The Laboratory of Prof. Mark Bathe at MIT uses nucleic acids (DNA and RNA) to engineer revolutionary new materials at the nanometer-scale, or nanoscale, where one nanometer is approximately 10,000x smaller than the thickness of an individual human hair.
One goal of these nanoscale materials is to enable the targeted, in vivo delivery of therapeutic nucleic acids such as siRNA, messenger RNA, and CRISPR to organs and tumors that are otherwise impossible to reach. Achieving this goal may help to develop cures for over 7,000 known genetic diseases, and cancer. Another goal of these nanoscale materials is to design new “qubits” that are the equivalent of “transistors” from conventional semi-conductor chips. Achieving this goal would enable highly parallel quantum computing at room temperature to augment conventional silicon computers that have reached the end of Moore’s Law. And a final goal of these nanoscale materials is to be able to write, store, and read massive datasets in a rapid, compact, and energy-efficient manner. Achieving this goal would offer the ability to make a low-cost, zettabyte-scale (1 trillion gigabytes) file system for the archival storage of all of the world’s information.
Structural DNA & RNA Nanotechnology
Natural DNA and RNA are present in all cells as the carriers of genetic information that is passed down through generations. In this work, we are using these nucleic acids as building materials at the nanometer-scale (nanoscale), which is 10,000x smaller than the thickness of a single human hair. We create complex 2D and 3D organized materials using nucleic acids, which we are applying to a broad range of revolutionary applications including: (1) mimicking viruses for vaccines and the targeted delivery of therapeutics such as CRISPR, messenger RNA, and siRNA; (2) organizing chromophores or dyes to mimic light-harvesting complexes to control quantum information for quantum sensing and computing; and (3) organizing high density light-emitting molecules for massive, exabyte-scale molecular data storage, retrieval, and computing. The overall size of the icosahedral structured DNA nanoparticle shown is approximately 40 nanometers, whereas the diameter of the duplex of DNA shown composing each edge of the nanoparticle is 2 nanometers, and the thickness of a human hair is approximately 10,000 to 100,000 nanometers.
Viral-like Nanoparticles for Vaccines & Therapeutic Delivery
Natural viruses contain proteins on their outer coat that enable them to evade the immune system, enter into cells, and integrate their genomic DNA into their host’s genome. Structured DNA nanoparticles can be used to mimic certain aspects of viruses in order to either target tissues and cells for delivery of therapeutic payloads, or activate immune cells for vaccination. In this research area we are using structured DNA and RNA nanoparticles to enable the targeted delivery of therapeutic siRNA, mRNA, and CRISPR to organs, tissues, and tumors to help find cures for genetic diseases and cancer, as well as to stimulate the immune system to make effective vaccines to protect against infectious diseases. The viral-like DNA nanoparticle shown is bearing 10 copies of an antigenic protein used for a vaccine application (the scale bar is 10nm).
Quantum Sensing, Information Processing, and Computing
Natural photosynthetic complexes consist of structured nanoscale assemblies of chlorophyll molecules that facilitate photon adsorption and energy transfer for the production of the chemical fuel ATP, which is the origin of energy for life on planet earth. Programmed self-assembly of synthetic DNA into precise 2D and 3D nanoscale architectures that mimic natural light-harvesting systems can now be used to organize synthetic chromophores to replicate key aspects of bacterial photosynthetic systems, controlling how energy and quantum information are transported at the nanoscale. In this research, we are making structured DNA assemblies with embedded chromophores to engineer new qubits (the information-bearing unit of quantum computers) to program new quantum information sensing, processing, and computing capabilities. Through our research, we might also discover new principles for efficiently harvesting energy from the sun. (Figure is courtesy Ella Maru Studio.)
Molecular Computing, Data Storage & Retrieval
The 4-letter ATGC code of DNA in our cells encodes approximately 1 gigabyte of information per human genome, packaged up neatly within the nucleus of the cell. Synthetic DNA can similarly be used as a storage medium to contain files and other data in an extremely compact manner such that the entire world’s information could in principle fit in the palm of our hand if encoded in DNA. However, retrieving information or files from such “pools” of data encoded in DNA is a highly non-trivial task, since this information is in principle unstructured and disorganized. An analogy would be finding a page or chapter from a book in the US Library of Congress if all of its books were simply piled into the center of a football stadium. In this research area our lab is using DNA nanoparticles to organize and structure data and information stored in DNA, and developing ways to both randomly access arbitrary pools of data ranging from 1 MB to 1 GB from a pool of 1 Exabyte of data (1 Exabyte is 1 billion GB), as well as to compute using these molecular datasets, ranging from machine learning to data sorting and image recognition. Figure from Scientific American.
Understanding Mutations associated with Schizophrenia & Autism
Neuronal synapses consist of hundreds of proteins organized at the sub-micron scale that facilitate synapse plasticity and signal transmission in normal brain development and function. While genetic studies have revealed numerous variations in neuronal synapse proteins that are associated with diseases such as Schizophrenia and Autism, it is unknown how these genetic variations impact neuronal synapse structure and signal transmission needed for normal brain function. In this research, we are applying synthetic nucleic acids to perform highly multiplexed imaging of synaptic proteins and their transcripts to resolve their sub-cellular localization, expression levels, and molecular associations. This research area aims to understand how genetic variations present in patients with Schizophrenia and Autism impact neuronal function to ultimately help develop therapeutic treatments for these debilitating diseases.
Coordination of RNAs for structural and enzymatic studies
RNAs perform a variety of important roles in cells, from acting as trans regulators (e.g. siRNA and lncRNA) of many cellular processes to catalyzing peptide bond formation in the ribosome, and carry the genetic information of retroviruses like HIV and Ebola. The structures of these RNAs play a critical role in their functions, and larger RNAs typically move through an ensemble of structural states to function. We are using nucleic acid origami to coordinate RNA structures for two branches of study: (1) to stabilize large RNAs in a single conformation at a time, enabling cryo-EM imaging and reconstruction of what otherwise would be highly noisy structures; and (2) to determine which components of ribonucleoprotein complexes like the ribosome are catalytic and work towards assembling protein-free or minimal-protein enzymes.