Abstract:
A matrix mixing robot includes a plurality of precision pumps (such as precision syringe pumps), a distributor and a processor system. Each pump, under the control of the processor system, draws an associated stock solution from a stock solution source, and pumps the drawn stock solution out through an outlet. The distributor, also under the control of the processor system, directs a stock solution from a particular pump outlet to a selected solution receptacle. A multi-port distribution valve may be associated with each precision pump. Each valve, under control of the processor system, can connect its associated pump to one the pump&#39;s inlets or outlets.

Description:
RELATED APPLICATIONS  
       [0001]    This application claims the benefit of U.S. Provisional Application No. 60/301,516, filed on Jun. 27, 2001, and is also a continuation-in-part of U.S. patent application Ser. No. 09/631,185, filed on Aug. 2, 2000, which claims the benefit of U.S. Provisional Application No. 60/146,737, filed on Aug. 2, 1999. The entire teachings of the above applications are incorporated herein by reference, although for the convenience of the reader, some parts may be repeated herein. 
     
    
     
       BACKGROUND OF THE INVENTION  
         [0002]    Macromolecular x-ray crystallography is an essential aspect of modern drug discovery and molecular biology. Using x-ray crystallographic techniques, the three-dimensional structures of biological macromolecules, such as proteins, nucleic acids, and their various complexes, can be determined at practically atomic level resolution. The enormous value of three-dimensional information has led to a growing demand for innovative products in the area of protein crystallization, which is currently the major rate limiting step in x-ray structure determination.  
           [0003]    One of the first and most important steps of the x-ray crystal structure determination of a target macromolecule is to grow large, well diffracting crystals with the macromolecule. As techniques for collecting and analyzing x-ray diffraction data have become more rapid and automated, crystal growth has become a rate limiting step in the structure determination process.  
           [0004]    Vapor diffusion is the most widely used technique for crystallization in modern macromolecular x-ray crystallography. In this technique, a small volume of the macromolecule sample is mixed with an approximately equal volume of a crystallization solution. The resulting drop of liquid (containing macromolecule and dilute crystallization solution) is sealed in a chamber with a much larger reservoir volume of the crystallization solution. The drop is kept separate from the reservoir, either by hanging from a glass cover slip or by sitting on a tiny pedestal. Over time, the crystallization drop and the reservoir solutions equilibrate via vapor diffusion of the volatile species. Supersaturating concentrations of the macromolecule are achieved, resulting in crystallization in the drop when the appropriate reservoir solution is used.  
           [0005]    The process of growing biological macromolecule crystals remains, however, a highly empirical process. Macromolecular crystallization is a hyperdimensional phenomena, dependent on a host of experimental parameters including pH, temperature, and the concentration of salts, macromolecules, and the particular precipitating agent (of which there are hundreds). A sampling of this hyperspace, via thousands of crystallization trials, eventually leads to the precise conditions for crystal growth. Thus, the ability to rapidly and easily generate many crystallization trials is important in determining the right conditions for crystallization. Also, since so many multidimensional data points are generated in these crystallization trials, it is imperative that the experimenter be able to accurately record and analyze the data so that promising conditions are pursued, while no further time, resources, and effort are spent on negative conditions.  
           [0006]    Recently, an international protein structure initiative has taken shape with the goal of determining the three dimensional structures of all representative protein folds. This massive undertaking in structural biology which may some day rival the human genome sequencing project in size and scope, is estimated to require a minimum of 100,000 x-ray structure determinations of newly discovered proteins for which no structural information is currently available or predicted. For perspective, the total number of reported novel crystal structures determined to date (spanning nearly 50 years of work) is only approximately 10,000.  
