VUMC researchers, supercomputing effort reveal antibody secrets

Using sophisticated gene sequencing and computing techniques, researchers at Vanderbilt University Medical Center (VUMC) and the San Diego Supercomputer Center have achieved a first-of-its-kind glimpse into how the body’s immune system gears up to fight off infection.

Their findings, published this week in the journal Nature, could aid development of “rational vaccine design,” as well as improve detection, treatment and prevention of autoimmune diseases, infectious diseases, and cancer.

“Due to recent technological advances, we now have an unprecedented opportunity to harness the power of the human immune system to fundamentally transform human health,” Wayne Koff, PhD, CEO of the Human Vaccines Project, which led the research effort, said in a news release.

The study focused on antibody-producing white blood cells called B cells. These cells bear Y-shaped receptors that, like microscopic antenna, can detect an enormous range of germs and other foreign invaders.

They do this by randomly selecting and joining together unique sequences of nucleotides (DNA building blocks) known as receptor “clonotypes.” In this way a small number of genes can lead to an incredible diversity of receptors, allowing the immune system to recognize almost any new pathogen.

Understanding exactly how this process works has been daunting. “Prior to the current era, people assumed it would be impossible to do such a project because the immune system is theoretically so large,” said James Crowe Jr. MD, director of the Vanderbilt Vaccine Center and the paper’s senior author.

“This new paper shows it is possible to define a large portion,” Crowe said, “because the size of each person’s B cell receptor repertoire is unexpectedly small.”

The researchers isolated white blood cells from three adults, and then cloned and sequenced up to 40 billion B cells to determine their clonotypes. They also sequenced the B-cell receptors from umbilical cord blood from three infants. This depth of sequencing had never been achieved before.

What they found was a surprisingly high frequency of shared clonotypes. “The overlap in antibody sequences in between individuals was unexpectedly high,” Crowe explained, “even showing some identical antibody sequences between adults and babies at the time of birth.”

Understanding this commonality is key to identifying antibodies that can be targets for vaccines and treatments that work more universally across populations.

The Human Vaccines Project is a nonprofit public-private partnership of academic research centers, industry, nonprofits and government agencies focused on research to advance next-generation vaccines and immunotherapies. This study was part of its Human Immunome Program, which aims to decode the genetic underpinnings of the immune system.

As part of a unique consortium created by the Human Vaccines Project, the San Diego Supercomputing Center applied its considerable computing power to working with the multiple terabytes of data. A central tenet of the Project is the merger of biomedicine and advanced computing.

“The Human Vaccines Project allows us to study problems at a larger scale than would be normally possible in a single lab and it also brings together groups that might not normally collaborate,” said Robert Sinkovits, PhD, who leads scientific applications efforts at the San Diego Supercomputer Center.

Collaborative work is now underway to expand this study to sequence other areas of the immune system, B cells from older people and from diverse parts of the world, and to apply artificial intelligence-driven algorithms to further mine datasets for insights.

The researchers hope that continued interrogation of the immune system will ultimately lead to the development of safer and highly targeted vaccines and immunotherapies that work across populations.

“Decoding the human immune system is central to tackling the global challenges of infectious and non-communicable diseases, from cancer to Alzheimer’s to pandemic influenza,” Koff said. “This study marks a key step toward understanding how the human immune system works, setting the stage for developing next-generation health products through the convergence of genomics and immune monitoring technologies with machine learning and artificial intelligence.”

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Crowe is the Ann Scott Carell Professor in the Vanderbilt University School of Medicine Departments of Pediatrics and Pathology, Microbiology & Immunology. Members of his lab who contributed to the study were first author Cinque Soto, PhD, Robin Bombardi, Andre Branchizio, Nurgun Kose, Pranathi Matta and Pavlo Gilchuk, PhD.

The study was also supported by institutional funding from VUMC.