Beacon Platform Research Articles

Industrial Internet-Driven Digital Transformation in Manufacturing: A Case Study of Foxconn's BEACON Platform

With the advancement of digital transformation in the manufacturing industry, the industrial internet has become a key technology for improving production efficiency and product quality, and achieving intelligent manufacturing. This paper takes Foxconn Technology Group as an example to explore how it has utilized the industrial internet platform BEACON for digital transformation, as well as the practical experience and effectiveness in this process. Foxconn has integrated cloud computing, the Internet of Things, big data, mobile internet, and smart factory technologies by constructing the BEACON platform, achieving automation, intelligence, and networking in production, and enhancing management efficiency and supply chain response speed. In addition, Foxconn also focuses on talent cultivation and corporate culture construction, developing a large number of talents with innovative thinking and digital skills through internal training and educational platforms. The research conclusion of this paper points out that the industrial internet is an important driving force for the digital transformation of the manufacturing industry, and proposes policy recommendations such as strengthening infrastructure construction, promoting in-depth integration of industry, academia, research, and application, and formulating and improving relevant policies and regulations to promote high-quality development and competitiveness enhancement of the manufacturing industry.

Combined approach of selective and accelerated cloning for microfluidic chip-based system increases clone specific productivity.

Improving current cell line development workflows can either focus on increasing the specific productivity of the cell lines or shortening timelines to reach the clinic as fast as possible. In this work, using the Beacon platform, we have combined two distinct protocols - early cloning with low-viability pools, and IgG membrane staining-, to concomitantly reach both objectives, and generate highly productive CHO clones in shorter timelines. Fast-sorting approaches using low-viability pools in combination with the Beacon platform have recently been reported to shorten CLD timelines. However, the low recovery led to a drastic reduction in the clone number obtained postcloning. Here, we report a combined approach of fast-sorting and fluorescent membrane staining. With this new protocol, the cells reach a correct recovery, allowing to fully exploit the Beacon screening capacities. In addition, by using a fluorescent staining recognizing the secreted IgG, we were able to enrich the fraction of highly secreting cells prior to cloning and we obtained significant increases in the cell's specific productivity. The combination of these two protocols has a synergistic effect, and as they help discarding the dead and nonproducing populations prior to cloning, they increase the throughput power of the Beacon platform and the detection of super productive clones.

Rapid isolation of pan-neutralizing antibodies against Omicron variants from convalescent individuals infected with SARS-CoV-2.

The emergence of SARS-CoV-2 Omicron subvariants haspresented a significant challenge to global health, as these variants show resistance to most antibodies developed early in the pandemic. Therapeutic antibodies with potent efficacy to the Omicron variants are urgently demanded. Utilizing the rapid antibody discovery platform, Berkeley Lights Beacon, we isolated two monoclonal neutralizing antibodies, 2173-A6 and 3462-A4. These antibodies were isolated from individuals who recently recovered from Omicron infections. Both antibodies, 2173-A6 and 3462-A4, demonstrated high affinity for the RBD and effectively neutralized pseudoviruses from various Omicron lineages, including BA.4/5, XBB.1.16, XBB.1.5, and EG.5.1. This neutralization was achieved through binding to identical or overlapping epitopes. The use of the Beacon platform enabled the rapid isolation and identification of effective neutralizing antibodies within less than 10 days. This process significantly accelerates the development of novel therapeutic antibodies, potentially reducing the time required to respond to unknown infectious diseases in the future.

