Researchers ask: Why does COVID-19 affect people differently?

Blood samples drawn from COVID-19-positive patients are helping researchers' efforts to identify and target the unique biologic factors that drive the disease.
Jan. 28, 2021
A man wearing a mask is out hiking.
Researchers are trying to determine why COVID-19 affects individuals differently. Photo: Getty Images.

A major research initiative on the University of Colorado Anschutz Medical Campus is making the fight against the novel coronavirus personal.

The effort, which aims to accelerate research into the roots of COVID-19, launched a major data set called COVIDome in a matter of months. Its source material is blood samples from patients who tested positive for COVID-19 and controls whose tests were negative. Through the COVIDome Explorer portal, researchers can analyze (see box below) the samples from a broad variety of biological perspectives.

The goal: identify specific patterns – changes in proteins, red blood cells or immune response, for example – that can illuminate the mechanisms underlying the diverse ways COVID-19 affects people. Why does COVID-19 affect people differently? With that information and the ability to compare it to patients untouched by the disease, researchers and clinicians aim to design targeted treatments to patients, based on their unique characteristics.

The motto of the COVIDome Project sums up that approach: “Nothing in the study of COVID-19 makes sense except under the light of precision personalized medicine.”

Why does COVID-19 affect people differently?

“COVID-19 is not one entity,” said Dr. Joaquin Espinosa, Professor of Pharmacology and executive director of the Linda Crnic Institute for Down Syndrome at the University of Colorado School of Medicine. Espinosa is a COVIDome principal investigator and project leader. “It manifests itself in very different ways in every individual. In order for us to make a difference in care, we need to understand how COVID-19 affects different people.”

It’s a question that has been one of the great puzzles of the disease, Espinosa noted.

“If you have 100 people infected with the same virus, you have a wide range of outcomes,” he said. “Every person is different. Some will not get sick at all, some will die, and everything in between. What are the mechanisms driving this massive diversity?”

Playing under the dome

Espinosa describes COVID-19 as a unique “data ecosystem” that allows research on many fronts by specialists with a variety of skill sets. It’s an open system that encourages researchers to collaborate and broaden their perspectives about the disease.

The raw material for the COVIDome Project comes from the University of Colorado COVID-19 Biobank, launched in March 2020 as a repository of COVID-19-positive blood samples for research under the guidance of Dr. Thomas Flaig, Vice Chancellor for Research and Professor of Medicine at CU Anschutz. Flaig works alongside Espinosa as COVIDome principal investigator and project leader.

“It is a remarkable effort and example of research collaboration,” Flaig said. “The productive outcome of this work is especially noteworthy considering the challenging nature of interacting with COVID-positive study participants, and the cooperation between the clinical teams and laboratories in this time of the pandemic.”

Inside the COVIDome

The COVIDome Explorer portal offers researchers access to a range of data sets they can use to analyze components of blood samples from the COVID-19 Biobank.

  • Transcriptome: Data on messenger RNA “transcripts,” or the process through which DNA makes messenger RNA, which carries the genetic information to make proteins.
  • Proteome: Proteins in the sample.
  • Cytokines: Substances that regulate immunity.
  • Metabolomics: Substances that regulate metabolism.
  • Immune maps: Immune cells, such as T-cells, B-cells and natural killer cells.
  • Seroconversion: Antibodies against SARS-CoV-2.

From the Biobank source, Espinosa and Flaig assembled a broad-based COVIDome Project team. In just a few months, the collaborators had built the structure for processing and analyzing samples. The blood samples also link to Health Data Compass, a warehouse of clinical data that is part of the Colorado Center for Personalized Medicine on the Anschutz Medical Campus.

The COVIDome was open for play, as Espinosa puts it, with researchers entering through the COVIDome Explorer online portal to analyze some 110 samples, a little over 70 of them COVID-19-positive.

Down Syndrome research created a framework for success

It was a quick timeline, but the team had a head start. Several years previously, Espinosa and colleagues at the Linda Crnic Institute for Down Syndrome had created the Crnic Institute’s Human Trisome Project. They aimed to explore some longstanding mysteries of people born with an extra chromosome 21 – the genetic cause of Down syndrome, or trisomy 21.

