TYPE I-D CRISPR-CAS SYSTEMS AND USES THEREOF Field of the Invention The present invention relates to methods of targeting, inhibiting expression of, or modifying nucleic acids, including for example, RNA, DNA or both RNA and DNA in a targeted manner using type I-D CRISPR-Cas systems, and to modified type I-D CRISPR-Cas systems. The present invention further relates to methods of detecting and tracking different nucleic acids using the type I-D CRISPR-Cas systems. Introduction to the Invention CRISPR-Cas (Clustered regularly interspaced short palindromic repeats-CRISPR associated proteins) are heritable prokaryotic adaptive immune mechanisms that provide cellular defence against mobile genetic elements such as phages and plasmids. CRISPR-Cas can be broken down into different types, types I-VI, each determined by ‘signature’ proteins. The mechanism of CRISPR-Cas can be broken down into three stages: 1. Adaptation 2. Processing 3. Interference. Interference involves a ribonucleoprotein effector complex that surveys invading nucleic acids. Upon recognition of a foreign complementary sequence, crRNA facilitates binding and the foreign sequence is degraded by Cas proteins. Type I (50%) and type III (25%) are the most abundant CRISPR-Cas systems. They are genetically diverse and have different methods of interference yet a similar complex architecture. Type I systems typically contain Cas5, Cas7, Cas6 and a Cas8 proteins, and upon specific binding to target DNA, a Cas3 helicase-nuclease is then recruited to degrade DNA. Usually two small subunits are present or none. In contrast, type III systems have no PAM-mediated target recognition, they have the intrinsic ability to specifically bind and cleave RNA by virtue of Cas7, non-specifically cleave single stranded (ss) DNA via Cas10, and multiple small subunits of Cas11 are present. Cyanobacteria represent an ancient and diverse phylum with key roles in marine, fresh water and terrestrial ecosystems, including global nitrogen and carbon cycling. They can be responsible for harmful toxic blooms and in biotechnology they are being developed as solar-powered biofactories. Cyanobacteria are under constant threat of phage infection and one mechanism used to counter these is the CRISPR-Cas defence system. Understanding CRISPR-Cas systems in cyanobacteria has attracted significant interest as such systems may have novel biotechnological applications. It has been found that cyanobacteria harbour a novel subtype of CRISPR-Cas system; the subtype I-D system. This system is of significant interest as it is abundant in cyanobacteria, and bioinformatic studies suggest it appears to be a chimera of type I and type III CRISPR systems. Some work has been done to study the subtype I-D system and it has been found to bind to both DNA and RNA in a strand-independent and sequence-specific manner, and also seems to target and bind DNA with different PAM requirements compared with other type I, type II (Cas9) and type V (Cas12) systems. The structure of the system, whilst being most related to known type I systems, is different in that it comprises a nuclease domain Cas3" as part of Cas10d within the core complex which then recruits a helicase Cas3’. The fact that this CRISPR-Cas system can bind specifically to both nucleic acids is potentially of great use in the field of biotechnology. In addition, the alternative PAM compared to other CRISPR systems could be useful for some target genes and/or organisms when there are no useful type II PAMs present. Furthermore, the type I-D system may provide a system with less toxic effects and reduced “off-site” targeting compared to other CRISPR Cas systems which have shown toxicity and demonstrate unhelpful off-target effects. In general there is a need for alternative CRISPR-Cas systems in the art. Cyanobacterial type I- D CRISPR-Cas systems present a possible alternative with many advantages mentioned above. However, the mechanistic and functional details of type I-D CRISPR-Cas systems are still emerging and the system is not currently controllable for use in biotechnological applications specifically directed towards single stranded or double stranded nucleic acids. The present invention sets out to address one or more of the above-mentioned problems in the art. Statements of Invention According to one aspect of the present invention, there is provided a method of targeting a target double-stranded nucleic acid sequence and a target single-stranded nucleic acid sequence comprising contacting the target sequences with a complex comprising: (a) Cas5d, Cas6d, Cas7d, Cas10d and Cas11d proteins; (b) a guide RNA complementary to the target double-stranded nucleic acid sequence; and (c) a guide RNA complementary to the target single-stranded nucleic acid sequence. In one example, the target nucleic acid sequences may encode the same protein. In one example, the target double-stranded nucleic acid sequence is DNA. In one example, the single-stranded nucleic acid sequence is RNA and/or ssDNA. In one example, Cas10d is a nuclease-deficient Cas10d. In one example, Cas7d is a nuclease- deficient Cas7d. In one example, the method further comprises contacting the target sequences with Cas3’ protein. Suitably contacting a target single-stranded nucleic acid sequence with Cas3’ protein. Suitably contacting the target single stranded nucleic acid sequnces with Cas3’ protein. According to another aspect of the present invention, there is provided a method of targeting a target single-stranded nucleic acid sequence comprising contacting the target sequence with a complex comprising: (a) Cas5d, Cas6d, Cas7d, Cas10d, and optionally Cas11d proteins; and (b) a guide RNA complementary to the target single-stranded nucleic acid sequence; wherein (i) the Cas10d protein is modified, (ii) Cas11d is not present, and/or (iii) the guide RNA targets a target single-stranded nucleic acid sequence adjacent to an single stranded-specific protospacer flanking sequence, such that the complex does not bind to double-stranded nucleic acids. In one example, the single-stranded nucleic acid sequence is RNA and/or ssDNA. In one example, the method does not target double-stranded nucleic acid sequences. In one example, the method does not target dsDNA. In one example, the Cas10d protein is modified. Suitably it is modified to disrupt the interaction of Cas10d with the protospacer adjacent motif such that the complex does not bind double-stranded nucleic acids. Suitably by mutation at position K326 in SEQ ID NO: 2 or a position corresponding thereto. In one example, the Cas11d protein is not present. In one example, the nucleic acid sequence encoding Cas10d and Cas11d is modified such that the Cas11d protein is not expressed. In one example, the nucleic acid sequence encoding Cas10d and Cas11d is modified in the coding region of Cas11d. In one example, nucleic acid sequence encoding Cas10d and Cas11d is modified in the start codon or in the ribosomal binding site of the coding region of Cas11d. In one example, the guide RNA targets a target single-stranded nucleic acid sequence adjacent to a single stranded-specific protospacer flanking sequence. Suitably the single stranded-specific protospacer flanking sequence is any PFS without a G in the first position. In one example, the single stranded-specific protospacer flanking sequence is AAC, ACG. In one example, Cas7d is a nuclease-deficient Cas7d. In one example, the method further comprises contacting the target single-stranded nucleic acid sequence with Cas3’ protein. According to yet another aspect of the present invention there is provided a method of targeting a target double-stranded nucleic acid sequence comprising contacting the target sequence with a complex comprising: (a) Cas5d, Cas6d, Cas7d, Cas10d, Cas11d proteins; and (b) a guide RNA complementary to the target double-stranded nucleic acid sequence; wherein (i) the Cas5d protein is modified, and/or (ii) the guide RNA targets a target double- stranded nucleic acid sequence adjacent to a double stranded-specific protospacer adjacent motif, such that the complex does not bind to single-stranded nucleic acids. In one example, the double-stranded nucleic acid is DNA. In one example, the method does not target single-stranded nucleic acids. In one example, the method does not target RNA and/or ssDNA. In one example, the Cas5d protein is modified. Suitably it is modified to disrupt the interaction of Cas5d with the protospacer flanking sequence such that the complex does not bind single-stranded nucleic acids. Suitably it is modified by mutation at position Q110 of SEQ ID NO:6 or a position corresponding thereto. In one example, the guide RNA targets a target double-stranded nucleic acid sequence adjacent to a double stranded-specific protospacer adjacent motif. Suitably the double stranded-specific protospacer adjacent motif is GTN, such as GTT, GTC. In one example, Cas10d is a nuclease deficient Cas10d. According to a further aspect of the present invention, there is provided a method of inhibiting the expression of a target double-stranded nucleic acid sequence and a target single- stranded nucleic acid comprising contacting the target sequences with a complex comprising: (a) Cas5d, Cas6d, Cas7d, nuclease-deficient Cas10d and Cas11d proteins, wherein Cas7d is optionally nuclease-deficient; (b) a guide RNA complementary to the target double-stranded nucleic acid sequence; and (c) a guide RNA complementary to the target single-stranded nucleic acid sequence In one example, the target double-stranded nucleic acid sequence is DNA. In one example, the target single-stranded nucleic acid sequence is RNA and/or ssDNA. In one example, the target nucleic acid sequences may encode the same protein. In one example, therefore the method is a method of inhibiting the transcription and translation of a target sequence. In one example, Cas7d may be nuclease-deficient. Suitably in such an example, Cas7d inhibits translation by binding to the target single stranded nucleic acid and blocking translational machinery. Alternatively, in one example, Cas7d is active and retains nuclease activity, for example it may be a wild type Cas7d protein. Suitably in such an example, Cas7d inhibits translation by cleaving the target single-stranded nucleic acid such that the single-stranded nucleic acid is truncated and cannot be properly translated. In one example, the method further comprises contacting the target sequences with Cas3’ protein. Suitably contacting a target single-stranded nucleic acid sequence with Cas3’ protein. According to yet a further aspect of the present invention there is provided a method of inhibiting the expression of a target single-stranded nucleic acid sequence, comprising contacting the target sequence with a complex comprising: (a) Cas5d, Cas6d, Cas7d, Cas10d, and optionally Cas11d proteins, wherein Cas7d is optionally nuclease-deficient; and (b) a guide RNA complementary to the target single-stranded nucleic acid sequence wherein (i) the Cas10d protein is modified, (ii) Cas11d is not present, and/or (iii) the guide RNA targets a target single-stranded nucleic acid sequence adjacent to an single stranded-specific protospacer flanking sequence, such that the complex does not bind to a double-stranded nucleic acid. In one example, the single-stranded nucleic acid sequence is RNA and/or ssDNA. In one example, the method does not target double-stranded nucleic acid sequences. In one example, the method does not target DNA. In one example, the method is a method of inhibiting the translation of a target sequence. In one example, the method does not inhibit transcription of the target sequence. In one example, Cas7d may be nuclease-deficient. Suitably in such an example, Cas7d inhibits translation by binding to the target single-stranded nucleic acid and blocking translational machinery. Alternatively, in one example, Cas7d is active, and retains nuclease activity, for example it may be a wild type Cas7d protein. Suitably in such an example, Cas7d inhibits translation by cleaving the target single-stranded nucleic acid such that the single-stranded nucleic acid is truncated and cannot be properly translated. In one example, the Cas10d protein is modified. Suitably it is modified to disrupt the interaction of Cas10d with the protospacer adjacent motif such that the complex does not bind double-stranded nucleic acids. Suitably the Cas10d protein is modified by mutation at position K326 of SEQ ID NO: 2 or a position corresponding thereto. In one example, the Cas11d protein is not present. In one example, the nucleic acid sequence encoding Cas10d and Cas11d is modified such that the Cas11d protein is not expressed. In one example, the nucleic acid sequence encoding Cas10d and Cas11d is modified in the coding region of Cas11d. In one example, nucleic acid sequence encoding Cas10d and Cas11d is modified in the start codon or in the ribosomal binding site of the coding region of Cas11d. In one example, the guide RNA targets a target single-stranded nucleic acid sequence adjacent to an single stranded-specific protospacer flanking sequence. Suitably the single stranded-specific protospacer flanking sequence is is any PFS without a G in the first position. In one example, the single stranded-specific protospacer flanking sequence is AAC, ACG. In one example, the method further comprises contacting the target single-stranded nucleic acid sequence with Cas3’ protein. In one example, the target single-stranded nucleic acid is RNA and the target RNA sequence is within an operon. According to another aspect of the present invention there is provided a method of inhibiting the expression of a target double-stranded nucleic acid sequence, comprising contacting the target sequence with a complex comprising: (a) Cas5d, Cas6d, Cas7d, nuclease-deficient Cas10d and Cas11d proteins; (b) a guide RNA complementary to the target double-stranded nucleic acid sequence, wherein (i) the Cas5d protein is modified, and/or (ii) the guide RNA targets a target double- stranded nucleic acid sequence adjacent to a double stranded-specific protospacer adjacent motif, such that the complex does not bind to single-stranded nucleic acids. In one example, the double-stranded nucleic acid is DNA. In one example, the method does not inhibit expression of single-stranded nucleic acids. In one example, the method does not inhibit expression of RNA and/or ssDNA. In one example, the method is a method of inhibiting the transcription of a target sequence. In one example, the method does not inhibit translation of the target sequence. In one example, the Cas5d protein is modified. Suitably it is modified to disrupt the interaction of Cas5d with the protospacer flanking sequence such that the complex does not bind single-stranded nucleic acids. Suitably it is modified by mutation at position at position Q110 of SEQ ID NO:6 or a position corresponding thereto. In one example, the guide RNA targets a target double-stranded nucleic acid sequence adjacent to double stranded-specific protospacer adjacent motif. Suitably the double stranded-specific protospacer adjacent motif is GTN, such as GTT, GTC. In one example, the target double-stranded nucleic acid sequence is a regulatory region. Suitably a regulatory region of a double-stranded nucleic acid which is not present in single-stranded nucleic acids, for example an RNA polymerase binding site, a promoter or repressor or activator binding site. According to yet another aspect of the present invention, there is provided a method of modifying a target double-stranded nucleic acid sequence and a target single-stranded nucleic acid, comprising contacting the target sequences with a complex comprising: (a) Cas5d, Cas6d, Cas7d, Cas11d, Cas10d, and Cas3’ proteins; (b) a guide RNA complementary to the target double-stranded nucleic acid sequence; and (c) a guide RNA complementary to the target single-stranded nucleic acid sequence In one example, the modification is cleavage. Suitably therefore the Cas10d and Cas7d are active. In one example the Cas3’ is modified. Suitably it is modified to enhance cleavage of the target double stranded nucleic acid sequence, suitably to enhance cleavage of single sites in the target double stranded nucleic acid sequence. Suitably, in order to achieve this, the Cas3’ protein is modified to reduce its helicase activity. In alternative examples, the Cas3’ protein is not modified, and may be a wild type Cas3’ protein. Suitably in such examples, the target double stranded nucleic acid sequence is cleaved by processive cleavage. In one example, the target double-stranded nucleic acid sequence is DNA. In one example, the single-stranded nucleic acid sequence is RNA and/or ssDNA. In one example, the target sequences may encode the same protein. According yet a further aspect of the present invention, there is provided a method of modifying a target single-stranded nucleic acid sequence comprising contacting the target sequence with a complex comprising: (a) Cas5d, Cas6d, Cas7d, Cas10d, optionally Cas11d proteins; and (b) a guide RNA complementary to the target single-stranded sequence, wherein (i) the Cas10d protein is modified, (ii) Cas11d is not present, and/or (iii) the guide RNA targets a target single-stranded nucleic acid sequence adjacent to an single stranded-specific protospacer flanking sequence, such that the complex does not bind to double-stranded nucleic acid sequences. In one example, the modification is cleavage. Suitably therefore Cas7d is active, for example it may be a wild type Cas7d protein. In one example, the single-stranded nucleic acid sequence is RNA and/or ssDNA. In one example, the method does not target double-stranded nucleic acid sequences. In one example, the method does not target DNA. In one example, the Cas10d protein is modified. Suitably it is modified to disrupt the interaction of Cas10d with the protospacer adjacent motif such that the complex does not bind double-stranded nucleic acids. Suitably the Cas10d protein is modified by mutation at position K326 of SEQ ID NO: 2 or a position corresponding thereto. In one example, the Cas11d protein is not present. In one example, the nucleic acid sequence encoding Cas10d and Cas11d is modified such that the Cas11d protein is not expressed. In one example, the nucleic acid sequence encoding Cas10d and Cas11d is modified in the coding region of Cas11d. In one example, nucleic acid sequence encoding Cas10d and Cas11d is modified in the start codon or in the ribosomal binding site of the coding region of Cas11d. In one example, the guide RNA targets a target single-stranded nucleic acid sequence adjacent to a single stranded-specific protospacer flanking sequence. Suitably the single stranded-specific protospacer flanking sequence is any PFS without a G in the first position. In one example, the single stranded-specific protospacer flanking sequence is is AAC, ACG. In one example, the method further comprises contacting the target single-stranded nucleic acid sequence with Cas3’ protein. According yet another aspect of the present invention there is provided a method of modifying a target double-stranded nucleic acid sequence comprising contacting the target sequence with a complex comprising: (a) Cas5d, Cas6d, Cas7d, Cas11d, Cas10d, Cas3’ proteins; and (b) a guide RNA complementary to the target double-stranded nucleic acid sequence, wherein (i) the Cas5d protein is modified, and/or (ii) the guide RNA targets a target double- stranded nucleic acid sequence adjacent to double stranded-specific protospacer adjacent motif, such that the complex does not bind to single-stranded nucleic acid sequences. In one example, the double-stranded nucleic acid is DNA. In one example, the method does not modify single-stranded nucleic acids. In one example, the method does not modify RNA and/or ssDNA. In one example, the modification is cleavage. Suitably therefore the Cas10d is active. In one example the Cas3’ is modified. Suitably it is modified to enhance cleavage of the target double stranded nucleic acid