Abstract:
A system for detecting electrical properties of a molecular complex is disclosed. The system includes an electrode electrically coupled to a molecular complex that outputs an electrical signal affected by an electrical property of the molecular complex, wherein the effect of the electrical property of the molecular complex on the electrical signal is characterized by an expected bandwidth. The system further includes an integrating amplifier circuit configured to receive the electrical signal from the electrode. The integrating amplifier circuit is further configured to selectively amplify and integrate a portion of the electrical signal over time within a predetermined bandwidth, wherein the predetermined bandwidth is selected at least in part based on the expected bandwidth.

Description:
CROSS REFERENCE TO OTHER APPLICATIONS 
       [0001]    This application claims priority to U.S. Provisional Patent Application No. 61/435,700 (Attorney Docket No. GENIP009+) entitled SYSTEM FOR COMMUNICATING INFORMATION FROM AN ARRAY OF SENSORS filed Jan. 24, 2011 which is incorporated herein by reference for all purposes. 
     
    
     BACKGROUND OF THE INVENTION 
       [0002]    Advances in micro-miniaturization within the semiconductor industry in recent years have enabled biotechnologists to begin packing their traditionally bulky sensing tools into smaller and smaller form factors, onto so-called biochips. It would be desirable to develop techniques for biochips. 
     
    
     
       BRIEF DESCRIPTION OF THE DRAWINGS 
         [0003]    Various embodiments of the invention are disclosed in the following detailed description and the accompanying drawings. 
           [0004]      FIG. 1  is a block diagram illustrating an embodiment of a sensor circuit  100  for measuring a physical property within a single cell in a biochip. 
           [0005]      FIG. 2  illustrates that with a constant noise floor, as the measured signal bandwidth decreases, the signal to noise ratio increases, thereby improving the sensitivity of sensor circuit  100  of  FIG. 1 . 
           [0006]      FIG. 3  is a circuit diagram illustrating an embodiment of a sensor circuit  300  for measuring a physical property, e.g., a current, within a single cell in a nanopore array. 
           [0007]      FIG. 4  is a circuit diagram illustrating a second embodiment of a sensor circuit  400  for measuring a physical property within a single cell in a nanopore array. 
           [0008]      FIG. 5  is a diagram illustrating a plot of the voltage at the output of the integrating amplifier in circuit  300  or circuit  400  versus time. 
           [0009]      FIG. 6  is a block diagram illustrating an embodiment of a cell array in a biochip. 
       
    
    
