NIH program harnesses DNA nanotechnology-driven barcoding and signal amplification technologies to map cells and their functions in the human body
By Benjamin Boettner
(BOSTON) — Wyss Institute nanotechnologist and systems biologist Peng Yin, Ph.D., has been selected as awardee of the Human BioMolecular Atlas Program (HuBMAP). The National Institute’s of Health’s program was recently founded to facilitate research on single cells within tissues with the ultimate goal to develop a framework that will allow scientists to map the human body’s cells with their functions.
Yin is a Core Faculty member at the Wyss Institute for Biologically Inspired Engineering at Harvard University and co-leader of its Molecular Robotics Initiative, and also Professor of Systems Biology at Harvard Medical School. Together with his team, he is planning to engineer a DNA nanotechnology-based approach for highly multiplexed detection of molecules within human cells in their natural tissue and organ context using advanced signal amplification methods.
HuBMAP’s goal is to create the basis for a much improved understanding of the relationship between cellular organization and function within the body’s tissues, as well as of the natural variability present in normal tissue organization. In the future, this could allow researchers to also identify critical changes that drive and occur with aging and in the transition of tissues from their healthy to diseased states.
Given the vast numbers of cells with their specific morphologies, interactions and functions in the human body, key to the program’s success will be the development of new high-throughput approaches that would have the ability to rapidly determine the presence and states of the multiple molecules within them. Presently, it is challenging to simultaneously and sensitively detect multiple molecules with high throughput in intact tissues, and important molecules that are present in only few copies can be difficult to detect even with cutting-edge low throughput methods.
An important part of the HuBMAP program therefore will be its support for such breakthrough technologies, as well as a public infrastructure hosting and providing the resulting data for a long-lasting impact of the effort. To overcome the roadblock hindering the multiplexed and ultra-sensitive detection of molecules, Yin’s team plans to leverage two of their previously published DNA nanotechnological approaches and further engineer them into a HuBMAP-enabling platform.
In essence, within their platform, the researchers plan to first tag multiple different molecules in the cells contained in a fixed intact tissue section with unique DNA bar codes that are attached to detection reagents such as molecule-specific antibodies. Using their primer exchange reaction (PER) method, the barcodes can then be extended into long, single-stranded concatemers of DNA that present tens to hundreds of binding sites for so-called fluorophore-bearing DNA imager strands at the molecules’ original locations. The imager strands, which are one of the components of the team’s DNA-Exchange-Imaging (DEI) method, are bound to the extended barcodes to enable the rapid sequential visualization of up to 30 different biomarkers across a fixed tissue with high sensitivity in a single experiment.
This workflow using the integrated method could significantly speed up HuBMAP’s cell-mapping effort via a broad collaboration within and beyond HuBMAP’s community.
“I am honored to be part of the HuBMAP program and believe that our DNA nano-technology-driven efforts that complement the program’s other lines of investigation can help bring this vision to life and unearth new and vital principles of tissue organization and function,” said Yin.