Yamuna Krishnan, a professor in the department of chemistry at the University of Chicago, has a challenging, yet exciting, task on hand. She and her team are on the path to “uncover new functions of DNA, which go beyond its traditional role as nature’s (life’s) genetic material".
Recently awarded the Infosys Prize 2017 in physical sciences by the Infosys Science Foundation, she is well known in scientific circles for manipulating DNA—the building blocks of life—to create biocompatible nanomachines that are not harmful or toxic to living tissue.
Nanomachines, which do not resemble machines as we know them, are only a nanometre wide—50,000 could be lined up across the width of a human hair. Researchers across the world have been designing these (also known as nanobots or nanodevices) for drug delivery and building complex nano-structures.
However, Krishnan’s lab creates “nanodevices using a scaffold (i.e., DNA) given to us by nature, and then puts these artificial biological devices back into the cell to probe the cell’s chemical environment", she explains in a recent interview.
Her lab has created “a new chemical imaging technology that uses DNA nanodevices as fluorescent reporters to quantify chemical messengers in living systems". By reporting on the whereabouts of various small molecules and ions in the cell, researchers can gain crucial insights into the metabolic state of the cell.
One can use this fundamental discovery for purposes like drug delivery or drug discovery, but Krishnan’s lab seeks to use it to understand the workings of a cell.
Krishnan points out that while gene-editing technologies such as CRISPR-Cas9, used to alter human genomes, are important, the world of medicine will still need a method to tell you about the progression of your disease, or whether your body is responding to treatment or therapy.
The applications of the technology, according to Krishnan, cover three areas—in understanding the molecular mechanisms of disease, diagnostics, and drug discovery. “This is exciting because we can now not only detect, but quantify, protein activity inside cells while they are inside a living organism. Therefore, we can now identify small molecule drugs with much greater ease inside living organisms or living cells non-invasively.
“By measuring chemicals that we could never see earlier, inside parts of the cell that we could never access earlier, we can get a whole new view of cell physiology and disease that would teach us about the basic aspects of how diseases develop," Krishnan says.
Other researchers make exquisitely shaped structures using DNA, but Krishnan explains that her lab’s “signature is minimalist—using the least amount of building material (DNA) to achieve a specific function".
Despite many researchers’ interest in using nanobots for drug delivery, Krishnan’s lab takes a broader view of our fundamental discovery. In addition to setting right specific rogue cells by either killing or reprogramming them, “we can also envisage probing diseased cells to understand the molecular origins of the disease itself, or evaluate the cell’s response to therapeutics, monitor disease progression, and so on", she says.
According to Krishnan, her lab seeks to use DNA like wool on the nanoscale to “knit" it into little nanobots and thereby harness DNA to map the chemical environments of cells inside whole, living organisms. These nanobots sense the levels of specific chemicals in the environment by glowing in different colours. Krishnan and her team graft chemical detectors on to the nanobots, which allow the nanobots to sense specific chemicals in the environment and glow accordingly, reflecting a colour that is associated with the chemical.
“We then integrate molecular motifs that act as homing devices so that these nanobots can sail into the nooks and crannies of living cells, and by measuring the levels of specific chemicals therein, can report on how healthy or diseased the cell is," she explains.
The question, though, is what these developments mean for the world of medicine, and DNA research.
Krishnan’s lab is in the process of making a DNA-sensor technology that is very “plug and play" so that researchers can easily use it to investigate live cells. Krishnan believes it may help the healthcare industry because “these can be used to monitor chemical signatures that can parametrize the metabolic state of the cell while it is alive". Thus, one can screen thousands of chemicals on diseased cells, and these DNA devices can help identify potential drug molecules.
Krishnan is in the process of launching a company based on this technology to diagnose neurodegenerative diseases. Her team will begin by targeting rare forms of neurodegenerative diseases that affect infants and children, to expedite governmental approvals for the technology.
She cites the example of diseases called lysosomal disorders that are extremely hard to diagnose (lysosomes are sacs of enzymes within cells that digest large molecules and pass the fragments on to other parts of the cell for recycling. Lysosomal Storage Diseases are a group of approximately 50 rare inherited metabolic disorders that result from defects in lysosomal function).
“Early diagnosis can buy the child a few decades of life, allowing early commencement of treatment," explains Krishnan, who is exploring the possibility of using the Infosys Prize money for this.
In its ninth year, the Infosys Prize comprises a purse of Rs65 lakh, a 22-carat gold medallion and a citation certificate. “One of the possibilities to use this award, which I am still stunned about, is to develop diagnostics for neurodegenerative diseases that affect infants, as this particular segment does not interest big pharma due to the limited profit margins. The life of a child is a worthy cause," she says.
Krishnan, who did her BSc from the University of Madras, and MS and PhD from the Indian Institute of Science, Bengaluru, was an associate professor at the National Centre for Biological Sciences, Bengaluru, before moving to Chicago in 2014. She believes that her college stint in India gave her “a well-rounded (and interdisciplinary) education".
“So right from an early age, I had started learning to freely engage peers in other areas. The same thing happened at the Indian Institute of Science, where I did my masters and PhD," she adds.
Even at the University of Cambridge, UK (she was a postdoctoral fellow there from 2001-05), her desire to interact with researchers of other disciplines “drove" her to seek out graduate students and postdoctoral researchers in biochemistry, physics, math and literature, even though she was in the chemistry department. “It was probably the single biggest factor in preparing me for a life in interdisciplinary science and trying to understand topics out of the reach of my curricular training," she says.
Going ahead, Krishnan wants to “take the fruits of our research as fast as possible to people across the globe to countries like India, China and Africa—not just the US and European markets". She concludes, “We need cheap, rapid, accurate and high throughput diagnostics for large populations, where these diseases can be screened for."
The winners were shortlisted from over 236 nominations by a jury comprising Prof. Pradeep K. Khosla (University of California, San Diego) for engineering and computer science; Prof. Amartya Sen (Harvard University) for humanities; Dr Inder Verma (Salk Institute of Biological Sciences) for life sciences; Prof. Srinivasa S. R. Varadhan (New York University) for mathematical sciences; Prof. Shrinivas Kulkarni (California Institute of Technology) for physical sciences; and Prof. Kaushik Basu (Cornell University and former senior vice-president, World Bank) for social sciences. It is the first time that three of the six winners of this award are women.