           [0007]    Using existing methods for the crystallization of proteins (random screens of conditions), the protein structure initiative will require a minimum of approximately 100 million crystallization trials. In addition, the biological information gleaned from genomic research in the protein structure initiative are expected to create even more demand for structural information. Specifically, the biotechnology and pharmaceutical industries are estimated to require upwards of ten fold more protein crystallization experiments (one billion) as a result of research and structure based drug design and the use of crystallized therapeutic proteins. This would require that each of the approximately 500 macromolecular crystallography labs worldwide be responsible for setting up approximately 2000 crystallization trials every working day of the year for five years. Currently, there is no known device available for setting up analysis macromolecular crystallization data on this scale.  
         SUMMARY OF THE INVENTION  
         [0008]    The preparation of crystal growth screening solutions is a tedious and time consuming endeavor. As such, high-throughput crystal growth demands that the construction of crystallization screening solutions be fully automated. To address this issue, the inventors have developed a method and system, an embodiment of which is called a “Matrix Maker”, for creating new crystallization screening solutions in a crystallization plate (drawing from, for example, 96 different stock solutions). A variation of the invention (“Drop Maker”) is capable of setting up crystallization drops in the plate once the screening solutions have been prepared in the plate.  
           [0009]    Another embodiment of the invention is capable of running chromatographic protein purification experiments by aspirating crude cell extracts from a sample plate and pumping them over a plurality of chromatography devices such as chromatography cartridges or columns. The chromatography devices are then washed by pumping a plurality of different elution buffers over the chromatography devices and collecting the liquids that flow through the chromatography devices into recipient containers. a single valve port serving as both inlet port and outlet port, and the connected pin being both a dispensing pin and an aspiration pin.  
           [0010]    According to an embodiment of the present invention, a system for mixing crystallization trial matrices includes a plurality of precision pumps (such as precision syringe pumps), a distributor and a processor system, which may contain one or more computer or digital processors. Each pump draws, under the control of the processor, an associated stock solution from a stock solution source, and pumps the drawn stock solution out through an outlet. The distributor, also under the control of the processor system, directs a stock solution from a particular pump outlet to a selected solution receptacle or holder.  
           [0011]    A multi-port distribution valve may be associated with each precision pump. Each valve, under control of the processor system, can at any time connect its associated pump to one of the inlets or outlets.  
           [0012]    In one embodiment, individual inlets of a particular pump may be connected to different stock solutions. Each outlet of a pump may be uniquely associated with an inlet, such that a particular stock solution always enters through one of said inlets and always exits through the associated outlet. Furthermore, each pump may have an inlet connected to a water/wash source, and an outlet for disposing of waste.  
           [0013]    In one embodiment, the distributor comprises one or more outlet manifolds which hold an array of dispensing pins that are connected to the outlet ports, and positioning means for aligning a particular pin over the desired solution receptacle. The dispensing pins may be made of stainless steel or some other suitable material. The distributor may also have an array of pins that are connected to tubing that is connected to one of the pump inlets. The pins and their associated lines may be used to aspirate or dispense liquids from solution receptacle container plates located beneath the distributor.  
           [0014]    The positioning means may include a gantry on which the outlet manifold is supported. The processor system may control the movement of the gantry in two or three dimensions. In one embodiment, multiple gantries may be used.  
           [0015]    Solution receptacles may be test tubes, crystallization plate wells, or other suitable containers (for example, Society for Biomolecular Screening type plasticware devices) that may be, for example, arranged in an array.  
           [0016]    In one embodiment, the processor controls the pumps, valves and gantry according to predefined recipes that describe which solutions are to be mixed, each destination solution receptacle, and solution volumes. These recipes may be viewed and edited by a user.  
           [0017]    In another embodiment, the processor may control the pumps, valves and gantry according to predefined protocols for purifying proteins chromatographically or for setting up crystallization plates. The protocols may be viewed and edited by a user. 
       
    
    
     BRIEF DESCRIPTION OF THE DRAWINGS  
       [0018]    The foregoing and other objects, features and advantages of the invention will be apparent from the following more particular description of preferred embodiments of the invention, as illustrated in the accompanying drawings in which like reference characters refer to the same parts throughout the different views. The drawings are not necessarily to scale, emphasis instead being placed upon illustrating the principles of the invention.  
