Step into associate professor Mark Bathe’s lab in the Department of Biological Engineering and you’ll find design and biology merging at the nanoscale. Under an electron microscope you might see a cornucopia of three-dimensional shapes—icosahedra, pyramids, and stars—all assembled from synthetic strands of DNA. “There’s no other molecular medium we can design and fabricate with such a versatility of geometries and precision at the nanoscale as DNA,” says Bathe ’98, SM ’01, PhD ’04.
And Bathe has added to that versatility: with graduate student Sakul Ratanalert, he recently developed software called DAEDALUS, which captures the complex rules of DNA construction in an algorithm that makes three-dimensional DNA design easier and more accessible to a wide range of scientists and engineers.
Most people think of the spiraling set of nucleic acids purely as the code of life. The strings of As, Ts, Cs, and Gs (adenine, thymine, cytosine, and guanine) in cells provide the blueprint for how living things behave and reproduce. And for nearly half a century bioengineers have creatively manipulated those sequences to change the way organisms function—breeding new pest-resistant plants, for example, or microbes that ferment medicines and chemicals.
But the double helix of DNA also possesses unique characteristics as a nano-building material. In 2006, Caltech researcher Paul Rothemund discovered that if he synthesized DNA letters in specific sequences, the molecular bonds that glue the As to Ts and Cs to Gs, and which come undone when DNA replicates, could be used to fold the DNA into two- and three-dimensional shapes. With a nod to both the precision and elegance of the technique, scientists dubbed it “DNA origami.”
The beauty of DNA origami is that once the components are collected, all it takes is a little shake and some Brownian motion—the random movement of particles in fluid—for these shapes to assemble themselves. The system uses a single long strand of DNA as scaffolding on which to stick smaller strings of letters. The DNA conforms to the shape as the letters bond to each other.
But the rules for designing DNA origami are difficult, if not arcane, and lining up nucleotides to fold into corresponding 3-D shapes can tax even the most brilliant minds. “It’s been limited to a small group of experts,” Bathe says. His software is changing that.
Rather than manually fiddling with sequences of nucleotides, DAEDALUS users design the target geometric structures they want, and the algorithm generates the corresponding nucleotide sequences to make them. “You give the software a high-level geometric shape, and then it will automatically produce that shape using DNA,” Bathe says.
In a sense, Bathe himself may be a perfect researcher for exploring how these geometries translate across scales. He’s part of an MIT legacy—the son of longtime engineering faculty member Klaus-Jürgen Bathe. Like his father, the younger Bathe earned his PhD in mechanical engineering; but from childhood, his interests skewed towards biology and medicine. “I’ve always wanted to build technologies that impact human health, more than cars or bridges, like my father,” he says. With DAEDALUS, Bathe has built a bridge of another kind, connecting designers of many disciplines with the tools of molecular biology.
Bathe is now working to harness his DNA nanoshapes to deliver drugs inside the body. Taking a cue from viruses that attach to cells to infect them, Bathe hopes to design a variety of DNA structures that deliver payloads of antibodies or even gene-editing enzymes such as Cas9 to diseased cells within the body. “The holy grail would be to edit the brain for treatment of diseases such as autism or schizophrenia, or cancer cells in malignant tumors,” Bathe says.