GB2194176A

GB2194176A - Sequence assembler for copolymers

Info

Publication number: GB2194176A
Application number: GB08620956A
Authority: GB
Inventors: Bruce Heywood Nicholson
Original assignee: Individual
Current assignee: Individual
Priority date: 1986-08-29
Filing date: 1986-08-29
Publication date: 1988-03-02
Anticipated expiration: 2006-08-29
Also published as: GB2194176B; GB8620956D0

Abstract

Apparatus for assembling oligomers where the order of assembly is important (e.g. oligopeptides, oligonucleotides and oligosaccharides) comprises a solid support on which, in operation of the apparatus, the growing oligomer is chemically bonded; a plurality of reaction vessels for containing reagents to produce said oligomer; transport means for transporting said solid support and immersing said solid support in and removing said solid support from reagent in each of said reaction vessels; and control means operatively connected to said transport means for controlling said transport means so as to immerse said solid support in said reaction vessels in an appropriate order.

Description

SPECIFICATION Sequence assembler for copolymers The present invention relates to apparatus for the sequential assembly of copolymers, which apparatus is particularly useful for the synthesis of oligonucleotides, but which may also be used for the synthesis of oligopeptides and oligosaccharides as well as other copolymers.

Specifically, the apparatus provides a means, which may be completely automated and operated under the control of an appropriate computer programme, for carrying out a multiplicity of sequential chemical reactions in an order which can be predetermined and which may be operated from start to finish without the need for human intervention.

In general terms, the sequence of chemical reactions involved in building up long chain compounds such as the oligomers referred to above can all be described in the same way as follows: (a) taking a solid support and bonding to it a compound forming one terminal of the desired oligomer,; (b) deprotecting or activating one end of the compound forming that terminal; (c) bonding to the deprotected or activated end of the aforementioned compound another compound (which may be different from or essentially the same as the first-mentioned compound) to form a chain of two compounds bonded through the first compound to the solid support,; (d) repeating the sequence of steps (b) and (c) as often as necessary to form a chain of the desired length; (e) if necessary, stopping chain growth at the growing terminal; and (f) if necessary, removing the oligomer from the solid support.

In the case of the preparation of oligonucleotides, the simple compounds employed in step (c) will be suitably protected and/or activated nucleotides. In the preparation of oligopeptides, the compounds employed in step (c) will be appropriately protected amino acids. In the case of the preparation of oligosaccharides, the compounds employed in step (c) will be appropriately protected simple sugars. In the case of other polymers, the compounds will be appropriately protected and/or activated monomer molecules. The chemical reactions involved in such syntheses are, however, well known and require no elaboration here.

Information on such synthesis can be found in a multitude of publications. For example, information on oligopeptide synthesis on solid supports is given by R.A. Houghten [proc. Natl.

Acad. Sci. U.S.A., 82, 5131-5135 (1985)] and a simple summary of oligonucleotide synthesis is given in "Oligonucleotide Synthesis", M.J. Gait ed., IRL press, Oxford/Washington D.C., ISBN 0-904147-74-6.

The synthesis of such oligomers as are referred to above, particularly oligonucleotides and oligopeptides, is of considerable interest in research and the various aspects of biochemistry and the typical researcher often has to synthesize large numbers of such oligomers which often contain from, say, 10 to 100 units, e.g. nucleotides or amino acids. Such synthesis is time-consuming, repetitious and boring and is an obvious candidate for mechanization. As a result, several attempts have been made to mechanize the sequence of reactions and provide "oligonucleotide machines" or "oligopeptide machines".A number of such machines are currently commercially available, but are only capable of synthesising up to four oligomers simultaneously, or, in the case of movable column machines, of synthesising analogues by moving a column (e.g. a glass tube with a filter at one end) for particular additions at particular points in the assembly sequence. In general, such machines are either fully automated and extremely expensive or cheaper but only semi-automated, requiring continual intervention by the researcher. There is clearly a demand, which is not currently being met, for a fully automated machine which is capable of being produced at a reasonable price.

One recent proposal for such a machine appears in British patent specification No.

2,158,075; the machine comprises a multiplicity (i.e. a large number) of rotatable plates each having a reaction chamber and a by-pass aperture and forming in effect a multitude of reaction chambers associated with a corresponding multitude of rotary valves. Such apparatus is capable of operating effectively, but has the disadvantage that it requires the plates to be under pressure during the feeding of reagents in order to prevent leakage of the reagents from between the plates but, on the other hand, requires that the pressure should be removed in order to allow the plates to move relative to one another.

