US20020108857A1 - Automated laboratory system and method - Google Patents

Abstract

An automated laboratory system and method allow high-throughput and fully automated processing of materials, such as liquids including genetic materials. The invention includes a variety of aspects that may be combined into a single system. For example, processing may be performed by a plurality of robotic-equipped modular stations, where each modular station has its own unique environment in which processes are performed. Transport devices, such as conveyor belts, may move objects between modular stations, saving movement for robots in the modular stations. Gels used for gel electrophoresis may be extruded, thus decreasing the time needed to form such gels. Robotically-operated well forming tools allow wells to be formed in gels in a registered and accurate way.

Description

• This application claims the benefit of the filing date under 35 U.S.C. §119 of U.S. provisional application No. 60/256,173, filed Dec. 18, 2000, which is hereby incorporated by reference in its entirety.[0001]
FIELD OF THE INVENTION
• This invention relates to automated laboratory processing, such as automated genomic research.[0002]
BACKGROUND OF THE INVENTION
• Various laboratory processes, such as those performed in genomic research, are largely performed by hand and/or with substantial human intervention at points in the process. Thus, performing such research can be time-consuming, labor-intensive and relatively low volume. Moreover, the required human intervention in semi-automated processes or manually-performed operations increases the likelihood that materials used in the process will become contaminated or that processes are not repeatable, e.g., will be performed in different ways during different tests.[0003]
SUMMARY OF THE INVENTION
• The inventors have developed a variety of unique tools, processes and devices that make high-throughput and fully-automated laboratory processes, such as those performed for genomic research, possible. Thus, the invention includes various aspects that may be used independently or in a variety of sub-combinations, and aspects may be combined into a single system or method for performing automated laboratory processes.[0004]
• In one illustrative embodiment, a plurality of modular stations may be combined into a single material processing system. Each modular station may perform at least one automated process in an overall process sequence. Each modular station may have its own controlled environment unique to the modular station within which to perform its processes, and may be capable of providing material for further processing by another module station without human handling of the material. That is, although two or more modular stations may be nominally controlled to have similar environmental conditions, e.g., the same temperature or humidity, the modular stations have their own unique environment since the environments of the modular stations are not well connected. Thus, processes may be performed at each modular station in a controlled environment that prevents cross-contamination between modular stations or contamination by outside sources. Further, since human handling of materials is not necessarily required to perform processes at a modular station, and processed material may be provided to another modular station for further processing without human intervention, the likelihood of contamination by human or other sources is decreased and the processing steps are more highly repeatable.[0005]
• In one illustrative embodiment, a method for processing genetic material, such as DNA, includes inputting a genetic material into an automated processing system, and performing at least amplification and separation processes using the genetic material without requiring human handling of the genetic material. Thus, in accordance with this illustrative embodiment, genetic material may be at least amplified, such as by a PCR process, and separated, such as by gel electrophoresis, without requiring any human handling of the genetic material. This is in contrast to amplification and separation processes typically performed in laboratories, in which a human is required to place and remove genetic material at a PCR processing station, and again handle the amplified genetic material so that it can be separated, e.g., by manually pipetting genetic material into wells formed in an agarose gel and submitting the gel to a voltage separation process. Such human handling at various steps in the processing may contaminate the genetic material and/or result in improper or imperfect processes being performed.[0006]
• In another illustrative embodiment, modular stations may operate to perform parallel processing of material samples. This is in contrast to other types of systems in which material samples or sample holders are processed serially. For example, the modular stations operating in accordance with one aspect of the invention may control a robot to remove several sample holders from a storage area and place the sample holders in a work tray. The robot may then perform the same or similar liquid handling procedures on the materials in the sample holders. Once the liquid handling processes are completed for all of the sample holders, the robot may move the sample holders to an area where they are transported to another modular station for further processing. This is only one example of a type of parallel processing that can save time and increase throughput since the robot can be tasked to perform several similar processes using a same tool, and then change tools to perform another set of processes. Using the example above, the robot may use a gripping tool to move sample holders to the work tray, then exchange the gripping tool for a liquid handling tool to perform liquid handling processes on the sample holders in the work tray. Only one tool exchange is needed to process multiple sample holders. In a serial process, the robot would position one sample holder in a work area, exchange tools, perform liquid handling processes on the sample holder, exchange tools again, move the sample holder from the work area so it can be transported to another modular station and retrieve another sample holder for processing. Other savings in addition to reduced tool exchanges may be realized using parallel processing. For example, all of the sample holders in a work tray may be scheduled to receive a same reagent mixed with the samples held in the holders, but in different amounts. Thus, the robot using the liquid handling tool may pick up a relatively large amount of the reagent from a reagent source (such as a reagent filled cup) and then deposit different amounts in the holders without returning to the source. This processing can avoid wasted movement of the robot between a reagent source and the holders. Parallel processing can be very effective in improving throughput when samples or sample holders to receive the same or similar processing are grouped together. Thus, in another illustrative embodiment, samples or sample holders that are planned to receive the same or similar processing may be grouped together for parallel processing, e.g., by a control system analyzing the process plans for each of the samples or sample holders and logically grouping the samples or sample holders together.[0007]
• In another illustrative embodiment, modular stations and the processes performed by them are controlled by a database-driven control system. Serial processing such as that described above allows for a simple control system since multiple ongoing processes and positions of sample holders need not be tracked simultaneously, or nearly simultaneously. The control system in this embodiment provides a much more flexible system, since the control system can support serial or parallel processing at the modular station level and/or at the process step level within each modular station. For example, the control system may use a relational database to track and implement processes within a system. Sample holders may each have their own unique identification, e.g., a bar code character string, that is associated one or more database tables that define the processing to be performed on the material in the sample holders. This type of control system arrangement can provide for a powerful and flexible system since a plurality of processing tables may be predefined and associated with samples or sample holders in different ways to provide different processing plans. For example, tables in the database may be constructed to describe/control Processes 1 through 4. A first sample holder may be associated with and processed according to the tables for[0008]Processes 2, 4 and 3, in that order. A second sample holder may be associated with and processed according to the tables forProcesses 2, 3 and 4, in that order. Thus, no structural change may be needed for the control system to provide different processing schemes for different samples, and there is no need to construct lengthy processing plans for each individual sample holder or sample. Instead, using the example above, predefined processing tables may be rearranged and associated with different sample holders to provide a plurality of different processing schemes. This type of relational-database driven control system can also allow more rapid analysis of planned processes when determining how to group sample holders for parallel processing. For example, a relatively simple determination may be made regarding which sample holders are associated with the table for Process 2. Those sample holder associated with Process 2 may be grouped together and processed in parallel, at least for that step in the process.