sequence, suitably to enhance cleavage of single sites in the target double stranded nucleic acid sequence. Suitably, in order to achieve this, the Cas3’ protein is modified to reduce its helicase activity. In alternative examples, the Cas3’ protein is not modified, and may be a wild type Cas3’ protein. Suitably in such examples, the target double stranded nucleic acid sequence is cleaved by processive cleavage. In one example, the Cas5d protein is modified. Suitably it is modified to disrupt the interaction of Cas5d with the protospacer flanking sequence such that the complex does not bind single-stranded nucleic acids. Suitably it is modified by mutation at position Q110 of SEQ ID NO:6 or a position corresponding thereto. In one example, the guide RNA targets a target double-stranded nucleic acid sequence adjacent to a double stranded-specific protospacer adjacent motif. Suitably the double stranded-specific protospacer adjacent motif is GTN, such as GTT, or GTC. According to another aspect of the present invention there is provided a method of detecting a target single-stranded nucleic acid and/or a target double-stranded nucleic acid in a sample, the method comprising: (a) contacting the sample with: a complex comprising (i) one or more of Cas5d, Cas6d, nuclease-deficient Cas7d, nuclease-deficient Cas10d, Cas11d proteins (ii) a guide RNA complementary to a target sequence in the target double-stranded nucleic acid and/or (iii) a guide RNA complementary to a target sequence in the single-stranded nucleic acid; wherein the complex is bound to a probe; (b) Incubating the sample with the complex for a suitable period of time to allow the complex to bind to a target single-stranded nucleic acid and/or a target double-stranded nucleic acid in the sample, and displace the probe; and (c) determining whether the probe can be detected. In one example the target single-stranded nucleic as is either ssDNA or RNA. In one example the target double-stranded nucleic acid is dsDNA. In one example, the method may only detect a target single-stranded nucleic acid, in which case the complex may be modified accordingly as explained herein. In other examples, the method may only detect a target double-stranded nucleic acid, in which case the complex may be modified accordingly as explained herein. In one example, the probe is a flourescent probe. According to yet another aspect of the present invention, there is provided a method of tracking a target single-stranded nucleic acid and/or a target double-stranded nucleic acid in a sample comprising: (a) contacting the sample with: a complex comprising (i) one or more of Cas5d, Cas6d, nuclease deficient Cas7d, nuclease deficient Cas10d, Cas11d proteins (ii) A guide RNA complementary to a target sequence in the target double-stranded nucleic acid and/or (iii) a guide RNA complementary to a target sequence in the target single-stranded nucleic acid; and an imaging agent optionally linked to the complex; (b) incubating the sample with the complex for a suitable period of time to allow the complex to bind to a target single-stranded nucleic acid and/or a target double-stranded nucleic acid in the sample, and optionally for the imaging agent to associate with the bound complex; (c) observing the imaging agent at a first time point; and (d) observing the imaging agent at one or more further time points In one example the target single-stranded nucleic as is either ssDNA or RNA. In one example the target double-stranded nucleic acid is dsDNA. In one example, the method may only track a target single-stranded nucleic acid, in which case the complex may be modified accordingly as explained herein. In other examples, the method may only track a target double-stranded nucleic acid, in which case the complex may be modified accordingly as explained herein. In one example, the imaging agent is linked to the complex. In one example, the imaging agent is a flourescent protein. According to yet another aspect of the present invention there is provided a nuclease- deficient Cas7d protein, comprising a mutation at position E101 of SEQ ID NO:4 or a position corresponding thereto, and optionally one or more further mutations. In one example, the Cas7d protein further comprises a mutation at position D119 of SEQ ID NO: 4 or a position corresponding thereto. In one example, the mutation at position E101 is E101A. In one example, the mutation at position D119 is D119A. In one example the nuclease deficient Cas7d protein comprises or consists of a sequence according to SEQ ID NO: 18. According to yet another aspect of the present invention there is provided a modified CRISPR type I-D complex comprising: (a) Cas5d, Cas6d, Cas7d, Cas10d, and optionally Cas11d proteins; (b) a guide RNA complementary to a target nucleic acid sequence, wherein the Cas10d protein is modified to disrupt the interaction of Cas10d with a protospacer adjacent motif such that the complex does not bind double-stranded nucleic acids. In one example, the Cas10d protein is modified by mutation at position K326 of SEQ ID NO: 2 or a position corresponding thereto. In one example, the Cas10d protein comprises or consists of a sequence according to SEQ ID NO:16. In one example, the complex of the thirteenth aspect is for use in methods of the invention targeting single stranded nucleic acids. According to yet another aspect of the present invention there is provided a modified CRISPR type I-D complex comprising: (a) Cas5d, Cas6d, Cas7d, Cas10d, and optionally Cas11d proteins; (b) a guide RNA complementary to a target nucleic acid sequence, wherein the Cas5d protein is modified to disrupt the interaction of Cas5d with a protospacer flanking sequence such that the complex does not bind single-stranded nucleic acids. In one example, the Cas5d protein is modified by mutation at position Q110 of SEQ ID NO:6 or a position corresponding thereto. In one example, the Cas5d protein comprises or consists of a sequence according to SEQ ID NO:20. In one example, the complex of the fourteenth aspect is for use in methods of the invention targeting double stranded nucleic acids. In one example, the complexes further comprise a Cas11d protein. In one example, the complexes further comprise a Cas3’ protein. In one example, the modified CRISPR type I-D complexes of the thirteenth or fourteenth aspects may comprise a nuclease-deficient Cas7d and/or nuclease-deficient Cas10d protein as described elsewhere herein. In one example, the modified CRISPR type I-D complexes of the thirteenth or fourteenth aspects may further comprise the nuclease deficient Cas7d according to the twelfth aspect. In one example, the modified CRISPR type I-D complexes of the thirteenth aspect comprise the nuclease deficient Cas7d according to the twelfth aspect. According to another aspect of the present invention there is provided one or more nucleic acids encoding the nuclease deficient Cas7d protein of the twelfth aspect, or the modified CRISPR type-I-D complex of the thirteenth and fourteenth aspects. According to another aspect of the present invention there is provided an expression vector, phage or virus comprising the one or more nucleic acids encoding the nuclease deficient Cas7d protein, or the modified CRISPR Type-I complex of the fifteenth aspect, or the nucleic acid of the eighteenth aspect. According to another aspect of the present invention there is provided a cell comprising the one or more nucleic acids encoding the nuclease deficient Cas7d protein, or the modified CRISPR Type-I complex of the fifteenth aspect, or the expression vector, phage or virus of the sixteenth aspect. According to another aspect of the present invention there is provided a nucleic acid sequence encoding a Cas10d protein and a Cas11d protein, wherein the nucleic acid sequence comprises a modification to increase expression of Cas11d therefrom. In one example, the modification comprises insertion of an IRES element upstream of the sequence that encodes Cas11d. According to yet another aspect of the present invention there is provided a method of expressing a CRISPR type I-D complex, the method comprising: (a) providing one or more nucleic acid sequences encoding Cas5d, Cas6d, Cas7d, Cas10d and Cas11d proteins; (b) providing one or more nucleic acid sequences encoding a guide RNA complementary to a target nucleic acid sequence; under conditions where the nucleic acid sequences of (a) are expressed and form a complex with (b), wherein the nucleic acid sequence(s) encoding Cas10d and Cas11d are modified to increase expression of Cas11d protein. In one example, a single nucleic acid sequence encoding Cas10d and Cas11d is provided according to the eighteenth aspect. In one example, a first nucleic acid sequence encoding Cas10d is provided and a second nucleic acid sequence encoding Cas11d is provided, wherein the first and second nucleic acid sequences are under the control of different promoters. In one example, the method is a method of expressing a CRISPR type I-D complex in a eukaryotic cell. Advantageously, the present inventors have found that type I-D CRISPR Cas systems can be effectively harnessed to selectively target either double-stranded nucleic acid sequences or single- stranded nucleic acid sequences, or indeed both at the same time, as desired. Current CRISPR-Cas systems used in biotechnology are limited. Cas9 and Cas13 are popular choices for gene editing, however Cas9 only targets DNA, and is limited by PAM requirements that restrict targeting to certain locations. Cas13 on the other hand can target RNA but causes widespread damage in bacterial cells. Furthermore, genomic architecture and RNA secondary structures can limit accessibility of Cas9 and Cas13, respectively. Unlike these two current systems, the type I-D CRISPR-Cas system can target both DNA and RNA. The inventors have discovered how the type I-D system achieves this, and in each case how it binds to DNA or RNA. In doing so the inventors have been able to direct the type I-D CRISPR Cas system to either double stranded nucleic acids such as dsDNA or single stranded nuicleic acids such as ssDNA or RNA exclusively, by tailoring the guide RNA or by modifying certain Cas protein components of the system. The ability to direct the type I-D CRISPR Cas system to target either double stranded or single stranded nucleic acids makes the system flexible and versatile for biotechnological applications. It allows inhibition of gene expression, or indeed gene editing, at both the transcriptional and translational levels using the same system. The inventors have further found that the application of the type I-D CRISPR Cas system to single stranded nucleic acids such as RNA offers further advantages. Single stranded nucleic acid binding by the type I-D CRISPR Cas system does not have the same PAM restrictions and is therefore able to target additional and different sequences than when targeting double standed nucleic acids, or indeed when using the Cas9 and Cas13 based systems. The natural Cas3’ helicase of the system can be used to flatten out structures making single-stranded nucleic acids more accessible to CRISPR-Cas techniques. Furthermore, the inventors have found that they can control the system to target individual genes within RNA operons. In summary, the inventors have realised methods of using type I-D CRISPR Cas systems to target, bind, modify, or inhibit expression of exclusively double-stranded or single-stranded nucleic acids. Definitions As used herein, the singular forms “a,” “an” and “the” are intended to include the plural forms as well, unless the context clearly indicates otherwise. Also as used herein, “and/or” refers to and encompasses any and all possible combinations of one or more of the associated listed items, as well as the lack of combinations when interpreted in the alternative (“or”). The term “about,” as used herein when referring to a measurable value such as an amount or concentration and the like, is meant to encompass variations of ± 10%, ± 5%, ± 1%, ± 0.5%, or even ± 0.1% of the specified value as well as the specified value. For example, “about X” where X is the measurable value, is meant to include X as well as variations of ± 10%, ± 5%, ± 1%, ± 0.5%, or even ± 0.1% of X. A range provided herein for a measurable value may include any other range and/or individual value therein. As used herein, phrases such as "between X and Y" and "between about X and Y" should be interpreted to include X and Y. As used herein, phrases such as "between about X and Y" mean "between about X and about Y" and phrases such as "from about X to Y" mean "from about X to about Y." The term “comprise,” “comprises” and “comprising” as used herein, specify the presence of the stated features, integers, steps, operations, elements, and/or components, but do not preclude the presence or addition of one or more other features, integers, steps, operations, elements, components, and/or groups thereof. As used herein, the transitional phrase “consisting essentially of” means that the scope of a claim is to be interpreted to encompass the specified materials or steps recited in the claim and those that do not materially affect the basic and novel characteristic(s) of the claimed invention. Thus, the term “consisting essentially of” when used in a claim of this invention is not intended to be interpreted to be equivalent to “comprising.” “Cell” refers to a prokaryotic or eukaryotic cell and is not limited. A cell may be derived from any bacteria, archaea, plant, animal, or yeast. A cell may be derived from a vertebrate or non- vertebrate animal. A cell may be derived from a non-human or human animal. A cell may be mammalian or non-mammalian. “adjacent” means next to a location, which may be directly next to, indirectly next to, or proximal to a location. When used with reference to a nucleic acid sequence, ‘adjacent’ may mean directly upstream or downstream of a location, with no nucleotide bases between the nucleic acid sequence and the location, or may mean proximal to a location with a few nucleotide bases between the nucleic acid sequence and the location, such as below 10 nucleotide bases for example. “base pairing affinity” and “complementarity" may be used interchangeably and refer to the ability of a nucleic acid to form hydrogen bond(s) with another nucleic acid sequence by either traditional Watson-Crick base pairing or other non-traditional types. The terms "complementary" or "complementarity," as used herein, refer to the natural binding of polynucleotides under permissive salt and temperature conditions by base-pairing. For example, the sequence "A-G-T" binds to the complementary sequence "T-C-A." Complementarity between two single-stranded molecules may be "partial," in which only some of the nucleotides bind, or it may be complete when total complementarity exists between the single-stranded molecules. The degree of complementarity between nucleic acid strands has significant effects on the efficiency and strength of hybridization between nucleic acid strands. As used herein, the term “percent sequence identity” or “percent identity” refers to the percentage of identical nucleotides in a linear polynucleotide sequence of a reference (“query”) polynucleotide molecule (or its complementary strand) as compared to a test (“subject”) polynucleotide molecule (or its complementary strand) when the two sequences are optimally aligned. In some examples, “percent identity” can refer to the percentage of identical amino acids in an amino acid sequence. As used herein “sequence identity” refers to the extent to which two optimally aligned polynucleotide or peptide sequences are invariant throughout a window of alignment of components, e.g., nucleotides or amino acids. “Identity” can be readily calculated by known methods including, but not limited to, those described in: Computational Molecular Biology (Lesk, A. M., ed.) Oxford University Press, New York (1988); Biocomputing: Informatics and Genome Projects (Smith, D. W., ed.) Academic Press, New York (1993); Computer Analysis of Sequence Data, Part I (Griffin, A. M., and Griffin, H. G., eds.) Humana Press, New Jersey (1994); Sequence Analysis in Molecular Biology (von Heinje, G., ed.) Academic Press (1987); and Sequence Analysis Primer (Gribskov, M. and Devereux, J., eds.) Stockton Press, New York (1991). As used herein, the phrase “substantially identical,” or “substantial identity” in the context of two nucleic acid molecules, nucleotide sequences or protein sequences, refers to two or more sequences or subsequences that have at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, and/or 100% nucleotide or amino acid residue identity, when compared and aligned for maximum correspondence, as measured using one of the following sequence comparison algorithms or by visual inspection. In particular examples, substantial identity can refer to two or more sequences or subsequences that have at least about 80%, at least about 85%, at least about 90%, at least about 95, 96, 96, 97, 98, or 99% identity. Throughout this specification in any context, optimal alignment may be determined using, for example, any of the Smith-Waterman algorithm, the Needleman-Wunsch algorithm, algorithms based on the Burrows-Wheeler Transform (e.g., the Burrows Wheeler Aligner), ClustalW, Clustal X, BLAT, Novoalign (Novocraft Technologies; available at www.novocraft.com), ELAND (Illumina, San Diego, CA), SOAP (available at soap.genomics.org.cn), and Maq (available at maq.sourceforge.net). For purposes of this invention “percent identity” may also be determined using BLASTX version 2.0 for translated nucleotide sequences and BLASTN version 2.0 for polynucleotide sequences. "Perfectly complementary" means about 100% nucleotide or amino acid residues are complementary. Suitably that all the contiguous residues of a nucleic acid sequence will hydrogen bond with the same number of contiguous residues in a second nucleic acid sequence. The term "substantially complementary" as used herein means at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, and/or 100% nucleotide or amino acid residues are complementary, when compared and aligned for maximum correspondence, as measured using one of the following sequence comparison algorithms or by visual inspection. Suitably at least a percentage proportion of the contiguous residues of a nucleic acid sequence will hydrogen bond with the same number of contiguous residues in a second nucleic acid sequence. This may also correspond to nucleic acids that hybridize under stringent conditions. As used herein, hybridization, hybridize, hybridizing, and grammatical variations thereof, refer to the binding of two complementary nucleotide sequences or substantially complementary sequences in which some mismatched base pairs are present. The conditions for hybridization are well known in the art and vary based on the length of the nucleotide sequences and the degree of complementarity between the nucleotide sequences. In some examples, the conditions of hybridization can be high stringency, or they can be low stringency depending on the amount of complementarity and the length of the sequences to be hybridized. As used herein, "stringent conditions" for hybridization refer to conditions under which a nucleic acid having complementarity to a target sequence predominantly hybridizes with the target sequence, and substantially does not hybridize to non-target sequences. Stringent conditions are generally sequence-dependent and vary depending on a number of factors. In general, the longer the sequence, the higher the temperature at which the sequence specifically hybridizes to its target sequence. Non- limiting examples of stringent conditions surrounding the nucleic acids, temperature, the nature of the hybridization method, and the composition and length of the nucleic acid molecules used. Calculations regarding hybridization conditions required for attaining particular degrees of stringency are discussed in Sambrook et al., Molecular Cloning: A Laboratory Manual (Cold Spring Harbor Laboratory