         [0019]    [0019]FIG. 1 is a schematic diagram illustrating the operation of an embodiment of the invention, called a “Matrix Maker Robot.” 
         [0020]    [0020]FIG. 2 is a schematic diagram illustrating the generation and use of matrix recipes.  
         [0021]    [0021]FIG. 3 is an illustration of an embodiment of the matrix maker of FIG. 2.  
         [0022]    [0022]FIG. 4 is an illustration showing an array of stock solution containers and the tubing through which the solution passes, as employed in the embodiment of FIG. 3.  
         [0023]    [0023]FIG. 5 is illustration showing the pumps in the embodiment of FIG. 3.  
         [0024]    [0024]FIG. 6A is an illustration showing, in the embodiment of FIG. 3, the outlet manifold mounted to a gantry.  
         [0025]    [0025]FIG. 6B is an illustration, similar to FIG. 6A, showing the gantry in a different position.  
         [0026]    [0026]FIG. 7 is a closeup illustration of the embodiment of FIG. 3, showing the dispensing pins sticking through the outlet manifold.  
         [0027]    [0027]FIG. 8 is a schematic diagram illustrating the operation of an embodiment of the invention, called the “Protein Maker-Drop Maker Robot.” 
         [0028]    [0028]FIG. 9 is an illustration showing, in the embodiment of FIG. 8, the outlet manifold mounted to a gantry. 
     
    
     DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENT  
       [0029]    A description of preferred embodiments of the invention follows.  
         [0030]    [0030]FIG. 1 is a schematic diagram illustrating the operation of an embodiment 2 of the invention, called a “Matrix Maker Robot.” This design has many important features.  
         [0031]    For example, an embodiment of the present invention uses positive pressure displacement of stock solutions through independently controlled precision syringe pumps, such that no disposable pipette tips are required. Viscous stock solutions can be delivered with high accuracy and speed through stainless steel outlet pins that do not come into contact with the recipient plasticware or reservoirs solutions as they are being created.  
         [0032]    Proven “workhorse” precision syringe pumps, such as those manufactured by Tecan Systems (formerly Cavro Scientific Instruments, Inc.), can be used, minimizing subsequent maintenance.  
         [0033]    Different sizes of syringes can be used to meet varying accuracy and scalability needs.  
         [0034]    More stock solutions can be added to the system as needed or demanded.  
         [0035]    Sterility of stock solutions can be maintained by eliminating open exposure to air.  
         [0036]    Finally, the appropriate volumes of stock solutions can be delivered directly to a crystallization plate or into sample tubes through the use of a manifold which is attached to a robotic gantry that can move in the X, Y and Z directions (e.g., lateral width, lateral depth and vertical directions). The outlet lines “shoot” stock solutions into the recipient plate (i.e., the individual solution receptacles).  
         [0037]    Despite extensive investigation, the inventors were unable to identify a commercial liquid handling device that met these specifications.  
         [0038]    Referring now to FIG. 1, plural (e.g., forty-eight) bottles  10  holding various stock solutions are directly connected via Teflon™ tubing  12  (of the shortest reasonable length) to the inlet ports of, for example twenty-four, individual precision syringe pumps  14 , such as Tecan Systems&#39; Cavro XL-3001. Each pump  14  is equipped with an 8-port distribution valve  16 . In the illustrated embodiment, each pump  14  is attached through its distribution valve  16  to inlet lines  18  for two (2) different stock solutions, at valve positions  1  and  8 .  
         [0039]    Each pump  14  has two outlet lines  20 , at valve positions  2  and  7 , one for each of the two stock solutions. These outlet lines  20  are attached via tubing  44  (with the shortest reasonable distance) to an array of stainless steel dispensing pins or nozzles  26  held by an outlet manifold  28 , which itself may be constructed from metal or some other suitable material.  
