Leo (Naiwen) Cui, Ph.D.

Leo (Naiwen) Cui, Ph.D.

Cambridge, Massachusetts, United States
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About

Deep-tech partner at FoundersX Ventures, venture capital firm with strong focus on…

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Experience

  • FoundersX Ventures Graphic

    FoundersX Ventures

    Cambridge, Massachusetts, United States

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    San Diego, California, United States

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    Irvine, California, United States

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    San Francisco Bay Area

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    California, United States

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    Waterloo, Ontario, Canada

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    Lagos, Lagos State, Nigeria

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    San Francisco Bay Area

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    London, England, United Kingdom

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    Boston, Massachusetts, United States

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    Boston, Massachusetts, United States

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    Boston, Massachusetts, United States

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    Cambridge, MA

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    Cambridge, Massachusetts, United States

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    Cambridge, MA

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    Waterloo, Ontario

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    Waterloo, Ontario

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    Coopersburg, Pennsylvania

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    Cambridge, Ontario

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    Cambridge, Ontario

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    Waterloo, Ontario

Education

Licenses & Certifications

Volunteer Experience

  • Broad Institute of MIT and Harvard Graphic

    Broad Summer Scholars Program (BSSP) pre-selection committee

    Broad Institute of MIT and Harvard

    - 1 month

    Education

  • Society for Science Graphic

    Grand Award Judge

    Society for Science

    - 1 month

    Education

  • Broad Institute of MIT and Harvard Graphic

    Broad Summer Scholars Program (BSSP) pre-selection committee

    Broad Institute of MIT and Harvard

    - 1 month

    Education

  • University of Waterloo Graphic

    Mentor in Women in Engineering program

    University of Waterloo

    - 1 year 1 month

    Education

  • Harvard University Graphic

    Judge at National Collegiate Research Conference

    Harvard University

    - 1 month

    Education

  • Assistant

    Graduate Student Research Conference (University of Waterloo)

    - 4 months

    Education

    Organized all the presentations from students in the 2011 Graduate Student Research Conference and communicated with graduate students when necessary.

  • Participant

    Shadow Program (University of Waterloo)

    - 5 months

    Social Services

    • Provided local and campus information to two new international students at University of Waterloo
    • Participated in local events; responded to their questions and concerns due to culture differences

Publications

  • Microfluidic Enrichment and Computational Analysis of Rare Sequences from Mixed Genomic Samples for Metagenomic Mining

    The CRISPR Journal

    Many powerful molecular biology tools have their origins in natural systems, including restriction modification enzymes and the CRISPR effectors, Cas9, Cas12, and Cas13. Heightened interest in these systems has led to mining of genomic and metagenomic data to identify new orthologs of these proteins, new types of CRISPR systems, and uncharacterized natural systems with novel mechanisms. To accelerate metagenomic mining, we developed a high-throughput, low-cost droplet microfluidic-based method…

    Many powerful molecular biology tools have their origins in natural systems, including restriction modification enzymes and the CRISPR effectors, Cas9, Cas12, and Cas13. Heightened interest in these systems has led to mining of genomic and metagenomic data to identify new orthologs of these proteins, new types of CRISPR systems, and uncharacterized natural systems with novel mechanisms. To accelerate metagenomic mining, we developed a high-throughput, low-cost droplet microfluidic-based method for enrichment of rare sequences in a mixed starting population. Using a computational pipeline, we then searched in the enriched data for the presence of CRISPR-Cas systems, identifying a previously unknown CRISPR-Cas system. Our approach enables researchers to efficiently mine metagenomic samples for sequences of interest, greatly accelerating the search for nature's treasures.