Press, Cold Spring Harbor, NY, 2001); and Tijssen, Laboratory Techniques in Biochemistry and Molecular Biology - Hybridization with Nucleic Acid Probes Part I, Chapter 2 (Elsevier, New York, 1993). The Tm is the temperature at which more than 50% of a given strand of a nucleic acid molecule is hybridized to its complementary strand. The following is an exemplary set of hybridization conditions and is not limiting: Very High Stringency (allows sequences that share at least 90% identity to hybridize) Hybridization: 5x SSC at 65 °C for 16 hours; wash twice: 2x SSC at room temperature (RT) for 15 minutes each; wash twice: 0.5x SSC at 65°C for 20 minutes each. High Stringency (allows sequences that share at least 80%> identity to hybridize) Hybridization: 5x-6x SSC at 65°C-70°C for 16-20 hours; wash twice: 2x SSC at RT for 5-20 minutes each; wash twice: lx SSC at 55°C-70°C for 30 minutes each. Low Stringency (allows sequences that share at least 50%> identity to hybridize); hybridization: 6x SSC at RT to 55°C for 16-20 hours; wash at least twice: 2x-3x SSC at RT to 55 °C for 20-30 minutes each. Methods of the invention may be in vitro, for example they are performed using a synthetic mix of the reaction components in a suitable buffer system. In some in vitro examples there is used a cell-free transcription/translation system. Methods of the invention may be employed occurring ex vivo, for example in a cell or cell culture. In ex vivo treatments, diseased cells may be removed from the body, treated with the products/methods of the invention, and then transplanted back into the patient. Ex vivo modification has an advantage of allowing the target cell population to be well defined and the specific dosage of therapeutic molecules delivered to cells to be specified. In vivo examples are also provided. In vivo modification can be used advantageously from this disclosure and the knowledge in the art. A “fragment” or “portion” of a nucleic acid will be understood to mean a nucleotide sequence of reduced length relative (e.g., reduced by 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20 or more nucleotides) to a reference nucleic acid or nucleotide sequence and comprising a nucleotide sequence of contiguous nucleotides that are identical or almost identical (e.g., 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% identical) to the reference nucleic acid or nucleotide sequence. Such a nucleic acid fragment or portion according to the invention may be, where appropriate, included in a larger polynucleotide of which it is a constituent. In some examples, a fragment of a polynucleotide can be a fragment that encodes a polypeptide that retains its function which may be termed a ‘functional fragment’. A “native” or “wild type” nucleic acid, nucleotide sequence, polypeptide or amino acid sequence refers to a naturally occurring or endogenous nucleic acid, nucleotide sequence, polypeptide or amino acid sequence. Thus, for example, a “wild type mRNA” is a mRNA that is naturally occurring in or endogenous to the organism. A “homologous” nucleic acid is a nucleic acid naturally associated with a host cell into which it is introduced. As used herein, the terms “nucleic acid,” “nucleic acid molecule,” “nucleic acid construct,” “nucleotide sequence” and “polynucleotide” refer to single-stranded or double-stranded nucleic acids, such as RNA or DNA that is linear or branched, single or double-stranded, or a hybrid thereof. The term also encompasses RNA/DNA hybrids. When dsRNA is produced synthetically, less common bases, such as inosine, 5-methylcytosine, 6-methyladenine, hypoxanthine and others can also be used for antisense, dsRNA, and ribozyme pairing. For example, polynucleotides that contain C-5 propyne analogues of uridine and cytidine have been shown to bind RNA with high affinity and to be potent antisense inhibitors of gene expression. Other modifications, such as modification to the phosphodiester backbone, or the 2'-hydroxy in the ribose sugar group of the RNA can also be made. The nucleic acid constructs of the present disclosure can be DNA or RNA, but are preferably DNA. Thus, although the nucleic acid constructs of this invention may be described and used in the form of DNA, depending on the intended use, they may also be described and used in the form of RNA. As used herein, the term “nucleotide sequence” refers to a heteropolymer of nucleotides or the sequence of these nucleotides from the 5' to 3' end of a nucleic acid molecule and includes DNA or RNA molecules, including cDNA, a DNA fragment or portion, genomic DNA, synthetic (e.g., chemically synthesized) DNA, plasmid DNA, mRNA, and anti-sense RNA, any of which can be single-stranded or double-stranded. The terms “nucleotide sequence” “nucleic acid,” “nucleic acid molecule,” “nucleic acid construct,” “oligonucleotide,” and “polynucleotide” are also used interchangeably herein to refer to a heteropolymer of nucleotides. Except as otherwise indicated, nucleic acid molecules and/or nucleotide sequences provided herein are presented herein in the 5’ to 3’ direction, from left to right and are represented using the standard code for representing the nucleotide characters as set forth in the U.S. sequence rules, 37 CFR §§1.821 - 1.825 and the World Intellectual Property Organization (WIPO) Standard ST.25. A “5’ region” as used herein can mean the region of a polynucleotide that is nearest the 5’ end. Thus, for example, an element in the 5’ region of a polynucleotide can be located anywhere from the first nucleotide located at the 5’ end of the polynucleotide to the nucleotide located halfway through the polynucleotide. A “3’ region” as used herein can mean the region of a polynucleotide that is nearest the 3’ end. Thus, for example, an element in the 3’ region of a polynucleotide can be located anywhere from the first nucleotide located at the 3’ end of the polynucleotide to the nucleotide located halfway through the polynucleotide. An element that is described as being “at the 5’end” or “at the 3’end” of a polynucleotide (5’ to 3’) refers to an element located immediately adjacent to (upstream of) the first nucleotide at the 5’ end of the polynucleotide, or immediately adjacent to (downstream of) the last nucleotide located at the 3’ end of the polynucleotide, respectively. The present invention now will be described hereinafter with reference to the accompanying drawings and examples, in which examples of the invention are shown. This description is not intended to be detail all the different ways in which the invention may be implemented, or all the features that may be added to the instant invention. For example, features illustrated with respect to one example may be incorporated into other examples, and features illustrated with respect to a particular example may be deleted from that example. Thus, the invention contemplates that in some examples of the invention, any feature or combination of features set forth herein can be excluded or omitted. In addition, numerous variations and additions to the various examples suggested herein will be apparent to those skilled in the art in light of the instant disclosure, which do not depart from the instant invention. Hence, the following descriptions are intended to illustrate some particular examples of the invention, and not to exhaustively specify all permutations, combinations and variations thereof. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. The terminology used in the description of the invention herein is for the purpose of describing particular examples only and is not intended to be limiting of the invention. Further features and examples of the aspects of the invention will be described hereinbelow under the headed sections. Any feature in any section may be combined with any aspect in any workable combination. Description Type I-D CRISPR-Cas Complex The invention relates to methods of using a type I-D CRISPR-Cas complex to target, bind, inhibit expression of, or modify a target nucleic acid sequence. In an example according to the present invention, each type I-D CRISPR-Cas complex comprises one or more Cas proteins and a guide RNA complementary to the target nucleic acid sequence. The ‘type I-D complex’ or ‘the complex’ as referred to herein indicates a type I-D CRISPR Cas complex comprising one or more Cas proteins, modified or unmodified, as defined herein and a guide RNA complementary to the target nucleic acid sequence. In an example according to the present invention the type I-D complex typically comprises the following Cas proteins: Cas5d, Cas6d, Cas7d, and Cas10d. In an example the Cas10d protein comprises a Cas3" domain. Suitably Cas3" is part of Cas10d. Suitably Cas3" is the nuclease domain of Cas10d. It may be possible to provide Cas3" as a separate protein, therefore in examples where Cas10d is included in the complex, optionally Cas3" may be included as a separate Cas protein. Suitably however, unless stated otherwise, Cas10d incorporates Cas3" and any reference herein to Cas10d includes therefore a reference to Cas3". Optionally, the type I-D complex may further comprise a Cas3’ protein. Suitably the Cas3’ protein is a helicase. Advantageously, the Cas3’ helicase can be used to flatten secondary structures present within single-stranded nucleic acid sequences. Suitably the Cas3’ helicase is only functional in the presence of ATP. Suitably therefore in the methods of the invention in which Cas3’ is used, a source of ATP is also present. Optionally, the type I-D complex may comprise one or more Cas11d proteins. Suitably the Cas11d proteins are stabilising proteins. Suitably, Cas10d, Cas5d, Cas6d and Cas7d proteins of the type I-D complex assist in target recognition in combination with the guide RNA . In some examples, the type I-D complex may only comprise Cas10d, Cas5d, Cas6d and Cas7d proteins. Suitably, modification, in particular cleavage, is carried out by the Cas10d and Cas7d proteins of the type I-D complex. Suitably Cas10d carries out cleavage of double-stranded nucleic acids. Suitably Cas7d carries out cleavage of single-stranded nucleic acids. In some examples, the type I-D complex comprises Cas proteins for target recognition. In some examples therefore, the type I-D complex comprises Cas5d, Cas6d, Cas7d, Cas10d, and Cas11d. Suitably in such examples, the complex is capable of targeting both double-stranded and single- stranded nucleic acids. Suitably Cas10d and Cas7d may be active or inactive. In some examples therefore, the type I-D complex comprises Cas5d, Cas6d, Cas7d, Cas10d, and Cas11d. Suitably in such examples, the complex is capable of targeting double-stranded nucleic acids. In some examples therefore, the type I-D complex comprises Cas5d, Cas6d, Cas7d and Cas10d. Suitably in such examples, the complex is capable of targeting single-stranded nucleic acids. In some examples, the type I-D complex comprises Cas proteins for target binding and inhibition of expression. In some examples therefore, the type I-D complex comprises Cas5d, Cas6d, Cas7d which may optionally be nuclease deficient, nuclease deficient Cas10d, and Cas11d. Suitably in such examples, the complex is capable of inhibiting expression of both double-stranded and single- stranded nucleic acids. Suitably Cas10d and optionally Cas7d are nuclease deficient. In some examples, Cas7d may be nuclease deficient, in other examples it may be active, or wild type. In some examples therefore, the Type I-D complex comprises Cas5d, Cas6d, Cas7d, nuclease deficient Cas10d, and Cas11d. Suitably in such examples, the complex is capable of inhibiting expression of double-stranded nucleic acids. In some examples therefore, the Type I-D complex comprises Cas5d, Cas6d, Cas7d which may optionally be nuclease deficient and Cas10d. Suitably in such examples, the complex is capable of inhibiting expression of single-stranded nucleic acids. In some examples, Cas7d may be nuclease deficient, in other examples it may be active, or wild type. In some examples, the Type I-D complex comprises Cas proteins for target recognition and modification. In some examples therefore, the Type I-D complex comprises Cas5d, Cas6d, Cas7d, Cas10d, Cas3’, and Cas11d. Suitably in such examples, the complex is capable of modifying both double-stranded and single-stranded nucleic acids. Suitably Cas10d and Cas7d are active. In some examples therefore, the Type I-D complex comprises Cas5d, Cas6d, Cas7d, active Cas10d, Cas3’, and Cas11d. Suitably in such examples, the complex is capable of modifying double- stranded nucleic acids. In some examples therefore, the Type I-D complex comprises Cas5d, Cas6d, active Cas7d and Cas10d. Suitably in such examples, the complex is capable of modifying single-stranded nucleic acids. Suitably Cas5d protein recognizes a PAM or PFS. Suitably a PAM or PFS adjacent to the target nucleic acid sequence. Suitably Cas7d binds to the guide RNA and is necessary for targeting the Type I-D complex to the target nucleic acid sequence. Suitably Cas7d also cleaves single-stranded nucleic acid sequences. Suitably multiple Cas7d proteins may be present in the Type I-D CRISPR complex, suitably seven Cas7d proteins may be present. Suitably Cas6d processes the guide RNA. Suitably Cas10d includes Cas3" as explained above. Suitably Cas10d cleaves double-stranded nucleic acid sequences. Suitably Cas10d performs remodelling of the target nucleic acid sequence and the Cas3" domain performs degradation of the target nucleic acid. Suitably Cas10d also has a role in recognising a PAM adjacent to a target double-stranded nucleic acid sequence. Suitably Cas10d may recognise a PAM adjacent to a target double-stranded nucleic acid sequence in combination with Cas5d. Suitably Cas10d may cleave one or both strands of double stranded nucleic acid sequences. Suitably in the presence of a functional Cas3’ helicase, Cas10d cleaves both strands. Suitably in the absence of a functional Cas3’ helicase, Cas10d cleaves the non-target strand of a double stranded nucleic acid sequence. Suitably by functional Cas3’ helicase it is meant that the Cas3’ is provided with ATP. Suitable Cas proteins may be derived from any bacterial or archaeal species. Examples of suitable species include: Microcystis aeruginosa, Acetohalobium arabaticum, Ammonifex degensii, Anabaena cylindrica, Anabaena variabilis, Caldicellulosiruptor lactoaceticus, Caldilinea aerophila, Clostridium algicarnis, Crinalium epipsammum, Cyanothece sp., Cylindrospermum stagnale, Haloquadratum walsbyi, Halorubrum lacusprofundi, Methanocaldococcus vulcanius, Methanospirillum hungatei, Natrialba asiatica, Natronomonas pharaonis, Nostoc punctiforme, Phormidesmis priestleyi, Crematoria acuminata, Picrophilus torridus, Spirochaeta thermophila, Stanieria cyanosphaera, Sulfolobus acidocaldarius, Sulfolobus islandicus, Synechocystis sp., Thermacetogenium phaeum, Thermofilum pendens, etc. Suitably the Cas proteins used in the present invention are derived from a cyanobacterium. Suitably the Cas proteins used in the present invention are derived from Synechocystis sp. Suitably the Cas proteins used in the present invention are derived from strain Synechocystis sp. PCC 6803. Suitably Cas5d may also be known by the names ‘csc1’ or ‘slr7013’. Any references to Cas5d herein may be used interchangeably with csc1 or slr7013. Suitably Cas5d comprises a sequence according to SEQ ID NO:6 or a functional fragment thereof, an orthologue or homologue thereof, or a sequence having at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, and/or 100% identity thereto. Suitably Cas6d may also be known by the name ‘slr7014’. Any references herein to Cas6d herein may be used interchangeably with slr7014. Suitably Cas6d comprises a sequence according to SEQ ID NO:8 or a functional fragment thereof, an orthologue or homologue thereof, or a sequence having at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, and/or 100% identity thereto. Suitably Cas7d may also be known by the name ‘csc2’ or ‘slr7012’. Any references herein to Cas6d herein may be used interchangeably with csc2 or slr7012. Suitably Cas7d comprises a sequence according to SEQ ID NO:4 or a functional fragment thereof, an orthologue or homologue thereof, or a sequence having at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, and/or 100% identity thereto. Suitably Cas10d may also be known by the name ‘csc3’ or ‘slr7011’. Any references herein to Cas10d herein may be used interchangeably with csc3 or slr7011. Suitably Cas10d comprises a sequence according to SEQ ID NO:2 or a functional fragment thereof, an orthologue or homologue thereof, or a sequence having at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, and/or 100% identity thereto. Suitably Cas11d may also be known by the name ‘small subunit’ or ‘ssu’. Any references herein to Cas11d may be used interchangeably with ‘small subunit’ or ‘ssu’. Suitably Cas11d comprises a sequence according to SEQ ID NO:12 or a functional fragment thereof, an orthologue or homologue thereof, or a sequence having at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, and/or 100% identity thereto. Suitably Cas3’ may also be known by the name ‘slr7010’. Any references herein to Cas3’ herein may be used interchangeably with slr7010. Suitably Cas3’ comprises a sequence according to SEQ ID NO:10 or a functional fragment thereof, an orthologue or homologue thereof, or a sequence having at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, and/or 100% identity thereto. The type I-D CRISPR Cas complex may be used in any of the methods herein, in a method of targeting a nucleic acid sequence, a method of inhibiting expression of a nucleic acid sequence, or a method of modifying a nucleic acid sequence. Nuclease Deficient Cas7d or Cas10d In some aspects of the invention it is desirable to use a type I-D CRISPR complex where the Cas proteins with nuclease activity are modified to be nuclease deficient so that they do not cleave the target nucleic acid sequence. Suitably such nuclease deficient Cas proteins may also be referred to herein as ‘inactive’. Suitably nuclease deficient Cas proteins may be used in any of the methods of the invention except the methods of modifying target nucleic acid sequences. Suitably nuclease deficient Cas proteins are used in the methods of the invention concerned with binding, inhibiting expression of target nucleic acid sequences, detecting target nucleic acid sequences or tracking target nucleic acid sequences. Suitably in such methods, cleavage of the target sequence is undesirable. Suitably Cas7d and Cas10d are nucleases. Suitably one or both of these proteins may be nuclease deficient. Suitably Cas7d cleaves single-stranded nucleic acids. Suitably Cas10d cleaves double-stranded nucleic acids. Suitably in such methods concerned with double-stranded target nucleic acid sequences, Cas10d is present and is nuclease deficient. Suitably in such methods concerned with single-stranded target nucleic acid sequences, Cas7d is present and is nuclease deficient. Suitably in such methods concerned with double and single-stranded target nucleic acid sequences, both Cas7d and Cas10d are present and are nuclease deficient. Suitably, by ‘nuclease deficient’, it is meant that the Cas7d and Cas10d proteins may be modified to reduce the nuclease activity to less than the nuclease activity of a corresponding wild type Cas7d or Cas10d protein. Suitably nuclease deficient Cas7d and Cas10d may be produced by modification of the protein, suitably modification of the amino acid sequence. Suitably by modification of the or each active site of the Cas7d and Cas10d proteins. Suitably the Cas7d protein may be modified to substantially remove nuclease activity. Suitably this may be achieved by mutation of the single active site, which is operable to cleave a single- stranded nucleic acid sequence. Suitably this may be regarded as a ‘dead’ Cas7d protein. Suitably the Cas10d protein may be modified to reduce the nuclease activity to substantially remove nuclease activity. Suitably this may be achieved by mutation of the active