Machine learning‐enabled epileptiform spike detection stratifies patient subpopulations with Alzheimer’s disease

AbstractBackgroundA subpopulation of patients with Alzheimer’s disease exhibit epileptiform activity and have more rapidly progressing disease. Manual identification of these pathological events is infeasible at scale and machine learning tools may establish epileptiform activity as an actionable biomarker for stratification and endpoints within clinical trials.MethodsRoutine EEGs from 90 subjects with AD and 39 subjects with MCI from the Beacon data repository were analyzed via the Beacon Platform harnessing an ML‐enabled interictal epileptiform discharge (IED) detection algorithm, and by expert visual inspection.ResultsIEDs were found in 17 of the 90 subjects with AD (19%), and 8 out of the 39 MCI subjects (20%). In subcategorization, 13% (9 / 71) of AD subjects without epilepsy had IEDs, while 42% (8/19) of AD subjects with epilepsy had IEDs. In the AD/no epilepsy subgroup there were 24 patients taking an Anti‐Seizure Medication (ASM), and 4% (1/24) had IEDs (versus 17% (8/47) of the AD without epilepsy group that were not on ASMs).ConclusionMachine learning augmented detection of IEDs allows for rapid, quantitative identification of individuals with subclinical epileptiform activity in patients with AD and MCI. These results demonstrate that AI‐detectable IEDs are seen in a sizable minority of AD patients without epilepsy and in MCI patients, and more commonly in AD patients with epilepsy. Ultimately, automated analysis of EEG data is a promising way to stratify patients and track disease progression while enriching clinical trials with subjects most likely to respond to next‐generation treatments.

Abstract PR10: High-throughput functional and multi-omic single-cell characterization to elucidate ovarian intratumor and microenvironmental heterogeneity

Abstract The genetic and functional complexity of bulk tumor tissue and its associated microenvironment, comprising heterogeneous cellular clones, has become more evident due to rapid advances in single-cell and deep-sequencing technologies. In this research, we present methods to better characterize clonal diversity from patient-derived cell lines and tumor biopsies at the single-cell level. We will profile intratumor and microenvironmental heterogeneity through single-cell selection, single-cell DNA and RNA sequencing, and real-time functional data. In addition to genetic data, single-cell real-time growth dynamics alongside CA125 secretion will be discussed as real-time functional assays. This approach uses bulk or discriminate selection of cells based on phenotype across a broad range of cellular inputs. Targeted cells from the tumor and its microenvironment were manipulated using light-induced dielectrophoresis into holding areas on the BLI Beacon platform for single-cell isolation and/or culture for monitoring growth kinetics and conducting functional screening. Hundreds to thousands of independent cells or batches were selected from resected tumor and adjacent tissue; genomic DNA was amplified and characterized using Ion Torrent AmpliSeq targeted panels and/or MissionBio Tapestri scDNA-Seq. Collectively this genomic data were used to identify cellular clonality and better address the degree of clonal heterogeneity across these tumors when compared to bulk sequencing. Specifically, growth kinetics, differential expression, and TP53 mutation profiling will be discussed in the context of several pilot primary tumor-derived samples. Orthogonal RNA-Seq data obtained using 1,500-5,000 cells per sample for 3’ mRNA scRNA-Seq on the 10X Genomics Chromium platform will also be discussed. Through the integration of these technologies, we hope to showcase an efficient and comprehensive method for assessing intratumor and microenvironmental heterogeneity. This abstract is also being presented as Poster B53. Citation Format: Kristin G. Beaumont, Austin Hake, Ying-Chih Wang, Hardik Shah, Kimaada Allette, Wissam Hamou, Arpit Dave, Christina Andreou, Maya Strahl, Hanane Arib, Alesia Antoine, Ethan Ellis, Melissa Smith, Peter Dottino, John Martignetti, Eric E. Schadt, Robert P. Sebra. High-throughput functional and multi-omic single-cell characterization to elucidate ovarian intratumor and microenvironmental heterogeneity [abstract]. In: Proceedings of the AACR Special Conference on Advances in Ovarian Cancer Research; 2019 Sep 13-16, 2019; Atlanta, GA. Philadelphia (PA): AACR; Clin Cancer Res 2020;26(13_Suppl):Abstract nr PR10.