    Other authors
    See publication

  • CSF1R inhibition by a small molecule inhibitor affects hematopoiesis and the function of macrophages

    PNAS

    Colony-stimulating factor 1 receptor (CSF1R) inhibition has been proposed as a method for microglia depletion, with the assumption that it does not affect peripheral immune cells. Here, we show that CSF1R inhibition by PLX5622 indeed affects the myeloid and lymphoid compartments, causes long-term changes in bone marrow-derived macrophages by suppressing interleukin 1β, CD68, and phagocytosis but not CD208, following exposure to endotoxin, and also reduces the population of resident and…

    Colony-stimulating factor 1 receptor (CSF1R) inhibition has been proposed as a method for microglia depletion, with the assumption that it does not affect peripheral immune cells. Here, we show that CSF1R inhibition by PLX5622 indeed affects the myeloid and lymphoid compartments, causes long-term changes in bone marrow-derived macrophages by suppressing interleukin 1β, CD68, and phagocytosis but not CD208, following exposure to endotoxin, and also reduces the population of resident and interstitial macrophages of peritoneum, lung, and liver but not spleen. Thus, small-molecule CSF1R inhibition is not restricted to microglia, causing strong effects on circulating and tissue macrophages that perdure long after cessation of the treatment. Given that peripheral monocytes repopulate the central nervous system after CSF1R inhibition, these changes have practical implications for relevant experimental data.

    See publication

  • Single Molecule Protein Detection with Attomolar Sensitivity Using Droplet Digital Enzyme-Linked Immunosorbent Assay

    ACS Nano

    Many proteins are present at low concentrations in biological samples, and therefore, techniques for ultrasensitive protein detection are necessary. To overcome challenges with sensitivity, the digital enzyme-linked immunosorbent assay (ELISA) was developed, which is 1000× more sensitive than conventional ELISA and allows sub-femtomolar protein detection. However, this sensitivity is still not sufficient to measure many proteins in various biological samples, thereby limiting our ability to…

    Many proteins are present at low concentrations in biological samples, and therefore, techniques for ultrasensitive protein detection are necessary. To overcome challenges with sensitivity, the digital enzyme-linked immunosorbent assay (ELISA) was developed, which is 1000× more sensitive than conventional ELISA and allows sub-femtomolar protein detection. However, this sensitivity is still not sufficient to measure many proteins in various biological samples, thereby limiting our ability to detect and discover biomarkers. To overcome this limitation, we developed droplet digital ELISA (ddELISA), a simple approach for detecting low protein levels using digital ELISA and droplet microfluidics. ddELISA achieves maximal sensitivity by improving the sampling efficiency and counting more target molecules. ddELISA can detect proteins in the low attomolar range and is up to 25-fold more sensitive than digital ELISA using Single Molecule Arrays (Simoa), the current gold standard tool for ultrasensitive protein detection. Using ddELISA, we measured the LINE1/ORF1 protein, a potential cancer biomarker that has not been previously measured in serum. Additionally, due to the simplicity of our device design, ddELISA is promising for point-of-care applications. Thus, ddELISA will facilitate the discovery of biomarkers that have never been measured before for various clinical applications.

    See publication

  • Evolution on the Biophysical Fitness Landscape of an RNA Virus

    Molecular Biology and Evolution

    Viral evolutionary pathways are determined by the fitness landscape, which maps viral genotype to fitness. However, a quantitative description of the landscape and the evolutionary forces on it remain elusive. Here, we apply a biophysical fitness model based on capsid folding stability and antibody binding affinity to predict the evolutionary pathway of norovirus escaping a neutralizing antibody. The model is validated by experimental evolution in bulk culture and in a drop-based microfluidics…

    Viral evolutionary pathways are determined by the fitness landscape, which maps viral genotype to fitness. However, a quantitative description of the landscape and the evolutionary forces on it remain elusive. Here, we apply a biophysical fitness model based on capsid folding stability and antibody binding affinity to predict the evolutionary pathway of norovirus escaping a neutralizing antibody. The model is validated by experimental evolution in bulk culture and in a drop-based microfluidics that propagates millions of independent small viral subpopulations. We demonstrate that along the axis of binding affinity, selection for escape variants and drift due to random mutations have the same direction, an atypical case in evolution. However, along folding stability, selection and drift are opposing forces whose balance is tuned by viral population size. Our results demonstrate that predictable epistatic tradeoffs between molecular traits of viral proteins shape viral evolution.