site, which is operable to cleave the non-target strand of a double-stranded nucleic acid sequence. Suitably this may be regarded as a ‘dead’ Cas10d protein. In one aspect of the invention, there is provided a nuclease deficient Cas7d protein, comprising a mutation at position E101 of SEQ ID NO:4 or a position corresponding thereto, and optionally one or more further mutations. In one example, the Cas7d protein further comprises a mutation at position D119 of SEQ ID NO:4 or a position corresponding thereto. In one example, the mutation at position E101 of SEQ ID NO:4 or a position corresponding thereto is E101A. In one example, the mutation at position D119 of SEQ ID NO:4 or a position corresponding thereto is D119A. Suitably the nuclease deficient Cas7d protein comprises a sequence according to SEQ ID NO: 18, an orthologue or homologue, or functional fragment thereof, or a sequence having at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, and/or 100% identity thereto, wherein the nuclease deficient Cas7d protein retains the mutations identified above or mutations at corresponding positions thereto. Suitably the nuclease deficient Cas7d protein consists of a sequence according to SEQ ID NO: 18 In a further aspect of the invention there may be provided a type I-D CRISPR Cas complex comprising the nuclease deficient Cas7d protein of the invention. Nuclease deficient Cas10d is known in the art (Lin et al. 2020). Suitably nuclease deficient Cas10d comprises a mutation at position D116 of SEQ ID NO:2 or a position corresponding thereto, and optionally one or more further mutations. Suitably the nuclease deficient Cas10d protein comprises a sequence according to SEQ ID NO: 14, an orthologue or homologue, or functional fragment thereof, or a sequence having least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, and/or 100% identity thereto, wherein the nuclease deficient Cas10d protein retains the mutations identified above or mutations at corresponding positions thereto. Suitably the nuclease deficient Cas10d protein consists of a sequence according to SEQ ID NO: 14. Suitably the nuclease deficient Cas7d or Cas10d proteins may be comprised in the modified type I-D CRISPR Cas complexes of the thirteenth and fourteenth aspects of the invention. Therefore in some examples, the Cas10d protein may be modified to be nuclease deficient and may also be further modified to disrupt the interaction of Cas10d with a protospacer adjacent motif as described further hereinbelow. Modified type I-D Complex In some examples of the invention, a modified type I-D complex may be used. By modified it is meant that one or more of the components of the type I-D complex have been changed such that the complex is different to that of a reference wild type complex. In some examples, components of the complex may be removed entirely. In some examples, the polypeptide sequences forming one or more of the proteins used in the complexes have been mutated such that one or more amino acid residues are different to those of a reference wild type polypeptide sequence. Suitably the type I-D complex may be modified to direct it to target only double-stranded nucleic acids or only single-stranded nucleic acids. In some examples, the Cas10d protein is modified. Suitably it is modified to disrupt the interaction of Cas10d with a protospacer adjacent motif such that the complex does not bind double- stranded nucleic acids. Suitably this may be in addition to, or separate from, modifications described above to form a nuclease deficient Cas10d. In one example, the Cas10d protein is modified by mutation at one or more positions selected from: K326, K369, Y437, G433, K329, K566, Q552 and/or Q553 in SEQ ID NO:2 or a position corresponding thereto. In one example, the Cas10d protein is modified by mutation at position K326 in SEQ ID NO:2 or a position corresponding thereto, and optionally one or more further mutations at positions selected from K369, Y437, G433, K329, K566, Q552 and/or Q553 in SEQ ID NO:2, or positions corresponding thereto. Suitably these positions are involved in PAM recognition. In one example, the Cas10d protein is modified by mutation at positions K326 and K369, positions K326 and Y437, positions K326 and G433, positions K326 and K329, positions K326 and K566, K326 and Q552 and/or positions K326 and Q553 in SEQ ID NO:2 or positions corresponding thereto. In one example, the Cas10d protein is modified by mutation at positions K326 and K369 and Y437, positions K326 and K369 and G433, positions K326 and K369 and K329, positions K326 and K369 and K566, positions K326 and K369 and Q552, and/or positions K326 and K369 and Q553 in SEQ ID NO:2 or positions corresponding thereto. In one example, the Cas10d protein is modified by mutation at positions K326 and Y437 and G433, positions K326 and Y437 and K329, positions K326 and Y437 and K566, positions K326 and Y437 and Q552, and/or positions K326 and Y437 and Q553 in SEQ ID NO:2 or positions corresponding thereto. In one example, the Cas10d protein is modified by mutation at positions K326 and G433 and K329, positions K326 and G433 and K566, positions K326 and G433 and Q552, and/or positions K326 and G433 and Q553, in SEQ ID NO:2 or positions corresponding thereto. In one example, the Cas10d protein is modified by mutation at positions K326 and K329 and K566, positions K326 and K329 and Q552, and/or positions K326 and K329 and Q553 in SEQ ID NO:2 or positions corresponding thereto. In one example, the Cas10d protein is modified by mutation at positions K326 and K566 and Q552 and Q553 in SEQ ID NO:2 or positions corresponding thereto. Suitable further exemplary combinations of mutations which may be present in the Cas10d protein will be envisaged by the skilled person, some examples are provided as follows, but are not limited thereto: In one example, the Cas10d protein is modified by mutation at positions K326 and K369 and Y437 and G433, K326 and K369 and Y437 and K329, K326 and K369 and Y437 and K566, K326 and K369 and Y437 and Q552 and/or K326 and K369 and Y437 and Q553 in SEQ ID NO:2 or positions corresponding thereto. In one example, the Cas10d protein is modified by mutation at positions K326 and Y437 and G433 and K329, K326 and Y437 and G433 and K329, K326 and Y437 and G433 and K566, K326 and Y437 and G433 and Q552, and/or K326 and Y437 and G433 and Q553 in SEQ ID NO:2 or positions corresponding thereto. In one example, the Cas10d protein is modified by mutation at positions K326 and K369 and G433 and K329, at positions K326 and K369 and G433 and K566, at positions K326 and K369 and G433 and Q552, and/or positions K326 and K369 and G433 and Q553 in SEQ ID NO:2 or positions corresponding thereto. In one example, the Cas10d protein is modified by mutation at positions K326 and K369 and K329 and K566; at positions K326 and K369 and K329 and Q552; and/or at positions K326 and K369 and K329 and Q553 in SEQ ID NO:2 or positions corresponding thereto. In one example, the Cas10d protein is modified by mutation at positions K326 and K369 and K566 and Q552 in SEQ ID NO:2, and/or positions K326 and K369 and K566 and Q553 or positions corresponding thereto. In one example, the Cas10d protein is modified by mutation at positions K326 and K369 and Y437 and G433 and K329, at positions K326 and K369 and Y437 and G433 and K566, at positions K326 and K369 and Y437 and G433 and Q552 and/or at positions K326 and K369 and Y437 and G433 and Q553 in SEQ ID NO:2 or positions corresponding thereto. In one example, the Cas10d protein is modified by mutation at positions K326 and K369 and Y437 and K329 and K566, at positions K326 and K369 and Y437 and K329 and Q552, and/or at positions K326 and K369 and Y437 and K329 and Q553 in SEQ ID NO:2 or positions corresponding thereto. In one example, the Cas10d protein is modified by mutation at positions K326 and K369 and Y437 and K566 and Q552 and/or at positions K326 and K369 and Y437 and K566 and Q553 in SEQ ID NO:2 or positions corresponding thereto. In one example, the Cas10d protein is modified by mutation at positions K326 and K369 and Y437 and G433 and K329 and K566; K326 and K369 and Y437 and G433 and K329 and Q552 and/or K326 and K369 and Y437 and G433 and K329 and Q553 in SEQ ID NO:2 or positions corresponding thereto. In one example, the Cas10d protein is modified by mutation at positions K326 and K369 and Y437 and G433 and K329 and K566 and Q552 and Q553 in SEQ ID NO:2 or positions corresponding thereto. In one example, the Cas10d protein is modified by mutation at position K326 in SEQ ID NO:2 or a position corresponding thereto. Suitably any of the above positions are modified by a substitution mutation. Suitably substitution with an alternative neutral amino acid. Suitably substitution with alanine. In one example, the Cas10d protein is modified by mutation K326A in SEQ ID NO:2 or a position corresponding thereto. In one example, the modified Cas10d protein comprises a sequence according to SEQ ID NO:16, or a functional fragment thereof, an orthologue or homologue thereof, or a sequence having at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, and/or 100% identity thereto, wherein the modified Cas10d protein retains the mutations identified above or mutations at corresponding positions thereto. Suitably the modified Cas10d protein consists of a sequence according to SEQ ID NO: 16. Suitably other Cas10d proteins from different organisms, such as an orthologue or homologue, having different amino acid sequences may be used in the methods of the present invention, and may be modified at a position which corresponds to those listed above in SEQ ID NO:2 as determined by aligning SEQ ID NO:2 with said other amino acid sequences. The skilled person will be aware of how to produce such an alignment, and how to identify the corresponding residues to those listed. This is what is meant by the term ‘position corresponding thereto’. In one aspect of the invention there is provided a type I-D CRISPR Cas complex comprising said modified Cas10d protein. Suitably this modified type I-D CRISPR Cas complex is used in methods where it is desired to target only single-stranded nucleic acid sequences. In some examples the Cas5d protein is modified. Suitably it is modified to disrupt the interaction of Cas5d with a protospacer flanking sequence such that the complex does not bind single- stranded nucleic acids. In such an example, suitably the Cas5d protein is modified by mutation at position Q110 in SEQ ID NO: 6 or a position corresponding thereto, and optionally one or more further mutations. Suitably position Q110 is involved in PFS recognition. Suitably any of the above positions are modified by a substitution mutation. Suitably substitution with an alternative neutral amino acid. Suitably substitution with alanine. In one example, the Cas5d protein is modified by mutation Q110A in SEQ ID NO:6 or a position corresponding thereto. In some examples, the Cas5d protein is alternatively or additionally modified to disrupt the interaction of Cas5d with a protospacer adjacent motif such that the complex does not bind double- stranded nucleic acids. Suitably such a modified Cas5d protein is used in combination with a modified Cas10d protein as described above. In such an example, the Cas5d protein is modified by mutation at position K114 in SEQ ID NO:6 or a corresponding position thereto, and optionally one or more further mutations. Suitably position K114 is involved in PAM recognition. In one example, the Cas5d protein may be modified by mutation at position Q110 and position K114 in SEQ ID NO: 6 or a position corresponding thereto. Suitably any of the above positions are modified by a substitution mutation. Suitably substitution with an alternative neutral amino acid. Suitably substitution with alanine. In one example, the Cas5d protein is modified by mutation K114A in SEQ ID NO:6 or a position corresponding thereto. In one example, the modified Cas5d protein comprises a sequence according to SEQ ID NO:20, or a functional fragment thereof, an orthologue or homologue thereof, or a sequence having at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, and/or 100% identity thereto, wherein the modified Cas5d protein retains the mutations identified above or mutations at corresponding positions thereto.. Suitably the modified Cas5d protein consists of a sequence according to SEQ ID NO: 20. In one example, the modified Cas5d protein comprises a sequence according to SEQ ID NO:95, or a functional fragment thereof, an orthologue or homologue thereof, or a sequence having at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, and/or 100% identity thereto, wherein the modified Cas5d protein retains the mutations identified above or mutations at corresponding positions thereto. Suitably the modified Cas5d protein consists of a sequence according to SEQ ID NO: 95. Suitably other Cas5d proteins, from different organisms, such as an orthologue or homologue, having different amino acid sequences may be used in the methods of the present invention, and may be modified at a position which corresponds to that of Q110 or K114 of SEQ ID NO:6 as determined by aligning SEQ ID NO:6 with said other amino acid sequences. The skilled person will be aware of how to produce such an alignment, and how to identify the corresponding residues. This is what is meant by the term ‘position corresponding thereto’. In one aspect of the invention there is provided a type I-D CRISPR Cas complex comprising said modified Cas5d protein. Suitably this modified type I-D CRISPR Cas complex is used in methods where it is desired to target only double-stranded nucleic acid sequences. Suitably in such an aspect the Cas5d protein is modified by mutation at position Q110 in SEQ ID NO: 6 or a position corresponding thereto, and optionally one or more further modifications. In one aspect of the invention there is provided a type I-D CRISPR Cas complex comprising said modified Cas5d protein. Suitably this modified type I-D CRISPR Cas complex is used in methods where it is desired to target only single-stranded nucleic acid sequences. Suitably in such an aspect the Cas5d protein is modified by mutation at position K114 in SEQ ID NO: 6 or a position corresponding thereto, and optionally one or more further modifications. In one aspect of the invention there is provided a type I-D CRISPR Cas complex comprising said modified Cas10d protein and said modified Cas5d protein. Suitably this modified type I-D CRISPR Cas complex is used in methods where it is desired to target only single-stranded nucleic acid sequences. Suitably in such an aspect, the Cas10d protein may be modified by mutation at one or more positions selected from: K326, K369, Y437, G433, K329, K566, Q552 and/or Q553 in SEQ ID NO:2 or a position corresponding thereto and optionally one or more further modifications, and the Cas5d protein is modified by mutation at position K114 in SEQ ID NO:6 or a corresponding position thereto, and optionally one or more further modifications. In some examples, the Cas11d protein of the type I-D complex is not present. In type I-D complexes, the nucleic acid sequence encoding Cas10d also encodes Cas11d via an internal start codon and RBS. In one example, the nucleic acid sequence encoding Cas10d and Cas11d is modified such that the Cas11d protein is not expressed. In one example, the nucleic acid sequence encoding Cas10d and Cas11d is modified in the coding region of Cas11d. In one example, the nucleic acid sequence encoding Cas10d and Cas11d is modified in the start codon or in the ribosomal binding site of the nucleic acid sequence encoding Cas11d. Suitably the start codon may be modified to CTG. Suitably the ribosome binding site may be modified to AGGGTAA (SEQ ID NO:97). Suitably both the start codon may be modified to CTG and the ribosome binding site may be modified to AGGGTAA (SEQ ID NO:98). Alternatively, the start codon and/or the ribosome binding site may be scrambled. In one example, the nucleic acid sequence encoding Cas10d and Cas11d is modified to insert a stop codon upstream of the nucleic acid sequence encoding Cas11d. Suitably in such an example, a truncated Cas10d protein is expressed. In some examples, therefore, the type I-D CRISPR Cas complex does not comprise a Cas11d protein. Suitably this modified type I-D CRISPR Cas complex is used in methods where it is desired to target only single-stranded nucleic acid sequences. In some aspects of the invention where it is desired to target only double-stranded nucleic acid sequences, then the type I-D CRISPR Cas complex comprises a modified Cas5d protein and does comprise a Cas11d protein. In some aspects of the invention where it is desired to target only single-stranded nucleic acid sequences, then the type I-D CRISPR Cas complex comprises a modified Cas10d protein, optionally a modified Cas5d protein, and does not comprise a Cas11d protein. Suitably any of the modified type I-D CRISPR Cas complexes described herein may also comprise a nuclease deficient Cas7d and/or nuclease deficient Cas10d protein as described above. In one example the Cas3’ is also modified. Suitably it is modified to enhance cleavage of the target double stranded nucleic acid sequence, suitably to enhance cleavage of single sites in the target double stranded nucleic acid sequence. Suitably, in order to achieve this, the Cas3’ protein is modified to reduce its helicase activity. Suitably any known mutation may be used to modify the Cas3’ protein to reduce its helicase activity. Suitably any mutation in the helicase motif DEXD/H (SEQ ID NO: 93). Suitably the Cas3’ protein may comprise a mutation at position D198 and/or E199 of SEQ ID NO:10 or may comprise mutations at a corresponding position thereto, and optionally one or more further mutations.Suitably the Cas3’ protein may comprise the mutations D198A and/or E199A. Suitably the Cas3’ protein may therefore comprise a sequence according to SEQ ID NO:93. In one example, the modified Cas3’ protein comprises a sequence according to SEQ ID NO:93, or a functional fragment thereof, an orthologue or homologue thereof, or having at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, and/or 100% identity thereto, wherein the modified Cas3’ protein retains the mutations identified above or mutations at corresponding positions thereto. Suitably the modified Cas3’ protein consists of a sequence according to SEQ ID NO: 93. Suitably other Cas3’ proteins, from different organisms, such as an orthologue or homologue, having different amino acid sequences may be used in the methods of the present invention, and may be modified at a position which corresponds to that of D206 or E207 of SEQ ID NO:10 as determined by aligning SEQ ID NO:10 with said other amino acid sequences. The skilled person will be aware of how to produce such an alignment, and how to identify the corresponding residues. This is what is meant by the term ‘position corresponding thereto’. In one aspect of the invention there is provided a type I-D CRISPR Cas complex comprising said modified Cas3’ protein. Suitably this modified type I-D CRISPR Cas complex is used in methods where it is desired to target only double-stranded nucleic acid sequences. In alternative examples, the Cas3’ protein is not modified, and may be a wild type Cas3’ protein. Suitably in such examples, the target double stranded nucleic acid sequence is cleaved by processive cleavage. Guide RNA The guide RNA is a nucleic acid molecule that forms a Type I-D CRISPR-Cas complex with the Cas proteins described herein. Suitably the guide RNA directs the Cas proteins to the correct target nucleic acid sequence. Suitably the guide RNA forms a complex with the target recognition Cas proteins. Suitably with at least Cas10d, Cas5d, Cas6d and Cas7d. Suitably the guide RNA is bound by Cas7d. Suitably the guide RNA is bound in a complex comprising Cas10d, Cas5d, Cas6d and Cas7d and optionally other Cas proteins described herein. Suitably the guide RNA comprises a nucleic acid sequence, suitably an RNA sequence, of between 30 nucleotides