Programmable probiotics for detection of cancer in urine

Danino, Tal; Prindle, Arthur; Kwong, Gabriel A.; Skalak, Matthew; Li, Howard; Allen, Kaitlin; Hasty, Jeff; Bhatia, Sangeeta N.

doi:10.1126/scitranslmed.aaa3519

Cited by 358 publications

(299 citation statements)

References 65 publications

(90 reference statements)

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“…In a recent study, probiotic bacteria (termed, PROP-Z) engineered to express both lacZ and the luxCDABE operon, were used to target, visualize, and diagnose liver metastasis (57). Importantly, the stability of the synthetic circuitry within PROP-Z was secured by using a dual-maintenance strategy that included the expression of the Bacillus subtilis alp7 gene (leading to filament production that ensures equal plasmid segregation upon cell division) (58), as well as a toxin-antitoxin system that forces the cell to either maintain the plasmid or die (59).…”

Section: In Vivo Diagnosticsmentioning

confidence: 99%

Synthetic biology devices for in vitro and in vivo diagnostics

Slomovic

Pardee

Collins

2015

Proc. Natl. Acad. Sci. U.S.A.

296

228

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There is a growing need to enhance our capabilities in medical and environmental diagnostics. Synthetic biologists have begun to focus their biomolecular engineering approaches toward this goal, offering promising results that could lead to the development of new classes of inexpensive, rapidly deployable diagnostics. Many conventional diagnostics rely on antibody-based platforms that, although exquisitely sensitive, are slow and costly to generate and cannot readily confront rapidly emerging pathogens or be applied to orphan diseases. Synthetic biology, with its rational and short design-to-production cycles, has the potential to overcome many of these limitations. Synthetic biology devices, such as engineered gene circuits, bring new capabilities to molecular diagnostics, expanding the molecular detection palette, creating dynamic sensors, and untethering reactions from laboratory equipment. The field is also beginning to move toward in vivo diagnostics, which could provide near real-time surveillance of multiple pathological conditions. Here, we describe current efforts in synthetic biology, focusing on the translation of promising technologies into pragmatic diagnostic tools and platforms.synthetic biology | diagnostics | biosensing | synthetic gene networks | nanobiotechnology

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Section: In Vivo Diagnosticsmentioning

confidence: 99%

Synthetic biology devices for in vitro and in vivo diagnostics

Slomovic

Pardee

Collins

2015

Proc. Natl. Acad. Sci. U.S.A.

296

228

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“…Here, we establish a mathematical framework for synthetic biomarkers, a class of activity-based probes that amplify disease-derived signals into urine for easy analysis (3,(21)(22)(23)(24). We use model formulations based on a size-tunable PEG core conjugated with protease substrates in a mouse model of colorectal cancer (CRC).…”

mentioning

confidence: 99%

Mathematical framework for activity-based cancer biomarkers

Kwong

Dudani

Carrodeguas

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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Advances in nanomedicine are providing sophisticated functions to precisely control the behavior of nanoscale drugs and diagnostics. Strategies that coopt protease activity as molecular triggers are increasingly important in nanoparticle design, yet the pharmacokinetics of these systems are challenging to understand without a quantitative framework to reveal nonintuitive associations. We describe a multicompartment mathematical model to predict strategies for ultrasensitive detection of cancer using synthetic biomarkers, a class of activity-based probes that amplify cancerderived signals into urine as a noninvasive diagnostic. Using a model formulation made of a PEG core conjugated with protease-cleavable peptides, we explore a vast design space and identify guidelines for increasing sensitivity that depend on critical parameters such as enzyme kinetics, dosage, and probe stability. According to this model, synthetic biomarkers that circulate in stealth but then activate at sites of disease have the theoretical capacity to discriminate tumors as small as 5 mm in diameter-a threshold sensitivity that is otherwise challenging for medical imaging and blood biomarkers to achieve. This model may be adapted to describe the behavior of additional activity-based approaches to allow cross-platform comparisons, and to predict allometric scaling across species.compartmental modeling | activity-based probes | cancer diagnostics | urine biomarkers | nanomedicine T he clinical management of cancer is increasingly dependent on the discovery of new biomarkers and the development of ultrasensitive technologies to detect them at a stage when therapeutic interventions may be effective (1, 2). However, despite their growing importance, biomarkers lack predictive power to impact patient outcomes during the earliest stages of disease. The challenges are multifaceted: Biomarkers are shed from tumors at rates that vary by four orders in magnitude (3), are significantly diluted in blood, and circulate for short periods. Recent mathematical studies showed that tumors may remain undetectable with blood biomarkers for an entire decade following tumorigenesis, reaching 1-2.5 cm in diameter (4, 5). To increase sensitivity, major research areas include the development of ultrasensitive in vitro diagnostic platforms (6-11), as well as methods to increase biomarker production by solid tumors (12, 13). These approaches are designed to measure the quantity, or abundance, of a disease biomarker.In contrast to abundance-based methods, activity-based probes are a class of agents that are administered in prodiagnostic form but produce strong diagnostic signals after enzymatic activation (14, 15). These approaches rely on disease-associated enzymes as catalysts to produce a detection signal, of which proteases are particularly potent because the cleavage of peptide bonds is irreversible, and a single protease can cleave many substrates to amplify signals. However, activity-based probes operate within a narrow time window and are activated by offtarget...

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“…Synthetic microbes, as a kind of cell therapy, have broad potential for future applications in human disease treatment. For example, bioengineers have been designing various engineered bacteria to perform different specialized functions, such as detection and diagnosis of diseases [75] and production of therapeutics [76] and their delivering [77], which can self-eliminate after therapy [78]. With the development of synthetic biology, the future directions of bacterial cell therapy systems will set a variety of abilities in one and will be smarter as autonomous microbial Bphysicians^ [79].…”

Section: Manipulation Of Motile Microbes: Their Exploitation As Micromentioning

confidence: 99%

Fabrication of nanocomposites and hybrid materials using microbial biotemplates

Shi

Ullah

et al. 2017

Adv Compos Hybrid Mater

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Microbes are important part of life that vary in sizes and shapes, diverse surface chemistry and biology, and porous nature of their cell walls. Besides their importance in industrial processes such as fermentation, these serve as biotemplates and provide a biomimetic approach for fabrication of multifarious complex constructs with predefined features, ordered composites and hybrid nanomaterials, microdevices, and micro/nanorobots through various strategies. The template or building blocks for such approaches can be bacterial, algal, and fungal cells or virus particles. Here, we have summarized recent advancements in biofabrication based on live microbes. Using engineering approaches and suitable methods, live microbes can be manipulated as functional Bmicro/nanodevices and -robots^to further perform biological functions such as replication, distribution, motility, formation of colonies, and secretion of metabolites at will. Biofabrication based on microbes provides effective methods to control and manipulate microbes as functional live building blocks to create micro/nanodevices and -robots for biomedical and energy applications.

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Programmable probiotics for detection of cancer in urine

Cited by 358 publications

References 65 publications

Synthetic biology devices for in vitro and in vivo diagnostics

Synthetic biology devices for in vitro and in vivo diagnostics

Mathematical framework for activity-based cancer biomarkers

Fabrication of nanocomposites and hybrid materials using microbial biotemplates

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