• In another illustrative embodiment, an automated material processing system having a plurality of modular stations may use a non-robotic transport system to move material between the modular stations. For example, one or more conveyor belts may interconnect modular stations to perform material transport. The conveyors may be bi-directional so that material can be moved in either direction between modular stations. By using the non-robotic transport system, robots in each of the modular stations may move a more limited amount when transferring material from one modular station to another. That is, a robot need not be required to physically move a material to a location that is accessible by another robot in a next modular station so that the other robot can pick up the material and move it for further processing. Instead, the robot need only be required to place the material on a conveyor belt, for example, within the robot's own modular station. The conveyor can then move the material to a next modular station where a robot associated with the next modular station can access the material. This savings in robot movement can speed processes within a modular station (because of the more limited movement requirements of the robot), as well as greater physical separation between modular stations. Greater physical separation between modular stations may be useful for allowing easier human access, e.g., for repair, monitoring or other activities, and/or allow better isolation between environments within each modular station.[0009]
• In another illustrative embodiment, a modular station may include a robot controlled liquid handler, or pipetting, tool that is used to move liquid material within the modular station. The liquid handler may be a multi-channel device having a plurality of plungers, one plunger associated with each channel, to control the amount of fluid material that is drawn into and expelled from each pipette tip. Such plunger arrangements are well known in the art, but in this illustrative embodiment, plunger movement is controlled by a linear servo motor and linear encoder. The linear servo motor and/or linear encoder provide a much more rapid and accurate operation of the liquid handler than rotary stepper motor-driven pipetting systems known in the art, because the linear servo motor, with position and/or velocity feedback from the linear encoder, can move the plungers much faster and more accurately than a stepper motor system. The liquid handler tool may change the pipette tips used for each of the channels as is known in the art. However, in one illustrative embodiment, the liquid handler can confirm that the pipette tips have been removed and/or are properly positioned on the liquid handler using one or more sensors. For example, the liquid handler may move the attached pipette tips near a photosensor that detects the presence or absence of pipette tips at each of the channels. If a pipette tip is missing or misaligned, the liquid handler can eject one or more of the tips and replace the missing or misaligned tips as needed.[0010]
• In another illustrative embodiment, gel material, such as that used to separate genetic material in an electrophoresis process, is formed by extrusion. This is in contrast to typical gel-forming methods, in which warm liquid material is poured into a tray and allowed to set in a gel form within the tray. Using the extrusion process in this embodiment, liquid gel material may be supplied into an extrusion cavity between two cooled plates. As the liquid material moves along the cavity between the plates, the liquid is cooled and forms a gel that is extruded from the cavity. This process allows gels to be formed at a much more rapid pace as compared to conventional methods.[0011]
• In one illustrative embodiment, a gel extruder includes a reservoir that holds relatively warm liquid material, such as an agarose mixture. This liquid material is supplied by a pump under pressure to an input side of an extruder cavity. The extruder cavity is formed by substantially parallel metal plates that are cooled, e.g., by a circulating chilled liquid such as water. Pressure of the incoming liquid material into the extruder cavity forces the liquid material along the extruder cavity and between the plates. The plates on either side of the cavity cool the liquid so that a semi-solid gel is formed and forced out of the extruder cavity. The gel extruder may also include a cutting device to cut the extruded gel into desired sizes and/or shapes, as well as a gel loading mechanism that places cut gels into trays or other carriers. The extrusion, cutting and tray loading process may be fully automated and not require any human handling or operation in the process.[0012]
• In another illustrative embodiment, constituent portions of a material, such as genetic fragments in a liquid, may be separated using an automated process. For example, a robot-controlled tool may form wells in gel material and subsequently fill the wells with a liquid material to be separated, e.g., by gel electrophoresis. The robot may use a comb-like element that is inserted into the gel by the robot to form the wells. The comb-like element may be heated, for example, by electro-resistance heating, so that heated tines of the comb-like element form the wells in the gel. The robot may then exchange the comb-like well forming element for a liquid handling device, such as a pipetting device described above. Since the robot was used to form the wells in the gel, the robot can easily register the well positions formed in the gel with pipette tips in the liquid handling tool. Other portions of the separation process may also be automated, such as by having a robot move a gel that has wells filled with material to be separated to an electrophoresis voltage station, where the gel is subjected to an electric field to separate the material. The electrophoretically-separated material may be automatically picked, e.g., by a coring process, using a robotic picking tool. The robot may use a vision system to identify and select separated material in the gel for picking. The picked, separated material may be used in further processing, such as further analysis, testing and so on.[0013]
• These and other aspects of the invention will be apparent from the detailed description and claims below.[0014]
BRIEF DESCRIPTION OF THE DRAWINGS
• Illustrative embodiments incorporating various aspects of the invention are described with reference to the following drawings, in which like reference numerals reference like elements, and wherein:[0015]
• FIG. 1 is a schematic block diagram of a material processing having a plurality of modular stations in an illustrative embodiment;[0016]
• FIG. 2 is a schematic diagram of a liquid handling modular station in an illustrative embodiment;[0017]
• FIG. 3 is a schematic diagram of a sample holder storage box in an illustrative embodiment;[0018]
• FIG. 4 is a schematic diagram of a liquid handling device in an illustrative embodiment;[0019]
• FIG. 5 is a schematic diagram of a tray feeder in an illustrative embodiment;[0020]
• FIG. 6 is a schematic diagram of a gel extruder in an illustrative embodiment;[0021]
• FIG. 7 is a schematic diagram of an automated material separation apparatus having a well former and liquid handling device in an illustrative embodiment;[0022]
• FIG. 8 is a schematic diagram of an automated material picker having vision capability in an illustrative embodiment; and[0023]
• FIG. 9 is a schematic diagram of an automated plating arrangement in an illustrative embodiment.[0024]
DETAILED DESCRIPTION
• Illustrative embodiments that incorporate various aspects of the invention are described below in connection with the figures. However, it should be understood that the invention is not limited to the illustrative embodiments described below.[0025]
• FIG. 1 is a schematic diagram of a[0026]material processing system100 in an illustrative embodiment in accordance with the invention. In this illustrative embodiment, thematerial processing system100 includes three modular stations1 that are interconnected by transport devices2. Although in this illustrative embodiment, thematerial processing system100 includes three modular stations1, systems may include any suitable number of modular stations. Further, modular stations1 may be interconnected by two or more transport devices2. Moreover, although thematerial processing system100 is shown as being a linear arrangement of modular stations, parallel arrangements of modular stations1 or other suitable arrangements may be used. For example, in this illustrative embodiment, a single modular station1B communicates with the modular stations1A and1C. However, the modular station1B may be replaced with two or more modular stations1 that communicate with the modular stations1A and1C. Such parallel processing arrangements may be used to improve the throughput of thesystem100, e.g., where the processes performed by the modular station1B take significantly longer than processes performed by the modular stations1A and1C.