to about 100 nucleotides in length. Suitably the guide RNA comprises a nucleic acid sequence of between 40 to 100, 50 to 100, 60 to 100, 70 to 100, 40 to 90, 50 to 90, 60 to 90, 70 to 90, 40 to 80, 50 to 80, 60 to 80, 70 to 80 nucleotides in length. Suitably the guide RNA comprises a nucleic acid sequence of 72 nucleotides in length. Suitably the guide RNA comprises a targeting sequence which is complementary to the target nucleic acid sequence. This may also be known as a spacer sequence. Suitably the targeting sequence may be about 20 nucleotides to about 70 nucleotides in length, (e.g., about 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50 nucleotides in length, and any value or range therein). Suitably the targeting sequence is about 35 nucleotides in length. Suitably, the targeting sequence comprises between 20 to 50, 20 to 45, 30 to 40, 32 to 37 nucleotides which are complementary to the target nucleic acid sequence. Suitably longer complementary sequences provide higher sequence specificity to the guide RNA and a higher stability. Advantageously, the targeting sequence of the guide RNA in a type I-D complex is longer than conventional CRISPR-Cas systems. Suitably the complementarity between the targeting sequence and that target nucleic acid sequence is sufficient for the targeting sequence of the guide RNA to hybridise to the target nucleic acid sequence and direct sequence-specific binding of the CRISPR type I-D complex. Suitably the targeting sequence (spacer) may be fully complementary to a target nucleic acid sequence (e.g., 100% complementary to a target sequence across its full length). In some examples, the targeting sequence may be substantially complementary (e.g., at least about 80% complementary (e.g., about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 98.5%, 99%, 99.5%, or more complementary)) to a target nucleic acid sequence. Thus, in some examples, a targeting sequence may have one, two, three, four, five or more mismatches that may be contiguous or noncontiguous as compared to a target nucleic acid sequence. In some examples, every 6 ^th nucleotide of the targeting sequence is a mismatch with the target nucleic acid sequence. Suitably in such an example, the 6 ^th , 12 ^th , 18 ^th , 24 ^th , 30 ^th etc. nucleotide of the targeting sequence is a mismatch with the target nucleic acid sequence. Suitably the complementarity between the targeting sequence and the target nucleic acid sequence is at least 95%, 96%, 97%, 98%, 98.5%, 99%, 99.5% or 100%. Suitably, the 5’ region of a targeting sequence (spacer) may be fully complementary to a target nucleic acid sequence while the 3’ region of the targeting sequence may be substantially complementary to the target nucleic acid sequence. Suitably this 5’ region of the targeting sequence (spacer) may be known as a seed sequence. Accordingly, the 5’ region of a targeting sequence, or ‘seed sequence’, may comprise the first 8 nucleotides at the 5’ end, the first 10 nucleotides at the 5’ end, the first 15 nucleotides at the 5’ end, or the first 20 nucleotides at the 5’ end of the targeting sequence. Suitably the seed sequence may be about 100% complementary to a target nucleic acid sequence, while the remainder of the targeting sequence may be about 80% or more complementary to the target nucleic acid sequence. Suitably, at least the first eight contiguous nucleotides at the 5’ end of the targeting sequence, except the 6 ^th nucleotide, are fully complementary to the portion of the target nucleic acid sequence adjacent to the PAM or PFS (suitably forming a “seed sequence”). Thus, in some examples, the seed sequence may comprise the first 8-10 nucleotides of the 5’ end of each of one or more targeting sequence(s), which first 8-10 nucleotides, except the 6 ^th nucleotide, are fully complementary (100%) to the target nucleic acid sequence, and the remaining portion of the one or more targeting sequence(s) (3’ to the seed sequence) may be at least about 80% complementarity (e.g., about 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, or 100% complementarity) to the target nucleic acid sequence. Suitably with the exception of every 6 ^th nucleotide position. Suitably the guide RNA recognises and targets target nucleic acid sequences adjacent to a PAM or PFS, suitably immediately adjacent. Suitably the guide RNA recognises and targets target nucleic acid sequences downstream of a PAM in the 5’ to 3’ direction. Suitably the guide RNA recognises and targets target nucleic acid sequences upstream of a PFS in the 5’ to 3’ direction. Suitable PAM sequences or PFS sequences are described elsewhere herein in relation to the target nucleic acid sequence. For double stranded nucleic acid sequences such as dsDNA, suitably the PAM is selected from GTN. Suitably the PAM comprises a G in the first position and T in the second position. In one example, the guide RNA targets a target nucleic acid sequence adjacent to a double stranded-specific protospacer adjacent motif. Suitably the double stranded-specific protospacer adjacent motif is GTN, such as GTA, GTT, GTC, GTG. For single stranded nucleic acid sequences such as RNA or ssDNA, suitably the PFS is AAC or ACG. Suitably the PFS does not comprise a G in the first position. In one example, the guide RNA targets a target nucleic acid sequence adjacent to an single stranded-specific protospacer flanking sequence. Suitably the single stranded-specific protospacer flanking sequence is AAC. Suitably, in addition to the targeting sequence, the guide RNA further comprises one or more Cas binding sequences. Suitably the guide RNA comprises a 5’ Cas binding sequence and a 3’ Cas binding sequence. Suitably the 3’ Cas binding sequence binds to Cas6. Suitably therefore it may be known as a Cas6 binding sequence. Suitably the 5’ Cas binding sequence binds to Cas10d and Cas5. Suitably the 5’ Cas binding sequence may be known as the handle of the guide RNA. Suitably the 3’ Cas binding sequence comprises two complementary regions of nucleotides that hybridise to form a double-stranded RNA duplex. Suitably a first complementary region and a second complementary region. Suitably the length of the 3’ Cas binding sequence is suitable to enable the guide RNA to interact and bind to one or more Cas proteins, suitably to Cas6. Suitably the 3’ Cas binding sequence comprises between 10-70 nucleotides, 20-60 nucleotides, 25-50 nucleotides. In one example, the 3’ binding sequence Cas comprises 29 nucleotides. Suitably the dsRNA duplex comprises between 2-45 bp, 3-30 bp, 4-20 bp. Suitably the dsRNA duplex comprises 4 bp. Suitably the dsRNA duplex further comprises one or more intervening nucleotides located between the first complementary region and the second complementary region. Suitably the intervening nucleotides comprise between 2-10 nucleotides, suitably between 3 to 8 nucleotides, suitably between 4 to 6 nucleotides, suitably 5 nucleotides. Suitably the complementarity between the two complementary regions of nucleotides that form the dsRNA duplex is at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%. Suitably the methods of the invention may comprise one, or more than one guide RNA. Suitably each guide RNA may target a different target nucleic acid sequence. Suitably the methods of the invention may comprise a guide RNA complementary to a target double-stranded nucleic acid sequence; and a guide RNA complementary to a target single-stranded nucleic acid sequence. In some examples, two guide RNAs are used. In other examples, this may be achieved by one guide RNA. Suitably therefore in some examples the methods may comprise a guide RNA which is complementary to both the target double-stranded nucleic acid sequence and the target single-stranded nucleic acid sequence. Suitably in such examples, the target nucleic acid sequence must be the same, and must be present in both double stranded and single stranded nucleic acids, such as a target nucleic acid sequence within a coding region or exon. Suitably therefore references to a guide RNA complementary to a target double-stranded nucleic acid sequence and a guide RNA complementary to a target single-stranded nucleic acid sequence in the methods herein may be a reference to one guide RNA capable of performing both functions. An exemplary guide RNA sequence is provided herein according to SEQ ID NO: 21. Suitable guide RNA sequences which may be used in the Type I-D CRISPR-Cas system of the invention may be designed to bind the target nucleic acid sequence. The skilled person will be aware of tools in the art to design guide RNA sequences to target particular target nucleic acid sequences. Target nucleic acid sequence A target nucleic acid sequence is a nucleic acid sequence to be targeted by the type I-D CRISPR Cas system. Suitably the target nucleic acid sequence may be double-stranded or single-stranded. In one example, the target double-stranded nucleic acid sequence is DNA. In one example, the target single- stranded nucleic acid sequence is RNA and/or ssDNA. Suitably the target nucleic acid sequence may be any region of dsDNA, ssDNA or RNA. Suitably a target DNA may include genomic DNA, cDNA, mitochondrial DNA, plastid DNA, viral DNA, prokaryotic DNA, phage DNA, plasmid DNA, cosmid DNA, synthetic DNA, for example. Suitably the target DNA maybe in vivo, ex vivo or in vitro. Suitably the target DNA is genomic DNA. Suitably genomic DNA may be located in the genome of an organism. Suitably therefore the target nucleic acid sequence may be in the genome of an organism. The term “genome,” as used herein, refers to both chromosomal and non-chromosomal elements (i.e., extrachromosomal (e.g., mitochondrial, plasmid, a chloroplast, and/or extrachromosomal circular DNA (eccDNA)) of a target organism. As used herein, “extrachromosomal” refers to nucleic acid from a mitochondrion, a plasmid, a plastid (e.g., chloroplast, amyloplast, leucoplast, proplastid, chromoplast, etioplast, elaiosplast, proteinoplast, tannosome), and/or an extrachromosomal circular DNA (eccDNA)). In some examples, an extrachromosomal nucleic acid may be referred to as “extranuclear DNA” or “cytoplasmic DNA.” In some examples, a plasmid may be targeted (e.g., the target nucleic acid sequence is located on a plasmid). In some examples, a target nucleic acid sequence may be located on a mobile element (e.g., a transposon, a plasmid, a bacteriophage element (e.g., Mu), a group I and group II intron). Suitably a target RNA may include mRNA, and non-coding RNAs such as tRNA, rRNA, sRNA, siRNA, iRNA, miRNA. Suitably the target RNA is mRNA. Suitably the target RNA maybe in vivo, ex vivo or in vitro. Suitably the target nucleic acid sequence is not limited. Suitably the target nucleic acid sequence may be any region of any nucleic acid sequence adjacent to a PAM/PFS, suitably immediately adjacent to a PAM/PFS. Suitably the target nucleic acid sequence may be any region of a nucleic acid sequence which is downstream of a PAM, or upstream of a PFS. Suitably the target nucleic acid sequence may be any region of a nucleic acid sequence at the 3’ end of a PAM, or at the 5’ end of a PFS. Suitably the target nucleic acid sequence is located immediately adjacent to the 3’ end of a PAM (protospacer adjacent motif) or is located immediately adjacent to the 5’ end of a PFS (protospacer flanking sequence) (e.g., 5’-PAM-Protospacer-3’ or 3’-PFS-Protospacer-5’). Suitably therefore the target nucleic acid sequence may also be known as a protospacer sequence. Advantageously the PAM/PFS for type I-D CRISPR systems exists at a high frequency in higher organisms, therefore many targets compared to conventional CRISPR/Cas systems. Suitably the PAM is selected from GTN. Suitably the PAM comprises a G in the first position and T in the second position. In one example, the guide RNA targets a double stranded-specific protospacer adjacent motif. Suitably the double stranded-specific protospacer adjacent motif is GTN, such as GTC, GTT, GTA, GTG. Suitably the PFS is AAC or ACG . Suitably the PFS does not comprise a G in the first position. In one example, the guide RNA targets an single stranded-specific protospacer flanking sequence. Suitably the single stranded-specific protospacer flanking sequence is AAC. Suitably, the target nucleic acid sequence may be located in intragenic regions, intergenic regions, a coding region, a non-coding region or a regulatory region of a target nucleic acid sequence. Suitably in some examples, the target nucleic acid sequence may be chosen so as to target only single-stranded nucleic acids such as RNA or double-stranded nucleic acid such as DNA. Suitable target nucleic acid sequences present only in single stranded nucleic acids may be mature RNA splice junctions, polyA regions for example. Suitable target nucleic acid sequences present only in double stranded nucleic acids may be non-coding regions, transcriptional regulatory sequences such as promoters, for example. Suitably the chosen target nucleic acid sequence, such as a regulatory sequence, is present only in a double-stranded nucleic acid sequence, in methods directed towards double-stranded nucleic acid sequences. Suitably the chosen target nucleic acid sequence, such as a regulatory sequence, is present only in a single-stranded nucleic acid sequence, in methods directed towards single-stranded nucleic acid sequences. Suitably the target nucleic acid sequence may be located in a target gene, which can be in the upper (sense, coding) strand or in the bottom (antisense, non-coding) strand. Suitably the target gene may be one in which it is desired to decrease or inhibit expression thereof. Suitably the target gene may therefore be a gene which when expressed causes a detrimental effect. Suitably the target gene may be a gene which causes or contributes to a disease or physiological condition. Suitably, a target gene may encode a transcription factor or regulatory element. In some examples, a target gene may encode non-coding RNA, including, but not limited to, tRNA, rRNA, sRNA, miRNA, siRNA, piRNA (piwi-interacting RNA) and lncRNA (long non-coding RNA). In some examples, a target nucleic acid sequence may be located in an intergenic region, optionally in the upper (plus) strand or in the bottom (minus) strand. In some examples where both double-stranded and single-stranded nucleic acid sequences are targeted, suitably the target nucleic acid sequence may encode the same target, suitably the same target gene. Suitably therefore the same gene may be targeted at both the transcriptional and translational level. Suitably a target gene may be located in a sequence in vivo, ex vivo or in vitro. Suitably a target gene may be located within a target organism. Suitably a target organism may be a prokaryote or a eukaryote. Suitably the target organism is a bacterium, a virus, an archaeon, a fungus, plant, or an animal. Methods relating to Double-stranded Nucleic Acid Sequences The present invention relates to the finding that type I-D CRISPR Cas system can be directed to either double-stranded nucleic acids or single-stranded nucleic acids exclusively, by tailoring the guide RNA or by modifying certain Cas components of the system. Suitable guide RNAs and modified Cas proteins for such purposes have been described above. Suitably in any of the methods relating to double-stranded nucleic acid sequences, one or more of the following features of the type I-D CRISPR complex is present. Suitably in the methods comprising targeting double-stranded nucleic acid sequences, the methods comprising inhibiting expression of double-stranded nucleic acid sequences, the methods comprising modifying double- stranded nucleic acid sequences, the methods comprising detecting or tracking double-stranded nucleic acid sequences, one or more of one or more of the following features of the type I-D CRISPR complex is present. Suitably the following features cause the type I-D CRISPR Cas system to specifically target double-stranded nucleic acid sequences, suitably to exclusively target double-stranded nucleic acid sequences. Suitably the following features cause the type I-D CRISPR Cas system not to target single- stranded nucleic acid sequences. Suitably Cas5d, Cas6d, Cas7d, Cas10d, and Cas11d proteins are present in the type I-D CRISPR complex for double-stranded methods. Suitably for methods where cleavage of the target double- stranded nucleic acid is not desired, the Cas10d protein is a nuclease deficient Cas10d protein as described elsewhere herein. Suitably for the system to target double stranded nucleic acid sequences, (i) the Cas5d protein is modified, and/or (ii) the guide RNA targets a target double stranded nucleic acid sequence adjacent to a double stranded-specific protospacer adjacent motif, such that the complex does not bind to single-stranded nucleic acids. In one example, the Cas5d protein is modified. Suitably it is modified to disrupt the interaction of Cas5d with the protospacer flanking sequence such that the complex does not bind single-stranded nucleic acids. Suitably it is modified by mutation at position Q110 of SEQ ID NO:6 or a position corresponding thereto. Further possible modifications of the Cas5d protein are described above. In one example, the guide RNA targets a target double stranded nucleic acid sequence adjacent to double stranded-specific protospacer adjacent motif. Suitably the double stranded-specific protospacer adjacent motif is GTC. Further details of the double-stranded specific guide RNA are described above. Suitably any combination of the features of (i) and (ii) are present in the methods relating to double-stranded nucleic acid sequences. Suitably (i) and (ii) may be present. Suitably only (i) may be present. Suitably only (ii) may be present. Suitably in methods relating to both double-stranded nucleic acid sequences and single- stranded nucleic acid sequences, any of these features may be present alone or in combination. Methods relating to Single-stranded Nucleic Acid Sequences The present invention relates to the finding that type I-D CRISPR Cas system can be directed to either double-stranded nucleic acids or single-stranded nucleic acids exclusively, by tailoring the guide RNA or by modifying certain Cas components of the system. Suitable guide RNAs and modified Cas proteins for such purposes have been described above. Suitably in any of the methods relating to single-stranded nucleic acid sequences, one or more of the following features of the type I-D CRISPR complex is present Suitably in the methods comprising targeting single-stranded nucleic acid sequences, the methods comprising inhibiting expression of single-stranded nucleic acid sequences, the methods comprising modifying single-stranded nucleic acid sequences, the methods comprising detecting or tracking single-stranded nucleic acid sequences, one or more of one or more of the following features of the type I-D CRISPR complex is present. Suitably the following features cause the type I-D CRISPR Cas system to specifically target single-stranded nucleic acid sequences, suitably to exclusively target single-stranded nucleic acid sequences. Suitably the following features cause the type I-D CRISPR Cas system not to target double-stranded nucleic acid sequences. Suitably Cas5d, Cas6d, Cas7d, Cas10d, and optionally Cas11d proteins are present in the type I-D CRISPR complex for single-stranded methods. Suitably for methods where cleavage of the target single-stranded nucleic acid is not desired, the Cas7d protein is a nuclease deficient Cas7d protein as described elsewhere herein. Suitably for the system to target single stranded nucleic acid sequences, (i) the Cas10d protein is modified, (ii) Cas11d is not present, and/or (iii) the guide RNA targets a target single stranded nucleic acid sequence adjacent to an single stranded-specific protospacer flanking sequence, such that the complex does not bind to double-stranded nucleic acids. In one example, the Cas10d protein is modified. Suitably it is modified to disrupt the interaction of Cas10d with the protospacer adjacent motif such that the complex does not bind double-stranded nucleic acids. Suitably by mutation at position K326 of SEQ ID NO:2 or a position corresponding thereto. Further possible modifications of the Cas10d protein are described above. Optionally, the Cas5d protein may also be modified, suitably in a different manner to that required for double stranded targeting, as explained elsewhere hereinabove. Suitably for targeting single stranded nucleic acids, the Cas5d protein may be modified by mutation at position K114 in SEQ ID NO:6 or a corresponding position thereto. In one example, the Cas11d protein is not present. In one example, the nucleic acid sequence encoding Cas10d and Cas11d is modified such that the Cas11d protein is not expressed. In one example, the nucleic acid sequence encoding Cas10d and Cas11d is modified in the coding region of Cas11d. In one example, nucleic acid sequence encoding Cas10d and Cas11d is modified in the start codon or in the ribosomal binding site of the coding region of Cas11d. Possible modifications are described hereinabove. In one example, the guide RNA targets a target single stranded nucleic acid sequence adjacent to an single stranded-specific protospacer flanking sequence. Suitably the single stranded-specific protospacer flanking sequence is AAC or ACG. Further details of the singe stranded specific guide RNA are described above. Suitably any combination of the features of (i), (ii) and (iii) are present in the methods relating to single-stranded nucleic acid sequences. Suitably (i) and (ii) may be present. Suitably (i) and (iii) may be present. Suitably (ii) and (iii) may be present. Suitably (i), (ii) and (iii) may be present. Suitably (i) may be present. Suitably (ii) may be present. Suitably (iii) may be present. Suitably in any methods where feature (ii) is not being used, then the type I-D CRISPR complex may comprise Cas11d proteins. Suitably in methods relating to both double-stranded nucleic acid sequences and single- stranded nucleic acid sequences, any of these features may be present alone or in combination. Contacting The methods of the invention comprise contacting the target sequence with a type I-D CRISPR Cas complex. Suitably the step of contacting may comprise contacting the target sequence with the complex in vitro, in vivo, or in a cell in vitro/ex vivo. As used herein, “contact,” contacting,” “contacted,” and grammatical variations thereof, refers to placing the components of a desired reaction together under conditions suitable for carrying out the desired reaction. The methods and conditions for carrying out such reactions are well known in the art (See, e.g., Gasiunas et al. (2012) Proc. Natl. Acad. Sci. 109:E2579-E2586; M.R. Green and J. Sambrook (2012) Molecular Cloning: A Laboratory Manual. 