    See publication

  • Single-cell sequencing leads a new era of profiling transcriptomic landscape

    Journal of Biox-x Research

    Understanding the complexity of biological systems requires a comprehensive analysis of their cell populations. Ideally, this should be done at the single cell level, because bulk analysis of the full population obscured many critical details due to artifacts introduced by averaging. However, this has been technically challenging due to the cumbersome procedure, low throughput, and high costs of performing analysis on a single-cell basis. Excitingly, technical improvements in single-cell RNA…

    Understanding the complexity of biological systems requires a comprehensive analysis of their cell populations. Ideally, this should be done at the single cell level, because bulk analysis of the full population obscured many critical details due to artifacts introduced by averaging. However, this has been technically challenging due to the cumbersome procedure, low throughput, and high costs of performing analysis on a single-cell basis. Excitingly, technical improvements in single-cell RNA sequencing are making it economically practical to profile the transcriptomics of large populations of cells at the single-cell level, and have yielded numerous results that address important biological and medical questions. Further development of the technology and data analysis will significantly benefit the biomedical field by unraveling the function of individual cells in their microenvironments and modeling their transcriptional dynamics.

    See publication

  • A mix-and-read drop-based in vitro two-hybrid method for screening high-affinity peptide binders

    Nature Scientific Report

    Drop-based microfluidics have recently become a novel tool by providing a stable linkage between phenotype and genotype for high throughput screening. However, use of drop-based microfluidics for screening high-affinity peptide binders has not been demonstrated due to the lack of a sensitive functional assay that can detect single DNA molecules in drops. To address this sensitivity issue, we introduced in vitro two-hybrid system (IVT2H) into microfluidic drops and developed a streamlined…

    Drop-based microfluidics have recently become a novel tool by providing a stable linkage between phenotype and genotype for high throughput screening. However, use of drop-based microfluidics for screening high-affinity peptide binders has not been demonstrated due to the lack of a sensitive functional assay that can detect single DNA molecules in drops. To address this sensitivity issue, we introduced in vitro two-hybrid system (IVT2H) into microfluidic drops and developed a streamlined mix-and-read drop-IVT2H method to screen a random DNA library. Drop-IVT2H was based on the correlation between the binding affinity of two interacting protein domains and transcriptional activation of a fluorescent reporter. A DNA library encoding potential peptide binders was encapsulated with IVT2H such that single DNA molecules were distributed in individual drops. We validated drop-IVT2H by screening a three-random-residue library derived from a high-affinity MDM2 inhibitor PMI. The current drop-IVT2H platform is ideally suited for affinity screening of small-to-medium-sized libraries (10^3–10^6). It can obtain hits within a single day while consuming minimal amounts of reagents. Drop-IVT2H simplifies and accelerates the drop-based microfluidics workflow for screening random DNA libraries, and represents a novel alternative method for protein engineering and in vitro directed protein evolution.

    Other authors
    • Huidan Zhang
    • Nils Schneider
    • Ye Tao
    • Haruichi Asahara
    • Zhiyi Sun
    • Stephan A. Koehler
    • Tom F. A. de Greef
    • Alireza Abbaspourrad
    • David A. Weitz
    • Shaorong Chong
    See publication

  • Label-free single-cell protein quantification using a drop-based mix-and-read system

    Nature Scientific Report

    Quantitative protein analysis of single cells is rarely achieved due to technical difficulties of detecting minute amounts of proteins present in one cell. We develop a mix-and-read assay for drop-based label-free protein analysis of single cells. This high-throughput method quantifies absolute, rather than relative, amounts of proteins and does not involve antibody labeling or mass spectrometry.

    Other authors
    • Alireza Abbaspourrad
    • Huidan Zhang
    • Ye Tao
    • Shaorong Chong
    • David A. Weitz
    • etc.
    See publication

  • Model of droplet generation in flow focusing generators operating in the squeezing regime

    Microfluidics and Nanofluidics

    Flow focusing generators have been widely used to generate droplets for many applications which call for accurate physical models that describe the droplet formation process in such configurations for design and operation purposes. Most existing models are empirical correlations obtained based on extensive experimental results and thus very sensitive to their own data sets. A comprehensive model that involves less parameter fitting by incorporating more theoretical arguments and thus has an…