• In this illustrative embodiment, the[0027]material processing system100 performs liquid material handling processes as well as genetic material amplification and separation processes. Thus, although amaterial processing system100 in accordance with the invention may be arranged to perform any other suitable process or set of processes, in this illustrative embodiment, thematerial processing system100, its modular stations1, and other portions are described in connection with performing a genetic material handling, amplification and separation process. Thematerial processing system100 in this embodiment includes a liquid handling modular station1A, an amplification modular station1B, and a separation modular station1C. As their names suggest, the liquid handling modular station1A receives input genetic material, e.g., DNA fragments in a liquid solution, and performs the various liquid handling procedures needed to perform at least the amplification portions of the process. That is, the liquid handling modular station1A can divide the input liquid material samples into multiple samples that are subjected to further processing. A more detailed description of the liquid handling processes performed in the modular station1A is provided below.
• The amplification modular station[0028]1B receives liquid material samples, e.g., in a plurality of microtiter plates or other sample holders, from the modular station1A by the transport device2A and subjects the liquid material in the microtiter plates to amplification processes, such as those performed in typical polymerase chain reaction (PCR) processes. Thus, a robot within the amplification modular station1B may place the microtiter plates in a PCR thermocycling device, which performs at least some, if not all, of the temperature cycling steps needed to perform PCR amplification of the genetic material.
• Liquid material processed by the amplification modular station[0029]1B may be sent back by the transport device2A to the liquid handling modular station1A, if necessary for further liquid handling processes, or may be transferred by the transport device2B to the separation modular station1C. The separation modular station1C may use the received liquid material, e.g., again in microtiter plates, to separate the various constituents in the liquid material samples in each well of the microtiter plates. Any suitable separation process may be performed, such as capillary electrophoresis, gel ectrophoresis, and so on. In this illustrative embodiment, the materials are separated using a gel electrophoresis process. Thus, a robot in the separation modular station1C may use a liquid handling device to place liquid material in the microtiter plate wells into wells formed in a gel material. The gels may be automatically produced using a gel extrusion process described in more detail below. Moreover, the robot may use a well-forming tool to automatically form wells in the gels. The robot may then subject the gels to an electric field at a voltage station and pick selected portions of the separated material once the electrophoresis process is complete.
• The fully-automated nature of the[0030]material processing system100 means that a human operator may input liquid material into the liquid handling modular station1A and not again handle the liquid material or any other tools or other materials used in the process. Instead, for example, the human operator may receive separated genetic material from the gels at the separation modular station1C.
• FIG. 2 shows an illustrative embodiment of a liquid handling modular station[0031]1A. In this illustrative embodiment, the modular station1A has aframe11 in the form of a box-like structure including uprights at four comers and is covered by atop surface12.Skirt panels13 enclose a lower portion of theframe11 on four sides of the modular station1A. Theseskirt panels13 may have doors, access panels, or any other suitable features to allow access to equipment located under awork surface14 that extends between the frame uprights at the top edges of theskirt panels13. A variety of different types of equipment may be located in the space covered by theskirt panels13 and thework surface14, such as air filters, heat exchangers, air conditioning devices, liquid storage tanks, electric service panels, computer hardware, and so on. Although in FIG. 2 the upper portion of the modular station1A above thework surface14 is shown as being open, this work space between thework surface14 and thetop surface12 is preferably enclosed by panels extending between theframe11 uprights. The enclosing panels may be made of a transparent or semitransparent material, such as glass or an acrylic material, and may also have doors to allow access to the work space. These enclosing panels may allow the environment in which processes are performed by the modular station1A to be controlled. For example, the humidity, temperature and other environmental features inside the enclosed work space may be controlled, e.g., air or other gas mixtures in the work space may be filtered, such as by an HEPA filter or other filtering device, and so on.
• In this illustrative embodiment, although the modular station[0032]1A may be arranged to perform different functions, the modular station1A in this embodiment performs liquid handling processes for genetic amplification and screening. Liquid material samples are provided insample holder16, such as commonly used microtiter plates, that are loaded intohotels15. Thehotels15 may include a plurality of vertically-oriented shelves152 (see FIG. 3) on which thesample holders16 are placed.Hotels15 may be loaded into astorage box17, e.g., by opening a door on an enclosing panel of the modular station1A and placing thehotel15 into thestorage box17. Loading ofhotels15 into thestorage box17 may be done manually, or by machine.
• FIG. 3 shows a schematic diagram of a[0033]storage box17 in an illustrative embodiment. Thestorage box17 is enclosed on its six sides so that the environment in which thehotels15 are stored can be controlled. That is, in one aspect of the invention, the environment within thestorage box17 may be different from the environment within the enclosed work space or other work areas in the modular station1A. Sides of thestorage box17 may have access doors or other features to allow thehotels15 to be placed inside thestorage box17 and/or to allow removal ofsample holders16 from thehotels15. In this illustrative embodiment, thehotels15 havehooks151 that allow thehotels15 to be hung on one ormore belts172. Although only onebelt172 is shown in FIG. 3, two ormore belts172 may extend aroundvertical shafts171 in thestorage box17. Theshafts171 may rotate as shown in FIG. 3 so that thebelts172 are driven in a rotary direction. Driving thebelts172 in the rotary direction creates a carousel-type arrangement in which thehotels15 can be moved in a rotary fashion in thestorage box17. Theshafts171 may be driven by a motor drive system (not shown) that is positioned below thework surface14 and may be controlled so thatparticular hotels15 and/orparticular sample holders16 are positioned at any desired position within thestorage box17. For example, each of thehotels15 may have a bar code or other machine readable identification code so that eachhotel15 can be uniquely identified. For example, a bar code label on thehotel15 may be read by a bar code reader as thehotels15 are loaded into thestorage box17. Each of thesample holders16 may similarly have a machine readable code so that eachsample holder16 can be uniquely identified. Again, the machine readable codes on thesample holders16 may be read as an associatedhotel15 is loaded into thestorage box17 or while thehotels15 are moved within thebox17. Knowing whichsample holders16 are supported on whichshelf152 in whichhotel15 may allow a control system to drive thebelts172 to position ahotel15 at a desired position in thebox17, e.g., so that aparticular sample holder16 can be accessed.
• It should be understood that as with all of the embodiments described herein, the illustrative embodiment shown in FIG. 3 depicts only one possible way in which[0034]samples holders16 or other carriers of the liquid material may be handled. For example,hotels15 may not be made removable from thestorage box17, and instead thesample holders16 may be individually loaded onto theshelves152 in thehotels15 while thehotels15 are in thestorage box17. Alternately, thehotels15 may not be used at all, and instead thesample holders16 may be stored in other ways. For example, thestorage box17 may include a plurality of vertically-oriented shelves that are open to access from both the outside of the modular station1 A (so thatsample holder16 may be placed on the shelves from the outside) and from inside the modular station1A (so that a robot or other device can remove thesample holder16 from the shelves).