4th Ed., Cold Spring Harbor Laboratory Press, Cold Spring Harbor, NY). Suitably the methods may be performed in a cell-free system in vitro. Alternatively the methods may be performed in a cell, in vitro, ex vivo, or in vivo. Suitably when the methods are performed in a cell, the method comprises introducing the type I-D complex into the cell. Suitably introducing the Cas proteins and the guide RNA into the cell. Suitably, the Cas proteins may be introduced into the cell as one or more proteins, or as one or more nucleic acids encoding the Cas proteins, suitably which may be DNA. Suitably the guide RNA may be introduced into the cell as one or more nucleic acids encoding the guide RNA, suitably which may be RNA or DNA. In some examples, for example, the Cas proteins can be introduced as a DNA sequence encoding the Cas proteins upon a vector, or as a protein, whereas the guide RNA can be introduced either as a DNA sequence encoding the guide RNA upon a vector, or as an in vitro transcript. Suitably the Cas proteins or one or more nucleic acids encoding them, or the guide RNA or one or more nucleic acids encoding it may be introduced into the cell simultaneously, separately, or sequentially. Alternatively, the Cas proteins and guide RNA may be contacted to form a complex in vitro which complex may then be introduced into the cell. Suitably the one or more nucleic acids may be comprised on one or more vectors as described below. In some examples, the one or more nucleic acids of the invention may be stably or transiently introduced into a cell. Introducing,” “introduce,” “introduced” (and grammatical variations thereof) in the context of a nucleic acid or protein and a cell means presenting the nucleic acid sequence or protein of interest to the cell (e.g., host cell) in such a manner that the nucleic acid sequence or protein gains access to the interior of a cell and includes such terms as “conjugation”, “transformation,” “transfection,” and/or “transduction.” The terms “conjugation”, “transformation,” “transfection,” and “transduction” as used herein refer to the introduction of a heterologous nucleic acid or protein into a cell. Such introduction into a cell may be stable or transient. Thus, in some examples, a host cell or host organism is stably transformed with the nucleic acids. In other examples, a host cell or host organism is transiently transformed with the nucleic acids. As used herein, the term “stably introduced” means that the nucleic acid sequence is stably incorporated into the genome of the cell, and thus the cell is stably transformed with the polynucleotide. When a nucleic acid is stably transformed and therefore integrated into a cell, the integrated nucleic acid is capable of being inherited by the progeny thereof, more particularly, by the progeny of multiple successive generations. “Transient transformation” in the context of a nucleic acid sequence means that a polynucleotide is introduced into the cell and does not integrate into the genome of the cell. Suitably introducing the one or more nucleic acids into the cell may be by transformation or transduction. Suitably the one or more nucleic acid sequences can be introduced into a cell in a single transformation event, in separate transformation events. Suitably methods of transfection or transformation may include calcium-phosphate mediated, electroporation, liposome mediated, exosome mediated, gene gun, microinjection, agrobacterium mediated transfection or transformation, for example. Suitable methods for carrying out such transfection will be known to a person skilled in the art, and are further described below. For comprehensive reviews about procedures for getting proteins or nucleic acids into cells the context of this invention, see Marschall ALJ, Frenzel A, Schirrmann T, et al. “Targeting antibodies to the cytoplasm” mAbs. (2011) 3:3–16; Gu Z, Biswas A, Zhao M, Tang Y “Tailoring nanocarriers for intracellular protein delivery” Chem. Soc. Rev. (2011) 40:3638 – 3655. Du J, Jin J, Yan M, Lu Y “Synthetic nanocarriers for intracellular protein delivery” Curr. Drug Metab. (2012) 13:82–92. Various physical methods of disrupting the cell membrane are useful, such as microinjection and electroporation (see Zhang Y, Yu L-C. “Microinjection as a tool of mechanical delivery” Curr. Opin. Biotechnol. (2008) 19:506–510) have been proposed for delivering compounds ranging from small molecules to proteins. Sharei A, Zoldan J, Adamo A, et al. “A vector-free microfluidic platform for intracellular delivery” Proc. Natl. Acad. Sci. (2013) 110: 2082 – 2087 describes a microfluidic device that transiently disrupts the plasma membrane through physical constriction. Silicon “nanowires” that pierce the cell membrane have also been reported Shalek AK, Robinson JT, Karp ES, et al. “Vertical silicon nanowires as a universal platform for delivering biomolecules into living cells” Proc. Natl. Acad. Sci. (2010) 107:1870–1875. There are also peptide-based strategies using cell penetrating peptides (CPP) which can enhance permeability of the nucleic acids or proteins. For example the TAT peptide can be covalently coupled. Also, an amphiphilic CPP Pep-1 can noncovalently complex and translocate peptide and protein cargos Morris MC, Depollier J, Mery J, et al. “A peptide carrier for the delivery of biologically active proteins into mammalian cells” Nat. Biotechnol. (2001) 19: 1173–1176. Lipofection is described in e.g., U.S. Pat. Nos. 5,049,386, 4,946,787; and 4,897,355) and lipofection reagents are sold commercially (e.g., Transfectam ^TM and Lipofectin ^TM ). Cationic and neutral lipids that are suitable for efficient receptor-recognition lipofection of polynucleotides include those of Felgner, WO 91/17424; WO 91/16024. There is also for example substance P (SP), an 11-residue neuropeptide which can be conjugated to the nucleic acids or proteins (Harford-Wright E, Lewis KM, Vink R, Ghabriel MN. “Evaluating the role of substance P in the growth of brain tumors” Neuroscience (2014) 261: 85–94. There are also various pore- or channel-forming proteins of bacterial origin which may be used to translocate nucleic acids or proteins into cells. Chatterjee S, Chaudhury S, McShan AC, et al. “Structure and biophysics of type III secretion in bacteria. Biochemistry (Mosc)” (2013) 52: 2508–2517 teaches a sophisticated secretion system which transport proteins directly from the bacterial cytoplasm to the eukaryotic host. Doerner JF, Febvay S, Clapham DE. “Controlled delivery of bioactive molecules into live cells using the bacterial mechanosensitive channel MscL” Nat. Commun. (2012) 3: 990 describes functional expression of an engineered bacterial channel (MscL) in mammalian cells, the opening and closing of which could be controlled chemically. Alternatively, the cholesterol-dependent cytolysin (CDC) family of pore-forming toxins, which are capable of forming macropores up to 30nm in diameter may be useful as “reversible permeabilization” reagents for delivering nucleic acids or proteins into cells. (See Dunstone MA, Tweten RK. “Packing a punch: the mechanism of pore formation by cholesterol dependent cytolysins and membrane attack complex/perforin-like proteins” Curr. Opin. Struct. Biol. (2012) 22: 342–349; Provoda CJ, Stier EM, Lee K-D. “Tumor cell killing enabled by listeriolysin O- liposome-mediated delivery of the protein toxin gelonin.” J. Biol. Chem. (2003) 278: 35102–35108; and Pirie CM, Liu DV, Wittrup KD. “Targeted cytolysins synergistically potentiate cytoplasmic delivery of gelonin immunotoxin” Mol. Cancer Ther. (2013) 12: 1774–1782. In addition to pore- or channel-forming proteins, the membrane-translocating domains of bacterial toxins have been proposed as a modular tool that can be fused to, and enhance the intracellular delivery of, other proteins (see Sandvig K, van Deurs B. “Membrane traffic exploited by protein toxins” Annu. Rev. Cell. Dev. Biol. (2002) 18: 1–24; Johannes L, Römer W. “Shiga toxins — from cell biology to biomedical applications” Nat. Rev. Microbiol. (2010) 8: 105–116. Additionally, Lawrence MS, Phillips KJ, Liu DR. “Supercharging proteins can impart unusual resilience” J. Am. Chem. Soc. (2007) 129: 10110–10112 provides “supercharged” GFP, a variant engineered to have high net positive charge (+36), and certain human proteins with naturally high positive charge (see Cronican JJ, Thompson DB, Beier KT, et al. “Potent delivery of functional proteins into mammalian cells in vitro and in vivo using a supercharged protein” ACS Chem. Biol. (2010) 5: 747–752; or Cronican JJ, Beier KT, Davis TN, et al. “A class of human proteins that deliver functional proteins into mammalian cells in vitro and in vivo” Chem. Biol. (2011) 18: 833–838 have been reported to translocate across the cell membrane. There are also virus-based strategies for packaging of the proteins or nucleic acids into virus-like particles (see Kaczmarczyk SJ, Sitaraman K, Young HA, et al. Protein delivery using engineered virus- like particles. Proc. Natl. Acad. Sci. (2011) 108: 16998–17003) or attaching them to an engineered bacteriophage T4 head (see Tao P, Mahalingam M, Marasa BS, et al. “In vitro and in vivo delivery of genes and proteins using the bacteriophage T4 DNA packaging machine” Proc. Natl. Acad. Sci. (2013) 110: 5846–5851) has been reported to enhance cytosolic delivery. Further, there are lipid and polymer-based strategies. The proteins or nucleic acids of the invention may be encapsulated in liposomes (see Torchilin V. Intracellular delivery of protein and peptide therapeutics. Drug Discov Today Technol. (2008) 5:e95–e103) or complexed with lipids. Regarding the latter strategy, lipid formulations that have been successful in the transfection of DNA may be used. For example, a formulation based on a mixture of cationic and neutral lipids. Similarly, polymer-based formulations that have been successfully used for nucleic acid transfections have also been examined for their ability to “transfect” proteins. For example, polyethylenimine (PEI) or poly-β-amino esters (PBAEs) which may be in the form of biodegradable nanoparticles. Also inorganic material-based strategies may be used; for example including silica, carbon nanotubes, quantum dots, or gold nanoparticles. Another method is available which is induced transduction by osmocytosis and propanebetaine ((iTOP) (see D’Astolfo, D. S. et al. Efficient intracellular delivery of native proteins. Cell 161, 674–690 (2015). This method allows efficient delivery of CRISPR–Cas complexes into a wide variety of primary cell types. The iTOP approach enables virus-free transduction of native proteins and does not rely on additional peptide tags, which may interfere with protein function or editing efficiency and is particularly effective for transduction of cell types that are refractory to other delivery methods. For more information see Wen Y. Wu (2018) Nature Chem Biol. 14: 642-651. In one example, one or more nucleic acids encoding Cas proteins may be introduced into the cell by conjugation. In one example, conjugation is carried out by transer of genetic material from one bacterium to another through direct contact. Suitably therefore a donor bacterium is prepared comprising the one or more nucleic acids encoding Cas proteins and comprising a nucleic acid sequence encoding an F-factor. Suitably the donor bacterium delivers the one or more nucleic acids encoding Cas proteins to other cells, suitably other bacterial cells. Such conjugation techniques are described in Woodall C.A. (2003) DNA Transfer by Bacterial Conjugation. In: Casali N., Preston A. (eds) E. coli Plasmid Vectors. Methods in Molecular Biology, vol 235. Humana Press. https://doi.org/10.1385/1- 59259-409-3:61, for example. Targeting/Binding Some methods of the invention relate to targeting a target nucleic acid sequence using the type I-D CRISPR Cas system. Upon contacting the target nucleic acid sequence with the type I-D complex, the system is cultured or incubated under suitable conditions for targeting to occur at the target sequence. Suitably therefore the methods may comprise step of culturing or incubating the complex and the target nucleic acid sequence. Suitably if contacting occurs in a cell free system, then the complex and the target nucleic acid sequence are cultured or incubated under suitable cell free conditions for targeting to occur at the target sequence. Suitable cell free culture techniques are known to the skilled person. For example, using the conditions defined in commercial cell-free kits available from myTXTL, Arbor Biosciences, or PUREsystem. Suitably if contacting occurs within a cell, then after introduction of the complex and the target nucleic acid sequence into the cell, the cell is cultured under suitable conditions for targeting to occur at the target sequence. Suitably the culture conditions are determined by the skilled person according to the type of cell and species of cell which harbours the complex. Suitable cell culture techniques are known to the skilled person. For example, suitable mammalian cell culture conditions may be found in Phelan, K. and May, K.M. 2017. Mammalian cell tissue culture techniques. Current Protocols in Molecular Biology, 117, A.3F.1–A.3F.23. doi: 10.1002/cpmb.31 Suitably targeting as used herein may comprise binding. Suitably therefore the methods of targeting may be methods of binding. Suitably therefore the complex binds to the target nucleic acid sequence. Suitably in the methods of targeting described herein, only the Cas proteins required for target recognition are required, suitably only Cas10d, Cas5d, Cas6d and Cas7d are required although other Cas proteins may be present. Suitably in these methods, the complex may comprise active nuclease domains Cas10d and/or Cas7d, or may comprise nuclease deficient Cas10d and/or Cas7d. Preferably in the methods of targeting or binding, the complex comprises nuclease deficient Cas10d and/or Cas7d. Nuclease deficient Cas10d and/or Cas7d are described elsewhere herein. In some examples of said methods, the complex may further comprise a functional protein. Suitably the functional protein may be operable to perform a function at the target nucleic acid sequence. Suitably the functional protein may be covalently attached to one or more of the Cas proteins. Suitably the functional protein may be fused to one of the Cas proteins, which may otherwise be known as a chimeric protein. Suitably therefore there is provided a fusion protein comprising a Cas protein and a functional protein. Suitably the complex of the invention may comprise said fusion protein, one or more further Cas proteins, and a guide RNA. Suitably the guide RNA and the Cas proteins may target the functional protein to a target nucleic acid sequence. Suitably the functional protein may then exert an action on the target nucleic acid sequence. Suitably an action which is additional to the inhibition of expression or modification possible with the Type I-D complex alone. Suitably the functional protein is an enzyme. Suitably the functional protein may be a restriction enzyme, methylase, demethylase, polymerase, acetylase, de-acetylase, base editor. Suitably the functional protein may be a histone methylase, histone demethylase, histone acetylase, or histone de- acetylase. Suitably therefore the functional protein may modify the epigenetic status of the target nucleic acid sequence. Suitably the functional protein may be a visual agent such as a detection agent or tracking agent as described further elsewhere herein. Suitably the functional protein may be a flourescent protein or a part of a flourescent protein which may be operable to associate with another part of a flourescent protein to form a whole flourescent protein, otherwise known as a split fluorescent protein. Suitably therefore the functional protein may label the target nucleic acid sequence. Suitably the functional protein may be a transcription factor or a module thereof. Suitably the functional protein may be a transcriptional activator or repressor. Suitably therefore the functional protein may activate or repress expression of the target nucleic acid sequence. Suitably therefore, the methods of targeting a target nucleic acid sequence may be methods of targeting target nucleic acid sequences for alteration by a functional protein. Suitably methods of altering a target nucleic acid sequence. Suitably by epigenetic alternation, alteration of expression, or labelling of the target nucleic acid sequence. Suitably in such methods, the target nucleic acid sequence is contacted with (a) Cas5d, Cas6d, Cas7d, Cas10d and Cas11d proteins; (b) a functional protein, which may be fused to one of the Cas proteins; (c) a guide RNA complementary to the target double and/or single-stranded nucleic acid sequence. Suitably the system is then cultured or incubated under suitable conditions for targeting to occur at the target sequence and for the functional protein to exert an action on the target nucleic acid sequence. Suitably therefore the methods may comprise step of culturing or incubating the complex comprising the functional protein and the target nucleic acid sequence. Suitably if contacting occurs in a cell free system, then the complex comprising the functional protein and the target nucleic acid sequence