Inside Back Cover: Biotechnology Journal 1/2020

The fully integrated Beacon cell culture system enables the manipulation, culturing and assaying of thousands of clones on a single nanofluidic chip. The Beacon platform allows for the generation of clonally derived cell lines of known phenotypic identity with a superior clonality data package, detailed tracking, rapid verification of clonal origin, and 99 % assurance of clonality. This is reported by Kim Le, Christopher Tan, Huong Le, Jasmine Tat, Ewelina Zasadzinska, Jonathan Diep, Ryan Zastrow, Chun Chen,and Jennitte Stevens in article 1900247.

Assuring Clonality on the Beacon Digital Cell Line Development Platform.

During biomanufacturing cell lines development, the generation and screening for single-cell derived subclones using methods that enable assurance of clonal derivation can be resource- and time-intensive. High-throughput miniaturization, automation, and analytic strategies are often employed to reduce such bottlenecks. The Beacon platform from Berkeley Lights offers a strategy to eliminate these limitations through culturing, manipulating, and characterizing cells on custom nanofluidic chips via software-controlled operations. However, explicit demonstration of this technology to provide high assurance of a single cell progenitor has not been reported. Here, a methodology that utilizes the Beacon instrument to ensure high levels of clonality is described. It is demonstrated that the Beacon platform can efficiently generate production cell lines with a superior clonality data package, detailed tracking, and minimal resources. A stringent in-process quality control strategy is established to enable rapid verification of clonal origin, and the workflow is validated using representative Chinese hamster ovary-derived cell lines stably expressing either green or red fluorescence protein. Under these conditions, a >99% assurance of clonal origin is achieved, which is comparable to existing imaging-coupled fluorescence-activated cell sorting seeding methods.

A novel mammalian cell line development platform utilizing nanofluidics and optoelectro positioning technology

Generating a highly productive cell line is resource intensive and typically involves long timelines because of the need to screen large numbers of candidates in protein production studies. This has led to miniaturization and automation strategies to allow for reductions in resources and higher throughput. Current approaches rely on the use of standard cell culture vessels and bulky liquid handling equipment. New nanofludic technologies offer novel solutions to surpass these limits, further miniaturizing cell culture volumes (105 times smaller) by growing cells on custom nanofluidic chips. Berkeley Lights’ OptoElectro Positioning technology projects light patterns to activate photoconductors that gently repel cells to manipulate single cells on nanofluidic culturing chips. Using a fully integrated technology platform (Beacon), common cell culture tasks can be programmed through software, allowing maintenance and analysis of thousands of cell lines in parallel on a single chip. Here, we describe the ability to perform key cell line development work on the Beacon platform. We demonstrate that commercial production Chinese hamster ovary cell lines can be isolated, cultured, screened, and exported at high efficiency. We compare this process head to head with a FACS‐enabled microtiter plate‐based workflow and demonstrate generation of comparable clonal cell lines with reduced resources. © 2018 American Institute of Chemical Engineers Biotechnol. Prog., 34:1438–1446, 2018

A simple method of constructing microfluidic solid-state quantum dot molecular beacon array for label-free DNA detection

Solid-state molecular beacons show great potential for label-free biomarker detection, however, it is challenging to construct robust and homogenous quantum dot molecular beacon microarrays in a microfluidic platform. Here, we report a simple and cost-effective method of constructing a mercaptopropionic acid quantum dot (MPA-QD) microarray in a microfluidic platform using a PDMS through-hole structure. This method combines soft lithography and surface functionalization to achieve uniform QD immobilization in a microfluidic network. With the simple fabricated quantum dot microarray sensor integrated in the microfluidic device, label-free biomarker detection was performed with high efficiency, specificity and sensitivity. We performed cardiovascular biomarker detection, and our microfluidic QD molecular beacon platform achieved target DNA sequence identification at a low concentration of 1 nM/L.

