For the first time, scientists are completely sequencing the human immune system, which is billions of times larger than the human genome. In a new study published in Nature by the Human Vaccines Project, researchers sequenced an important part of this large and mysterious system – the genes encoding the circulating B cell receptor repertoire.
Sequencing these receptors in both adults and infants, the researchers found surprising overlaps that could provide potential new antibody targets for vaccines and therapeutic agents across populations. As part of a major multi-annual initiative, this work aims to define the genetic basis for people's ability to respond and adapt to a huge number of diseases.
Led by researchers at Vanderbilt University Medical Center and the San Diego Supercomputer Center, this progress is possible due to the merger of biological research with high-powered border supercomputing. While the human genome project sequenced the human genome and led to the development of new genomic tools, it did not accept the size and complexity of the human immune system.
"A continued challenge in the field of human immunology and vaccine development has been that we do not have extensive reference data for what the normal healthy immune system looks like," said James E. Crowe, Jr., MD, Vanderbilt University Medical Center Vanderbilt University Medical Center Vanderbilt Vaccine Center , senior author of the new paper, published online in nature on February 13. "Before the present time, people assumed that it would be impossible to do such a project because the immune system is theoretically so large, but this new paper shows that it is possible to define a large part, since the size of each person's B cell receptor repertoire is unexpected small. "
The new study specifically looks at part of the adaptive immune system, the circulating B cell receptors responsible for the production of antibodies considered to be the main determinant of human immunity. The receptors randomly select and join gene segments that form unique sequences of nucleotides called receptor "clonotypes". In this way, a small number of genes can lead to an incredible variety of receptors, allowing the immune system to recognize almost any new pathogen.
Conducting leukapheres on three single adults cloned the researchers and sequenced up to 40 billion cells to sequence the combinations of gene segments including the circulating B cell receptors, resulting in a sequencing depth never before done. They also sequenced umbilical cord blood from three infants. The idea was to collect a large amount of data on some individuals, rather than the traditional model for collecting only a few data points on many.
"The overlap in antibody sequences between individuals was unexpectedly high," explains Crowe, "even showing some identical antibody sequences between adults and babies at birth." Understanding this commonality is the key to identifying antibodies that can be targets for vaccines and treatments that work more universally across populations.
One key issue was whether the shared sequences across individuals were a result of random rather than the result of any common common biological or environmental factor. To address this problem, the researchers developed a synthetic B cell receptor repertoire and found that "the overlap was observed experimentally was significantly greater than expected by chance," said Robert Sinkovits, Ph.D., of the San Diego Supercomputer Center at the University of California. California, San Diego.
As part of a unique consortium created by the Human Vaccines Project, the San Diego Supercomputer Center applied its significant computing power to work with the multiple terabyte data. A central basis for the project is the merger of biomedicine and advanced data processing. "The project Human Vaccines allows us to study problems on a larger scale than is normally possible in a single laboratory and it also collects groups that normally do not cooperate," says Sinkovits.
Continued collaboration is now underway to expand this study, including: sequencing of other areas of the adaptive immune system, the T cell repertoire; add additional demographics such as supercentenary and international populations; and apply AI-driven algorithms to further my datasets for insights. The goal is to continue interrogating the shared components of the immune system to develop safer and highly targeted vaccines and immunotherapies that work across the population.
"Due to the latest technological advances, we now have an unprecedented opportunity to harness the power of the human immune system to fundamentally transform human health," says Wayne Koff, Ph.D., Managing Director of the Human Vaccines Project. "Decoding the Human Immune System is central to managing the global challenges of communicable and non-communicable diseases, from cancer to Alzheimer's to pandemic flu. This study marks an important step towards understanding how the human immune system works, enabling the development of next-generation health products through the convergence of genomics and immuno-monitoring techniques with machine learning and artificial intelligence. "
This article has been published from materials provided by the Human Vaccines Project. Note The material may have been edited for length and content. For further information, please contact the source provided.
High frequency of shared clonotypes in human B cell receptor repertoires. Cinque Soto, Robin G. Bombardi, Andre Branchizio, Nurgun Kose, Pranathi Matta, Alexander M. Sevy, Robert S. Sinkovits, Pavlo Gilchuk, Jessica A. Finn & James E. Crowe Jr. Nature, February 13, 2019, https://doi.org/10.1038/s41586-019-0934-8.