are cultured or incubated under suitable cell free conditions for targeting to occur at the target sequence and for the functional protein to exert an action on the target nucleic acid sequence. Suitable cell free culture techniques are known to the skilled person. Suitably if contacting occurs within a cell, then after introduction of the complex comprising the functional protein and the target nucleic acid sequence into the cell, the cell is cultured under suitable conditions for targeting to occur at the target sequence, and for the functional protein to exert an action on the target nucleic acid sequence. Suitably the culture conditions are determined by the skilled person according to the type of cell and species of cell which harbours the complex. Suitable cell culture techniques are known to the skilled person. Inhibiting Expression Some methods of the present invention relate to inhibiting expression of a target nucleic acid sequence using the type I-D CRISPR Cas system. This may sometimes be otherwise referred to as ‘CRISPRi’. By inhibiting expression it is meant that expression of the target nucleic acid sequence is suppressed. Suitably transcription and/or translation of the target nucleic acid sequence is suppressed. Suitably suppression or inhibition means that the expression of the target nucleic acid sequence is reduced compared to the typical expression of the target nucleic acid sequence without suppression, for example as compared to the typical expression of the target nucleic acid sequence in a wild type cell or organism. Suitably if the method is a method of inhibiting expression of a double-stranded sequence then it may be a method of inhibiting transcription of a target sequence. Suitably if the method is a method of inhibiting expression of a single-stranded sequence then it may be a method of inhibiting translation of a target sequence. Suitably if the method is a method of inhibiting expression of a double-stranded sequence and a single-stranded sequence, then it may be a method of inhibiting both transcription and translation of a target sequence. Upon contacting the target nucleic acid sequence with the complex, the system is cultured or incubated under suitable conditions for inhibition to occur at the target sequence. Suitably if contacting occurs in a cell free system, then the complex and the target nucleic acid sequence are cultured or incubated under suitable cell free conditions for inhibition of expression to occur at the target sequence. Suitable cell free culture techniques are known to the skilled person. Suitably if contacting occurs within a cell, then after introduction of the complex and the target nucleic acid sequence into the cell, the cell is cultured under suitable conditions for inhibition of expression to occur at the target sequence. Suitably the culture conditions are determined by the skilled person according to the type of cell and species of cell which harbours the complex. Suitable cell culture techniques are known to the skilled person as noted above. Suitably in such methods only the Cas proteins required for target recognition are required, suitably only Cas10d, Cas5d, Cas6d and Cas7d are required although other Cas proteins may be present. Suitably in such methods, the complex comprises nuclease deficient Cas proteins, suitably nuclease deficient Cas10d and/or Cas7d, such that binding still occurs at the target nucleic acid sequence but cleavage does not occur. In some examples, such methods may still comprise an active Cas7d protein which is capable of cleaving single stranded nucleic acid sequences, as explained above. Suitably in such methods, the target nucleic acid sequence may be located within the coding region of a gene sequence or a regulatory region of a gene sequence. Suitably the regulatory region is operably linked to a gene sequence. Suitably it is desired to inhibit expression of said gene sequence. Suitably this may be achieved by inhibiting expression of the gene sequence directly by targeting the gene sequence, or may be achieved by inhibiting expression of the gene sequence indirectly by targeting a regulatory region operably linked to the gene sequence. Suitably by binding to the target nucleic acid sequence, the complex inhibits expression of said nucleic acid sequence by blocking the transcription or translational machinery. Modifying Some methods of the present invention relate to modifying a target nucleic acid sequence using the type I-D CRISPR Cas system. Upon contacting the target nucleic acid sequence with the complex, the system is cultured or incubated under suitable conditions for modification to occur at the target sequence. Suitably if contacting occurs in a cell free system, then the complex and the target nucleic acid sequence are cultured or incubated under suitable cell free conditions for modification to occur at the target sequence. Suitable cell free culture techniques are known to the skilled person. Suitably if contacting occurs within a cell, then after introduction of the complex and the target nucleic acid sequence into the cell, the cell is cultured under suitable conditions for modification to occur at the target sequence. Suitably the culture conditions are determined by the skilled person according to the type of cell and species of cell which harbours the complex. Suitable cell culture techniques are known to the skilled person as noted above. Suitably the modification is cleavage, suitably cleavage of the target nucleic acid sequence. Suitably the cleavage may be double-stranded cleavage of a double-stranded nucleic acid sequence, or single-stranded cleavage of a double-stranded nucleic acid sequence (otherwise known as nicking), or single-stranded cleavage of a single-stranded nucleic acid sequence. Suitably in methods directed towards modification of a single stranded nucleic acid sequence, single strand cleavage takes place. Suitably carried out by Cas7d. Suitably in methods directed towards modification of a double stranded nucleic acid sequence, single or double strand cleavage may take place. Suitably carried out by Cas10d. Suitably, in the presence of a functional Cas3’ helicase, Cas10d may carry out double strand cleavage of a double stranded nucleic acid sequence. Suitably in the absence of a functional Cas3’ helicase, Cas10d may carry out single strand cleavage of a double stranded nucleic acid sequence. Suitably any method of modification described herein may comprise more than one type I-D CRISPR Cas system. Suitably in some examples a plurality of type I-D CRISPR Cas systems may be used in any one method, suitably in any one step of modification. Suitably each type I-D CRISPR Cas system may be targeted to a different target nucleic acid sequence. Suitably in some examples a pair of type I-D CRISPR Cas systems may be used. Suitably a pair of type I-D CRISPR-Cas systems each comprising active Cas10d proteins capable of cleaving a target double-stranded nucleic acid sequence may be used. Suitably each Cas10d protein is capable of cleaving a single strand of the target double- stranded nucleic acid sequence. Suitably therefore a first type I-D CRISPR Cas system cleaves a first strand of the target double stranded nucleic acid sequence, and a second type I-D CRISPR Cas system cleaves a second strand of the target double stranded nucleic acid sequence. Suitably in such methods, the Cas proteins required for target recognition and target cleavage are required, suitably Cas5d, Cas6d, Cas7d, and Cas10d,are required although other Cas proteins may be present. In methods relating to double stranded nuclec acid sequences, suitbaly Cas11d protein is also present. Suitably the guide RNA hybridises to the target nucleic acid sequence, and interacts with the complex of Cas proteins to target them to the correct target nucleic acid sequence. Then the cleavage domain of the complex, i.e. Cas10d or Cas7d, cleaves the target nucleic acid sequence at a cleavage site. In examples where the target nucleic acid is a single stranded nucleic acid sequence, after cleavage has occurred, expression of the cleaved single stranded nucleic acid sequence is inhibited. For example, translation of the RNA into a protein is inhibited. In examples where the target nucleic acid sequence is a double-stranded nucleic acid sequence, after cleavage has occurred, the cleaved nucleic acid sequence is repaired, and the target double- stranded nucleic acid sequence is modified at the cleavage site. For example, the DNA may contain a modification at the cleavage site which may inhibit or change transcription of the DNA into mRNA. Suitably the cleaved nucleic acid sequence is repaired by Non-Homologous End Joining (NHEJ) at the cleavage site. Suitably this is error-prone and introduces modifications into the target nucleic acid sequence. Suitably the modification may be a deletion, insertion, substitution or a combination thereof. Suitably the target nucleic acid sequence may therefore be modified by a deletion, insertion, substitution or a combination thereof, suitably at the cleavage site. Suitably in the methods of modifying of the invention, a donor nucleic acid sequence may also be provided. In the case of a method in a cell, the donor nucleic acid is introduced into the cell together with the Cas proteins and the guide RNA. The donor nucleic acid sequence suitably comprises a sequence which encodes a desirable gene. In addition it may comprise 5’ and 3’ end portions having high homology to the nucleic acid sequences upstream, and downstream of the target nucleic acid sequence. Suitably in this example, the donor nucleic acid sequence is integrated into the target nucleic acid sequence at the cleavage site. Suitably by homologous recombination repair (HDR). Suitably a desirable gene may be a wild type gene, optionally the wild type gene may be inserted to replace a defective gene which may be the cause of a disease or condition. Detecting/Tracking The present invention further relates to a method of detecting or tracking a target single- stranded nucleic acid and/or a target double-stranded nucleic acid in a sample. Suitably the method comprises a first step of contacting the sample with: a type I-D CRISPR complex, and a probe or an imaging agent. Suitably the type I-D CRISPR complex comprises the target recognition Cas proteins and a guide RNA. Suitably only Cas10d, Cas5d, Cas6d and Cas7d are required although other Cas proteins may be present. In methods relating to double stranded nucleic acid sequences, suitably Cas11d protein is also present. Suitably Cas5d, Cas6d, nuclease deficient Cas7d, nuclease deficient Cas10d, and Cas11d proteins may be present. Suitably the complex comprises nuclease deficient Cas proteins, suitably nuclease deficient Cas10d and/or Cas7d, such that binding still occurs at the target nucleic acid sequence but cleavage does not occur. Suitably the guide RNA may be complementary to a target sequence in the target double- stranded nucleic acid and/or complementary to a target sequence in the single-stranded nucleic acid. Suitably in methods where it is desired to detect or track a double-stranded nucleic acid, then the guide RNA is complementary to a target sequence in the target double-stranded nucleic acid. Suitably in methods where it is desired to detect or track a single-stranded nucleic acid, the guide RNA is complementary to a target sequence in the single-stranded nucleic acid. Suitably some methods may detect or track both types of nucleic acid, in which case both a guide RNA complementary to a target sequence in the target double-stranded nucleic acid and a guide RNA complementary to a target sequence in the single-stranded nucleic acid may be present. Alternatively, one guide RNA may be present which is complementary to a target sequence in the target double-stranded nucleic acid and complementary to a target sequence in the single-stranded nucleic acid, as explained hereinabove. Suitably the probe or imaging agent is linked to the type I-D CRISPR complex, suitably to a Cas protein of the type I-D CRISPR complex. Suitably the probe is bound to the type I-D CRISPR complex. In one example, the probe or imaging agent comprises one or more flourescent proteins. In one example, the probe or imaging agent may comprise a part of a flourescent protein which may be operable to associate with another part of a flourescent protein to form a whole flourescent protein, otherwise known as a split fluorescent protein. In one example, a first part of a split flourescent protein is linked to a Cas protein of a first type I-D CRISPR complex and a second part of a split flourescent protein is linked to a Cas protein of a second type I-D CRISPR complex. Suitably both complexes are targeted to adjacent target nucleic acid sequences by guide RNAs complementary to adjacent sequences on the target ncleic acid. Suitably once both complexes bind to the target nucleic acid sequence, the first and second parts of the flourescent protein associate together and fluoresce. Suitable examples of fluorescent proteins include GFP, RFP, YFP, CFP, or other well known derivatives thereof. Suitably the imaging agent is an example of a functional protein which is linked to a Cas protein of the CRISPR complex as described elsewhere herein. Suitably the guide RNA directs the Cas proteins to bind to the target nucleic acid sequence and thereby directs the linked imaging agent to the target nucleic acid sequence. Suitably the sample may be a biological sample. Suitably the sample may be a biological fluid such as blood, plasma, sputum, saliva, CSF and the like. Suitably therefore the method may be a method of detecting or tracking a nucleic acid sequence in a biological fluid. Suitably the sample may be a cell, or may be a cell lysate. Suitably the cell may be in vitro or may be within an organism in vivo. Suitably therefore the method may be a method of detecting or tracking a target nucleic acid sequence in a cell. Suitably the method further comprises a step of incubating the sample with the type I-D CRISPR complex for a suitable period of time to allow the CRISPR complex to bind to a target single- stranded nucleic acid and/or a target double-stranded nucleic acid in the sample. Suitably if incubating occurs in a cell free system, then the complex and the sample are incubated under suitable cell free conditions for binding to occur at the target nucleic acid sequence. Suitable cell free incubation techniques are known to the skilled person. Suitably if incubating occurs within a cell, then after introduction of the complex into the cell, the cell is incubated under suitable conditions for binding to occur at the target nucleic acid sequence. Suitably the incubation conditions are determined by the skilled person according to the type of cell and species of cell which harbours the complex. Suitable cell culture techniques are known to the skilled person. Preferably the method of detection is carried out in a cell free system. Preferably the method of tracking is carried out in a cell. Suitably the method of detection makes use of a probe which is bound to the type I-D CRISPR complex. Suitably the probe is a flourescent probe, which suitably comprises one or more flourescent molecules attached thereto. Suitably binding of the complex to a target nucleic acid sequence in a sample diplaces the bound probe from the complex. Suitably the displacement of the bound probe causes a change in fluorescence of the probe. Suitably this change in fluorescence is detected in step (c). Suitably step (c) may comprise determing or detecting a change in flourescence of the probe. In some arrangements of the probe, determining whether the probe can be detected comprises detecting the probe. In such arrangements, this may comprise determing an increase in flourescence from the probe. In some arrangements of the probe, determining whether the probe can be detected comprises not detecting the probe. In such arrangements, this may comprise determining a decrease in fluorescence from the probe. There are various suitable arrangements of the probe which may be used to detect displacement in favour of the complex binding to a target nucleic acid sequence. Suitably, the probe is a single stranded nucleic acid such as RNA or DNA. Suitably the probe comprises one or more of a fluorophore, quencher, donor or accepter linked thereto. In some examples, the probe comprises a fluorophore and a quencher; or a donor and acceptor linked thereto. Suitably in such an example, the probe comprises a fluorophore and a quencher linked to either end thereof. Alternatively, in such an example, the probe comprises a donor and acceptor linked to either end thereof. In some examples, the type I-D complex may also comprise a fluorescent agent, suitably the compex may comprise one of a fluorophore, quencher, donor or accepter linked thereto. In one example, the type I-D complex may comprise a fluorophore while the probe comprises a quencher or vice versa. In another example, the the type I-D complex may comprise a donor while the probe comprises an acceptor, or vice versa. Suitably when the fluorophore and quencher are in proximity to each other, no fluorescence is detected. Suitably when the fluorophore and quencher are separated, the fluorophore will fluoresce. Suitably when the donor and the accepter are in proximity to each other, fluoresence is detected. Suitably when the donor and acceptor are separated, fluorescence is not detected. Suitably the probe may comprise region of complementarity, suitably such that the probe forms a duplex. Suitably this occurs in examples where the probe comprises a fluorophore and a quencher linked to either end thereof, or where the probe comprises a donor and acceptor linked to either end thereof. Suitably therefore the probe retains the flurophore and quencher in proximity, or the donor and accepter in proximity. This state of the probe may be termed a ‘closed’ state. Suitably the probe is bound to the type I-D complex by way of the guide RNA. In one example, the guide RNA comprises a sequence which is complementary to the duplex-forming sequence of the probe. Suitably therefore the guide RNA binds to the complementary region of the probe and prevents it forming a duplex. Suitably therefore the probe is bound to the complex in an ‘open’ state. Suitably wherein the fluorophore and a quencher are separated or wherein the donor and acceptor are separated. Suitably upon contacting the complex with a target nucleic acid sequence, the guide RNA is displaced from the probe and instead binds to the target nucleic acid sequence. Suitably the displaced probe then forms a duplex, in the closed state. Suitably wherein the fluorophore and a quencher are in proximity or wherein the donor and acceptor are in proximity. Suitably in an example where the probe comprises a fluorophore and a quencher linked to either end, the detection step comprises detecting a decrease in fluorescence in the presence of a target nucleic acid sequence. Suitably in an example where the probe comprises a donor and acceptor linked to either end, the detection step comprises detecting an increase in fluorescence in the presence of a target nucleic acid sequence. In an example where the type I-D complex comprises one of a fluorophore, quencher, donor or accepter linked thereto, suitably where the type I-D complex may comprise a fluorophore while the probe comprises a quencher or vice versa, or where the type I-D complex may comprise a donor while the probe comprises an acceptor, or vice versa, suitably the guide RNA comprises a sequence which is complementary to the probe. Suitably therefore the guide RNA binds to the probe and brings the probe and the complex together such that the fluorophore is in proximity to the quencher, or the donor is in proximity to the acceptor. Suitably upon contacting the complex with a target nucleic acid sequence, the guide RNA is displaced from the probe and instead binds to the target nucleic acid sequence. Suitably the fluorophore and quencher are then