I have now discovered a novel machine employing the solid support concept but which enables the disadvantages of the prior machines to be overcome.

In its broadest aspect, the present invention provides apparatus for the synthesis of oligomers, including oligopeptides, oligonucleotides and oligosaccharides, and comprising: a solid support on which, in operation of the apparatus, the growing oligomer is chemically bonded; a plurality of reaction vessels for containing reagents to produce said oligomer; transport means for transporting said solid support and immersing said solid support in and removing said solid support from reagent in each of said reaction vessels; and control means operatively connected to said transport means for controlling said transport means so as to immerse said solid support in said reaction vessels in an apprnpnate order.

The control means preferably comprises a computer appropriately programmed to keep track of the or each solid support and to ensure that it is immersed in the appropriate reaction vessel in the appropriate order.

We prefer that the reaction vessels should be mounted in an ordered array, which could, for example, be circular, rectangular or spiral.

The number of reaction vessels will, of course, depend upon the number of different compounds which it is desired to introduce into the oligomer. In the case of oligopeptides, a minimum of 20 reaction vessels would normally be required, but more may be provided, e.g. two or more of the vessels could contain the same reagent, if that reagent is a commonly used one. In the case of oligo nucleotides-, a minimum of 4 vessels would be required for the four natural nucleotides, but additional vessels may be required for "unnatural" nucleotides and/or for duplication of some of the nucleotides. In general, about 30 vessels would be the maximum that is likely to be required.

The reaction vessels are preferably arranged in an ordered array in a coordinate-determined system, which could be orthogonal or polar.

The transport means comprises means for moving the reaction vessels and/or solid support relative to each other and means for picking up and putting down the solid support.

The means for moving the reaction vessels and/or solid support relative to each other may comprise means moving the reaction vessels, or means moving the solid support or means moving both the reaction vessels and the solid support. In the case of a rectangular or spiral array of reaction vessels, it is generally more convenient merely to move the solid support, rather than-the reaction vessels. If desired, however, limited movement of the reaction vessels may be permissible. In the case of a circular array of reaction vessels, movement of the reaction vessels, the solid supports or both is possible.

In a preferred embodiment of the invention, the solid support is transported by the transport means to the appropriate one of the reaction vessels, is dropped into that vessel (preferably gently, so as to avoid splashing) and then, if desired, the transport means may move to another reaction vessel to pick up the solid support immersed therein and transport it elsewhere. This allows several reactions to be carried out simultaneously employing the same reagents, although with the option of employing different combinations of reagents or employing the reagents in different orders, so as to make a number of different oligomers simultaneously.

Since the reagents employed in processes of the type with which this invention is concerned are liquid, it is probable that the solid support, upon removal from the reaction vessel, will entrain with it a certain quantity of the liquid reagent and some of this reagent may drip from the removed solid support. Provided that the solid support, at the time of the drip, is over the reaction vessel from which it has just been removed (so that the drip falls into that reaction vessel) or, at least, is not over another reaction vessel, there will be no problem. However, if the solid support is over another reaction vessel at the time when the drip drips, this will cause contamination of the reagent in that other reaction vessel and may result in a subsequent incorrect synthesis. This problem can be overcome in several ways.For example: as the solid support is removed from the reaction vessel and whilst it is still over that reaction vessel, the transport means may be caused to shake, so as to shake the solid support and thus encourage any drips to leave then; upon removal of the solid support from the reaction vessel, the solid support or the reaction vessel(s) may be moved so that the solid support is held briefly over a drip tray remote from or adjacent to the reaction vessel(s) for sufficient time to allow any drips to fall onto the drip tray; or the path of the solid support upon leaving each reaction vessel may be so selected as to avoid the solid support travelling over other reaction vessels until the solid support has been washed.

