JEFF NIVALA
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 Improving the molecular to digital interface for <fast, scalable, accessible, secure> molecular information systems

Integration of silicon and biomolecular systems is a promising direction of research that is motivated by potentially transformative outcomes, including new ways to build hybrid computer systems that integrate molecular data storage and processing with electronics, automated synthetic biology design-build-test- learn processes; and novel substrates for generalizable integration of electronics and life. While biomolecular computers cannot achieve the fast time scales at which semiconductor-based devices operate, biological parts have unique advantages. For example, they can be vastly smaller in scale, energetically efficient, and massively parallel. They can also more easily interface with natural biological systems for “near-data” processing. These features potentially enable wetware devices to perform in environments that traditional hardware cannot (e.g. inside the body), and even achieve sufficient computational throughput for otherwise expensive data processing tasks. Hence, the fast progress happening in DNA data storage, hybrid silicon-biomolecular sensors, and synthetic biology. However, continued progress in these areas calls for 1) more scalable mechanisms of accessing and operating on molecular data; 2) more efficient means of communication between electronic and molecular components; and 3) the ability to better understand how to reliably design and build biological components and systems at scale. 
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Molecular Information Storage and Scalable Communication Systems in Synthetic Biology and Nanotechnology
Biology has evolved complex information storage and processing networks through cellular connections and molecules that participate in highly specific interactions, for example through Watson-Crick base pairing of nucleic acids and protein-based molecular recognition. On the other hand, modern semiconductor-based computing devices store and transmit information electronically. Thus, a key challenge in designing synthetic bio-nano hybrid systems that simultaneously harness the advantages of both biological and semiconductor-based technologies is in engineering interfaces that allow for real-time communication across disparate components. To address this, we build new molecular technologies (that can be used both in-vitro and in-vivo) to store and transmit information in the form of single-molecule nanopore-addressable molecular barcodes made of synthetic DNA and proteins.

Related pubs:​
  • Zhang K*, Chen YJ*, Doroschak K, Strauss K, Ceze L, Seelig G, Nivala J. A nanopore interface for high bandwidth DNA computing. bioRxiv. 2021. 
  • Cardozo N*, Zhang K*, Doroschak K*, Nguyen A, Siddiqui Z, Bogard N, Strauss K, Ceze L, Nivala J. Multiplexed direct detection of barcoded protein reporters on a nanopore array. Nat. Biotechnol. 20121.   
  • Ney P, Organick L, Nivala J, Ceze L, Kohno T. DNA sequencing flow cells and the security of the molecular digital interface. Privacy Enhancing Securities Symposium. 2021. 
  • Doroschak K, Zhang K, Queen M, Mandyam A, Strauss K, Ceze L, Nivala J. Rapid and robust assembly and decoding of molecular tags with DNA-based nanopore signatures. Nat. Comms. 11, Article number: 5454. 2020. ​
  • Cardozo N*, Zhang K*, Doroschak K, Nguyen A, Siddiqui Z, Strauss K, Ceze L, Nivala J. Multiplexed direct detection of barcoded protein reporters on a nanopore array. 2019.  https://www.biorxiv.org/content/10.1101/837542v1
  • Shipman SL*, Nivala J*, Macklis JD, Church GM. Molecular recordings by directed CRISPR spacer acquisition. Science. 353(6298). PMID 27284167. 2016.
    *equal contribution
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  • Nivala J, Shipman SL, Church GM. Spontaneous CRISPR-loci generation in-vivo by non-canonical spacer integration. Nat. Microbiol. (3):310-318. 2018.
  •  Shipman SL, Nivala J, Macklis JD, Church GM. CRISPR-Cas encoding of a digital movie into the genomes of a population of living cells. Nature. 547. 345-349. PMID: 28700573. 2017.
Nanopore Proteomics:
​towards single-molecule protein sequencing and PTM detection


While genomic analysis illuminates the blueprints used by organisms to store and propagate information, proteins are the principal active ingredients in the recipe of life. Thus, our ability to understand and engineer complex biological processes hinges on elucidating the structure and function of whole proteomes -- robust technologies to identify and characterize proteins are vital to this effort. Towards this goal, a primary focus of our research is developing new methods of protein analysis. Currently, we're advancing nanopore sensing technology for interrogation of intact protein strands and peptide fragments. This process results in a series of ionic current blockade data that, when combined with machine learning, can be diagnostic of protein/peptide structure at the single-molecule level. This work represents the first steps towards developing the principles of this technology as a general platform for protein and post-translational modification (PTM) identification, and is aimed at achieving the resolution required to fully grasp the complexities of the proteome.

​Related pubs:
  • ​Motone K, Cardozo N, Nivala J. Herding cats: label-based approaches in protein translocation though nanopore sensors for single-molecule protein sequence analysis. iScience. ​2021.
  • Cardozo N*, Zhang K*, Doroschak K, Nguyen A, Siddiqui Z, Strauss K, Ceze L, Nivala J. Multiplexed direct detection of barcoded protein reporters on a nanopore array. 2019.  https://www.biorxiv.org/content/10.1101/837542v1
  • Nivala J, Marks DB, Akeson M. Unfoldase-mediated protein translocation through an α-hemolysin nanopore. Nature Biotechnol. (3):247-50. PMID: 23376966. 2013.
  • Nivala J, Mulroney L, Li G, Schreiber J, Akeson M. Discrimination among protein variants using an unfoldase-coupled nanopore. ACS Nano. 23;8(12):12365-75. PMID: 25402970. 2014.
CyBio Security
Technological advances in biotechnology, especially next-generation DNA sequencing and direct-to-consumer genotyping, have created exponentially more biological data. To reach this scale, biotechnology pipelines have increasingly relied on automation and computation in the molecular data-processing workflow: biological samples are processed at scale using robotic equipment; molecular sensors, like DNA sequencers, have become specialized computers with peripheral sensors designed to read molecules; and extensive data processing and digital storage is required to manage and make use of this data. All of this computation raises potential security issues that are more typically associated with computer systems. As part of a collaboration with the UW CSE Security Lab and Tech Policy Lab, we explore cybio security vulnerabilities in DNA data-processing workflows, from physical sample processing through reading DNA into digital information and eventual data analysis.
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Related pubs:
  • ​Ney P, Bhattacharya A, Ward D, Ceze LH, Kohno T, Nivala J. Doctoring Direct-to-Consumer Genetic Tests with DNA Spike-Ins. bioRxiv. 2022.
  • Ney P, Organick L, Nivala J, Ceze L, Kohno T. DNA sequencing flow cells and the security of the molecular digital interface. Privacy Enhancing Securities Symposium. 2021. 
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