Orchestrating Bulk Data Transfers across Geo-Distributed Datacenters

As it has become the norm for cloud providers to host multiple datacenters around the globe, significant demands exist for inter-datacenter data transfers in large volumes, e.g., migration of big data. A challenge arises on how to schedule the bulk data transfers at different urgency levels, in order to fully utilize the available inter-datacenter bandwidth. The Software Defined Networking (SDN) paradigm has emerged recently which decouples the control plane from the data paths, enabling potential global optimization of data routing in a network. This paper aims to design a dynamic, highly efficient bulk data transfer service in a geo-distributed datacenter system, and engineer its design and solution algorithms closely within an SDN architecture. We model data transfer demands as delay tolerant migration requests with different finishing deadlines. Thanks to the flexibility provided by SDN, we enable dynamic, optimal routing of distinct chunks within each bulk data transfer (instead of treating each transfer as an infinite flow), which can be temporarily stored at intermediate datacenters to mitigate bandwidth contention with more urgent transfers. An optimal chunk routing optimization model is formulated to solve for the best chunk transfer schedules over time. To derive the optimal schedules in an online fashion, three algorithms are discussed, namely a bandwidth-reserving algorithm, a dynamically-adjusting algorithm, and a future-demand-friendly algorithm, targeting at different levels of optimality and scalability. We build an SDN system based on the Beacon platform and OpenFlow APIs, and carefully engineer our bulk data transfer algorithms in the system. Extensive real-world experiments are carried out to compare the three algorithms as well as those from the existing literature, in terms of routing optimality, computational delay and overhead.

Visible and red emissive molecular beacons for optical temperature measurements and quality control in diagnostic assays utilizing temperature-dependent amplification reactions.

Quality control requirements imposed on assays used in clinical diagnostics and point-of-care-diagnostic testing (POCT), utilizing amplification reactions performed at elevated temperatures of 35 to 95°C are very stringent. As the temperature of a reaction vessel has a large impact on the specificity and sensitivity of the amplification reaction, simple tools for local in situ temperature sensing and monitoring are required for reaction and assay control. We describe here a platform of stem-and-loop structured DNA hairpins (molecular beacons, MBs), absorbing and emitting in the visible and red spectral region, rationally designed for precise temperature measurements in microfluidic assays for POCT, and their application for temperature measurements in a common DNA-based molecular biological assay utilizing thermophilic helicase-dependent amplification (tHDA). Spectroscopic studies of these MBs, rationally designed from DNA sequences of different thermal stabilities, chosen not to interact with the DNA probes applied in the nucleic acid amplification assay, and temperature-dependent fluorescence measurements of MB-assay mixtures revealed the suitability of these MBs for temperature measurements directly in such an assay with a temperature resolution of about 0.5°C without interferences from assay components. Combining two spectrally distinguishable MBs provides a broader response range and an increase in temperature sensitivity up to 0.1°C. This approach will find future application for temperature monitoring and quality control in commercialized diagnostics assays using dried reagents and microfluidic chips as well as assays read out with tube and microplate readers and PCR detection systems for temperature measurements in the range of 35 to 95°C. Graphical abstract Molecular beacon platform for optical temperature measurements and quality control in diagnostic assays.

Abstract B097: Analyze and recover functionally defined single immune cell clones through Opto-Electro-Positioning technology

