The NIH Director’s Pioneer Award funds High-Risk, High-Reward Research conducted by exceptionally creative scientists proposing pioneering approaches.
“My entire group is excited about this opportunity to embark on an ambitious new direction to map organelles electrochemically. Over ten years, we developed our ion-sensing technology at two Universities in different countries. I’m looking forward to exploring previously uncharted spaces inside the cell armed with this technology. Of course, my group would not be here without the intensely stimulating environment of UChicago: it celebrates risk-taking. It nurtures a culture of learning from failure - the heart and soul of exploring the unknown.”
Yamuna is a chemist who learned how to mold DNA into specific nanoscale shapes. One can do this with DNA because it is essentially a thread that is only 2 nm thick so that you can knit it into shapes on that length scale, and these shapes can be engineered to have specific functions.
She started her lab at the National Center for Biological Sciences in Bangalore, India, 17 years ago as the only chemist in an institute full of biologists. There, she became captivated by organelles inside our cells. Organelles are nanoscale compartments inside cells. They have a little border made out of a membrane that encloses a space inside called the lumen. And each type of organelle performs specific functions for the cell, just like organs of our bodies perform very specific functions for our body. Collectively, organelles work collaboratively to produce, degrade, modify and transport biomolecules around the cell, and they do so by performing specific reactions inside their lumens. To the chemist in Krishnan, organelles looked like nanoscale biochemical reactors inside the cell, and she wanted to know more about the chemical environment of the lumens of organelles. But then she found that very little was known about these inner spaces inside our cells, so curiosity drove her to build technology using DNA nanodevices to measure ions inside organelles.
These spaces have remained unexplored because they have proved highly challenging for chemists to analyze for three reasons. The first is the chemical and analytical challenge of creating ion sensors and measuring their absolute levels inside a living system.
The second is the biological challenge of accessing these sub-cellular spaces with accuracy. This is a Russian doll problem on the nanoscale - one has to probe a very small space inside an organelle inside a cell, which is inside a living organism. Finally, how does one design sensors to quantitate chemicals when one has no idea of the parameters one will encounter in that space? Even if all these obstacles are overcome, the final challenge is that most organelles are acidic, and acidity interferes with ion-sensing chemistry. Because this is such a complex problem, these spaces remained unstudied, unmapped, and therefore under-utilized in our current understanding of health and disease.
Once they succeeded in measuring ions in these previously inaccessible spaces, Krishnan realized that her lab had pulled off a coup. They had made an “Amazon-style” delivery platform for biological systems: delivery with organelle-level precision. The Pioneer award will enable Krishnan to use her organellar ion-mapping technology to develop a new field of in situ organelle electrophysiology and develop an understanding of the electrical behavior of organelle membranes in neurodegenerative disease.