In part, the nature of the solid support will be dictated by the nature of the reactions involved. For example, in the synthesis of oligonucleotides, the solid support could be formed of polystyrene, to which a shorter oligonucleotide has been covalently linked (Letsinger et al, Nucleic Acids Research 1975, volume 2, pages 773-786), cellulose (Crea and Horn, Nucleic Acids Research 1980, volume 8, pages 2331-2348), polyacrylamide (Gait et al, Nucleic Acids Research 1982, volume 10, pages 6243-6254), silica (Caruthers et al, Tetrahedron Letters, 1980, volume 21, pages 719722), controlled-pore glass (Sproat et al, Tetrahedron Letters, 1983, volume 24, pages 5771-5774 and Giles, American Biotechnology Laboratory, November-December 1985, "Advances in Automated DNA Synthesis") and many other types of material. In the case of oligopeptide synthesis, the solid support may be, for example, any of those listed above for use in oligonucleotide synthesis.

A useful form of support comprises a rigid macroporous inorganic material, for example macroporous kieselguhr, in the pores of which is entrapped a material forming one end of the oligomer to be prepared. For example, a dimethylacrylamide-based monomer mixture can be polymerized in the presence of such a macroporous inorganic material. Alternatively, dimethylacryloylsarcosine may be incorporated into a polymerizing mixture for forming a polyam ide-type polymer, such as a nylon, to produce a functionalized nylon or similar compound; this may be done in such a way as to form the functionalized polymer in the pores of a macroporous inorganic material, as explained above, or to form the functionalized polymer into fibres, as explained below.

The physical form of the solid support may vary widely. The principal requirements determining the physical form are that the support should allow unrestricted access by the reagents to growing molecular chains attached to the support, that the support should be essentially inert to the reagents, as well as to any wash liquids or other materials with which they may come into contact and that the whole of the support should be capable of being moved as an entity, without, for example, parts dropping off. Various forms are possible. For example, the solid support can be formed into a felt or paper, in which case, provided that it is properly made, it will remain intact throughout the sequence of reactions. Alternatively, it could be formed into a thread and wound around a holder, e.g. bobbin.Alternatively, it could be in particulate form (e.g. in the form of beads, powder or granules) and held in a porous container.

The latter technique is described by Houghten [proc. Natl. Acad. Sci. U.S.A., 82, 5131-5135 (1985)]. The Houghten method has been graphically described as the "tea bag method". In this method, the particulate solid support is contained within porous containers made of, for example, a polypropylene mesh. The containers may be in the form of bags sealed at the open end, hence their description as "tea bags".

If desired, the flexible, porous "tea bag" may itself be supported within or on a suitable holder. Alternatively, the solid support may be supported within a rigid container provided with apertures of a size such that the solid support cannot escape but liquid reagent can flow into and out of the container and around the solid support within the container.

A suitable design is illustrated hereafter in the accompanying drawings.

The material from which the or any container for the solid support is made is not critical to the invention and materials which may be employed are well known to those skilled in the art. Examples include glass, polytetrafluoroethylene (which is particularly desirable in the production of oligonucleotides), polyamides, such as the nylons (particularly desirable for the production of oligopeptides) and polypropylene.

Another useful form of solid support comprises a fibrous polymer (which may itself be "functionalized" to permit the formation of one end of the oligomer, or may be coated with an appropriate coating for that purpose).

The fibres may then be formed into a suitable form for use as a solid support, e.g. to form a knitted, woven or non-woven (e.g. felted) fabric. Preferably the fibres are formed into a felt or paper.

Of course, with certain types of solid support, such as the rigid macroporous inorganic material or felt referred to above, no additional container or holder may be required.

Where the solid support is in the form of a felt, this is preferably formed of an aramid or nylon. If desired, the solid support may be coated with a suitable coating to provide functional groups to which the oligomer may be attached. For example, in the case of the oligopeptides, a suitable coating would be a polymer formed from acryloylsarcosine methyl ester and/or acrylamide monomers or a copolymer of acrylolsarcosine methyl ester and one or more of the monomer precursors of a nylon. In the case of the oligonucleotides, a suitable coating would be polyamide, cellulose or polystyrene. Where appropriate functional or functionalized polymers can be formed into fibres which can produce the felt, no additional coating may be required.

It is desirable that the progress of the reaction should be monitored and, accordingly, the apparatus preferably additionally comprises means for examining the solid support and determining the extent of reaction. The nature of such means will, of course, depend upon the nature of the reactions involved and the method chosen to detect them. For example, in the preparation of oligopeptides, which involves a series of acylation reactions, the acylation may conveniently be monitored by assessing the concentration of the light-absorbing moiety of the acylation agent in the reaction vessel after removal of the solid support.

