1. Field of the Invention
This invention relates generally to measuring and analyzing ion channel activity and, more particularly, to a method and system for quantifying measurements of activity from a plurality of different ion channels with standardized values having a real time context, enabling the entire electrophysiology of an organism to be mapped and evaluated.
2. Description of the Prior Art
Ion channels are embedded in the plasma membranes of all cells and are well known as pore-forming membrane proteins which perform a substantial number of vital functions for the cell on which it is present. While the study of ion channels is relatively new, ion channels are now known to be integral components of the nervous system of living organisms as well as components in a many biological processes involving rapid changes in cells. There are over 300 types of ion channels; but when classified by the type of ions, ion channels may be categorized as chloride channels, potassium channels, sodium channels, calcium channels, proton channels, or non-selective cation channels.
Irregularities or other disruptions in the function of ion channels in an organism are known to be associated with disease or dysfunction in the organism. Indeed, the association between irregularities in particular ion channels and certain disorders or diseases is well known. Such ion-based diseases include cystic fibrosis, long QT syndrome, and Brugada syndrome, and typically have devastating consequences for the organism afflicted therewith. Providing treatment for ion-based diseases customarily involves protocols which are designed to address an irregularity in the particular ion channel known to be associated with the targeted disease.
Thus, diagnosing the irregularities which cause ion based diseases, as well as the development of treatment protocols therefor, necessarily depends on the ability to measure activity of ion channels. Patch clamping is a common technique for measuring the activity of a single or multiple ion channels to enable it to be quantified and studied. In this regard, conventional medical care practices are often based on utilizing measurements for activity of a particular, targeted ion channel, which have been obtained through patch clamping, to identify irregularities in the activity of the targeted ion channel and develop treatment protocols directed at specific molecular mechanisms in an attempt to rectify the identified irregularity.
While the ability to identify irregularities in ion channel activity, diagnose diseases associated with such irregularities, and develop treatment protocols designed to address the irregularity represents a substantial improvement in the available medical care for a patient afflicted with a ion-based disease, a problem which still exists is the conventional diagnoses and treatments for ion-based disease typically only take into account information concerning the ion channel associated with a particular disease sought to be treated. For example, if cystic fibrosis is based on irregularities within the chloride ion channel, conventional diagnoses are based solely on the activity of the chloride channel, with the activity of the other ion channels are ignored. Such an approach is inherently limited, however, because all treatment protocols are likely to affect the activity of not just the targeted ion channel, but of a plurality of ion channels. Moreover, the differences in the activity of a patient's other ion channels contribute to one person's cystic fibrosis being completely different than another person's; and may necessitate a completely different treatment protocol based on how it will affect the activity of all of the patient's ion channels. Consequently, if there is no consideration for the ion flux in each ion channel in a patient, as well as how such ion flux will be affected by a particular treatment, the same treatment protocol which may be helpful for one patient may not provide optimal-results for another patient.
A related problem in the conventional diagnoses and treatment of ion-based diseases is that the current technique to quantify channel activity for a certain ion channel lacks both standardization (and units of measurement) and real time parameters. Because of this lack of standardization, it is impossible under conventional methods to analyze the entire human electrophysiology with any existing perspective. And because current techniques lack real time parameters, the ability to map such electrophysiology data with time frame parameters vital for the most accurate diagnosis is non-existent.
In order to more accurately predict, as well as to interpret, a patient's response to treatments for ion based diseases, such as excitable cell drugs, the patient's entire excitable cell physiology must be measured, standardized, mapped, and compared to desirable baseline values. Thus, there remains a need for a method and system which enables measured activity of a plurality of ion channels to be quantified with standardized values and given a real time context. It would be helpful if such a method and system for quantifying ion channel activity was able to summarize the activity of four key voltage gated ion channels for each excitable cell type (cardiac, pancreatic, beta, neuron, nephron etc.). It would be additionally desirable for such a method and system to facilitate comparisons of such summaries obtained from a given patient over a representative period of time to a database compiled using theoretical healthy channel activities for each organ, thus enabling a diagnosis to be configured based on the entire excitable cell physiology of the patient. It would further be desirable if such a method and system was embodied in a device which not only processed data from each excitable cell type, but also integrated flow cytometry, electrophysiology, and cell-cell differentiation to actually obtain data streams from each excitable cell type to be processed.