Abstract Cancer patients mount protective innate and adaptive immune responses against tumor cells. Since such responses are able to control or even cure eliminate cancer if harnessed properly, identifying clonal adaptive immune cells targeting tumor cells with designated function is extremely valuable but remains challenging. We provide evidence here that the combination of the Opto-Electro-Positioning (OEP) technology and the nanofluidic culture enables high throughput screening and harvesting functionally defined immune cells through single cell based analysis. Immune cells can be maneuvered deterministically through OEP into defined nanofluidic culture space which supports efficient antigen specific T/B cell clonal expansion and functional profiling ex vivo. The viable T/B cell colonies with designated functions can subsequently be harvested after analysis for downstream applications including rapid expansion, antigen receptor sequencing, and epigenetic analysis etc. Integration of these two basic technologies with computer controlled automation leads to our Beacon platform that allows researchers to screen tens of thousands of live single immune cells simultaneously. The system is also exceptionally efficient in investigating immune cell population from the tumor biopsies that are typically of low cellularity. In summary, the OEP and nanofluidic device based Beacon solution provides researchers an “all-purpose” single cell based discovery platform for both basic and clinical oncology investigations. Citation Format: Xiaohua Wang, Yelena Bronevetsky, Guido Stadler, Kristin Beaumont, Xiaoyan Robert Bao, Saki Shimizu, Duane Smith, Kevin Chapman. Analyze and recover functionally defined single immune cell clones through Opto-Electro-Positioning technology [abstract]. In: Proceedings of the Second CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; 2016 Sept 25-28; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2016;4(11 Suppl):Abstract nr B097.

Implementation of Arithmetic Functions on a Simple and Universal Molecular Beacon Platform.

Diverse advanced logic circuits are fabricated to implement arithmetic functions based on a simple and single molecular beacon platform, including half adder, half subtractor, full adder, full subtractor, and a digital comparator. Dual fluorescence outputs are generated in parallel and a constant threshold value is set to build all the logic circuits. The developed enzyme-free DNA system provides a novel prototype for the design of high-level molecular logic circuits on a biomolecular platform.

Implementation of Electronic Chemotherapy Ordering: An Opportunity to Improve Evidence-Based Oncology Care

The degree to which electronic health records (EHRs) enhance the quality of patient care depends on use of the system to monitor and improve practice. In planning the transition to Epic's Beacon electronic chemotherapy ordering platform, we saw an opportunity to measure our performance and increase evidence-based practice. Advanced planning began 2 years before implementation and included formation of a chemotherapy council charged with reviewing references and approving each chemotherapy protocol; a readiness assessment; design of electronic flow-sheet adherent with Oncology Nursing Society guidelines. To monitor use of evidence-based treatments, we created a novel quality metric: the rate of evidence-based adherence (REBA). A full infusion schedule was maintained through implementation, with a transient 1-month increase in wait time. Our overall REBA of 0.86 significantly exceeded our prespecified goal of 0.80 (P = .001). REBA varied from 0.50 to 0.95 between disease groups. Antiemetic use increased by 20% after Beacon implementation. Provider satisfaction at 8 months ranged from 76% to 80%. The transition to electronic chemotherapy ordering offers an institution the chance to develop evidence-based oncology practice, standardize supportive care, and enhance patient safety. The key elements that made our transition so successful were (1) extensive involvement of oncology leadership, (2) use of a chemotherapy council to enforce evidence-based practice, (3) ongoing collaboration between clinical operations and information technology. Finally, the REBA is a powerful tool to monitor adherence to evidence-based chemotherapy prescribing.

A versatile graphene-based fluorescence “on/off” switch for multiplex detection of various targets

We have designed a versatile molecular beacon (MB)-like probe for the multiplex sensing of targets such as sequence-specific DNA, protein, metal ions and small molecule compounds based on the self-assembled ssDNA–graphene oxide (ssDNA–GO) architecture. The probe employs fluorescence “on/off” switching strategy in a single step in homogeneous solution. Compared to traditional molecular beacons, the proposed design is simple to prepare and manipulate and has little background interference, but still gives superior sensitivity and rapid response. More importantly, this ssDNA–GO architecture can serve as a universal beacon platform by simply changing the types of ssDNA sequences for the different targets. In this work, the ssDNA–GO architecture probe has been successfully applied in the multiplex detection of sequence-specific DNA, thrombin, Ag +, Hg 2+ and cysteine, and the limit of detection was 1 nM, 5 nM, 20 nM, 5.7 nM and 60 nM, respectively. The results demonstrate that the ssDNA–GO architecture can be an excellent and versatile platform for sensing multiplex analytes, easily replacing the universal molecular beacon.