This is conveniently done by providing an ultraviolet lamp, a filter (to give monochromatic UV radiation) and a detector. Differences in ultraviolet absorption may be looked for before and after acylation either in the whole volume of reagent in the reaction vessel or in the input flow or output flow. In the case of oligonucleotide synthesis, where trityl groups are employed as protecting groups, the acid removal of such groups may be similarly monitored but, in this case, a preferred means comprises a light emitting diode (preferably green) and a detector.

The degree of acylation in oligopeptide synthesis may also be determined after removal of the solid support from the reaction vessel, and preferably after rinsing the solid support (e.g. in dimethylformamide) by passing ultraviolet light (preferably at about 304 nm) onto the solid support. In this case, the solid support itself is preferably investigated.It would only be necessary to look at one of four things: 1) the attenuation due to absorption of fluorenyl derivatives, 2) the 410 nm fluorescence of the fluorenyl derivatives, e.g. in complex with dimethylformamide, 3) the fluorescence of a wave-shifter or secondary fluor in troduced to give light emission at longer and more easily measurable wave length, or 4) the scintillation of a solid fluor introduced into the column, which, depending upon the fluor choserf, could increase in visible fluorescence when 304 nm light is attenuated by passage through the fluorenyl containing solutions (either bound or free) or the direct entrapment of such fluors in the columns, e.g. during manufacture, will utilize radiationless energy transfer to higher emission wave length.

A variety of methods is available for picking up and putting down the solid support, the nature of such methods depending, to some extent, on the nature of the solid support and upon whether it is or is not present in a container or holder.

In one embodiment of the invention, each solid support is attached to or is contained in a- container attached to a magnet and the transport means comprises an arm having a ferromagnetic material and an electromagnet such that, in the preferred case, when the electromagnet in the arm is switched off, the magnet associated with the solid support is attracted to and magnetically adheres to the ferromagnetic material whereas, when the eiectromagnet is switched on, the magnet in the solid support is repelled from the arm.

Alternatively, the solid support may be associated with à ferromagnetic material and an electromagnet may be placed in the arm, so that, when the electromagnet is switched on, the ferromagnetic material, and hence the solid support, are attracted to the arm whereas, when it is switched off, no such attraction exists and the ferromagnetic material, and hence the solid support, fall away under the influence of gravity.

The advantage of the former arrangement, in which the solid support is associated with a magnet, is that coupling of the magnet associated with the solid support with the ferromagnetic material in the arm can be monitored by a Hall effect transistor place above the ferromagnetic material. The ferromagnetic material is preferably- a steel plate.

Alternatively, a mechanica! grab, which may be of a variety of conventional designs, may be used to pick up and put down the solid support. The magnetic coupling technique, however, has the advantages of simplicity and of reducing the numbers of moving parts.

After reaction of the solid support with the reagent in a reaction vessel, the solid support is then preferably washed and simultaneously, previously or subsequently the material coupled to the solid support is deprotected or activated in preparation for the next reaction step.

This may be achieved by providing one or more containers containing a washing fluid and/or deprotecting or activating reagent and preferably such containers are of sufficient size to take two or more of the solid supports. Where, however, the container holds two or more solid supports, it is important that the container should be capable of holding them in an ordered array that can be organized or memorized by the computer controlling the apparatus.

Where, as is preferred, a large container (preferably a single such container, although more than one may be provided, if required) capable of holding several solid supports to subject them to steps (e.g. washing or deprotection) in common is provided, it is necessary that the container must either keep the solid supports in the same place, so that the location of each solid support is known, or allow them to move in a restricted fashion, so that their position or order is always known.

The latter is preferred. This may be achieved by forming the container as a channel or tube such that, for example, the first solid support to enter the channel or tube is also the first to leave. A channel or tube has the further advantage that it forms a theoretical multiplate column, in which the flow of reagent or other material, e.g. washing solvent, is such that the first solid support in line is washed with clean solvent or other material, which then passes on to wash the second, and so on. This makes for more efficient use of solvent and reagents than simple immersion in the same column of solvent, and is more suitable than a batchwise system.

Because the order of the solid supports is preserved, it is thereafter possible to remove each solid support and place it in the next appropriate reaction vessel.