For example, people with Down syndrome have unusual protection against solid tumor cancers but are also highly vulnerable to blood cancers. They are also at greater risk for developing Alzheimer’s disease and dementia and for a variety of autoimmune disorders. As it is for those studying COVID-19, the question for Down syndrome researchers is why the discrepancies, Espinosa said.

The Human Trisome Project set out to build a framework for answering that: create a biobank with samples from blood draws and mouth swabs. That material forms the basis for the TrisomExplorer, a portal for researchers to explore the biological pathways underlying Down syndrome. Thus far, the database has samples from some 700 patients and controls gathered across 43 states. It has spawned a host of investigations.

Flaig immediately recognized the expertise Espinosa had at his fingertips for creating a database to study COVID-19. But Espinosa has an additional motivation. His own research concludes that people with Down syndrome are at high risk for developing severe cases of COVID-19. That gave him “a vested interest” in developing the COVIDome Project, he said.

Dr. Joaquin Espinosa created the framework for COVIDome helping to answer the questions as to why COVID-19 affects people differently.
Dr. Joaquin Espinosa created the framework for COVIDome and is helping to answer the questions as to why COVID-19 affects people differently. Photo by UCHealth.

A collaborative effort focused on understanding COVID-19

Difficult as it is to say anything good about COVID-19, the disease has helped to drive collaboration between researchers, clinicians, information specialists and others to a remarkable degree, said Dr. Andrew Monte, an emergency medicine physician, medical toxicologist and researcher at CU who is a co-investigator and member of the clinical data team for the COVIDome Project.

“The pandemic has brought scientists together to solve a single problem like no other instance in our history,” Monte said. “The amount of scientific collaboration that has come together to solve this problem is in and of itself an incredible undertaking.”

Monte offers a good example of that collaboration. He is an investigator who runs a biorepository through the Emergency Department at UCHealth University of Colorado Hospital. With those samples, he’s studied genetic variations in patients that predict the safety and effectiveness of various drugs.

With the advent of the pandemic, Monte began getting consents to use blood samples from Emergency Department patients who test positive for COVID-19 and contributing them to the COVID-19 Biobank. As a clinical co-investigator with the COVIDome Project, he said he collaborates with basic scientists by providing feedback to them about the “clinical variables” that affect COVID-19 patients, such as oxygen levels and kidney and liver injury.

With only a relative handful of treatment alternatives for COVID-19 patients, developing new medications is vital to improving their care, Monte said. The COVIDome offers the chance for researchers to isolate a change in a biologic pathway – a protein or immune cell, for example – and select or develop drugs that target the pathway, Monte said.

Dr. Thomas Flaig joins Espinosa as principal investigator and project leader of COVIDome. Photo by UCHealth.

“Understanding the underlying biology of the disease allows us to choose medications that are more likely to be effective and less likely to cause adverse drug effects,” he said.

More blood samples from COVID-19 patients provide more opportunities

For now, when COVIDome researchers choose a data set they can also analyze by sex and age group (all or 21 and older). Espinosa said more samples could bring more choices, such as analyzing by comorbidities or race.

The racial question is of particular interest to Monte, who noted that Hispanics make up a disproportionate percentage of the patient population in the intensive care units at University of Colorado Hospital.

“Discrepancies like that suggest there are genetic and biologic reasons [for the difference],” Monte said. “That is exactly the kind of thing I hope we can examine as we enroll more patients in the Biobank and improve their care.”

For his part, Espinosa believes the open-access, collaborative approach of the Human Trisome and COVIDome projects could change medical research and our understanding of many diseases fundamentally.

Emergency medicine physician Dr. Andrew Monte is a co-investigator and clinical data team member with COVIDome. Photo by UCHealth.
Emergency medicine physician Dr. Andrew Monte is a co-investigator and clinical data team member with COVIDome. Photo by UCHealth.

“We are bringing together people who understand different areas,” Espinosa said. “The work keeps evolving. My hope is that it can be done relatively cheaply for all medical conditions.”

For a detailed discussion of the COVIDome Project, watch a YouTube video of a November 19 townhall led by Drs. Espinosa and Flaig.

About the author

Tyler Smith has been a health care writer, with a focus on hospitals, since 1996. He served as a writer and editor for the Marketing and Communications team at University of Colorado Hospital and UCHealth from 2007 to 2017. More recently, he has reported for and contributed stories to the University of Colorado School of Medicine, the Colorado School of Public Health and the Colorado Bioscience Association.