    Flow focusing generators have been widely used to generate droplets for many applications which call for accurate physical models that describe the droplet formation process in such configurations for design and operation purposes. Most existing models are empirical correlations obtained based on extensive experimental results and thus very sensitive to their own data sets. A comprehensive model that involves less parameter fitting by incorporating more theoretical arguments and thus has an improved applicability is urgently needed to guide the design and operation of flow focusing generators. This work presents a 3D physical model describing the droplet formation process in microfluidic flow focusing generators that operate in the squeezing regime where droplet size is usually larger than the channel width. This model incorporates an accurate geometric description of the 3D droplet shape during the formation process, an estimation of the time period for the formation cycle based on the conservation of mass and a semi-analytical model predicting the pressure drop over the 3D corner gutter between the droplet curvature and channel walls, which allow an accurate determination of the droplet size, spacing and formation frequency. The model considers the influences of channel geometry (height-to-width ratio), viscosity contrast, flow rate ratio and capillary number with a wide variety. This model is validated by comparing predictions from the model with experimental results obtained through high-speed imaging.

    Other authors
    • Xiaoming Chen
    • Tomasz Glawdel
    • Carolyn Ren
    See publication

Patents

  • Microfluidic Sequencing Techniques

    Issued US WO 2018/017794 Al

    The present invention generally relates to microfluidics and to the determination of cells. In some aspects, primers able to introduce restriction sites into certain amplified nucleic acids are used. The primers may introduce restriction sites into normal (wild-type) nucleic acids, but be unable to introduce restriction sites into mutant nucleic acids, e.g., due to a mismatch in the nucleic acid sequences caused by the mutant. After amplification, the nucleic acids may be exposed to a suitable…

    The present invention generally relates to microfluidics and to the determination of cells. In some aspects, primers able to introduce restriction sites into certain amplified nucleic acids are used. The primers may introduce restriction sites into normal (wild-type) nucleic acids, but be unable to introduce restriction sites into mutant nucleic acids, e.g., due to a mismatch in the nucleic acid sequences caused by the mutant. After amplification, the nucleic acids may be exposed to a suitable restriction enzyme, which may cleave normal nucleic acids but not the mutant nucleic acids. In this way, mutant nucleic acids may be relatively quickly identified. In some embodiments, cells may be contained within microfluidic droplets and assayed to determine the mutant cells. In certain cases, the nucleic acids may be amplified within droplets and attached to suitable tags, e.g., prior to breaking or merging the droplets and sequencing of the nucleic acids.

    See patent

  • Determination of rna in blood or other fluids

    Filed US US2019153427A1

    Extracting or separating nucleic acids from biological samples, e.g. pure separation or isolation methods; Conditions, buffers or apparatuses therefor by means of a solid support carrier, e.g. particles, polymers by chromatography, e.g. electrophoresis, ion-exchange, reverse phase

    See patent

  • FORMATION OF COLLOIDS OR GELS WITHIN DROPLETS

    Filed US PCT/US17/41053

    The present invention generally relates to microfluidic droplets and, including forming gels within microfluidic droplets. In some aspects, a fluid containing agarose or other gel precursors is transported into a microfluidic droplet, and caused to harden within the droplet, e.g., to form a gel particle contained within the microfluidic droplet. Surprisingly, a discrete gel particle may be formed even if the fluid containing the agarose or other gel precursor, and the fluid contained within the…

    The present invention generally relates to microfluidic droplets and, including forming gels within microfluidic droplets. In some aspects, a fluid containing agarose or other gel precursors is transported into a microfluidic droplet, and caused to harden within the droplet, e.g., to form a gel particle contained within the microfluidic droplet. Surprisingly, a discrete gel particle may be formed even if the fluid containing the agarose or other gel precursor, and the fluid contained within the microfluidic droplet, are substantially immiscible. Other aspects of the present invention are generally directed to techniques for making or using such gels within microfluidic droplets, kits containing such gels within microfluidic droplets, or the like.