• In this illustrative embodiment, the modular station[0035]1A includes a robot that performs many of the processing steps performed in the modular station1A. Therobot18 in this embodiment is an inverted three-axis cylindrical robot that is mounted on a linear gantry. The gantry19 includes a pair oflinear rails191 that support acrossbar192 extending between therails191. Only one of thelinear rails191 is shown in FIG. 2 for clarity, but theunshown rail191 may be located nearer thetop surface12 than therail191 shown in FIG. 2 so that easier access may be had to the work space. In this case, thecrossbar192 may have an upwardly extending bracket (not shown) or other element to engage with therail191 near thetop surface12. Thecrossbar192 may be driven under precise positional control along thelinear rails191, and therobot18 is mounted to thecrossbar192 so that it may be precisely positioned along the length of thecrossbar192. Therobot18 may manipulate a tool20, or pod, to perform various functions. For example, the tool20A shown in FIG. 2 may be a liquid handling device that operates under the robot control. Therobot18 may interchange tools20. For example, atool holder21 may support one or more alternate tools20, such as the tool20B, so that therobot18 can drop one tool20 on thetool holder21 and pick up an alternate tool20. Thetool holder21 may take a variety of forms, including a flat table surface on which the tools20 may be placed or have customized tool holding features for supporting each tool20 used by therobot18.
• In this illustrative embodiment, the alternate tool[0036]20B may be a robotic gripping tool that enables therobot18 to pick up, move and otherwise handlesample holders16 or other objects in the modular station1A. Thus, for example, therobot18 may pick up the gripping tool20B and use the tool20B to grasp and remove asample holder16 from ahotel15 in thestorage box17. Thesample holder16 may be withdrawn from thestorage box17 through an access173 in thestorage box17. The access173 may be covered by a door that is automatically opened and closed to allow access by therobot18. Therobot18 may place thesample holder16 in any suitable position for performing processes. For example, thesample holder16 may be placed in awork tray22. Thework tray22 may have a plurality of sample holder positions22A, e.g., formed by recessed portions in thetray22, that serve to keep thesample holders16 in place on thework tray22. Thework tray22 may include heating or cooling coils so that liquid samples in thestorage holders16 are maintained at a desired temperature. The temperature may be controlled for each individual position22A or for each group of positions22A, e.g., for each group of six positions22A on thework tray22. Of course, although asingle work tray22 is shown in FIG. 2, the modular station1A may include any number ofwork trays22 that each have any number of sample holder positions22A. It should be understood, however, thatsuch work trays22 are optional, and even if provided, therobot18 may perform operations on asample holder16 that is not located within awork tray22.
• When performing liquid handling operations, the[0037]robot18 typically will pick up and use a liquid handling tool20A to move liquid samples to and fromsample holders16 or other containers. FIG. 4 shows a schematic diagram of a liquid handling tool20A in an illustrative embodiment. The liquid handling tool20A includes anadapter201 that provides a quick connect/disconnect between therobot18 and the tool20A and allows both mechanical and electrical connection between therobot18 and the tool20A.Such adapters201 are well-known and used widely by robots having interchangeable tools. Theadapter201 is connected to abody202 which may include a frame to support the tool20A, electrical wiring and components, sensors, or other suitable devices. Connected to thebody202 is apipetting block203 which has a plurality ofpipetting channels204. Eachpipetting channel204 includes a pipette tip holder204A that extends from a lower side of thepipette block203. The pipette tip holders204A each communicate with a corresponding cylinder bore (not shown) in thepipetting block203. Each of these cylinder bores has a plunger204B positioned within the bore and extending through a top surface of theblock203. One or more seals (not shown) within the cylinder bores create an airtight seal between the plungers204B and the cylinder bore so that as the plungers204B are moved upward or downward relative to thepipetting block203, liquid may be withdrawn into or expelled from pipetting tips204C (only one shown in FIG. 4) attached to the tip holders204A. Upper ends of the plungers204B are attached to abar205 so that when alinear servo motor206 moves thebar205 upward or downward along the direction shown by the double-headed arrow in FIG. 4, the plungers204B are correspondingly moved in their respective cylinder bores and liquid material may be controllably withdrawn into and expelled from pipette tips204C attached to the tip holders204A.
• Use of a[0038]linear servo motor206 to control the movement of the plungers204B provides a significant advancement over typical liquid handling devices in which the plunger204B movement is controlled by a rotary stepper motor. Also included in this illustrative embodiment is alinear encoder207 which also provides a significant advance over existing liquid handling systems. Thelinear encoder207 provides a much more accurate indication of plunger204B position and movement, and thus allows thelinear motor206 to more accurately control the volume of liquid material withdrawn into and expelled from each of the pipette tips204C. Accurate volume control can be very important in some applications as the liquid sample material may be very expensive and/or the volume of liquid material expelled from a pipette tip204C may influence the results of further processing. For example, if an insufficient volume of a liquid material is placed into a well in a microtiter plate by the liquid handling tool20A, further processing of that liquid sample, such as amplification and separation, may not be performed properly or provide desired results.
• It should be understood that the liquid handling tool[0039]20A shown in FIG. 4 is only a schematic diagram for a liquid handling tool20A. Thus, the particular construction and operation of the liquid handling tool20A may vary from that shown in FIG. 4. For example, attached drawings of a 12-channel pipetter illustrate in a much more detailed way how such a liquid handling tool20A may be constructed.
• When performing liquid handling operations, the[0040]robot18 may control the liquid handling tool20A to change pipette tips204C attached to the pipette tip holders204A on the tool20A. Such tip changing may be performed for various reasons, including preventing sample cross-contamination. Replacement pipette tips204C may be supplied by atray feeder23 shown in FIG. 2. A more detailed view of an illustrative embodiment for atray feeder23 is shown in FIG. 5. In this embodiment, thetray feeder23 includes arack231 that supports a vertical stack ofpipette tip trays233. Each of thepipette tip trays233 includes a plurality of pipette tips204C. Suchpipette tip trays233 are well-known and widely used in the art. Atip tray extractor232 moves abottommost tip tray233 from left to right, as shown in FIG. 5 so that thetip tray233 may be accessed by therobot18. Thetip tray extractor232 may be implemented in a variety of different ways. In this illustrative embodiment, theextractor232 includes a push rod232A that pushes thebottommost tip tray233 onto thework surface14. The push rod232A may engage with any suitable portion of thetip tray233. In an alternate embodiment, thetip tray extractor232 may be positioned on thework surface14 and may pull, rather than push, thetip trays233 onto thework surface14. Once thetip tray233 is suitably positioned on thework surface14, e.g., by walls or other surfaces (not shown) that guide and hold thetip tray233 in a known position, a gripping tool20B on therobot18 may remove a lid233A from thetip tray233, thereby exposing the pipette tips204C in thetray233. Of course, the robot10 need not be used to remove the lid233A, or thetip trays233 may be supplied without lids233A. With the pipette tips204C exposed and the liquid handling tool20A attached to therobot18, the tip holders204A may be aligned with tips204C in thetray233 and inserted into a corresponding tip204C. Thetray feeder23, the liquid handling tool20A or other suitable device may include the capability to determine whether pipette tips204C are properly secured to the tip holders204A for each of thechannels204. For example, each of the tips204C may be moved past a photosensor that detects the presence or absence of each of the tips204C. If one or more of the tips204C are missing or misaligned with a tip holder204A, new tips204C may be placed onto the tip holders204A. For example, the tips204C may be removed from the tip holders204A in any suitable way, such as by engaging the tips204C with an ejector bar (not shown) on the liquid handling tool20A that pushes the tips204C off of the tip holders204A. Other devices may be used to confirm that tips204C are properly positioned on tip holders204A, such as mechanical switches that change state only when a tip204C is properly positioned on a holder204A, video camera confirmation, and so on. Pipette tips204C may be ejected from the tip holders204A so that the rejected tips204C are placed into atip tray233.Tip trays233 having rejected pipette tips204C may be removed from thework surface14 and stacked, for example, in a way similar to that in thetray feeder23.