         [0040]    Each pump  14  also has two waste outlet lines  22 , for example at valve positions  3  and  6 , through which waste is dumped into a waste container  42 . In addition, each pump  14  has two water inlet lines  24 , for example at valve positions  4  and  5 , connected to a water/wash supply  40 .  
         [0041]    The outlet manifold  28  is mounted to a robotic gantry system  48  (see, for example, FIG. 6A) that can move the outlet manifold  28  in the X, Y, and Z directions/dimensions. The twenty-four pumps  14  are controlled by a controller  32 . The robotic gantry  48  is controlled by a gantry controller  34 . The pump/valve controller  32  and the gantry controller  34  shown in FIG. 1 may comprise both software components and hardware components (collectively, generally referred to as a processor system).  
         [0042]    In one embodiment, the stock solution bottles  10 , inlet lines  12 , valves  16 , and syringe pumps  14  are comprised of chemically resistant materials such as Teflon™, polyetheretherketone (also known as PEEK™), glass, and stainless steel, such that the entire liquid path can withstand extreme pHs, high ionic strengths, and organic solvents. In this embodiment, the entire liquid path can be sterilized with chemical reagents such as ethanol, followed by extensive water washing and priming with filter sterilized stock solutions.  
         [0043]    Solution receptacles, into which the various solutions are delivered, may be placed on a platform below the outlet manifold  28 . For example, the solution receptacles may be wells arranged in an array on a crystallization plate  36 , or tubes held in a tube rack  38 . Multiple plates and/or tube racks may be positioned on the platform, and the software programmed accordingly to fill the containers of the various plates and tube racks.  
         [0044]    In a preferred embodiment, the solution receptacles are stationary while the delivery system is positioned by the robotic gantry  48 .  
         [0045]    Software  30 , such as Crystal Monitor™, available from Emerald BioStructures, Inc., of Bainbridge Island, Wash., provides for simple creation of a “recipe” for making a new set of screening solutions in the desired recipient crystallization plate  36  or rack  38  of tubes.  
         [0046]    For example, the software  30  may have the ability to capture distance constraint information on plasticware and tube racks. The software can also calculate the volume of stock solutions needed to create a new crystallization screening matrix. It also has a knowledge base of the viscosity of each stock solution.  
         [0047]    Database (DB) tables and graphical user interface (GUI) modules of software  30  may be used to perform the following: a) map stock solutions to physical positions on the invention; b) map stock solution inlet lines to valve positions on syringe pumps; c) map stock solution outlet lines to valve positions on syringe pumps; d) map stock solution outlet lines to outlet manifold pin positions on the gantry; and e) provide a knowledge base of titration curves for the final pHs achieved from mixing variable quantities of buffer stocks at 1 pH unit above and below the pKa of the buffer.  
         [0048]    [0048]FIG. 2 is a schematic diagram illustrating the generation and use of the recipes. A user  101  may communicate with software  30  such as Crystal Monitor through a graphical user interface (GUI) driver  103 , to define the system configuration as well as crystallization trial matrix solution specifications. A calculator  105  portion of the software  30  generates the “recipes”, which may be stored, for example, in a table  107  in a database  109 . Note that the system configuration information may also be stored in a table  108  in the same or a different database. The GUI driver  103  and calculator  105  may be integral parts of, for example, the matrix manager software described in U.S. Application Ser. No. 09/631,185.  
         [0049]    Robot mixer control software  111  also contains a GUI driver  113 , which may be launched by the Crystal Monitor program  30 . The robot mixer control software  111  allows the user  101  to directly view and edit the contents of the recipe table  107 .  
         [0050]    Crystal Monitor 30 is able to launch the robot mixer driver  115  upon an appropriate user action. Based on the configurational information  108  and the recipes  107 , the robot mixer driver  115  can generate a sequence of instructions or commands to control the matrix maker robot  200 , by driving the syringe pumps  14 , valves  16  (FIG. 1), and gantry  48  (see FIG. 3) in precise concert and sequence to deliver the appropriate stock solutions into the desired recipient containers.  
