John Reif and his students share a passion for interdisciplinary work. It’s the challenge of learning new subjects that has led the professor and his students into the emerging field of nanoscience — in particular, into research on DNA self-assembly and molecular programming.
“My training since Day 1, even as an undergraduate, has been very interdisciplinary,” Reif said. “I like to find emerging areas that seem like they have promise. It’s a little edgy to do that because you have to learn fairly large bodies of literature. I try to do my homework.”
Part of the work includes finding students with a similar interest and willingness to learn and train in new subjects, like the chemistry and biochemistry needed to execute an experiment’s protocols. The mixture of experiments and theory work that Reif’s students do provides them with challenges beyond the computer science field alone, said Nikhil Gopalkrishnan, who just earned his doctorate this spring, and Ph.D. candidates Harish Chandran, Sudhanshu Garg and Tianqi Song.
In particular, Chandran, who expects to graduate in the summer, likes the ability to adapt techniques that were developed in computer science for processing information to self-assembly techniques for building matter at the nanoscale.
“There’s a great opportunity for computer scientists to see certain things that chemists and biologists fail to take notice of,” he said. “It’s always good to look at the field through the computational lens and see obvious things that people are missing in the landscape.”
The process of self-assembly moves away from the top-down construction methods used widely in engineering and manufacturing processes and takes advantage of the highly programmable nature of DNA to build from the bottom up at the molecular scale. Self-assembly is the main unifying theme at the Foundations of Nanoscience conference that Reif founded nine years ago and is the main topic of research in Reif’s lab.
In previous years, his lab experimentally demonstrated a number of firsts for self-assembled DNA nanostructures: the first molecular-scale computations, the first programmable molecular-scale patterning, and the first synthetic molecular-scale robotic devices that walked on self-assembled DNA nanostructures without outside mediation.
For his doctorate, Gopalkrishnan grew a 3-dimensional DNA crystal he designed with Reif using DNA self-assembly. The process, which is intended to serve as the scaffolds for organizing and crystallizing proteins, has allowed them to demonstrate the second-ever, rationally designed 3D DNA crystal. Through crystallization, the structure and, thus, function of a protein can be determined.
“The function of proteins is critical to understanding how biology works,” Gopalkrishnan said. “Everything the cell does is determined by how the protein works. So understanding the proteins is a step toward understanding how biology works.”
The idea of using DNA as a medium to host and crystallize proteins, which typically don’t crystallize well, was the brainchild of NYU’s Ned Seeman, considered the father of DNA nanotechnology. Several years ago, Seeman developed the first macroscopic DNA crystal. Reif and his students now are trying to develop different crystal structures that will host proteins.
“We need to improve the quality of the crystals, and we need to figure out how to host proteins in them,” Gopalkrishnan said. “It took 20 years for Seeman to make a DNA crystal of sufficient quality. It’s just about getting there. But the power of this technique is that if you can get it to work for the first protein, probably you can get it to work for a whole host of proteins.”
Reif and his students also are using DNA self-assembly to help with early and inexpensive detection of HIV and chlamydia. Standard antibody tests are cheap but can only be performed about a month after infection, even though disease still can be transmitted in those first weeks. Tests that rely on chain reactions for sensitive detection of the DNA sequences characterizing an infectious disease are expensive because of the required investment of time and technicians to perform the tests. The goal for Reif and his students is to create an automated early detection system that can be used quickly and easily in remote villages in Africa or India, where there is no access to electricity, labs or cold storage.
Their system, tested only in a test tube so far, uses self-assembling nanostructures combined with autocatalytic reactions to amplify the presence of a disease marker by quickly replicating it. The group is developing protocols for their experiment. The aim is a test that could be as simple as dropping serum into a solution, with detection easily signaled, such as through a change in the solution’s color.
“The techniques that we developed are universal in the sense that they can be applied across multiple diseases,” Chandran said. “So although we are trying to detect a specific disease, our system can be adapted to detect a different disease.
“It’s a very long drawn effort,” he added, “and it’s going to take much more time to get it to a stage where we can actually make it as street-level as a pregnancy test.”
In collaboration with Microsoft Research, Reif and his students also are working on building faster, more sophisticated DNA circuits with fewer errors.
“Theoretically it is possible to perform any computation that you can perform on your laptop or any computing device using these chemical reaction circuits,” Chandran said.
Microsoft’s interest is in creating biological circuitry and biological computational devices that, in the distant future, can be embedded in organisms. In their major effort so far, Reif’s group has worked out computer simulations of how their circuits will behave when built in the lab. They’ve developed strategies to increase the speed of the circuits and are working on reducing computing errors to 10 or fewer. They also are trying to increase the complexity of their circuits, noting that Caltech Professor Erik Winfree has built modest-sized circuits involving up to 70 DNA gates. His DNA circuits can compute the square root of any number between 0 and 15. Reif’s group is trying to scale the number of gates up to the thousands to build circuits that can compute the square root of the first 1,000 or 10,000 numbers.
“We want to be able to reach up to a level of complexity where we start performing biologically useful tasks,” Chandran said.
Reif is the A. Hollis Edens professor of computer science and also serves a few weeks a year as a distinguished adjunct professor in the Faculty of Computing and Information Technology at King Abdulaziz University in Saudi Arabia, where he is working on a novel cost-efficient solar concentrating system he invented.