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Molecular detector

Molecular detector description/claims

This invention was developed at least in part using funds and/or facilities of the United States Government, particularly funds provided through grants USDA TH 2002-06107 and CDC E11/CCE021836-01. The United States Government may have certain rights in the invention.

The present disclosure concerns an electronic detection device and process for detecting biological agents and biomolecules. More specifically, the present disclosure is directed to an electrical signal generation process, which reports biological interaction events, and provides an electronic device useful for single, multiple and array detection of biological agents and biological molecules including, without limitation, tissues, biopsy samples, cells, yeast, fungus, bacteria, viruses, nucleic acids, proteins, peptides, carbohydrates and other biological molecules.

The development of rapid, accurate methods for detecting pathogenic microbes and diagnostic biomolecules are longstanding goals of medical scientific researchers. After September 11th, 2001, detection of biowarfare agents using such methods also has become a high priority for national defense. Various techniques have been developed in an attempt to achieve these goals.

Advanced electronic technologies and devices with their high speed, high density and programmable features show great potential in the development of biosensors. Established semiconductor manufacturing techniques allow large-scale production of reliable devices at low cost, and in multiplexed formats. Moreover, such electronic detection devices can provide near real time data that is valuable for national security and to improve health care and food safety diagnosis.

The link between molecular interaction and electronic signal generation represents an important feature for designing an electronic detection process that can be utilized to selectively detect particular biological target agents. Complicated interactions between different biomolecules, and their poor electrical properties, however, present difficulties for generating electronic signals that can be used to identify biological recognition events and/or provide quantitative data concerning such events. Thus, development of a unique and universal signal generation process and corresponding electrical circuitry are highly desirable for developing electronic biomolecular detectors to meet the challenges of medical diagnostics and national defense.

The present disclosure is directed to embodiments of a device and a process for generating detectable electronic signals that represent the recognition and interaction of biological agents and biomolecules, whereby, specific biomolecular interaction events are identified with electronics. Moreover, a universal signal generation process is provided that is designed to interchangeably address the complexity of biomolecular interactions.

In one embodiment, signal molecules that carry an electronic charge and corresponding affinity binding molecules that specifically bind the signal molecules are used to bring an electrical charge to a detection surface. Specifically, signal molecules are captured by affinity binding molecules bound to a detection surface, which results in an increased electronic charge in the vicinity of the surface. The detection device can further include spacer molecules that are bound to the detection surface to form a non-conducting surface that helps alleviate non-specific binding on the detection surface. Electronic circuitry also is provided that is capable of recognizing the presence of the electronic charges induced on the detection surface upon specific binding of the signal molecules by the affinity binding molecules.

Signal molecules, which have a recognition head that specifically binds to an affinity binding molecule on a detection surface and a charged tail that increases the charge at the detection surface, are produced from a signal probe that serves to report the presence of a specific target molecule in a sample, for example, a particular DNA sequence or protein to be detected. The signal probe, which specifically binds to target molecules immobilized in a reaction vessel, includes a recognition component for binding to the target, and a nucleic acid template that codes for the signal molecule. Transcription (and in some embodiments translation) of the template portion of the signal probe (in the presence of appropriate enzymes and substrates) is used to produce the signal molecule. Since the recognition component can be varied to detect different target molecules, while the template portion coding for the signal molecule can be the same regardless of the target, a single type of detection surface having a particular affinity binding molecule that specifically binds the signal molecule can be used to detect a multitude of different target molecules. Furthermore, since the template portion of the signal probe can be used to produce multiple copies of the signal molecule by repeated transcription (and possibly translation), amplification of the signal due to the presence of a target is possible.

In a working embodiment, an in vitro transcription DNA template is provided that can be linked to many different biomolecules directly and/or indirectly to form a signal probe. The signal molecules produced by in vitro transcription of the DNA template thus can be used for detecting a wide spectrum of biological agents and biomolecules on one or more devices. In a particular embodiment, in vitro transcription of a DNA template generates signal molecules that include an RNA aptamer as the recognition head, which signal molecules specifically bind to corresponding affinity molecules on a detection surface. The charged tail (e.g., a poly-A tail) of the signal molecule produced from the template serves to provide a detectable electric charge at the detection surface. Alternatively, peptides having an electronic charge and that bind to affinity molecules on a detector surface can be produced using coupled transcription/translation. Thus, one aspect is to present biological recognition events as changes of electrical properties on a detection surface. Such changes in the electrical properties of a detection surface can be recorded with appropriate electronic circuitry.

The disclosed molecular detector also provides a unique electronic circuitry that can be used to detect the presence of small quantities of electronic charge, such as the induced electronic charge resulting from charged signal molecules binding to affinity molecules at a detection surface. Such circuitry can be used to provide qualitative and quantitative data, and also can be used with other biomolecular detection schemes that produce charge as a component of the detection mechanism.

Current semiconductor fabrication techniques have the capacity to build anywhere from thousands to millions of transistors on a single chip. This capacity facilitates multiple array detection by applying numerous affinity binding molecules on different detection surfaces of a single chip. Consequently, the disclosed method and device for detecting biological agents and molecules on electronic devices can be extended to other field-effect sensing devices, such as silicon or non-silicon nanowires. In a working embodiment, the detection surface includes the gate of a field effect transistor.

Disclosed embodiments of the device can be manufactured using well-established manufacturing processes to produce low cost electronic devices. Since the device can be produced inexpensively relative to many current diagnostic devices, in one embodiment, the device is disposable to avoid cross contamination in the detection process. Moreover, according to yet another embodiment, the device can be integrated with microfluidics to provide a high-throughput detection system that, by virtue of its dimensions, can also enhance the strength of molecular interactions, thereby leading to greater sensitivity.

FIG. 1 is a schematic diagram depicting one embodiment of a disclosed process for detecting a target agent, such as, without limitation, DNA, RNA, proteins, carbohydrates or cells.

• Provisional Patent
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