         [0051]    The robot mixer driver  115  takes into account several considerations, including, but not limited to, the following:  
         [0052]    (1) The final pH&#39;s for buffers are achieved by delivering the appropriate volumes of stock buffers which bracket the buffer pKa by +/−1 pH unit (with reference to experimentally determined titration curves);  
         [0053]    (2) The delivery sequence for different chemical types should be optimized;  
         [0054]    (3) Travel distances should be minimized;  
         [0055]    (4) Scheduling of pump wash cycles should be efficient; and  
         [0056]    (5) “Chemical compatibility” features may be provided that warn the user that chemical precipitation would occur upon mixing certain chemicals (e.g., Ca2+ and phosphate are incompatible).  
         [0057]    The table below illustrates a few exemplary rows (recipes) as might be defined in the recipe table  107 . Although twelve columns are shown, it would be understood by one skilled in the art that other columns can be added for various purposes. However, only those columns needed to demonstrate the present invention are shown.  
         [0058]    The “Dispensation No.” is simply an identifier to identify a particular row in the table  107 . Here, ten recipe rows are shown, having dispensation numbers from  58168  to  58177  respectively.  
         [0059]    The matrix mixer driver  115  may be capable of controlling multiple mixer robots  200 . Therefore, the “Robot ID” column serves to identify the particular robot  200  to which the row pertains. Here, all rows pertain to robot # 2 .  
         [0060]    A matrix may be given a name, specified in the “Matrix Name” column.  
         [0061]    A robot may be capable of processing multiple trays simultaneously. Each tray maybe identified by a unique identifier. Here, all of the rows pertain to tray # 12  of robot # 2 .  
         [0062]    “Reagent No.” specifies which stock solution bottle ( 10  from FIG. 1) is to be pumped, and the “Row” and “Col” columns specify the position of the receiving container that is to receive the identified stock solution. The “Vol” column indicates the volume to be dispensed, here in microliters.  
         [0063]    So, for example, the first five rows, identified as dispensation numbers  58168  through  58172 , direct that various stock solutions (from bottles numbered  19 ,  45 ,  11 ,  13  and  1  respectively) be dispensed into the container positioned at row  1 , column  1 , for tray  12  at robot  2 , resulting in a 2-milliliter solution. The next five rows, identified as dispensation numbers  58173  through  58177  specify the solution to be mixed in the receptacle/container at row  1 , column  2  of the same tray.  
         [0064]    The “Asp”, “Disp”, and “Drop” flags are simply flags used to indicate whether a respective particular operation has been done yet. For example, in the row for dispensation no.  58170 , the Asp flag (=Yes) indicates that aspiration has been performed, that is, the reagent from bottle  11  has been drawn into the corresponding pump  14 . The Disp flag (=No) indicates that the stock solution has not yet been dispensed from the pump  14 .  
         [0065]    After dispensation, a drop of the stock solution may be hanging from the end of the dispensing pin. To prevent this drop from falling into and contaminating the dispensed solutions when the gantry is moved, an additional “drop” operation may be performed to draw back the drop (say about 5 microliters) into the dispensing pin. The “Drop” flag indicates whether this operation has been performed.  
         [0066]    Finally, the status flag is used to indicate current status to the Crystal Monitor software  30  (FIG. 1).  
                                                                                                                             Dispensation   Robot   Matrix   Tray   Reagent               Asp   Disp   Drop   Status       No   ID   Name   TD   No   Row   Col   Vol   Flag   Flag   Flag   Flag                                58168   2   matrix001   12   19   1   1   200   No   No   No   1       58169   2   matrix001   12   45   1   1   80   No   No   No   1       58170   2   matrix001   12   11   1   1   367.5373   Yes   No   No   1       58171   2   matrix001   12   13   1   1   32.46267   Yes   Yes   No   1       58172   2   matrix001   12   1   1   1   1320   Yes   Yes   Yes   1       58173   2   matrix001   12   19   1   2   200   Yes   Yes   Yes   1       58174   2   matrix001   12   45   1   2   80   Yes   Yes   Yes   1       58175   2   matrix001   12   11   1   2   312.7144   Yes   Yes   Yes   1       58176   2   matrix001   12   13   1   2   87.28554   Yes   Yes   Yes   1       58177   2   matrix001   12   1   1   2   1320   Yes   Yes   Yes   1                  
 
         [0067]    The matrix mixer driver  115  can accommodate various syringe sizes (e.g., 0.25 to 25 mL) and syringe speeds, different volume settings, etc.  