The Applicant's invention described herein provides for a method and system adapted to allow channel activity over a plurality of ion channels to be quantified with standardized values and given a real time context to enable the results to be compared between ion channels within a given patient or with normal human electrophysiology (or normals) for a particular ion channel. The primary steps of Applicant's method for quantifying measurements of activity from a plurality of different ion channels include measuring real time data from a plurality of ion channels, generating standardized values from the real time ion channel data, and summarizing the activity of four key voltage gated ion channels for each excitable cell type from the standardized values. When in operation, the method and system allows diagnoses of ion based diseases to include, and recommended or possible treatment protocols for ion based diseases to be configured with, standardized, real time data from a patient's entire excitable cell physiology. As a result, many of the limitations imposed by the prior art are removed.
A method and system through which input electrophysiological data from a patient or model organism can be integrated within a computational backend environment where the input parameters are combined to quantify and output voltage-gated channel activity having picoamperes/second units. The computational backend environment then diagnoses membrane excitability conditions based on the comparison of the channel activity quantification to a theoretical database of channel activity quantifications. In this regard, the computational backend environment can quantify electrophysiological data in a way which allows for an accurate diagnosis and output of treatment options based on the quantification of several ion channels.
The software implemented method and system comprises the primary steps of providing measurements of a subject's ion channel activity for a plurality of voltage gated ion channels, processing the measurements of ion channel activity, and interpreting the processed measurements of ion channel activity. The measurements of ion channel activity of a subject include measurements representing the number of active channels for each ion and measurements of the rate of flow of ions for each channel for a representative time frame. Processing the measurements of ion channel activity results in the calculation of a standardized value for channel activity from the number of active channels for each ion and data related to the rate of flow of ions for four specified key voltage gated ion channels: sodium, calcium, potassium, and chloride, for each excitable cell type measured. Interpreting the processed measurements of ion channel activity is performed through mapping of the entire electrophysiology of a subject to enable comparisons to the electrophysiology for both known disorders and healthy baselines, as well as consideration in the diagnosis and development of treatment protocols of how each ion channel will be affected by the protocol. In addition, prior to processing, the software implemented method and system may also perform a step of configuring electronic files containing the measurements of ion channel activity, if such files are in a non-readable file format, to enable the underlying the measurements to be extracted and populated into readable file formats.
It is an object of this invention to provide a method and system which enables measured activity of a plurality of ion channels to be quantified with standardized values and given a real time context.
It is another object of this invention to provide a method and system for quantifying ion channel activity which is able to summarize the activity of four key voltage gated ion channels for each excitable cell type.
It is yet another object of this invention to provide a method and system which compares such summaries obtained from a given patient over a representative period of time to a database compiled using theoretical healthy channel activities for each organ, thus enabling a diagnosis to be configured based on the entire excitable cell physiology of the patient.
It is still another object of this invention to provide a method and system embodied in a device which not only processed data from each excitable cell type, but also integrated flow cytometry, electrophysiology, and cell-cell differentiation to actually obtain data streams from each excitable cell type to be processed
These and other objects will be apparent to one of skill in the art.
a is a block diagram of representative data values and calculations for data collection for conventional ion channel activity calculations.
b depicts an equation for channel activity for conventional ion channel activity calculations.
Referring now to the drawings and in particular
Measured (or raw) ion channel activity data is defined as electronic files containing measurements of ion channel activity at a given time or over a defined time period. As such, measured ion channel activity data includes measurements relating to the number of active channels for four specified key voltage gated ion channels, sodium, calcium, potassium, and chloride, for each excitable cell type measured, as well as the flow of ions through the channels during the course of a predetermined, representative time frame. The measured ion channel activity data may include either measured ion channel activity data which is being captured at or around the time of quantification, measured ion channel activity data which from historical captures which has been stored, or both. This measured ion channel activity data is provided to the data handling software application to be processed and output as processed ion channel data having standardized values with time perspective. Through this processing, channel activity measurements are quantified in a manner which enables comparisons of values between ion channels within a given patient or with baseline values (including normals, whether theoretical of from analysis of past quantifications, known diseases, and historical quantifications) for a particular ion channel.
