Yamuna Krishnan has spent years making tiny DNA machines to probe what really goes on inside cells of the human body. Natural biological devices, many of which function at the molecular or nano level, can be harnessed to peek into cells, whether healthy or diseased, and understand the processes within. Krishnan’s DNA nanomachines, also called nanobots, do just that. They provide a microscopic vehicle to transport chemicals into cells to analyse the cells’ environments.
Krishnan first started this work at the National Centre for Biological Research in Bangalore, and now continues her research as a professor at the University of Chicago. She has won this year’s Infosys Prize in Physical Sciences for 2017.
Krishnan spoke to Scroll.in about what her research means for the understanding and treatment of disease. Here are edited excerpts of the conversation.
How do your DNA nanodevices help detect disease?
DNA can be used to measure a fundamental property of the cell, the pH. My lab seeks to use DNA, like wool on the nanoscale, to knit it into little nanobots and thereby harness DNA to map chemical environments of cells inside whole, living organisms. These nanobots sense levels of specific chemicals in the cell environment by glowing in different colours. We graft chemical detectors on to the nanobots that change colour when in contact with particular chemicals.
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.
For example, we showed this in certain endocytic compartments and secretory organelles [which are cell components that are involved in sending proteins and lipids to the cell membrane and in releasing materials outside cells]. The level of chloride homeostasis, an internally established equilibrium in the cells, is changed in those suffering from cystic fibrosis. Similarly, levels of calcium, reactive oxygen species, hydrogen peroxide and nitric oxide may be disturbed in others with particular disease conditions. We have always wanted to measure them; these levels predict the differences between a healthy cell and a diseased cell. Here is where the DNA nanobot can come in and tell us the changes in pH due to above mentioned processes.
What are the applications of such a device?
Applications are in three areas – in diagnostics, in drug discovery and to understand the molecular mechanisms of disease.This is exciting because we can now not only detect, but also 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.
We are launching a company to take a new class of diagnostics forward for neurodegenerative diseases. There are common neurodegenerative diseases called dementias that affect the elderly, but there are rare neurodegenerative diseases called lysosomal disorders that affect children. We are coming up with early stage diagnostics for both classes of neurodegenerative diseases.
The diagnostic procedures for lysosomal disorders in infants are still in the stone age. Until the child is four or five, parents are unaware of the situation and then when they find out, it is too late. In India, recently there was a report that said that about 250 people in Kerala have a lysosomal storage disorder because of a genetic flaw. The diagnosis will improve the quality of life of treated individuals.
[Lysosomal storage diseases are inherited metabolic diseases that are characterised by an abnormal build-up of various toxic materials in the body’s cells as a result of enzyme deficiencies. There are nearly 50 of these disorders altogether, and they may affect different parts of the body, including the skeleton, brain, skin, heart, and central nervous system.
There is no cure for lysosomal storage disorders, and there are not yet specific treatments for many of these diseases. ]
As proteins in the cell move from one place to another, other biomolecules can hitch a ride on them and be delivered to a destination point. This could be a therapeutic process, such as in lysosomal disorders where the protein in the ribosome does not function because of a genetic flaw. The correct protein could be delivered. Similarly in enzyme replacement therapy, the above process can be used to deliver the correct enzyme. These therapeutic processes will take time.
[A ribosome cell organelle made up of protein and RNA that is involved essential processes like translating genetic information in DNA to build new protein.]
Can the above procedures be followed in living patients?
One of the fastest ways to apply this technology to benefit human health is in in-vitro diagnostics. This involves taking a pinprick of blood and then querying specific cells with our DNA devices to then reveal the metabolic status of the cell, and therefore the patient. To use it to deliver therapeutics will take much longer timescales due to the need for governmental approvals and satisfying all the regulatory aspects before it can be available widely to the public.
Before one tries it on a real person, one has to go through a lot of rules and regulations. That is why we are concentrating on developing diagnostics, drug discovery and research. Therapeutics will have to wait for government approval.
Will your diagnostics be available in India?
That is the reason I moved to Chicago. So that the fruits of our research could be available to people everywhere in India, China, Africa etc, not just the United States markets and European markets. We need cheap, rapid, accurate and high throughput diagnostics for large populations, where these diseases can be screened for.