat and kill cancer in various tumor types. He is now applying these validated methods to study the biology of coronaviruses and their interactions with host cells.

Dr. Califano and his collaborators have analyzed gene expression profile data generated from SARS-CoV infected and mock-infected epithelial cells to identify the proteins responsible for maintaining the transcriptional state of infection response. (SARS-CoV is closely related to the current novel coronavirus SARS-CoV-2 and produces a similar response in patients.) They’ve applied the computational method, OncoTreat, developed by the Califano lab, and have already identified several promising drugs to potentially treat COVID-19, including drugs used to treat rheumatoid arthritis as well as several kinase and transport protein inhibitors. Dr. Califano and his team are hoping to obtain access to novel SARS-CoV-2-infected cells to repeat their analyses and to screen a larger number of drugs beyond those selected for oncology.

Dr. Califano also is collaborating with Dr. Sagi Shapira to generate RNA sequencing-based biomarkers from nasal swab tests that can predict the need for hospitalization and intensive care. The researchers will analyze patient cell samples from swab tests by using rapid-turnaround, next-generation sequencing methods that capture both the infection status and complex immune response profiles. Using Dr. Califano’s computational methods, the researchers hope to identify master regulator-based markers to predict clinical outcomes based on the transcriptional profiles of easily accessible samples. The hope is to be able to rapidly inform doctors how to best triage COVID-19 patients upon diagnosis.

COVID-19 Genomics

Raul Rabadan, PhD, co-leader of the HICCC’s Cancer Genomics and Epigenomics research program and professor of systems biology at Columbia, is an expert in uncovering patterns of evolution in biological systems—in particular, RNA viruses and cancer. He has developed computational methods to study cancer genetics and to elucidate biological understanding of how tumors evolve over time, in such complex cancers as pancreatic ductal adenocarcinoma and glioblastoma. Dr. Rabadan and his collaborators are now applying these validated methods to assess individuals’ predispositions to COVID-19. Why do some patients who test positive for COVID-19 experience severe symptoms and complications—in some cases their illness results in death—whereas other COVID positive patients do not?

Dr. Raul Rabadan is investigating individuals’ predispositions to COVID-19.

Dr. Rabadan and his group are taking a deep dive into the genetics of COVID-19, with the hope of identifying biomarkers of COVID-19 severity and that can lend to immediate management of patients at risk, including cancer patients. They are already leveraging their cancer genomics expertise and algorithms to analyze the UK Biobank data (comprising 500,000 individuals, with genetic and clinical data) and patient data from Columbia University Irving Medical Center and NewYork-Presbyterian Hospital, as well as transcriptomic data from lung aspirates and patient electronic health records. “This effort will help us to better understand the SARS-CoV-2 mechanism of action,” says Dr. Rabadan, “and to define risk groups with greater precision, in particular those with other conditions, such as cancer.”

Real-time Resources for Researchers

Several members at the HICCC have been directly involved in establishing the COVID-19 Biobank (COB), a new resource for researchers to combat the challenges of the COVID-19 pandemic. Announced March 30 and in partnership with NewYork-Presbyterian Hospital, the new biobank at Columbia University Irving Medical Center will be crucial in collecting, processing, storing, and disseminating biological specimens, biomarkers, and clinical and related data for researchers at Columbia and beyond. Columbia’s Department of Pathology and Cell Biology has established a COVID-19 clinical pathological lab and intend to facilitate access to residual clinical samples. The primary focus will be to enroll COVID-19 positive patients but will also aim to enroll all patients who have been tested for the novel coronavirus at CUIMC and NewYork-Presbyterian to cast a wide net of samples.

The launch of this collaborative initiative was led by HICCC members Drs. Muredach Reilly, Wendy Chung, Kevin Roth, and David Goldstein, along with Drs. George Hripcsak, Krzysztof Kiryluk, Soumitra Sengupta, Steve Spitalnik, and Eldad Hod.

Rapid Antiviral Drug Development

The lab of Dr. Alejandro Chavez is working to identify antiviral drugs for novel coronavirus.

Studies in the enzyme protease has led to breakthrough antiviral therapies, most notably to treat HIV and viral hepatitis. For the past two years, Alejandro Chavez, MD, PhD, a member of the HICCC’s Precision Oncology and Systems Biology program and assistant professor of cell biology and pathology, has worked with his lab on innovative methods to rapidly identify protease inhibitors to viruses. Their method enables them to investigate multiple viral proteases at once, including those from over a dozen different coronaviruses, to identify inhibitors to block them. By looking at multiple coronavirus protease at a time their group hopes to identify a novel pan-coronavirus protease inhibitor. While the need is pressing for a treatment that works against COVID-19, Dr. Chavez stresses, “This is the third time we’ve seen a coronavirus strain. We know this will continue to happen, and it’s time once and for all we identify a compound that has broad activity against coronavirus, not just COVID-19.”

Dr. Chavez is working as part of a collaborative effort at Columbia to identify antiviral drugs for novel coronavirus, led by David Ho, MD, founding scientific director of the Aaron Diamond AIDS Research Center and professor of medicine at Columbia. HICCC member Brent Stockwell, PhD, a member of the HICCC’s Precision Oncology and Systems Biology program and professor of biological sciences and chemistry, also is working with Dr. Ho and others on SARS-CoV-2 viral protease inhibitors with the goal to develop a cure.

“We have a chance of doing something significant here—and we are going to try,” adds Dr. Chavez. “A lot of us are actively working on the problem. There are tough days ahead, but we are going to get there. It is just a matter of time.”

-Melanie A. Farmer

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