• With the pipette tips[0041]204C properly positioned on the liquid handling tool20A, therobot18 may use the tool20A to perform any suitable liquid handling processes, such as moving liquid materials from onesample holder16 toother sample holders16, other microtiter trays, etc.Sample holders16 that are ready for processing by a next modular station, such as the amplification modular station1B, are placed by the robot18 (using the gripping tool20B, for example) so that the transport device2A can move thesample holders16 to the modular station1B. The transport device2A may include at least one conveyor belt or other device suitable for moving thesample holders16. The conveyor belt may be bi-directional so that objects may be moved in either direction between the modular stations1A and1B. Although devices other than conveyor belts may be used by the transport device2A, the devices used are preferably non-robotic to spare the expense and complexity of a robot to simply move objects from one position to another. Thus, conveyor belts, slides, or other relatively simple devices are preferably used by the transport devices2.
• Using a transport device[0042]2A, such as a conveyor belt, also allows for better isolation between modular stations1A and1B, since the modular stations1A and1B or the transport device2A may include one or more doors that are automatically opened and closed to permit objects to move between the stations1A and1B. The non-robotic transport device2A also saves therobot18 from unnecessary movement since therobot18 need not movesample holders16 or other objects so that a robot within the modular station1B can pick up thesample holder16 or other object where therobot18 left it. Thus, therobot18 is left more free to perform other processes, thereby potentially increasing the number of operations that may be performed by therobot18 in a given time period.
• Using the transport devices[0043]2 may also allow easier interconnection and/or change in relationships between modular stations1. For example, asystem100 may originally be configured to have the arrangement shown in FIG. 1, i.e., one liquid handling modular station1A that communicates with one amplification modular station1B which communicates with one separation modular station1C. However, if the liquid handling modular station1A is able to perform its processes fast enough to provide work for two amplification modular stations1B, a second modular station1B may be added and the transport device2A relatively inexpensively reconfigured to transport objects between the liquid handling modular station1A and both of the amplification modular stations1B. No other changes need be made to the liquid handling modular station1A or the preexisting amplification modular station1B regarding how objects are moved between the two. Thus, the transport devices2 allow may allow true modularity of thesystem100 components to be realized.
• Once[0044]sample holders16 are moved to the modular station1B, arobot18 arranged similarly to that shown in FIG. 2 and using a gripping tool20B, may pick up thesample holder16 and perform further processing on the liquid material in thesample holder16. For example, therobot18 may placesample holders16 into a PCR thermocycling device and again remove thesample holders16 once the thermocycling processing is complete. The modular station1B may include a plurality of PCR thermocycling devices, e.g., up to 32 devices, so thatmultiple sample holders16 may be processed at one time. For example, the modular station1B may include sixteen PCR devices that are all serviced by asingle robot18.
• As in the modular station[0045]1A, the modular station1B may read machine-readable codes on each of thesample holders16 to confirm the identify of thesample holders16 and to ensure that an appropriate process is performed on the liquid material in thesample holders16 and/orgroup sample holders16 for parallel processing. For example, after confirming the identity of asample holder16, thesample holder16 may be placed in a PCR device which is then programmed (automatically by a system controller) to perform the appropriate process on the liquid material. Thus, each of the modular stations1 may operate semi-autonomously to perform processes within the modular station1 under the overall system-level control of a central controller, e.g., a programmed general purpose computer or other data processing apparatus. For example, the central controller may maintain a database ofsample holders16, thehotels15 that eachsample holder16 is associated with, the identity of liquid samples associated with each sample holder16 (eachsample holder16 may be a 96-well, 384-well or larger-number well plate that has 96, 384 or a larger number of individual liquid material samples), and the processes that are to be performed on each liquid sample in eachsample holder16. Accordingly, upon receiving asample holder16, each modular station1 may confirm the identity of thesample holder16 and receive instructions from the central controller regarding the processes to be performed on liquid material samples in thesample holders16. The central controller may use a relational database arrangement by which eachsample holder16 or sample in aholder16 is associated with one or more process tables in the database. The process tables may include predefined processing steps, including definitions of materials to be used in the processing of the samples. The process table association for each sample orsample holder16 may be hierarchical, e.g., so that higher level process tables refer to lower level process tables that define standard processes. By using a relational database-driven control system, lengthy and detailed processing plans need not be generated for each sample orsample holder16. Instead, a sample orsample holder16 may be associated with one or more process tables which together define the processes to be performed. The central controller may also schedule the sequence of processing operations and direct the modular stations1 to perform processes onparticular sample holders16, or samples within asample holder16, in a particular order. For example, the central controller may analyze the process tables associated withsample holders16 to identify whichsample holder16 should be grouped together for parallel processing. This may be done by determining whichsample holders16 are associated with a same process table. Once parallel processing groups are determined, the central controller can instruct the modular stations to process thesample holders16 accordingly, e.g., the modular station1A may be instructed to place sixsample holders16 in awork tray22, perform a same or similar set of liquid handling processes on thesample holders16, and then move thesample holders16 to a next processing step. The central controller can also schedule when processes are to be performed based on expected processing times for steps in an overall processing plan. Alternately, a processing plan, including parallel processing group definitions, may be provided to the central controller, e.g., by a user entering the plan at a central controller interface.
• The central controller may also store a plurality of defined protocols, e.g., an association of one or more predefined process tables, that may be selected by a user, e.g., using a graphical user interface, for a set of samples to be processed by the[0046]system100. For example, a user may specify that “Protocol135” is to be used for a set of samples that are being input into thesystem100. Thus, a user need not specifically define the particular protocol parameters each time a set of samples are provided for processing. Instead, the user may select one or more of a set of defined protocols that themselves define the processing steps, etc. for the protocol. Based on the selected protocol(s), the system controller may schedule and implement the processing to be performed, which may include reconfiguring a processing plan previously developed and currently being implemented by thesystem100. (The processing plan may include a list of material samples, orsample holders16, the processes to be performed on them by the modular stations1, and the order in which the processes are to be performed. As processes are performed, the plan may be updated to reflect that steps have been completed, allowing a next process to be started, and so on.) Of course, the central controller may provide an interface so that a user can explicitly define the process tables, processes and/or materials to be performed and used in a protocol, and/or allow the user to select a predefined protocol/process table and modify one or more processes or materials used in the predefined protocol/process table.
• Samples that have completed the amplification processing in the amplification modular station[0047]1B may be transported by the transport device2A back to the liquid handling modular station1A, if necessary for further liquid handling processes, or forwarded to the separation modular station IC by the transport device2B. The separation modular station1C may be equipped with arobot18 in a way similar to that shown in FIG. 2. Thus, therobot18 in the modular station IC can pick up and movesample holders16 so that separation processing steps can be performed on the liquid material samples.
