“It’s a very sophisticated naturally occurring device. The ribosome basically turns food into babies,” says professor Yamuna Krishnan.    
This article originally appeared in the Fall 2014 issue of Inquiry, the biannual publication produced for University of Chicago Physical Sciences Division alumni and friends.
Chemistry switches
Yamuna Krishnan builds chemical tools with nucleic acids.

Professor Yamuna Krishnan has always loved making things. When she was a child, she and her sister would cook meals, make invisible ink, and grow sugar and salt crystals. They would use whatever they could find in their mother’s kitchen and father’s garden to create something new.

Thinking she would carry this passion for building into a career, Krishnan wanted to study architecture. Yet at Women’s Christian College in Chennai, India, she took a chemistry course, where she felt both engaged and adept. She changed fields and now works with chemical architectures, using nucleic acids to build biocompatible synthetic nanoscale machines.

A DNA icosahedron (black) held together with aptamers—molecules designed to bind to a specific target—(red) encapsulates molecular cargo (green). A trigger (gray hexagons), folds back the aptamers, opening the icosahedron and releasing the cargo.

Krishnan’s work is influenced by naturally occurring nucleic devices. She cites the ribosome, the cellular machine that arranges amino acids from our diet into all the proteins that make up the human body, using RNA’s template. “It’s a very sophisticated naturally occurring device,” she says. “The ribosome basically turns food into babies.”

She enjoys the challenge of complex organizations, where “multitudes of processes perform in concert.” Such complex systems, common in biology’s realm, have become fodder for chemists, notes chemistry chair Richard Jordan. Advances in technology—spectroscopy, microscopy, imaging, and molecular and computational modeling—have allowed chemists to move from studying “relatively simple systems, like conventional organic or inorganic chemicals at a very detailed level,” to complex systems, like the processes that work together to make up a living organism.

The I-switch, a DNA pH sensor, functions in a soil-dwelling roundworm’s coelomocytes that serve as scavenger cells for the worm. Image courtesy Yamuna Krishnan.

Krishnan joined the University this summer, one of four biologically inclined chemists hired to help the department both reflect and advance chemistry’s changing landscape. Throughout the past decade, the field has expanded “beyond the classical core areas of organic, inorganic, and physical chemistry into other areas of science where a molecular level of understanding is beneficial,” says Jordan. Those areas include materials science and chemical biology, which both involve complex systems.

There’s no clear distinction between chemical biology and the better-known field of biochemistry, Jordan says, but there may be differences in ultimate intention: “Chemical biology describes trying to determine the structures and reactivity of key biomolecules in living systems, how they interact, how they control the processes of life.” Chemical biologists hope to “not only study what’s going on but to manipulate and change it,” relying heavily on chemical synthesis—engineering reactions to create a desired product.

One way chemical biologists like Krishnan exploit synthesis is by building molecular tools designed to enter a living cell and perform a particular function. For instance, the ability to measure pH inside an organelle could help to detect and treat diseases. Just as a fever can indicate illness in humans, acidic conditions can indicate illness in cells; lysosomal storage disorders, including Tay-Sachs disease, are associated with acidic conditions in the lysosome. The challenge is getting a tool to work as well in a complex living organism as it does in a petri dish.

At her previous institution, India’s National Centre for Biological Sciences in Bangalore, Krishnan developed the first—and as yet only—such device: the I-switch. The DNA-based device “uses a structure called the i-motif, which is at the heart of its switching mechanism,” explains Krishnan.

Compared to the complex ribosome, the I-switch is an extremely simple structure that resembles a pair of tongs, closing up under acidic conditions and remaining open under neutral conditions. Attaching molecules called fluorophores, which glow green in the open state, red in the closed state, and yellow and orange in between, Krishnan created a pH meter, a sort of internal litmus test. The switch has thus far worked in worms, and Krishnan hopes eventually to implement it in other living organisms.

Also in Bangalore, Krishnan’s lab developed a 3-D nanostructure with a hollow center, called a DNA icosahedron, that helps deliver macromolecules, like drugs or bio-imaging agents, directly where they’re needed. The 20-faced capsule has the most complex solid shape possible to maximize volume and minimize open spaces where the cargo could leak out.

To achieve the geometry, she engineered DNA sequences with regions that attract each other; under ideal conditions, the strands fold and connect into an icosahedron. Krishnan designed the structure as a sort of Trojan horse molecule, incorporating a responsive module that opens the capsule in the presence of a chemical trigger, releasing the cargo at its intended target and preventing degradation along the way.

At UChicago, Krishnan hopes to apply her synthetic nanomachines to disease models and also develop new devices. While continuing to link her work to detecting and treating disease, she also hopes to focus on fundamental issues of biology on a molecular level, a goal she shares with the department’s other new chemical biologists. She is excited to be back in the classroom. “The best way to connect with and integrate into a new environment is to teach a course,” Krishnan says. “I love teaching chemistry, and I have sorely missed that.”

Roll call

In addition to Krishnan, three other biofocused researchers joined the chemistry department this year.

Bryan Dickinson, assistant professor

  • Research areas: Synthetic chemistry, protein engineering, molecular evolution, and cell biology
  • Focus: Developing new technologies to study biological systems, in particular decoding mammalian metabolic regulation, to help understand the mechanisms of and therapeutics for metabolic disease
  • Means: Fluorescent probes, protein sensors, and reprogrammed enzymes

Raymond Moellering, assistant professor (January 1, 2015)

  • Research areas: Chemical biology, synthetic chemistry, biochemistry, and proteomics
  • Focus: Protein modifications and interaction networks in metabolic diseases; synthetically modified protein and peptide therapeutics
  • Means: Chemical proteomics, bioorganic synthesis, and cellular and in vivo model systems

Suriyanarayanan Vaikuntanathan, assistant professor

  • Research areas: Physical chemistry, soft condensed matter physics, and biophysics
  • Focus: Developing and using tools to study complex equilibrium and nonequilibrium systems with the goal of understanding how the organization and information processing of microscopic biological systems behave in a controlled way
  • Means: Theoretical and simulation methodologies and statistical mechanics

To learn more about chemistry department initiatives, please contact Brian Yocum at 773.702.3751 or byocum@uchicago.edu.