In your blood, right now, are thousands of bits of loose DNA. These short strands of genetic material come from all over your body. Old cells die and new ones take their place. “The tissues in your body are constantly replenishing,” says Iwijn De Vlaminck, Biomolecular Engineering. “Your lungs are about seven weeks old. Most cells that make up your immune system are only a couple of weeks old.” After cells live out their normal life cycle, they disintegrate. Pieces of DNA from the dead cells end up in the bloodstream.
Those discarded scraps of DNA, called circulating cell-free DNA or cfDNA, might seem inconsequential. But De Vlaminck has engineered blood tests that use cfDNA to quantify injury to solid-organ transplants. Now, with the help of a SARS-CoV-2 Seed Grant from Cornell’s Office of the Vice President for Research and Innovation (OVPRI), De Vlaminck is looking to cfDNA to cast light on a little-understood disease, Multisystem Inflammatory Syndrome in Children, that has emerged as a rare but life-threatening condition in children and teenagers who have been exposed to the virus that causes COVID-19.
Since announcing the seed grant program in March 2020, the OVPRI, in partnership with the Center for Vertebrate Genomics and the Center for Immunology, has awarded more than $384,000 to research projects dedicated to combating COVID-19 and the SARS-CoV-2 virus that causes it. The program gives innovative research collaborations a chance to prove the promise of their ideas and to secure external funding.
Initial funding under Phase I of the program went to 23 projects, many of them multidisciplinary collaborations. “The whole idea [of the SARS-CoV-2 Seed Grants] was to fund innovative, way-out ideas, sometimes high-risk stuff,” says Paula Cohen, Associate Vice Provost of Life Sciences Research.
Phase I recipients had a matter of weeks to prove the strength of their ideas. Then, in December 2020, a committee began selecting Phase I recipients who had generated the most promising data for additional Phase II funding that would allow them to carry their ideas even further.
“The two-phase structure was intended to put the pressure on,” Cohen says. “The whole world needed researchers to think quickly and act now.”
Assessing Many Organs with a Single Test
De Vlaminck takes a unique approach to medical research. “I am not a biologist by training, but I am interested in developing engineering tools to detect, diagnose, and study disease,” he says.
For Phase I of the project, De Vlaminck pulled together a team of 12 other researchers from the United States and Canada, including Charles Y. Chiu and Wei Gu of the University of California, San Francisco, Jerome Ritz and Francisco Marty at the Dana-Farber Cancer Institute in Boston, and Donald Vinh and Matthew Cheng of McGill University Health Center in Montreal, Canada.
“This work is only possible through the expertise of our collaborators,” De Vlaminck says. “The engineering happens in our lab, but they have the direct experience with patients. They know what’s important for understanding the disease and treating it.”
De Vlaminck’s team focused on adults with COVID-19. “Using cfDNA, we developed a blood test that can quantify the degree of injury to any cell type, tissue type, or organ that might be affected by the [SARS-CoV-2] virus,” De Vlaminck says.
Thanks to techniques devised by De Vlaminck’s lab, doctors and researchers can trace blood-borne cfDNA back to the types of cells, tissues, or organs it came from. The work was originally done for patients with graft-versus-host disease, a complication of bone marrow transplants that, like COVID-19, can attack multiple organs and tissues throughout the body.
The DNA in every cell of a person’s body is basically identical. How then could cfDNA from B lymphocyte cells be distinguished from cfDNA from liver cells? Each cell type relies on different genes to develop and function. Genes get tagged with various epigenetic markers depending on how they are used. A bit of DNA from a B cell is tagged differently than DNA from a heart cell or liver cell. De Vlaminck’s idea was to identify the organs and tissues that all those bits of blood-borne cfDNA come from by reading their chemical tags. The result gives doctors and researchers a measurement of the cell types in a patient’s body that have recently died.
“For COVID-19, that turns out to be very important,” De Vlaminck says. “Yes, this is a respiratory virus. It primarily affects the lungs. But in many patients, it’s really a multifactorial, systemic disease that can affect the liver, the kidneys, the gut, and more.”
“The idea of measuring the quantity of circulating cell-free DNA is very, very simple… This is a truly practical approach that could go nationwide or even worldwide.”
For clinicians, the best news may be that measuring the levels of cfDNA in a blood sample is easy and inexpensive—and that measurement alone turns out to be a reliable indicator of how severely COVID-19 is affecting a patient. “It’s important to be able to direct clinical care where it’s most urgently needed first,” De Vlaminck says.
Cohen, speaking of De Vlaminck’s project, says, “The idea of measuring the quantity of circulating cell-free DNA is very, very simple. We want to develop techniques that can be used at any hospital. This is a truly practical approach that could go nationwide or even worldwide.”
Multisystem Inflammatory Syndrome in Children
In late April 2020, doctors began to observe a sudden increase in the incidence of certain alarming symptoms among children and teenagers. The most extreme cases involved severe inflammation of the heart, blood vessels, and other organs. A few weeks later, the Centers for Disease Control and Prevention (CDC) named the condition Multisystem Inflammatory Syndrome in Children, or MIS-C. “MIS-C may actually be the worst of a number of COVID-19 diseases in children,” says De Vlaminck. The condition is extremely rare but dangerous. At the time of this writing, no one understands why a few children develop it while the vast majority do not, or why the disease disproportionately affects children who are Black or Latino.
“I have young kids,” De Vlaminck says. “Like a lot of people, initially I thought the only silver lining, maybe, for this whole pandemic was that it seemed not to affect children so much. But now there are obviously children where it doesn’t go well. And we need to figure out, what factors are driving that? What exactly is happening in these children? Hopefully, our lab can contribute to the knowledge there.”
Building on their Phase I findings, De Vlaminck and his collaborators are tailoring a cfDNA test for patients with MIS-C. “Our cfDNA test has the potential, in principle, to report on all tissues and organs and cell types simultaneously,” De Vlaminck explains. In other contexts, such as organ transplants, cfDNA tests can provide a level of detail exceeded only by taking a tissue sample and performing a biopsy. “Obviously, having a blood test is much friendlier for the patients,” De Vlaminck says.
The test might also elucidate why and how MIS-C develops in the first place. De Vlaminck’s great hope is that a cfDNA test might eventually detect MIS-C early or even identify children who are most at risk. “That potential remains to be proven, but it would be very valuable to identify MIS-C and treat patients early,” he says.
De Vlaminck’s work exemplifies the multidisciplinary research that the OVPRI aimed to foster with the seed grants. As Cohen explains, “A chemist or engineer is going to come at COVID-19 from a different angle than a virologist or infectious disease expert. They can help each other see a challenge completely differently.”
“The key to getting the best solution, I believe, is collaboration,” Cohen adds. “This is where Cornell’s strength is. It’s reflected in the Provost’s Radical Collaboration initiative. At its essence, the Cornell research community is collaborative and cross-cutting.”