     DETAILED DESCRIPTION 
       [0010]    The invention can be implemented in numerous ways, including as a process; an apparatus; a system; a composition of matter; a computer program product embodied on a computer readable storage medium; and/or a processor, such as a processor configured to execute instructions stored on and/or provided by a memory coupled to the processor. In this specification, these implementations, or any other form that the invention may take, may be referred to as techniques. In general, the order of the steps of disclosed processes may be altered within the scope of the invention. Unless stated otherwise, a component such as a processor or a memory described as being configured to perform a task may be implemented as a general component that is temporarily configured to perform the task at a given time or a specific component that is manufactured to perform the task. As used herein, the term ‘processor’ refers to one or more devices, circuits, and/or processing cores configured to process data, such as computer program instructions. 
         [0011]    In various embodiments, the techniques described herein are implemented in a variety of systems or forms. In some embodiments, the techniques are implemented in hardware as an application-specific integrated circuit (ASIC) or a field-programmable gate array (FPGA). In some embodiments, a processor (e.g., an embedded one such as an ARM core) is used where the processor is provided or loaded with instructions to perform the techniques described herein. In some embodiments, the technique is implemented as a computer program product which is embodied in a computer readable storage medium and comprises computer instructions. 
         [0012]    A detailed description of one or more embodiments of the invention is provided below along with accompanying figures that illustrate the principles of the invention. The invention is described in connection with such embodiments, but the invention is not limited to any embodiment. The scope of the invention is limited only by the claims and the invention encompasses numerous alternatives, modifications and equivalents. Numerous specific details are set forth in the following description in order to provide a thorough understanding of the invention. These details are provided for the purpose of example and the invention may be practiced according to the claims without some or all of these specific details. For the purpose of clarity, technical material that is known in the technical fields related to the invention has not been described in detail so that the invention is not unnecessarily obscured. 
         [0013]    Advances in micro-miniaturization within the semiconductor industry in recent years have enabled biotechnologists to begin packing their traditionally bulky sensing tools into smaller and smaller form factors, onto so-called biochips. These chips are essentially miniaturized laboratories that can perform hundreds or thousands of simultaneous biochemical reactions. Biochips enable researchers to quickly screen large numbers of biological analytes for a variety of purposes, from disease diagnosis to detection of bioterrorism agents. 
         [0014]    Typically, a biochip includes a large array of cells. For example, a biochip for nucleotide sequencing may contain thousands or millions of single cells in an array. Each cell includes a molecular complex composed of monomers that make up an oligomeric nanopore and a single strand of DNA, and anything bound to that single strand of DNA. The nanopore is a small hole in an electrically insulating membrane that can be used as a single-molecule detector. A nanopore may be formed using a biological material, such as α-hemolysin or MspA. A nanopore may be formed using a solid-state material, such as a semiconductor material. When a small voltage is applied across a molecular complex containing a nanopore, an ionic current through the molecular complex can be measured to provide information about the structure of a molecule transiting the molecular complex. In a single cell of the array, an electrical circuit may be used for controlling the electrical stimulus applied across a lipid bilayer which contains a nanopore, and for detecting the electrical patterns, or signatures, of a molecule passing through the nanopore. These patterns or signatures identify events of interest such as additions or subtractions to the molecular complex, or conformational changes to the molecular complex. In order to reduce the cost of the array, physically small single cells with highly sensitive sensors therein are desirable. 
         [0015]      FIG. 1  is a block diagram illustrating an embodiment of a sensor circuit  100  for measuring a physical property within a single cell in a biochip. As shown in  FIG. 1 , a physical property, e.g., a current, voltage, or charge, is detected by detector  102  as detected signal  104 . Sensor circuit  100  may be used to measure the mean value of detected signal  104  without sampling as described further below. 
         [0016]    In some embodiments, an initiation flag  106  resets an integrating amplifier  108  and starts a continuous integration of detected signal  104  over time. Integrated output  110  is compared with a trip threshold  114  using a comparator  112 . When integrated output  110  reaches trip threshold  114 , a trip flag  116  may be used as a feedback signal to integrating amplifier  108  for terminating the integration of detected signal  104 . For example, when trip flag  116  is “on” or asserted, the integration is terminated. The duration of time between the assertion of initiation flag  106  and the assertion of trip flag  116  is proportional to the mean value of detected signal  104 , e.g., the mean value of a current. Accordingly, the “on” and “off” of trip flag  116  (only 1 bit of information) may be sent from the cell to an external processor for calculating the mean value of detected signal  104 . Alternatively, the “on/off” information may be sent from the cell to an external storage for delayed processing. For example, the clock cycles at which initiation flag  106  and trip flag  116  are respectively asserted may be recorded in an external storage. The number of clock cycles between the two asserted flags may then be used to determine the mean value of detected signal  104  at a later time. 