In a preferred embodiment, a container is provided in the form of a tube containing a washing liquid (e.g. dimethylformamide) and a deprotecting or activating reagent and the solid supports are forced along the tube to wash and deprotect or activate them. In the case where the solid supports are associated with magnets, this may be achieved by a series of electromagnetic coils around the outside of the tube, which produces a solenoid effect. Phased switching of the electromagnetic coils under microprocessor control regulates the movement of the solid supports.

Momentary and intermittent reversal of the current through the electromagnetic coils allows a shaking action to be simulated. Preferably liquid flows in the tube from the bottom upwards, which allows air to be expelled more readily and a column effect to be achieved.

The tube is successively drained and refilled, the tube first being filled with a wash liquid and then, after one or more washing steps, with a deprotecting and/or activating reagent.

If desired, two or more such tubes (or other containers) may be provided, at least one for the wash liquid and at least one for the deprotecting and/or activating reagent.

Accordingly, in a preferred embodiment of the invention, the apparatus comprises: (a) a plurality of solid supports, on each of which, in operation of the apparatus, a growing oligomer is chemically bonded; (b) a plurality of reaction vessels in an ordered array for containing reagents to produce said oligomer; (c) at least one container for wash liquid and/or a deprotecting and/or activating reagent and capable of maintaining an ordered array of said solid supports; (d) transport means including coupling means for picking up and putting down said solid supports and immersing said solid supports in and removing said solid supports from reagent in each of said reaction vessels; (e) control means operatively connected to said transport means for controlling said transport means so as to immerse said solid supports in said reaction vessels in an appropriate order; and (f) means for feeding fresh reagent to said reaction vessels and container and, if necessary, for discharging spent reagent from said vessels and container.

In a still more preferred embodiment of the invention, the aforementioned ordered array is a circular array of reaction vessels which are preferably essentially cyiindrical in shape. The transport means preferably comprises an arm containing coupling means for coupling (more preferably magnetically) to the solid supports, and the array of reaction vessels and the transport means are arranged for relative rotary motion. The arm may, for example, be mounted upon an axle about which it can rotate and the axle can be mounted centrally or eccentrically of the array of reaction vessels.

Where the axle supporting the arm is mounted centrally, we prefer that the reaction vessels should remain stationary while the arm rotates. Where the axle is mounted eccentrically, the array of reaction vessels preferably rotates. In this latter case, the arm can pick up a solid support from a reaction vessel and rotate slightly to remove the solid support from above the reaction vessel and away from other reaction vessels and allow any drips to fall; the arm then returns to its original position and, before or after the arm has returned to its original position, the array of reaction vessels is rotated to permit the solid support to be immersed in another reaction vessel.If desired, between removal from the first-mentioned reaction vessel and immersion in the second-mentioned reaction vessel, the solid support may be washed and subjected to deprotecting and/or activating, as described above.

Where the solid support is contained or held by a container or holder, a variety of designs is possible, depending upon the nature of the solid support and the desired construction parameters of the apparatus. For example, where the container is a flexible mesh bag (e.g. the "tea bag" described above), this may be essentially square or rectangular and will normally have one open end temporarily closed in some appropriate manner. If desired, the closure may be by means of a clip which may itself be magnetic or may be made of a magnetic material, to facilitate magnetic coupling.

In an alternative preferred design, the container or holder is of generally cylindrical form, so that it may be placed in essentially cylindrical reaction vessels and passed through cylindrical tubes. In such a case, the container or holder is preferably made of a substantially inflexible or rigid material, which may either in itself be porous or may be provided with one or more (preferably several) apertures through which reagent may pass but the solid support may not pass.

The invention is further illustrated by the accompanying drawings, in which: Figure 1 illustrates a suitable circular array of reaction vessels, in which the coordinates determining the position of the vessels are polar; Figure 2 illustrates a rectangular array of reaction vessels, in which the coordinates determining the positions of the vessels are orthogonal and Figure 3 illustrates a spiral array of reaction vessels; Figure 4 shows a preferred design of container for the solid support in accordance with the invention as a cross-section taken on a plane passing through the long axis of the container; Figure 5 is a view similar to Figure 4, but showing a preferred design of holder for the solid support; Figure 6 shows a side view, partly in section, of a complete apparatus in accordance with a preferred embodiment of the invention;; Figure 7 shows another embodiment of apparatus of the invention.