• In this illustrative embodiment, the separation modular station[0048]1C separates genetic fragments in the liquid material samples using gel electrophoresis. In one illustrative embodiment, the separation modular station1C automatically creates the gels used to separate the genetic material. FIG. 6 is a schematic diagram of an automated gel extruder that may be used in the separation modular station1C. At the center of the apparatus is thegel extruder31 which is basically formed by a pair of parallel metal plates that are separated from each other to form anextrusion cavity32. In one illustrative embodiment, the plates are separated approximately 0.25 inches apart and form a 10-inchwide cavity32. Warm liquid material, e.g., including an agarose mixture, is supplied from areservoir33 under a pressure of approximately 16-20 psi by apump34 to a lower end of theextruder31. Theextruder31 is arranged at an angle so that the warm liquid material is injected at a position that is lower than the opposite end of thecavity32 where gels are extruded. This incline of theextruder31 prevents, at least initially, the liquid material from exiting theextruder31 before being cooled to form a gel. The metal plates of theextruder31 are cooled by a chilled liquid, such as water, that is circulated by a pump35. In this illustrative embodiment, aheat exchanger36 is provided to cool the circulating fluid and maintain the proper temperature of the plates in theextruder31. Theheat exchanger36 may include a chilling system, such as a heat pump or similar device. Atank37 is also provided to store the chilled fluid, but is not necessary.
• As the liquid material supplied by the[0049]pump34 travels through thecavity32 between the chilled metal plates, the material solidifies to form a gel at least at the point where the material exits theextruder cavity32. In this illustrative embodiment, the pressure of the incoming liquid material forces the gel out of theextruder31, but other mechanisms may be used to extrude the gel. The extruded gel is deposited onto a platform38, and once the extruded gel reaches a desired size, e.g., a 10×10 inch square of gel one quarter inch thick, aknife39 cuts the gel from theextruder31. In this illustrative embodiment, theknife39 is shown as having a blade that moves in a rotary motion to cut the gel, but the gel may be cut in other ways, such as by a guillotine-type blade that moves in a linear direction. Cutting of the gels may be controlled by photosensors, e.g., positioned on the platform38, that detect that the gel has reached a suitable size. Of course, controlling how and when the gels are cut may be performed in other suitable ways.
• Once the gel is cut, the platform[0050]38 may rotate about anaxis40 as shown in FIG. 6 to deposit the gel in atray41 or other suitable container or surface. To prevent the gel from dislodging from the platform38 as it rotates, a vacuum pump42 may withdraw air from the platform38 throughholes43 in the platform38. Withdrawal of the air by the pump42 provides sufficient suction to keep the gel in place until it is deposited in thetray41. Once the platform38 has rotated sufficiently, the pump42 may stop withdrawing air through theholes43 to release the gel from the platform38 and drop it into thetray41. Once the gel is deposited in thetray41, the platform38 may rotate back into position to receive another gel, and thetray41 having a gel placed in it may be picked up and moved by a robot (not shown) and anempty tray41 positioned in its place. It should be understood that flipping extruded and cut gels using the platform38 or other mechanism is not required. Instead, the gels may be extruded directly onto atray41 or other container or surface. Also, gel cutting may be combined with flipping the gels into atray41. For example, an edge of the platform38, or a cutting tool attached to the platform38, may cut the gel as the platform38 rotates toward thetray41. Other suitable mechanisms for handling the extruded gels will occur to those of skill in the art.
• The separation modular station[0051]1C may use thetrays41 carrying gels to separate amplified genetic material received from the amplification modular station1B. FIG. 7 shows a schematic diagram of another portion of the separation modular station1C in which wells are formed in the extruded and cut gels and the genetic material is placed in the wells in preparation for applying a voltage to the gels to separate the genetic material. In this illustrative embodiment, arobot18, which may be arranged similarly to that shown in FIG. 2, e.g., having a linear gantry and so on, uses a well formingtool20cto formwells411 in the gels. The well formingtool20cincludes a comb-like element210cthat is heated and pressed into the gels. In this embodiment, the comb-like element210chas one row of four tines, and thus forms four wells at a time in a gel. It should be understood, however, that the comb-like element210cmay have any suitable number of tines and may have multiple rows of tines. In this illustrative embodiment, the comb-like element210cis made, e.g., cut or stamped, from a metal plate and is heated by electro-resistant heating so that the tines burn or melt the wells into the gel. Current for heating the element210cis supplied through the adapter201c,but the element210cmay be heated in any suitable way. For example, the element210cmay normally be stored in atool holder21 where it is preheated and picked up by therobot18, e.g., picked up by a grippingtool20bthat grasps the element210c.The element210cmay be returned to thetool holder21 for reheating and/or exchange for another tool20 after having been used to formwells411 in a gel.
• Once[0052]wells411 are formed in a gel, aliquid handling tool20amay be used by therobot18 to place liquid samples in asample holder16 or other holder into thewells411. Since therobot18 formed thewells411 in the gel, therobot18 can more easily register the pipette tips204C on a liquid handling tool20A with thewells411 since the position of the tines on the comb-like element210crelative to therobot18 are known, the position of thepipetting channels204 relative to therobot18 are known, and the position of therobot18 where each of thewells411 was formed is known. From this information, the robot18 (or its control system) can determine the appropriate robot position to load each of thewells411 with liquid from thepipette tips204c.
• When the[0053]wells411 are loaded with liquid material, a voltage is then applied to the loaded gels to separate the genetic material in thewells411. Although using a voltage to separate genetic material using a gel is well known, in this embodiment, the separation modular station1C uses therobot18 or other tool to move thetrays41 ready for voltage application to a voltage station (not shown). The voltage station may accommodate a plurality oftrays41, such as twenty trays at any one time. Thus, twenty ormore trays41 may be subjected to a voltage separation process simultaneously. The voltage station may have a plurality of vertically oriented shelves onto which one ormore trays41 are placed. Once on a shelf in the voltage station, voltage electrodes may be inserted into the gel, e.g., by a robot or other automated device, and a suitable voltage applied.
• Once the material in the[0054]wells411 has been separated by the applied voltage, thetrays41 may be removed from the voltage station and selected portions of the separated material picked from the gels. For example, FIG. 8 shows a schematic diagram of an automated gel picking arrangement that may be used in the separation modular station1C. That is, the separation modular station1C (or other station) may have a robotically-controlled coring tool20dthat picks selectedareas412 having a desired portion of separated material. The coring tool20dmay be guided by a vision system that includes acamera51. The vision system, which may be a software module that is part of the robot control system50 (see FIG. 7), may use video images captured by thecamera51 to identify one ormore areas412 of the gel that have desired portions of the separated genetic material by image analysis. The vision system may also provide the location of theareas412 to therobot control system50 so that therobot18 and the coring tool20dcan be controlled to pick the selectedareas412. The pickedareas412 may be used for further processing by thematerial processing system100, such as extracting the genetic material from the pickedareas412 from the gel or other material, further amplification, other testing and so on. Alternately, the pickedareas412 may be output for further processing by manual processes or other automated devices.
• It should be appreciated that a variety of different automated processes may be performed by the modular stations[0055]1. For example, FIG. 9 shows a schematic diagram of a robotically-controlled grippingtool20bperforming an automated plating process. In this illustrative embodiment, the grippingtool20bgrasps and manipulates a platingwand91 to spread a liquid material in asample holder16. Such plating processes are typically manually performed to spread a material, such as a liquid containing a bacterial culture, on a growth medium. Performing the plating process automatically can prevent contamination and result in a more repeatable plating process being performed ondifferent sample holders16. The grippingtool20bcan retrieve the platingwands91 from awand holder92. In this embodiment, thewand holder92 has a cup-like shape to hold thewands91, but it should be understood that thewands91 may be held and/or provided to the grippingtool20bin any suitable way.
• While the invention has been described in conjunction with specific embodiments thereof, many alternatives, modifications, and variations will be apparent to those skilled in the art. Accordingly, embodiments as set forth herein are intended to be illustrative of the various aspects of the invention, not limiting. Various changes may be made without departing from the spirit and scope of the invention.[0056]

