RECOVER’s systems biology studies are helping uncover the complexities of Long COVID
RECOVER’s systems biology approach is generating 5 types of molecular data from blood samples donated by study participants to better understand what is happening in the bodies of people living with Long COVID.
Long COVID affects millions of people, but 2 people with the same symptoms may have very different things happening inside their bodies. Without understanding those underlying differences—the biological mechanisms, or processes within the body driving each person’s symptoms—treatments for Long COVID may not be precise enough to help.
To help identify these mechanisms, RECOVER researchers are using an approach called systems biology. By measuring molecules in the blood—such as DNA, RNA, proteins, and metabolites—and studying how they interact across multiple body systems at the same time, researchers can link molecular changes to the symptoms people experience. As Jessica Lasky-Su, ScD, MS, Chair of the RECOVER Systems Biology Coordinating Committee and lead principal investigator (PI), explained, “If we don’t actually have this molecular data, 2 people [with Long COVID] could look exactly the same [in terms of symptoms], but what’s actually going to help each one of them is very different.”
Through this collaborative effort, the RECOVER Systems Biology Coordinating Committee, led by Dr. Lasky-Su and Committee Vice-Chair and Cycle 1 co-PI Michelle Lamendola-Essel, DHSc, MS, is working toward new, more effective treatments that target the biological mechanisms behind Long COVID symptoms, not just the symptoms themselves—and toward better tools for diagnosing Long COVID in the first place.
A unique, tailored approach for a complex condition
Systems biology uses biosamples, powerful computers, and computer programs (called machine learning algorithms) to study the body as a dynamic, interconnected network. Instead of looking at one signal, like a single gene or protein, researchers can study many types of molecular data contained in the biosamples, organized by the type of molecule measured, known as “omics”.
Scientists use the suffix –omics to describe fields that study the complete set of a specific type of molecule in a biological sample, such as all the proteins in blood plasma. RECOVER’s multi-omics approach combines 5 of these fields—each capturing a different layer of what is happening in the body.
RECOVER’s systems biology effort is one of the most comprehensive studies of its kind, combining scale, diversity, and detailed biological data. This large-scale approach to Long COVID research is made possible by the design of RECOVER’s observational cohort studies.
During the first phase of the observational study, RECOVER observational study teams collected the same types of biosamples from almost 30,000 adults and children at multiple time points over 4 years. Because RECOVER’s systems biology studies use biosamples and data collected over time, researchers can understand how body systems change as symptoms persist, change, or resolve. Systems biology analyses are being conducted on samples from up to 12,000 of these participants, including about 9,000 adults and up to 3,000 children and young adults.
Looking at these many pieces of data at the same time helps researchers better understand how body systems interact and affect a person’s overall health.
“Systems biology is generating all this data and parsing through it to understand what’s happening in Long COVID,” said Dr. Lasky-Su. “We’re able to find things that we wouldn’t understand if we didn’t have molecular data. Those discoveries can point us toward the treatments most likely to work.”
Although other research studies use systems biology approaches, Dr. Lasky-Su said RECOVER’s systems biology study is among the largest and most comprehensive efforts of its kind. RECOVER’s approach includes:
- A collection of multiple -omics data types. Researchers are measuring 5 major types of -omics data in the same people: genomics (DNA), transcriptomics (RNA), proteomics (proteins), metabolomics (metabolites), and epigenomics (chemical marks on DNA). Many systems biology studies measure only one or two types. These huge amounts of data are extremely useful in gaining a more complete understanding. For example, Dr. Lasky-Su explained that 1 type of -omics data could help confirm (validate) findings from another type.
- A focus on high-quality, integrated data. The -omics measurements are made on blood samples collected from the same people at the same visits, allowing researchers to understand how multiple body systems may be affected in one individual. This helps create a more complete picture of what is happening inside the body.
- A large, diverse group of study participants with samples collected during and after the pandemic. RECOVER includes participants of all ages, sexes, and backgrounds from across the United States. The large group of people that RECOVER has included in its research can help capture how health has changed during and after the pandemic—something few study populations can shed light on.
This multifaceted approach is especially important because Long COVID is extremely complex. Dr. Lamendola-Essel explained, “There are over 200 symptoms of Long COVID. What causes that? It could be a protein, it can be a metabolite, it can be a whole system dysfunction, and you will never know if you only look at one thing.” What systems biology offers is that broader view—what's visible when researchers look at many data types at once.
Revealing new information through systems biology
Systems biology studies can help connect symptoms to complex interactions in a person’s body—and uncover patterns that may not be visible through clinical data alone. For example, a systems biology approach can help:
- Understand immune system activity. Researchers are identifying patterns and studying immune responses after an initial COVID-19 illness has resolved. Understanding immune responses may help explain Long COVID symptoms such as fatigue.
- Explain similar symptoms with different causes. Systems biology can reveal different underlying causes for similar Long COVID symptoms. For example, one person’s fatigue may be linked to immune system activity, whereas another’s may be related to problems with energy production in cells.
- Identify changes in metabolism. Researchers can measure small molecules called metabolites to see differences in how the body uses nutrients and produces energy. These changes may reflect how the body responds to stress or inflammation over time.
One of the most promising aspects of systems biology is its potential to reveal the biological mechanisms behind Long COVID symptoms and support the identification of possible treatments. By identifying biological patterns, researchers can:
- Define subtypes of Long COVID based on underlying biology.
- Develop biomarkers (measurable biological signals in the blood) that can help with diagnosis.
- Identify the treatments most likely to work based on the underlying biology driving their symptoms, including repurposed and new drugs.
Dr. Lasky-Su shared that RECOVER’s systems biology approach could fundamentally change how Long COVID is treated: “We could make really comprehensive biomarker panels that could classify what type of Long COVID you have and identify the treatments that are most likely to work for you. And understanding the biology gives us the targets we need to develop new, more effective drugs.” This means that treatments could one day be tailored to the biology of each individual rather than based on symptoms alone, and new drugs could be developed to counteract the mechanisms driving the condition.
Looking ahead: Turning data into answers
RECOVER’s systems biology effort will continue to be guided by a multidisciplinary team working across institutions and research centers. The work is overseen by a committee, which is led by Drs. Lasky-Su and Lamendola-Essel, and includes experts from across RECOVER’s collaborative network: data scientists, statisticians, clinicians, RECOVER Representatives, and researchers from the adult, pediatric, and autopsy studies.
The committee’s membership reflects RECOVER’s commitment to collaboration and to making sure research reflects the experiences of people affected by Long COVID. The systems biology team also works closely with specialized bioinformatics groups that extract, manage, and analyze large-scale -omics data.
RECOVER’s systems biology approach is still in its early stages, but momentum is growing as researchers are analyzing the large, complex datasets they’ve generated. The goal for the studies is not only to publish findings, but also to make systems biology data available and build a resource for the broader scientific community. After the datasets are cleaned and checked for quality, they will be shared via NHLBI BioData Catalyst® (BDC). BDC is a secure cloud-based ecosystem that hosts RECOVER datasets, as well as tools and resources to support research analysis and workflows.
Together, these efforts offer hope that systems biology will help researchers unravel the complexities of Long COVID—and bring us closer to answers, better care, and new treatments for the millions of people affected.
Explore RECOVER’s Systems Biology webpage
RECOVER’s new Systems Biology Studies webpage covers the basics of systems biology and its multi-omics approach, with links to research publications and updates from the study. This page is a clear starting point for understanding how RECOVER is connecting complex health data to Long COVID symptoms.