Referring now to
After the measured ion channel activity data has been configured, it is processed by the data handling software application to produce quantified measurements of ion channel activity. In this regard, processed (or quantified) ion channel activity data is defined as an electronic file having quantified measurements, providing standardized values having known units and enabling standardization across different ion channels and across different excitable cell types. The data handling software application is then configured to provide for comparisons of quantified measurements, through which the processed ion channel activity data is analyzed with other standardized measurement values, such as theoretical normals, providing perspective to the standardized values of the processed ion channel activity data across the entire electrophysiology of the patient from which the measured ion channel activity data was obtained.
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By augmenting the conventional data collection in such a manner, measured ion channel activity data which enables the data handling software application to calculate a channel activity value for an excitable cell to be quantified with known, easy to interpret units and with a time component can be collected. This is done by calculating channel activity from the number of active channels and the rate of ionic flux for any particular ion. Through the utilization of the measured rate of ionic flux for any particular ion as opposed to an open probability, a channel activity value is generated which can be expressed in picoamperes/second and which is calculated using either a real time data feed or historical data. Because channel activity is expressed with these standard units of measurement, channel activity values calculated by the data handling software application from this raw ion channel activity data can be compared, in context, with other channel activity values across different ion channels and across different excitable cell types.
The use of the number of active channels and the rate of ionic flux for any particular ion provides a key extension of the equation of
In the preferred embodiment, the data handling software application ion channel activity data is processed in SQL backend, where the incoming parameters of the number of active channels and the rate of ionic flux for any particular ion are used to produce several outputs for channel activity. Referring now to
It is contemplated that the activity database is initially populated with several thousand theoretical channel activity data points processed in accordance with the present method. It is further contemplated that as channel activity data points are generated through the processing of measured channel activity, and as additional ion based diseases are discovered and channel activity data points are measured and associated therewith, such measured channel activity data points and channel activity data points for membrane excitability disorders may be added to the activity database.
Referring now to
In any embodiment, a report on ion channel activity typically includes the calculated channel activity value of each measured voltage gated channel, and may include the number of active channels and information relating to the rate of ionic flux for any particular ion. A report on activity comparison provides diagnosis related information generated from the comparison of ion channel activity, in that standardized values for the different measured ion channels are compared and contrasted with standardized baseline values. Considering the entire electrophysiology of the patient, a parallel set of baseline values is sought and then matched with the patient. A diagnosis and treatment protocol is based on the diagnosis and optimal treatment for the matched baseline value. As such, it is contemplated that an activity database built in accordance with the present invention will additionally include suggested or ideal treatment protocols for known diseases. It is additionally contemplated that information related to lifestyle factors, and how they affect channel activity, may be included into the database as lifestyle factor data. In this regard, information related to the lifestyle of a patient seeking analysis of ion channel activity may be considered in the generation of a report. It is contemplated that such lifestyle factors would include dietary habits, exercise, stress levels, and chemical exposure among a host of others.
Referring now to
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Accordingly, the configuration process of ion channel data begins with identifying the file format of data provided. If the file format contains measurement values which are directly readable, the configuration process is not necessary and the data handling software application terminates the configuration process of ion channel data. If the file format does not contain directly readable measurement values, the emulator associated with the file format identified is run to enable the requisite measurements from the ion channel data extracted from the file format and populated in a directly readable file format. Once the requisite measurements for ion channel data are populated into a readable file format, the data handling software application terminates the configuration process of ion channel data.
The instant invention has been shown and described herein in what is considered to be the most practical and preferred embodiment. It is recognized, however, that departures may be made therefrom within the scope of the invention and that obvious modifications will occur to a person skilled in the art.