         [0068]    [0068]FIG. 3 is an illustration of an embodiment of the matrix mixer  200  of FIG. 2. Stock solution bottles  10  are seated along either side of the platform  60 . The stock solutions  10  are connected to the syringe pumps  14  via inlet tubing  12 . The pumps  14  and their 8-position valves  16  sit atop a housing  50 , which contains the gantry drive system for positioning the robotic gantry  48 .  
         [0069]    The outlet manifold  28  sits on the robotic gantry  48 . Outlet tubing  44  connects the pumps  14  with the dispensing pins  26  which deliver the various solutions.  
         [0070]    Here, the outlet manifold  28  has been positioned over a wash/waste receptacle  43  which sits on the platform or deck  60 . The wash/waste receptacle  43  shown is of sufficient size (with respect to area) such that as many as all of the syringes and outlet tubes  44  may be washed simultaneously.  
         [0071]    [0071]FIG. 4 is an illustration showing an array of stock solution containers  10  and the Teflon tubing  12  through which the solution passes, as employed in the embodiment of FIG. 3.  
         [0072]    [0072]FIG. 5 is an illustration showing the pumps  14  in the embodiment of FIG. 3. A first row of pumps  14  is located on top of the housing  50 . A second row of pumps  14  is located behind the first row and is not visible in the FIG. 5 view. As can be seen from the figure, each pump  14  is attached to an associated 8-position valve  16  previously described in detail.  
         [0073]    [0073]FIG. 6A is an illustration showing, in the embodiment of FIG. 3, the outlet manifold  28  mounted to the gantry  48 . Tubing  44  from the pump valve outlets  20  (FIG. 1) is brought to the outlet manifold  28 , and is connected to an array of dispensing pins  26 . A wash/waste receptacle  42  is located on a stable platform next to a tube rack  38 .  
         [0074]    [0074]FIG. 6B is an illustration similar to FIG. 6A showing the gantry  48  in a different position with respect to tube rack  38  and wash/waste receptacle  42 .  
         [0075]    The tube rack  38  may be positioned to the platform/deck  60  via mounting pins (not shown) that allow the tube rack to be accurately positioned yet easily removed as an entire unit. This worktable mounting pin system provides the flexibility to utilize various racks containing different quantities of test tubes or different size test tubes, micro-plates, etc.  
         [0076]    [0076]FIG. 7 is a closeup illustration of the embodiment of FIG. 3, showing the dispensing pins  26  sticking through the outlet manifold  28 . Here, one solution  54  is being delivered to a receiving test tube  52 , located in the test tube rack  38 . It should be understood that multiple solutions may be delivered or dispensed to multiple receiving containers simultaneously.  
         [0077]    In an alternate embodiment, several syringe pistons may be attached to a common drive, as for example, on the Cavro XL-3000-8. Thus, when one syringe piston is moving to deliver liquid, the other seven syringe pistons also move with the exact same stroke. However, the switch valves at the top end of each syringe are independently operated. Hence, when the XL-3000-8 performs a single liquid delivery cycle, the switch valve for the desired stock solution is the only one switched to the output position. The other stock solutions are pumped back into the stock bottles.  
