Systems Biology Studies

Systems biology is a powerful approach to medical research that brings together many different types of information to better understand health and disease. This approach examines the body’s building blocks at the molecular level, including DNA, RNA, proteins, and metabolites. Researchers then study how these molecules interact with one another to help explain clinical symptoms.

Systems biology studies can also look at how these molecules differ among people and change over time. By using advanced methods to create, organize, integrate, and explore very large amounts of data, systems biology can uncover patterns and associations that may not be easily detectable when looking at clinical data alone. Making these connections can lead to new insights into complex health conditions like Long COVID.

Long COVID can be different for everyone. It can cause different combinations of symptoms that affect almost every part of the body, from the brain to the heart, lungs, and stomach. These symptoms can start at different times, last for different amounts of time, and come and go. Although groups of people may experience similar Long COVID symptoms, such as fatigue (feeling very tired), the causes of each symptom can differ from person to person.

More than 30,000 people of all ages, sexes, and backgrounds have shared 82 million pieces of health data and 1.5 million biosamples with RECOVER over the last 4 years. The availability of so much data and so many biosamples, which are designed to be compatible across studies, represents a rare opportunity to use a systems biology approach to describe and explain Long COVID’s complexity.

Findings from RECOVER systems biology studies can help researchers:

• Identify the biological causes that can lead to Long COVID symptoms.
• Develop biomarkers (measurable biological signals) and tools to diagnose Long COVID.
• Find the most promising treatments by including existing drugs that could be repurposed and new drugs to develop.
• Guide the design of more targeted clinical trials.

Systems biology studies measure the many types of molecules found in blood samples and how they change in people with Long COVID. These studies also look at how changes in these molecules can lead to changes at a higher level—within individual body systems and across multiple body systems. A body system is a collection of organs, tissues, cells, and molecules that work together to perform a specific function, like digesting food or fighting infections.

Like RECOVER pathobiology studies, systems biology studies examine biosamples (such as small amounts of a person’s blood). Researchers generate very large collections of data (datasets) by taking measurements from these biosamples. These datasets can include millions of datapoints that help researchers:

• Measure which molecules of a specific type (like proteins) are present in the blood, and how much of each, in people with and without Long COVID.
• Look for patterns that could provide clues about what may be happening in cells, tissues, and organs throughout the body.
• Understand how these molecules interact with other molecules, including those produced by the body and those produced by SARS-CoV-2, the virus that causes COVID-19.

Like RECOVER electronic health record (EHR) studies, systems biology studies use advanced computer programs called machine learning algorithms to look for patterns in these very large datasets. These patterns can reveal how different biological mechanisms may lead to the same Long COVID symptoms. A biological mechanism includes not only molecules and cells but also the connections between them, the processes that result from these connections, and the effects of these processes.

Because RECOVER systems biology studies use data and biosamples collected by RECOVER observational cohort studies, researchers can use measurements taken at different points in time. This helps systems biology researchers understand how the health of people with Long COVID may change over time. Researchers can also identify which molecular changes are most closely linked to symptoms, which can help inform more precise efforts to diagnose and treat Long COVID.

What are “omics”?

Systems biology brings together scientists and clinicians with expertise in many different areas of biology and medicine. Many of these researchers specialize in “omics” technologies, which measure all, or nearly all, of the molecules of a particular type (for example, thousands of proteins in a blood sample) at the same time.

Because RECOVER’s systems biology program measures 5 types of omics data in the same people and integrates them to identify patterns, RECOVER takes what can be described as a “multi-omics” approach. What makes multi-omics approaches powerful is that when the different omics data are combined, researchers gain a more complete picture of what is happening in body systems affected by Long COVID.

RECOVER systems biology studies measure 5 types of omics data, each capturing a different layer of biology:

Genomics

Genomics is the study of a person’s complete set of deoxyribonucleic acid (DNA), called the genome. DNA contains the instructions the body uses to make molecules, such as proteins, that allow body systems to work. Genes are specific segments of DNA that carry these instructions. They are also hereditary, meaning parents pass them down to their children. RECOVER uses whole genome sequencing to read a person’s DNA and identify genetic variants (differences in the DNA code) that may influence Long COVID risk or how the condition develops.

Transcriptomics

Transcriptomics is the study of the complete set of ribonucleic acid (RNA) molecules in cells, called the transcriptome. RNA is made when cells copy (or “transcribe”) genes from DNA. Messenger RNA (mRNA) carries these instructions to the parts of the cell that build proteins, so measuring RNA shows which genes are turned on and how active they are. RECOVER measures RNA in blood using RNA sequencing.

Proteomics

Proteomics is the large-scale study of proteins. Proteins are large molecules, built from instructions in genes, that carry out most of the work in cells and tissues. For example, antibodies that fight infections are proteins, as is hemoglobin, which carry oxygen from the lungs to other parts of the body and the proteins that make up muscle tissue. RECOVER measures thousands of proteins circulating in blood plasma.

Metabolomics

Metabolomics is the study of metabolites, the small molecules that are made or used during metabolism. Metabolism is the set of chemical processes the body uses to turn food and drink into energy and into building blocks for cells. Metabolites include sugars, amino acids, and fats (lipids). Because metabolites reflect both the body’s own biology and exposures such as diet and medications, they provide a snapshot of what the body is doing at a given time. RECOVER measures more than 1,000 metabolites in blood plasma.

Epigenomics

Epigenomics is the study of the complete set of chemical marks on DNA (the epigenome), which help turn genes on or off without changing the DNA sequence itself. These marks can be influenced by factors such as infection, aging, behavior, and environment, and they can change how cells use their genes. RECOVER measures DNA methylation, a common type of epigenetic mark, at more than 900,000 locations across the genome.

RECOVER systems biology studies use biosamples contributed by up to 12,000 people—including about 9,000 adults and up to 3,000 children and young adults already enrolled in RECOVER’s adult and pediatric observational cohort studies.

These people include:

• Adults (people aged 18 and older).
• Babies, children, adolescents (aged 12 to 17) and young adults (aged 18 to 25).

All of these groups include both people with and without Long COVID.