In Figures 1-3, the reaction vessels are represented by circles and are shown in a circular, rectangular and spiral array respectively.

Referring to Figure 4 of the accompanying drawings, a container 1 made, for example, of polytetrafluoroethylene is shown in cross-section on a plane through its long axis; a section on a plane perpendicular to that shown would be circular. The container has a plurality of apertures 2 at each end and contains resin beads 3 for bonding to the growing oligomer, e.g. oligopeptide or oligonucleotide. At one end is mounted a magnet 4; if desired, the magnet 4 can extend axially through the whole of container 1, from one end to the other. An alternative embodiment is shown in Figure 5, which shows a holder 5, again made, for example, of polytetrafiuoroethylene.

This container 5 has apertures 2 at each end through which reagent may pass. A magnet 6 is mounted axially of the holder 5 and extends from one end of the holder to another. The holder is arranged to contain one or more "tea bags" 7 (only 1 shown) containing resin 8, which can be in the form of beads or other particulate form.

Referring now to Figure 6 of the accom panying drawings, which shows a complete apparatus in accordance with a preferred em bodiment of the invention, the apparatus is enclosed in a box 9. It includes an annular support 10, which itself is supported by a spider 11. The annular support 10 supports a plurality of reaction vessels, e.g. 12 and 13.

Pulley 14, attached to the spider 11, is driven by a motor (not shown), so as to allow the annular support, and hence the reaction ves sels, to rotate. Rotation of the annular support 10 allows each in turn of the reaction vessels, e.g. 12 and 13, to be presented to the solid support pick-up 15. The pick-up 15 is mdunted upon a vertical arm 16, which, in turn, is mounted upon a horizontal arm 17.

Horizontal arm 17 is attached to and rotatable with a lower axle 18, preferably of hexagonal cross-section. Axle 18 is caused to rotate by means of a toothed belt (not shown) engaging with a sliding pulley 19 at the bottom of the lower axle 18 and with a similar pulley 20 coupled to a motor, shown generally at 21.

Since the axle 18 is mounted eccentrically of the annular support 10, rotation of the lower axle 18 and hence the arms 16 and 17, will rotate the solid support pick-up 15 away from the array of reaction vessels.

An upper axle 22 is coupled to the axle 18, but is prevented from rotating with it. A lead screw (not shown) operating on the upper axle 22 and turned by pulley 23 driven via a toothed-belt (not shown) from pulley 24 and a motor (also not shown) causes the upper axle 22, and hence the lower axle 18 and the arms 16 and 17 and the support pick-up 15, to be raised and lowered.Hence, in operation, a solid support attached to a pick-up 1 5 can be lowered by appropriate operation of the pulley 23 attached to a lead-screw and upper axle 22; the electromagnetic or other connec tion between the pick-up 15 and the solid support can then be released, so that the solid support is deposited in reaction vessel 12 containing an appropriate liquid reagent (not shown); the pick-up 15 is then raised and the array- of reaction vessels is rotated by ro tation of the annular support 10 so as to pre sent to the pick-up 15 another reaction vessel containing a solid support which is to be re moved. The pick-up 15 is then lowered, the electromagnetic or other connection to the solid support is then activated and finally the pick-up is raised, thereby raising the solid sup port out of the reaction vessel.In order to prevent drips from the solid support contami nating other reaction vessels, the lower axle 18 is rotated, to cause the solid support to rotate away from the circle of reaction vessels supported by the annular support 10. The annular support 10 is then rotated until it has reached the appropriate position for the next operation to be carried out on the removed solid support, whereupon the lower axle 18, and hence the solid support, are rotated back into position.

This next operation is preferably a washing and deprotecting step. The washing and deprotecting is preferably carried out in a spiral tube 25 mounted around the outside of the array of reaction vessels. preferably, each end of the spiral tube 25 terminates in a reaction vessel, e.g. as in reaction vessel 13, so that the solid support can be placed into and removed from the spiral tube 25 in the same way as it is placed into and removed from the reaction vessels.

Each reaction vessel 12 is associated with a supply 26 of fresh solid reagent. This is metered through a screw feed dispenser 27 and dissolved in solvent fed through inlet 28 from a rotary valve 29 by a pipe (not shown). The fresh solution is then fed by means not shown to the reaction vessel 12.

An optical window is provided in reaction vessel 13.