         [0078]    In this embodiment, the stock solutions can be arranged such that they are attached to the 8-position syringe drivers in an order that provides minimal chance that a given syringe pump would have to operate through more than one cycle during the construction of a single crystallization solution. For example, stock solutions which have similar chemicals may be attached to the same 8-port precision syringe pump. Then, following recipes of table  107 , the matrix mixer driver  115  controls mixer robots  200  to pump/dispense through a subject syringe pump  14  once per cycle accordingly.  
         [0079]    [0079]FIG. 8 is a schematic diagram illustrating the operation of another embodiment  800  of the invention, called a “Protein Maker-Drop Maker Robot.” Solution inlet lines  801  are attached to an array of stainless steel pins or nozzles  26  held by a manifold  802 . The manifold  802  is mounted to a robotic gantry system  48  (see, for example, FIG. 6A), which is controlled by software  804  via a gantry controller  34 . The gantry controller  34  can control the movement of the manifold  802  in these orthogonal directions or dimensions. In this way, the pins  26  can be moved into sample plates  803  that contain desired solutions, which may be, for example, crude cell extracts containing protein, solutions containing purified protein, or chemical stock solutions. The pins, tubing and pumps involved are normally washed between aspiring different solutions to prevent contamination.  
         [0080]    Alternatively, some pins could be offset from the rest and used individually without interference by the other pins.  
         [0081]    Specified volumes of the solutions can be drawn into the inlet lines  801 , by the appropriate specified valve  16  (see, for example, FIG. 1) and pump  14  movements under the control of software  804  via the pump controller  32 . The solutions can be drawn into the syringe pumps  14 , and then pumped through chromatography cartridges  807 , via outlet lines  809 , after the valves  16  change position to connect the pump  16  contents to the outlet lines  809 .  
         [0082]    The chromatography cartridges  807  are attached to an array of stainless steel dispensing pins or nozzles  26  held by the manifold  802 . The solutions that flow through the chromatography cartridges  807  can be collected in collection plates  811 , by software  804  controlled gantry movements of the manifold  802 . Using specified pump  14  and valve  16  movements, the chromatography cartridges  807  can be washed with a plurality of different solutions (for example, wash buffer, equilibration buffer, elution buffers), which are attached to designated inlet valve  16  positions via additional inlet lines  813 . The solutions that flow through the chromatography cartridges  807  can be collected in collection plates  811 , by software  804  controlled gantry movements of the manifold  802 .  
         [0083]    Solutions from collection plates  811 , protein sample plates  815 , plates  817  containing detergents, plates  819  containing a set of ligands, and/or plates  821  containing crystallization screening solutions prepared from stock solutions by, for example, the matrix maker  200 , can be sequentially aspirated into solution inlet lines  801  and dispensed into crystallization plates  823  from the solution inlet lines  801  by the appropriate software  804  controlled pump  14 , valve  16 , and gantry  48  movements. The inlet lines  801  can be flushed with water between each aspiration and dispensing cycle. The water flush can be captured in the tip washer station  43  by the appropriate software  804  controlled pump  14 , valve  16 , and gantry  48  movements.  
         [0084]    It should be apparent to one skilled in the art that the Matrix Maker Robot 200 and the Protein Maker-Drop Maker Robot 800 embodiments enable scientists to prepare new crystallization screening solutions from stock solutions, purify proteins from crude cell extracts, and set up crystallization plates by drawing from solutions in plates that were produced by the same embodiments.  
         [0085]    [0085]FIG. 9 is a closeup illustration of the embodiment of FIG. 8, showing the dispensing pins  26  sticking through the outlet manifold  802 . Here, twenty four chromatography cartridges  807  are mounted onto the manifold  802  and attached to outlet lines  809 . Also shown are twenty-four inlet lines  801  that are attached to the manifold  802 . The gantry  48  is shown directing the movement of inlet pins  26  into a sample plate  803 . A collection plate  811  is also shown.  
         [0086]    While this invention has been particularly shown and described with references to preferred embodiments thereof, it will be understood by those skilled in the art that various changes in form and details may be made therein without departing from the scope of the invention encompassed by the appended claims.