         [0017]    In some embodiments, more accurate results may be obtained by integrating detected signal  104  over multiple integrating cycles. For example, the determined mean value of detected signal  104  may be further averaged over multiple integrating cycles. In some embodiments, initiation flag  106  is based at least in part on trip flag  116 . For example, initiation flag  106  may be re-asserted in response to trip flag  116  being asserted. In this example, trip flag  116  is used as a feedback signal for reinitializing integrating amplifier  108 , such that another cycle of integration of detected signal  104  may begin as soon as the previous cycle of integration is terminated. Re-asserting initiation flag  106  immediately after trip flag  116  is asserted reduces the portion of time when detector  102  generates a signal that is not integrated and thus not measured. The integration occurs over approximately the entire time that the signal is available. As a result, most of the information of the signal is captured, thereby minimizing the time to obtain an average value for the measured signal. 
         [0018]    Shot noise may corrupt trip flag  116  during certain integrating cycles. Accordingly, some embodiments may include logic to determine whether trip flag  116  has been corrupted by shot noise in a particular integrating cycle before trip flag  116  is saved or used for any calculation. 
         [0019]    The sensitivity of sensor circuit  100  is maximized by continuously integrating detected signal  102  without sampling. This serves to limit the bandwidth of the measured signal. With continuous reference to  FIG. 1 , trip threshold  114  and an integration coefficient A set the bandwidth of the measured signal. As integration coefficient A decreases or as trip threshold  114  increases, the measured signal bandwidth decreases.  FIG. 2  illustrates that with a constant noise floor, as the measured signal bandwidth decreases, the signal to noise ratio increases, improving the sensitivity of sensor circuit  100 . In some embodiments, the measured signal bandwidth can be dynamically adjusted by varying the trip threshold  114 . 
         [0020]      FIG. 3  is a circuit diagram illustrating an embodiment of a sensor circuit  300  for measuring a physical property, e.g., a voltage, within a single cell in a nanopore array.  FIG. 4  is a circuit diagram illustrating a second embodiment of a sensor circuit  400  for measuring a physical property within a single cell in a nanopore array. 
         [0021]    With reference to  FIGS. 3 and 4 , the S 1  control circuitry includes a comparator and other logic, e.g., logic for switching. The other components of circuit  300  (or circuit  400 ), including the differential pair, implement an integrating amplifier similar to that in  FIG. 1 . The input of circuit  300  (or circuit  400 ) is connected to a nanopore system local electrode. 
         [0022]      FIG. 5  is a diagram illustrating a plot of the voltage at  310  (or  410 ) in circuit  300  (or circuit  400 ) versus time. In  FIG. 5 , t trip  indicates the mean current flowing through a nanopore. Reducing the noise bandwidth reduces the noise associated with t trip . Accordingly, the mean current measurement will have a higher signal to noise ratio (SNR) and be more precise. 
         [0023]    The integrating amplifier generates signals within an expected bandwidth containing events of interest of the molecular complex. The integrating amplifier is configured to amplify only signals in the bandwidth of interest, and reject signals outside this bandwidth. Amplifying all signals amplifies mostly noise since the useful signal&#39;s bandwidth is much smaller than the detected signal, resulting in poor SNR. The bandwidth of interest may be limited by selecting appropriate values for C 1  and I O  in circuits  300  and  400 . In some embodiments, C 1  and I O  are selected to limit the bandwidth of interest between 0.3 Hz and 300 Hz. In some embodiments, the bandwidth of interest can be dynamically adjusted by varying the values of C 1 . 
         [0024]    In some embodiments, trip flag  116  for each of the cells are further synchronized with a global clock shared by all the cells within the biochip. For example, trip flag  116  that is synchronized with a global clock may be generated by a pulse generation circuit. After synchronization, trip flag  116  is a single pulse that is in phase with the global clock. 
         [0025]      FIG. 6  is a block diagram illustrating an embodiment of a cell array in a biochip. Each of the cells may contain a sensor circuit  100  for measuring a physical property within the cell as described above. As shown in  FIG. 6 , the cell array has m columns by n rows of single cells. All the cells in a given column share the same column line  302 , and all the cells in a given row share the same row line  304 . When trip flag  116  for a particular cell is asserted, the cell asserts its particular column line  302  and row line  304 . In order to reduce the pin count of the biochip, a column multiplexer  306  may be used to output a column number (0−2 m −1) to indicate which column line  302  has been asserted. Similarly, a row multiplexer  308  may be used to output a row number (0−2 n −1) to indicate which row line  304  has been asserted. For example, if trip flag  116  of the cell in the second column and the second row is asserted, the output column and row number is (1, 1). As long as only one cell asserts its trip flag  116  at a time, the reported column and row numbers are sufficient to uniquely identify which particular cell is asserted at a particular time. 
         [0026]    The above techniques have a number of advantages over other approaches. The integrating amplifier requires minimal die area and allows for each array site to have its own dedicated measurement circuit. This feature removes the necessity of routing sensitive analog signals to the array periphery and avoids the need for multiplexing, thereby reducing noise. The integrating amplifier requires no pre-amplifier, sample and hold, or anti-aliasing filter, further reducing die area and potential error sources. Since only a single flag is required to denote the completion of a measurement, the integrating approach is an efficient way to communicate data from each array site. Measurements are being made continuously (other than the brief time required to reset the integration capacitor) so data is being gathered almost 100% of the time. Furthermore, each cell and its associated measurement circuit operates autonomously, allowing each cell to track the state of the molecule being measured. As described above, the integrating approach also has inherent signal averaging and noise advantages. 
         [0027]    Although the foregoing embodiments have been described in some detail for purposes of clarity of understanding, the invention is not limited to the details provided. There are many alternative ways of implementing the invention. The disclosed embodiments are illustrative and not restrictive.