Claims (48)

1. A material processing system for performing a plurality of laboratory processing steps on a material sample, comprising:

a plurality of modular stations each performing at least one process in an overall process sequence, each modular station adapted to perform the at least one process in an automated way within a controlled environment unique to the modular station, at least one modular station adapted to provide material for processing to another modular station without human handling of the material.

2. The system ofclaim 1, wherein the material sample is a liquid.

3. The system ofclaim 1, wherein the material sample includes genetic material.

4. The system ofclaim 3, wherein a first modular station is adapted to perform an amplification process using the material sample, and a second modular station is adapted to perform a separation process on material provided from the first modular station resulting from the amplification process.

5. The system ofclaim 1, wherein at least one of the modular stations is adapted to perform liquid handling functions using the material sample.

6. The system ofclaim 5, wherein the at least one modular station includes a robotically controlled pipetting tool.

7. The system ofclaim 1, wherein at least one of the modular stations is adapted to perform a gel extrusion process.

8. The system ofclaim 1, wherein at least one of the modular stations is adapted to perform one of an automated amplification process using at least a portion of the material sample, an automated separation process using at least a byproduct formed from processing the material sample, an automated electrophoresis process, and an automated picking process of material resulting from an electrophoresis process.

9. The system ofclaim 1, further comprising at least one transport system that moves material between a first modular station and second modular station.

