by Matthew Eckwahl, PhD
Postdoctoral fellow in the Department of Biochemistry & Molecular Biology
Over a decade ago, artist-scientists first used “DNA origami” to create minuscule smiley faces sculptures. It turns out that DNA’s structural diversity is perfect for building more useful tiny machinery. University of Chicago scientists have taken a lead in developing DNA nanomachines with tremendous potential to help us better understand how cells work, diagnose diseases, and test new treatments.
Yamuna Krishnan is at the leading edge of developing DNA-based tools to home in on specific structures inside the living cell and decipher what is going on there. One powerful use of this technology: identify unhealthy states before disease ravages the body.
Krishnan, the only woman to have won the Infosys Prize in the physical sciences, once aspired to become an architect, so it’s fitting she now builds tools for finding genetic maladies. Her work focuses on the lysosome, the cell’s recycling center, which breaks down useless or toxic material to make new components. Like a city with a failed garbage collection system, if a cell’s lysosomes don’t function properly, there are major problems caused by a buildup of undigested cellular waste. Not surprisingly, genetic lysosome defects can result in a variety of human diseases.
Nearly 60 lysosomal storage disorders have been identified so far. Although individually rare, these diseases collectively occur in about one in 5,000 births and can be inherited from one or both parents. Symptoms vary widely depending on the type of cellular waste that accumulates and where in the body this occurs. Ultimately, the undigested material causes the affected organ to function less efficiently, leading to physical and mental impairments such as seizures, dementia, cardiac disorders, vision and hearing loss, and bone abnormalities. Lysosomal disorders usually arise in childhood, often without obvious symptoms, and many babies die suddenly within months or years of birth.
Although there is no cure for these disorders, an increasing number of treatments are available to reduce symptoms and prolong life—if diagnosis is made early. Faster, more accurate methods to detect lysosomal defects are thus essential.
Krishnan and colleagues have developed DNA nanodevices to uncover these metabolic disorders before it’s too late. To get these DNA nanobots to work, her team overcame several major challenges. First, they needed the devices to specifically target the lysosome. Within the cell, a bustling community with many different activity centers, the nanobot must have the exact molecular address to get to the lysosomal recycling center.
Next, the bot must distinguish healthy from defective lysosomes. Since the lysosome is the most acidic “organelle” within a cell, pH was chosen as a key indicator of lysosome health—just like high blood sugar levels can indicate diabetes. If a lysosome’s pH is off, it suggests something is probably wrong. Impressively, Krishnan’s nanobots can not only find the lysosomes, but also measure their acidity—changing color at different pH levels—without disturbing the other functions in living cells.
Krishnan’s newly created company, Esya, aims to deploy these DNA nanodevices to diagnose a wide range of lysosomal disorders, all from a simple blood draw. This should considerably speed up the testing process and provide a much better outcome for those at risk for disease. This tool could also be adapted to rapidly screen new drugs that normalize the lysosome’s acidity, making it easier and faster to discover improved treatment options.
Krishnan’s lab has developed nanobots that recognize other chemical changes in diseased lysosomes as well. In research reported last year, the Krishnan group created a DNA nanodevice to measure chloride ions—what we know as part of table salt—the first tool capable of sensing this important electrolyte inside a living cell. Their research showed that normal lysosomes have much higher chloride ion levels than defective ones, revealing the unexpectedly important role chloride plays in lysosomal biology— a valuable tool for unmasking lysosomal diseases that don’t affect pH.
Earlier this year, the Krishnan team reported another nifty nanobot that directly senses congestion from undigested material building up in the lysosomes. By reporting back on the gridlocked environment that is a hallmark of lysosomal disorders, this newest device may provide early warnings for other kinds of disorders, preventing future disaster.
It’s reassuring to know that if something is going wrong with your car, a flashing light will warn you before it’s too late. Likewise, the work of Krishnan and others highlights how DNA, life’s genetic material, can also help uncover potentially fatal human diseases and save lives.