Q+A: Raul Rabadan, PhD, and Understanding the Novel Coronavirus

Raul Rabadan, PhD, is an expert in uncovering patterns of evolution in highly dynamic biological systems, including in complex diseases like cancer. As the author of Understanding Coronavirus, a new book published by Cambridge University Press in June,  Dr. Rabadan, who originally began his academic career in mathematical physics, has set out to provide readers an accessible overview that quells misinformation about the novel virus, its origin, causes, and spread.

Dr. Rabadan co-directs the Cancer Genomics and Epigenomics research program at the Herbert Irving Comprehensive Cancer Center (HICCC), is professor of systems biology and of biomedical informatics at Columbia University Vagelos College of Physicians & Surgeons, and directs Columbia’s Program for Mathematical Genomics. He joined Columbia in 2008 right before the novel influenza, H1N1 or “swine flu”, emerged and quickly spread across the U.S. and the world.

At the time, Dr. Rabadan’s work honed in on understanding the genomic changes in a virus infecting a host and investigating how these changes contribute to the virus’ transfer to a different species. He continues to be fascinated by what can be gleaned from examining disease evolution.

When COVID-19 cases surged through the U.S., particularly in New York City in March, Dr. Rabadan—like many fellow scientists—contributed his research toward developing a treatment or vaccine. Scheduled to be on sabbatical this year, Dr. Rabadan instead remained quarantined with his family in New York City, shifting his attention to the new book and his own ongoing work in the genomics of cancer and COVID-19 research.

You were early to pivot your cancer-focused research to address SARS-CoV-2. What motivated you to focus on the virus?

I have been working on viruses and cancers for the last 15 years. The relation between viruses and cancers is fascinating. Around 20% of all cancers in the world are related to viruses, including some lymphomas, nasopharyngeal carcinomas, cervical and liver cancers, among many others. Many fundamental discoveries about the mechanisms of oncogenesis have been found through their relation with viruses.

Coronaviruses have not been linked to cancers but cancers and viruses share fundamental and abstract principles. They are both very fast-evolving systems and this evolution can be read through changes in their genomes. These changes follow certain rules that can be uncovered and modeled with the right set of approaches. Understanding these rules can hopefully help us to develop better ways of combating the associated diseases. For instance, some of these genomic changes in cancers and viruses could be associated to resistance to therapy. Reading and interpreting these changes could help to optimize therapeutic approaches.

How does your expertise in cancer, bioinformatics, and systems biology dovetail with virology research?

When I came to Columbia in 2008, I was very active in trying to understand the origins of pandemic viruses, mostly influenza pandemics. These pandemics occur every 30 years or so, and the last one was the H1N1 influenza of 2009. I was fascinated with understanding the genomic changes of a virus. In 2009, I was working on how influenza viruses infecting pigs and birds could generate new genetic combinations that enable them to infect and propagate in humans. We developed computational methods to identify genetic changes in these rapidly evolving systems. Many of these approaches were the seeds of the genomic work I have carried out with many colleagues at Columbia in cancer evolution since 2010.

My research is focused on understanding fast evolving biological systems by reading and modeling these changes in their genomes. Mathematical frameworks to identify relevant changes could lead to understanding basic mechanisms of evolution that can be applied to different biological systems. Learning from one system can help develop approaches to understand others.

What compelled you to write the book?

The first semester of 2020 was supposed to be my first sabbatical since I started at Columbia in 2008. With all sabbatical plans canceled I was absorbed in research related to the new coronavirus. As I was taking notes on scientific results I realized that there was a significant amount of confusing ideas, probably due to the fast pace of events involving the outbreak. Last year, I published a book on mathematical methods that we developed for analyzing genomic data. Talking to the editors of that book at Cambridge University  Press, I was motivated to organize notes and ideas to provide a landscape of what we currently know about the novel coronavirus: How is it related to other coronaviruses, including SARS; what do we know about its origins; how is it evolving; and how does it relate to previous pandemics?

In some ways, this book is a natural extension of work that I began several years ago. Shortly after I joined Columbia, and following the H1N1 flu pandemic, I organized a course on Mathematical Modeling of Infectious Diseases aimed at graduate students with an interest in a quantitative understanding of infectious diseases, and viruses in particular. Many of the notes used in the book came from this course: viruses and their genomes, recent and past outbreaks and pandemics, how genomic information could be used to learn about the viruses and their hosts. These notes provided a framework to conceptualize the current pandemic.

What do you hope readers will take away from this book?

The main goal is to conceptualize the current events we are living. There are many reference points in the horizon of our experience that can help to frame the current situation, and there are many things that still need to be learned. Previous pandemics have taught us about epidemiology and public health measures. The outbreak propelled research into coronaviruses, about their origin, associated diseases, and even therapies. Common circulating coronaviruses, viruses that are associated with mild respiratory infections, are also very interesting, as they have been with us for some time and they also have a zoonotic origin, meaning they can be transmitted from animals to humans. Although we can learn from these other outbreaks, the comparisons between these episodes can also have some dangers. For instance, the comparison with seasonal influenza has been quite misused, and is a poor metaphor for the current COVID-19 pandemic. I thought it could be useful for some people to learn about all these topics to help conceptualize the current situation.

What have you and your lab uncovered about the virus up to this point? What are you currently working on?

We are working on several aspects of the virus. COVID-19 is a disease caused by the virus SARS-CoV-2, but while an infection in an individual could be asymptomatic in another it could be deadly. In other words, COVID-19, the infectious disease, is a product of the virus and the individual. My work is mostly on genomics, and in this case, we are characterizing the genome of virus and the genome of the infected individuals. Some of the questions we are trying to answer are related to the origins of the virus: Where is it coming from? How is it evolving? Other sets of questions relate to the severity of the disease: Why do some patients have mild cases and others severe outcomes? There is an increasing amount of data that could help to address these questions.