10. The system ofclaim 9, wherein the at least one transport system includes a conveyor.

11. The system ofclaim 10, wherein a first robot associated with a first modular station is adapted to move an object to a first position so that the transport system can move the object to a second modular station to a second position where a second robot associated with the second modular station can access the object.

12. The system ofclaim 1, wherein at least one of the modular stations has a first environment and a second environment that is different than the first environment, and wherein the material sample is moved from the first environment to the second environment.

13. A method for processing genetic material, comprising:

inputting a genetic material into a material processing system; and

performing at least amplification and separation processes using the genetic material without human handling of the genetic material.

14. A material processing system for performing a plurality of laboratory processing steps on a material sample, comprising:

a plurality of modular stations each performing at least one process in an overall process sequence, each modular station adapted to perform the at least one process in an automated way; and

at least one transport device adapted to transport material for processing from a first modular station to a second modular station without human handling of the material.

15. The system ofclaim 14, wherein the at least one transport device includes a non-robotic device that moves the material from the first modular station to the second modular station.

16. The system ofclaim 14, wherein a transport device is arranged to transport material between pairs of modular stations.

17. The system ofclaim 16, wherein the transport device includes a conveyor.

18. The system ofclaim 14, wherein each modular station is adapted to perform the at least one process in an automated way within a controlled environment unique to the modular station.

19. The system ofclaim 14, wherein the material sample includes genetic material.

20. A liquid handling device comprising:

a body having at least one bore formed in the body;

a plunger slidably engaged with the body within the bore;

a pipette tip holder that fluidly communicates with the bore; and

a linear servo motor that drives the plunger to slide within the bore, sliding of the plunger causing fluid to move between the pipette tip holder and the bore.

21. The device ofclaim 20, further comprising:

a linear encoder that provides position information for the plunger.

22. A gel extruder for extruding gel material suitable for gel electrophoresis processing, comprising:

an extruder body including an extrusion cavity having a first end and a second end; and

a liquid material supply apparatus that supplies a liquid material to the first end of the extruder body;

wherein the liquid material cools within the extrusion cavity to form a gel that exits from the second end of the extrusion cavity.

23. The extruder ofclaim 22, wherein the extrusion cavity is arranged so that the first end is lower than the second end.

24. The extruder ofclaim 22, wherein the extruder body includes a pair of spaced plates that define two sides of the extrusion cavity.

25. The extruder ofclaim 24, wherein at least one of the plates is cooled by a chilled liquid.

26. The extruder ofclaim 22, wherein the liquid material supply device includes a pump that delivers the liquid material under pressure to the first end of the extrusion cavity.

27. The extruder ofclaim 26, wherein the pressure of the liquid material entering the first end of the extrusion cavity forces the gel to exit from the second end of the extrusion cavity.

28. The extruder ofclaim 22, further comprising a cutting device that cuts gels extruded from the second end of the extrusion cavity.

29. The extruder ofclaim 22, further comprising a rotatable platform that receives a gel exiting from the second end of the extrusion cavity and rotates to place a gel in a receiving area.

30. The extruder ofclaim 29, further comprising a vacuum pump that evacuates air from the platform and creates a suction force to secure gels to the platform.

31. A method for forming gels suitable for use in a gel electrophoresis process, comprising:

providing a liquid material at a first end of an extrusion cavity;

forming a gel in the extrusion cavity using the liquid material; and

extruding the gel from a second end of the extrusion cavity.

32. The method ofclaim 31, wherein the step of forming a gel comprises cooling the liquid material to form a gel.

33. The method ofclaim 31, wherein the step of providing a liquid material comprises providing the liquid material at a first end of the extrusion cavity that is lower than the second end of the extrusion cavity.

34. The method ofclaim 31, further comprising:

using the extruded gel in an electrophoresis process.

35. A well forming tool for forming wells in a gel that receive a liquid material, comprising:

a comb-like element having a body and a plurality of tines extending from the body, the tines adapted to be heated and inserted into the gel so that the tines each form a well in the gel suitable for receiving the liquid material.

36. A method for forming wells in a gel, comprising:

providing a comb-like element having a plurality of tines; and

inserting the plurality of tines into the gel to form one well for each tine.

37. The method ofclaim 36, further comprising:

heating the tines to a temperature sufficient to melt the gel.

38. The method ofclaim 36, further comprising:

grasping the comb-like element with a robotic-gripping tool.

39. A method for plating a sample in a holder, comprising:

providing a sample holder;

placing the sample in the sample holder; and

plating the sample in the sample holder using a robotically-controlled plating tool.

40. A method for performing a robotically-controlled liquid handling process, comprising:

providing a pipette tip tray having a lid over the tip tray; and

removing the lid from the tip tray using a robotically-controlled tool to expose the pipette tips for use by a liquid handling tool.

41. A method for performing a robotically-controlled liquid handling process, comprising:

providing a plurality of pipette tips;

placing the plurality of pipette tips on a robotically controlled liquid handling tool; and

automatically confirming that the plurality of pipette tips are properly positioned on the liquid handling tool.

42. The method ofclaim 41, wherein the step of automatically confirming comprises:

detecting each of the plurality of pipette tips using at least one sensor.

43. A method for picking selected material portions separated in a gel electrophoresis process, comprising:

providing a gel having a plurality of target areas;

identifying at least one of the target areas for picking; and

picking the identified at least one area using a robotically-controlled picking tool.

44. A modular station for performing automated liquid handling processes on liquid materials in a sample holder under robotic control, comprising:

a robot;

a liquid handling tool controlled by the robot; and

at least one work tray having at least one position in which a sample holder may be operated on by the liquid handling tool, the work tray adapted to allow control of at least a temperature near a sample holder in the at least one position.

45. A control system for a set of modular processing stations adapted to perform a plurality of different processes on samples in sample holders, comprising:

a storage device that stores a plurality of process tables, each process table defining a plurality of process steps; and

a central controller that associates each sample holder with at least one process table and generates control signals for each of the modular processing stations to perform processes on each sample holder.

46. The system ofclaim 45, wherein the storage device stores a relational database in which at least one process table refers to at least two other process tables.

47. The system ofclaim 45, wherein the storage device stores at least one protocol association list for a protocol, the association list including a list of process tables associated with the protocol.

48. The system ofclaim 45, wherein the central controller generates control signals for a modular processing station to parallel process at least two sample holders.

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