Researchers study single cells to ask why children generally fare better against COVID-19

Just three months ago, Alex K. Shalek and Jose Ordovas-Montanes were broadly studying single cell responses to inflammation, cancer, and various infections. Then COVID-19 arrived. 

Institute member Shalek and associate member Ordovas-Montanes of the Klarman Cell Observatory at the Broad Institute of MIT and Harvard quickly pivoted their research. 

Now, they are using their single-cell tools to learn which cell types SARS-CoV-2 attacks, characterize different therapeutic and prevention strategies, and uncover what causes protective responses in some patients and not others. The researchers have also been part of a significant change in the way science is being done.

Shalek is also the Pfizer-Laubach Career Development Associate Professor of Chemistry, a core member of the Institute for Medical Engineering and Science, and an extramural member of the Koch Institute for Integrative Cancer Research at MIT, as well as an associate member of the Ragon Institute. Ordovas-Montanes is a principal investigator at Boston Children’s Hospital, assistant professor at Harvard Medical School, and a former postdoctoral researcher in the Shalek lab.

They recently sat down with us over a Zoom call in a COVID-19 edition of a #WhyIScience Q&A to talk about a new study on COVID-19 disease in children, which is being done in collaboration with clinicians at Boston Children’s Hospital and scientists at the Broad as part of the Human Cell Atlas (HCA) initiative. They also talked about how their approach to research, and their field of single-cell genomics, have changed in the age of COVID. 

Q. What got you interested in studying pediatric patients’ responses to SARS-CoV-2?

Ordovas-Montanes: From some of the preliminary COVID-19 clinical observations, it was evident that kids, in general, are handling this viral infection better than adults, and there was something significant that we could learn from them. We figured we might have this ability to assemble a unique cohort, not to look at the most severe outcomes of disease, but rather to look into what seems to be working better in kids that allows them to generally avoid severe disease.

Shalek: We wanted an opportunity to study the cells that are infected and cells that are bystanders of the infection in children, and to understand how both are changing within the same tissue sample. This would enable us to uncover differences relative to other cohorts that have been shown to experience, on average, more severe disease. That is one of the most powerful aspects of single-cell RNA sequencing (scRNA-seq), whereas, in bulk RNA-sequencing, we would have lost the ability to resolve this information.

Q. Can you tell me a bit more about the study? 

Ordovas-Montanes: We plan to enroll children presenting symptoms consistent with a respiratory viral infection to the Emergency Department (ED) at Boston Children’s Hospital. Given current patterns, we anticipate identifying at least 20 SARS-CoV-2 positive patients and 20 patients with other RNA viral infections. We will also enroll a control group of 20 asymptomatic patients visiting the ED for minor injuries that aren’t related to COVID-19. We will be collecting nasopharyngeal swabs, the type used for viral testing, a sampling strategy that also lets us collect a considerable number of host cells off these swabs.

Shalek: Our research team at the Broad will then process the nasal scraping samples for scRNA-seq to identify constituent cell types, both infected and bystander. Using this data, we will identify specific genes and pathways associated with infection and, by comparing to other cohorts, factors associated with disease severity. 

We will be maintaining as much precaution as possible for the investigators handling any of these samples. We will be following physical distancing guidelines and have a tightly integrated pipeline to minimize risks to everyone that's involved in the experimental side of the study.

Q. How are you doing this study differently, given the pandemic?

Ordovas-Montanes: Unlike the traditional academic publishing process, given the pandemic, our overall mission for this study has shifted to prioritizing data release above deliverables such as pre-prints or publications. Even though we will be generating valuable data, with measurements taken from both cases and controls, we believe to fully maximize its potential, it requires the interpretation of the international research community. They should  be able to dive in and identify what's going on by comparing our datasets to multiple other datasets in cohorts of different ages. 

Shalek: The plan is to make all the data from this study publicly available via Broad’s Single Cell Portal as quickly as is possible. Collecting large datasets and making them rapidly accessible has been a priority for us. We want to support the community how we can, and empower as many people as is humanly possible –– to help accelerate our joint fight against COVID-19. Ultimately the data will also get added to the COVID-19 Cell Atlas, a comprehensive resource for exploring the cell-type-specific expression of SARS-CoV-2-linked genes. 

Q. What other changes have you seen in how single-cell science is being done in this public health emergency? 

Shalek: I’ve been amazed by the way in which the global scientific community has pulled together to tackle the pandemic –– by the willingness to collaborate, to share unpublished data, and to support one another at all levels. It’s been truly inspiring to see everyone work together and incredible to see how much it’s enabled us to accomplish in a short time. I hope we can figure out a way to maintain this sense of community going forward. 

Ordovas-Montanes: It hasn’t just been single-cell science that has changed, but rather many scientific efforts. We’ve had the opportunity to rapidly meet people both within our own institutions and around the world through collaborative groups at Boston Children’s Hospital, Massachusetts Consortium on Pathogen Readiness, the Chan Zuckerberg Initiative (which is funding the pediatric study), and even organically through Twitter. We hope to continue working with these colleagues on COVID-19 related efforts, and also on other fundamental questions in biology. One key element to keep in mind is to ensure that through these rapid changes, the practice of science keeps making progress towards a more equitable community.  

Q. What inspires you the most about the pediatric study and the other COVID-19-related work you are doing during the pandemic?

Shalek: That we can play a part in helping the community at large. When the data from this study gets merged with other datasets that are being collected by other labs around the world, it will help paint a more holistic view of the impact of SARS-CoV-2 and hopefully suggest new therapeutic and prophylactic strategies. 

Ordovas-Montanes: I think we are excited to be a small part of a broader vision. It is inspiring to be associated with the HCA, which has responded quickly to the COVID-19 pandemic. They managed to bring together a community of researchers around the world. We are looking forward to working with other teams across the globe to understand what single-cell sampling will teach us about the impact of SARS-CoV-2 on each individual or group of patients.