A second annular support 30 is provided beneath the first annular support 10 mounted on a second spider 31 driven by a pulley 34, in much the same way as is the first annular support 10. The second annular support drives the solid reagent containers 26 and may be moved synchronously with or independently of the first annular support 10.

Figure 7 shows an embodiment in which the selection means comprises a sliding carriage 41 on a travelling gantry 42 moved by wires (not shown) driven by servo-motors 43. The connecting head 44 is held in a tube 45 by a wire attached to a drum 46 driven by an electric motor (not shown) via a non-reversible screw, and may be lowered into a reaction vessel or raised and the tube pulled horizontal to catch drips.

Claims

1. Apparatus for the synthesis of oligomers and comprising: a solid support on which, in operation of the apparatus, the growing oligomer is chemically bonded; a plurality of reaction vessels for containing reagents to produce said oligomer; transport means for transporting said solid support and immersing said solid support in and removing said solid support from reagent in each of said reaction vessels; and control means operatively connected to said transport means for controlling said transport means so as to immerse said solid support in said reaction vessels in an appropriate order.

2. Apparatus according to Claim 1, in which said control means comprises a computer appropriately programmed to keep track of the or each solid support and to ensure that it is immersed in the appropriate reaction vessel in the appropriate order.

3. Apparatus according to Claim 1 or Claim 2, in which said reaction vessels are mounted in an ordered array.

4. Apparatus according to Claim 3, in which said ordered array is circular, rectangular or spiral.

5. Apparatus according to any one of Claims 1 to 4, in which at least 20 reaction vessels are provided.

6. Apparatus according to any one of Claims 1 to 4, in which at least 4 reaction vessels are provided.

7. Apparatus according to any one of Claims 1 to 6, in which no more than 30 reaction vessels are provided.

8. Apparatus according to any one of Claims 1 to 7, in which the reaction vessels are arranged in an ordered array in a coordinate-determined system, which is orthogonal or polar.

9. Apparatus according to any one of Claims 1 to 8, in which each solid support is attached to or is contained in a container attached to a magnet and the transport means comprises an arm having a ferromagnetic material and an electromagnet.

10. Apparatus according to Claim 9, in which the arrangement is such that, when the electromagnet in the arm is switched off, the magnet associated with the solid support is attracted to and magnetically adheres to the ferromagnetic material whereas, when the electromagnet is switched on, the magnet in the solid support is repelled from the arm.

11. Apparatus according to Claim 10, in which a Hall effect transistor is placed above said ferromagnetic material to monitor coupling of said magnet with said ferromagnetic material.

12. Apparatus according to any one of Claims 1 to 8, in which each solid support is attached to or is contained in a container attached to a ferromagnetic material and an electromagnet is placed in the arm, so that, when the electromagnet is switched on, the ferromagnetic material, and hence the solid support, are attracted to the arm.

13. Apparatus according to any one of Claims 1 to 12, comprising: (a) a plurality of solid supports, on each of which, in operation of the apparatus. a growing oligomer is chemically bonded; (b) a plurality of reaction vessels in an ordered array for containing reagents to produce said oligomer; (c) at least one container for wash liquid and/or a deprotecting and/or activating reagent and capable of maintaining an ordered array of said solid supports; (d) transport means including coupling means for picking up and putting down said solid supports and immersing said solid supports in and removing said solid supports from reagent in each of said reaction vessels,; (e) control means operatively connected to said transport means for controlling said transport means so as to immerse said solid supports in said reaction vessels in an appropriate order; and (f) means for feeding fresh reagent to said reaction vessels and container and, if necessary, for discharging spent reagent from said vessels and container.

14. Apparatus according to any one of Claims 1 to 13, in which said ordered array is a circular array of reaction vessels.

15. Apparatus according to Claim 14, in which the transport means comprises an arm containing coupling means for coupling to the solid supports, and the array of reaction vessels and the transport means are arranged for relative rotary motion.

16. Apparatus according to Claim 1, substatially as hereinbefore described with reference to and as shown in any one of the accompanying drawings.

17. A method of making an oligomer in apparatus according to any one of the preceding Claims, in which said solid support is progressively transported from one said reaction vessel to another and is reacted in said vessels to form a growing oligomer.

18. A method according to Claim 17, in which said oligomer is an oligopeptide, oligonucleotide or oligosaccharide.