    See patent

  • Systems and methods of cell-free protein synthesis in droplets and other compartments

    Issued US WO2016048994A2

    The present invention generally relates to cell-free protein synthesis in microfluidic droplets. Droplets may be used to encapsulate genetic information (DNA/RNA), and through cell-free protein synthesis, provide a linkage of the genetic information with the functional information, e.g., the activity of the expressed protein, and used to convert the functional information into a detectable signal, e.g., to allow sorting of the droplets and retrieve genetic information associated with the drops.…

    The present invention generally relates to cell-free protein synthesis in microfluidic droplets. Droplets may be used to encapsulate genetic information (DNA/RNA), and through cell-free protein synthesis, provide a linkage of the genetic information with the functional information, e.g., the activity of the expressed protein, and used to convert the functional information into a detectable signal, e.g., to allow sorting of the droplets and retrieve genetic information associated with the drops. In one set of embodiments, microfluidic droplets containing a cell-free protein synthesis system designed to detect protein-protein interaction (e.g., in vitro two-hybrid systems or IVT2H) can be used for high-throughput screening, e.g., of protein binders. This drop-based two-hybrid system may include two (or more) fusion proteins that can bind to each other such that their binding produces a complex that is able to produce a nucleic acid. The nucleic acid may be expressed to produce a protein. In certain embodiments, the protein may be produced within a cell-free system. The protein may be fluorescent or otherwise determinable, such that determination of the protein may be used to allow assays to occur within the droplets, to allow sorting of the droplets to occur, or the like, e.g., as discussed below, for instance, for screening or other applications.

    See patent

  • Methods and devices for determining pathogens and/or antibiotic susceptibility using digital droplet PCR and related techniques

    Filed U.S. Provisional Application No. 63/164,940

  • Droplet arrays for detection and quantification of analytes

    Filed US20210164971A1

    The invention provides high-sensitivity methods for detection and quantification of target analytes in liquid samples (e.g., biological or environmental samples). The methods can be multiplexed to allow simultaneous detection and quantification of multiple target analytes that are contained in the same sample. The invention also provides related compositions and kits.

    See patent

  • Sequencing of bacteria or other species

    Filed WO 2018/067792 A1

    The present invention generally relates to sequencing of cells such as bacteria or archeons. In one aspect, cells are lysed to release RNA, which is then polyadenylated and exposed to a sequencing having an identification portion and a poly-T portion, which associates with the RNA. These are then reverse transcribed to produce cDNA, which can then be studied, amplified, etc. In some cases, such reactions may be performed within droplets. The droplets can then be broken to release the cDNAs…

    The present invention generally relates to sequencing of cells such as bacteria or archeons. In one aspect, cells are lysed to release RNA, which is then polyadenylated and exposed to a sequencing having an identification portion and a poly-T portion, which associates with the RNA. These are then reverse transcribed to produce cDNA, which can then be studied, amplified, etc. In some cases, such reactions may be performed within droplets. The droplets can then be broken to release the cDNAs, which may be combined together for further sequencing, analysis, etc.

    See patent

Honors & Awards

  • NSERC PGS D

    NSERC

  • Arthur F Church Mechanical Engineering Award

    University of Waterloo

  • Term Dean’s Honours List

    University of Waterloo

  • Stackpole International Scholarship program

    Stackpole International

  • NSERC Undergraduate Student Research Award

    University of Waterloo

  • Term Dean’s Honours List

    University of Waterloo

  • Undergraduate Research Intern Award

    University of Waterloo

  • Term Dean’s Honours List

    University of Waterloo

  • Arthur F Church Mechanical Engineering Award

    University of Waterloo

  • Faculty of Engineering Upper-Year Scholarship (Top student in class)

    University of Waterloo

  • Sandford Fleming Foundation Junior Design Competition award

    University of Waterloo

  • Term Dean’s Honours List

    University of Waterloo

  • Sandford Fleming Foundation Junior Design Competition award

    University of Waterloo

  • Term Dean’s Honours List

    University of Waterloo

  • Term Dean’s Honours List

    University of Waterloo

  • Queen Elizabeth II Aim for the Top

    University of Waterloo

  • University of Waterloo President’s Scholarship

    University of Waterloo

  • Suncor Emerging Leaders Award in Engineering

    Suncor Energy

Languages

  • English

    Native or bilingual proficiency

  • Chinese (Mandarin)

    Native or bilingual proficiency

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