separated or the donor and acceptor are then separated. Suitably in an example where the probe or type I-D complex each comprise one of a fluorophore and a quencher, the detection step comprises detecting an increase in fluorescence in the presence of a target nucleic acid sequence. Suitably in an example where the probe or type I-D complex each comprise one of a donor and acceptor, the detection step comprises detecting a decrease in fluorescence in the presence of a target nucleic acid sequence. Suitably the step of detection may be carried out by a method relevant for detection of the probe that has been used. For example, in cases where the probe comprises a flourescent protein then detection may be carried out by observing the sample, suitably observing the sample under a microscope or using a flourescent plate reader such as Varioskan Lux from ThermoFisher Scientific. Suitably, detecting the probe comprises observing fluorescence in the sample. Suitably, detecting the probe comprises observing fluorescence in the sample using a microscope, or using a flourescent plate reader such as Varioskan Lux from ThermoFisher Scientific. Suitably, not detecting the probe comprises observing an absence of fluorescence in the sample. Suitably, not detecting the probe comprises observing an absence of fluorescence in the sample using a microscope or using a flourescent plate reader such as Varioskan Lux from ThermoFisher Scientific. Suitably the final steps of the method of tracking comprise observing the imaging agent at a first time point, and then observing imaging agent at one or more further time points. Suitably observing the imaging agent may be carried out by a method relevant for observing the imaging agent that has been used. For example, in cases where the imaging agent is a flourescent protein then observing may be carried out by observing the sample under a microscope, or using a flourescent plate reader such as Varioskan Lux from ThermoFisher Scientific, at a first time point and at a further time point. Suitably observing whether the imaging agent is present may comprise observing a location of the imaging agent, suitably using a microscope or using a flourescent plate reader such as Varioskan Lux from ThermoFisher Scientific. Suitably observing a first location of the imaging agent at a first time point, suitably using a microscope or using a flourescent plate reader such as Varioskan Lux from ThermoFisher Scientific. Suitably the first time point may be an amount of time after the incubation step. Suitably the amount of time is suitable for binding of the complex to occur at the target nucleic acid sequence. Suitably the one or more further time points are after the first time point. Suitably the one or more further time points may comprise a second time point. Suitably the second time point may be 1 second, 2 seconds, 5 seconds, 10 seconds, 20 seconds, 30 seconds, 1 minute, 2 minutes, 5 minutes, 10 minutes, 20 minutes, 30 minutes, 1 hour, 2 hours, 5 hours, 10 hours, 24 hours, 48 hours, 72 hours after the first time point. Suitably further time points may comprise a third, fourth, fifth, sixth time point, etc. Suitably the length of time between each time point may be 1 second, 2 seconds, 5 seconds, 10 seconds, 20 seconds, 30 seconds, 1 minute, 2 minutes, 5 minutes, 10 minutes, 20 minutes, 30 minutes, 1 hour, 2 hours, 5 hours, 10 hours, 24 hours, 48 hours, 72 hours. Suitably the length of time between each time point is about equal. Suitably therefore, observing the imaging agent at one or more further time points may comprise observing a second location of the imaging agent at a second time point, and optionally a third location, fourth location, fifth location, sixth location at a third, fourth, fifth, sixth time point for example, suitably using a microscope or using a flourescent plate reader such as Varioskan Lux from ThermoFisher Scientific. Suitably the location of the imaging agent may change between the first time point and the one or more further time points. Suitably this indicates that the target nucleic acid sequence has moved between the first time point and the one or more further time points, suitably between a first location and a second location respectively. Suitably the location of the imaging agent may be, if the method is carried out within a cell, in the cytosol, within the cell membrane or cell wall, or within an organelle such as the nucleus, golgi, endoplasmic reticulum, mitochondria, lysosome, plastids, vacuole, etc. Suitably therefore the method of tracking may be used to observe movement of the target nucleic acid sequence, suitably between different parts of a cell, for example from the nucleus to the cytosol. Nucleic Acids Nucleic acid sequences encoding the type I-D complex used in the invention or the modified type I-D complexes are provided herein. These nucleic acid sequences may be provided for introduction into a cell in order to form the complex and in order to carry out the methods of the invention within a cell. Suitably the or each Cas protein may be introduced into the cell as a protein, or as one or more nucleic acids encoding the or each Cas protein, suitably which may be DNA. Suitably the or each guide RNA may be introduced into the cell as one or more nucleic acids encoding the or each guide RNA, suitably which may be RNA or DNA. Suitably more than one Cas protein may be encoded on one nucleic acid sequence. Suitably the nucleic acid sequences encoding each Cas protein are linked to each other, suitably in any order. Suitably by a sequence encoding a cleavable linker. Suitably by a sequence encoding a cleavable peptide. Suitably the cleavable linkers are between each nucleic acid sequence encoding each Cas protein. Suitably the guide RNA may also be encoded on the same nucleic acid. Alternatively each Cas protein may be encoded on a separate nucleic acid. Suitably the guide RNA may be encoded on a separate nucleic acid. One example of nucleic acids encoding a type I-D CRISPR Cas complex are those nucleic acids shown in SEQ ID Nos 1, 3, 5, 7, 9 and 11 which encode the Cas proteins from a wild type type I-D complex from Synechocystis sp. PCC 6803, and SEQ ID NO:21 which is an exemplary guide RNA sequence. Alternatively, the Type I-D CRISPR Cas complex may comprise one or more modified Cas proteins, suitably selected from modified Cas7d, modified Cas10d, modified Cas5d proteins, or modified Cas3’ as described elsewhere herein. Suitably the nucleic acid sequence encoding a nuclease deficient Cas7d is shown in SEQ ID NO:17. Suitably the nucleic acid sequence encoding a nuclease deficient Cas10d is shown in SEQ ID NO: 13. Suitably the nucleic acid sequence encoding a modified Cas10d is shown in SEQ ID NO:15. Suitably the nucleic acid sequence encoding a modified Cas5d is shown in SEQ ID NO:19 or SEQ ID NO:94. Suitably the nucleic acid encoding a modified Cas3’ is shown in SEQ ID NO:92. Suitably when methods are performed in a eukaryotic cell, the one or more nucleic acids encoding the Cas proteins further comprise nuclear localising sequences (NLS). Suitable nuclear localisation sequences are known in the art. Suitably the one or more nucleic acids may comprise two NLS. Suitably a first NLS at the 5’ end of each nucleic acid sequence and a second NLS at the 3’ end of each nucleic acid sequence. In some examples, the or each nucleic acid of the invention may be regarded as an “expression cassette” or may be comprised within an expression cassette. As used herein, “expression cassette” means a recombinant nucleic acid construct comprising a nucleic acid sequence of interest (e.g., the polynucleotides encoding Cas polypeptides, and/or guide RNAs of the invention), wherein said nucleic acid sequence of interest is operably linked with at least one regulatory sequence (e.g., a promoter). Thus, some aspects of the invention provide expression cassettes designed to express the nucleic acid sequences of the invention. Suitably comprised on a vector. Suitably any features of the vector described below may also be regarded as features of an expression cassette. Suitable regulatory sequences are defined hereinbelow. Vectors Generally, the term "vector" herein refers to a nucleic acid molecule capable of transporting another nucleic acid to which it has been linked. Vectors include, but are not limited to, nucleic acid molecules that are single-stranded, double-stranded, or partially double-stranded; nucleic acid molecules that comprise one or more free ends, no free ends (e.g., circular); nucleic acid molecules that comprise DNA, RNA, or both; and other varieties of polynucleotides known in the art. Suitably one or more vectors may comprise one or more of the nucleic acids described herein which encode one or more of the Cas proteins or modified Cas proteins. Suitably one or more vectors may comprise one or more nucleic acids described herein that encode the or each guide RNA. Suitably the same vector may comprise one or more of the nucleic acids described herein which encode one or more of the Cas proteins or modified Cas proteins and one or more nucleic acids described herein that encode the or each guide RNA. Suitably two or more of the nucleic acids encoding the Cas proteins are comprised on a single vector, suitably all of the nucleic acids encoding the Cas proteins are comprised on a single vector. Suitably when several nucleic acids encoding the Cas proteins are comprised on a single vector, they are linked to each other, suitably in any order. Suitably by sequence encoding cleavable linkers. Suitably by cleavable peptides as described above. Suitable cleavable linkers may comprise a 2A self- cleaving peptide, T2A, P2A, E2A, F2A, for example. Suitably the one or more nucleic acids encoding the Cas proteins and one or more nucleic acids encoding the or each guide RNA may be comprised on the same vector or comprised on separate vectors. Some vectors are able to direct expression of genes to which they are operatively-linked. Such vectors are "expression vectors" and there will usually be regulatory elements, which may be selected on the basis of the host cells in which the expression takes place. This means the nucleic acid to be expressed is operably linked to the regulatory elements thereby resulting in expression of the nucleotide sequence whether in an in vitro transcription/translation system or in a host cell when the vector is introduced into the host cell. Suitably the one or more vectors comprising nucleic acids encoding the Cas proteins and one or more nucleic acids encoding the guide RNA further comprise one or more regulatory sequences. Suitably the regulatory sequences are operably linked to the nucleic acids encoding the Cas proteins and to the nucleic acids encoding the or each guide RNA. Suitably therefore the vector or vectors may comprise an expression cassette as defined hereinabove. By “operably linked” or “operably associated” as used herein, it is meant that the indicated elements are functionally related to each other, and are also generally physically related. Thus, the term “operably linked” or “operably associated” as used herein, refers to nucleotide sequences on a single nucleic acid molecule that are functionally associated. Thus, a first nucleotide sequence that is operably linked to a second nucleotide sequence means a situation when the first nucleotide sequence is placed in a functional relationship with the second nucleotide sequence. For instance, a promoter is operably associated with a nucleotide sequence if the promoter effects the transcription or expression of said nucleotide sequence. Those skilled in the art will appreciate that the control sequences (e.g., promoter) need not be contiguous with the nucleotide sequence to which it is operably associated, as long as the control sequences function to direct the expression thereof. Thus, for example, intervening untranslated, yet transcribed, sequences can be present between a promoter and a nucleotide sequence, and the promoter can still be considered “operably linked” to the nucleotide sequence. Suitable regulatory sequences control expression of the nucleic acid sequence and may include promoters, enhancers, terminators, internal ribosomal entry sites (IRES), and other expression control elements (e.g., transcription termination signals, such as polyadenylation signals and poly-U sequences) UTRs, ITRs, introns etc. For more information the average skilled person would refer to, for example, in Goeddel, (1990), Gene Expression Technology in Methods in Enzymology vol 185, Academic Press. Regulatory elements include those giving direct constitutive expression in many types of host cell and those that direct expression of the nucleotide sequence only in certain cells (i.e., tissue-specific regulatory sequences). A tissue-specific promoter directs expression primarily in a desired tissue of interest, such as blood, specific organs (e.g., liver, pancreas), or particular cell types. Regulatory elements may also direct expression in a temporal-dependent manner, such as in a cell-cycle dependent or developmental stage-dependent manner, which may or may not also be tissue or cell-type specific. A promoter useful with this invention can include, but is not limited to, constitutive, inducible, developmentally regulated, tissue-specific/preferred- promoters, and the like, as described herein. A regulatory element as used herein can be endogenous or heterologous. In some examples, an endogenous regulatory element derived from the subject organism can be inserted into a genetic context in which it does not naturally occur (e.g., a different position in the genome than as found in nature), thereby producing a recombinant or non-native nucleic acid. In some examples, promoters useful with the nucleic acid sequences described herein may be any combination of heterologous and/or endogenous promoters. Examples of suitable promoters include pol I, pol II, pol III (e.g. U6 and H1 promoters). Examples of pol II promoters include, but are not limited to, retroviral Rous sarcoma virus (RSV) LTR promoter (optionally with the RSV enhancer), the cytomegalovirus (CMV) promoter (optionally with the CMV enhancer), the SV40 promoter, the dihydrofolate reductase promoter, the β-acting promoter, the phosphoglycerol kinase (PGK) promoter, and the EF1α promoter. Examples of other suitable promoters may be bacterial or phage promoters, such as those described in https://parts.igem.org/Promoters/Catalog. In one example, the promoter may be a Synechocystis promoter, such as the psbA2 promoter for the D1 subunit from Synechocystis. In another example, the promoter may be an E. coli σ70 constitutive promoter. In some examples, inducible promoters can be used. Examples of inducible promoters include, but are not limited to, tetracycline repressor system promoters, Lac repressor system promoters, arabinose-inducible, copper-inducible system promoters, salicylate-inducible system promoters (e.g., the PR1a system), glucocorticoid-inducible promoters, and ecdysone-inducible system promoters. In one example, the inducible promoter is araBAD arabinose inducible promoter. Suitably the one or more nucleic acids encoding the Cas proteins are operably linked to a promoter which is a pol II promoter. Suitably the one or more nucleic acids encoding the or each guide RNA are operably linked to a promoter which is a pol III e.g. U6 or H1 promoter. As well as promoters, regulatory elements may include enhancer elements, such as WPRE; CMV enhancers; the R-U5' segment in LTR of HTLV-I; SV40 enhancer; and the intron sequence between exons 2 and 3 of rabbit β-globin. Suitably some bacterial promoters may comprise binding sites for regulatory elements such as activators. It will be appreciated by those skilled in the art that the design of the expression vector can depend on such factors as the choice of the host cell to be transformed, the level of expression desired, etc. Suitably the vector may also optionally include a transcriptional and/or translational termination region (i.e., termination region) that is functional in the selected host cell. A variety of transcriptional terminators are available and are responsible for the termination of transcription beyond the heterologous nucleotide sequence of interest and correct mRNA polyadenylation. The termination region may be native to the transcriptional initiation region, may be native to the operably linked nucleic acid sequence, may be native to the host cell, or may be derived from another source (i.e., foreign or heterologous to the promoter, to the nucleic acid sequence, to the host, or any combination thereof). Suitably the vector may also include a nucleotide sequence for a selectable marker, which can be used to select a transformed host cell. As used herein, “selectable marker” means a nucleotide sequence that when expressed imparts a distinct phenotype to the host cell expressing the marker and thus allows such transformed cells to be distinguished from those that do not have the marker. Such a nucleotide sequence may encode either a selectable or screenable marker, depending on whether the marker confers a trait that can be selected for by chemical means, such as by using a selective agent (e.g., an antibiotic and the like), or on whether the marker is simply a trait that one can identify through observation or testing, such as by screening (e.g., fluorescence). Of course, many examples of suitable selectable markers are known in the art and can be used in the expression cassettes described herein. In some examples, a selectable marker useful with this invention includes polynucleotide encoding a polypeptide conferring resistance to an antibiotic. Non-limiting examples of antibiotics useful with this invention include ampicillin, kanamycin, streptomycin, spectinomycin, gentamicin, tetracycline, chloramphenicol, and/ or erythromycin. Thus, in some examples, a polynucleotide encoding a gene for resistance to an antibiotic may be introduced into the organism, thereby conferring resistance to the antibiotic to that organism. Non-limiting examples of general classes of vectors include but are not limited to a viral vector, a plasmid vector, a phage vector, a phagemid vector, a cosmid vector, a fosmid vector, a bacteriophage, an artificial chromosome, or an Agrobacterium binary vector in double or single-stranded linear or circular form which may or may not be self-transmissible or mobilizable. A vector as defined herein can transform a prokaryotic or eukaryotic host either by integration into the cellular genome or exist extrachromosomally (e.g. autonomous replicating plasmid with an origin of replication). Additionally included are shuttle vectors by which is meant a DNA vehicle capable, naturally or by design, of replication in two different host organisms, which may be selected from actinomycetes and related species, bacteria and eukaryotic (e.g. higher plant, mammalian, yeast or fungal cells). A plasmid may be vector in accordance with this description, which is a circular double-stranded DNA loop into which additional DNA segments can be inserted, such as by standard molecular cloning techniques. Another type of vector is a viral vector, wherein virally-derived DNA or RNA sequences are present in the vector for packaging into a virus (e.g., retroviruses, replication defective retroviruses, adenoviruses, replication defective adenoviruses, and adeno-associated viruses). Viral vectors also include polynucleotides carried by a virus for transfection into a host cell. Certain vectors are capable of autonomous replication in a host cell into which they are introduced (e.g., bacterial vectors having a bacterial origin of replication and episomal mammalian vectors). Other vectors (e.g., non-episomal mammalian vectors) are integrated into the genome of a host cell upon introduction into the host cell, and thereby are replicated along with the host genome. Suitably the vector used is a plasmid. Suitably the vector is selected which is suitable for the cell or organism into which vector is to be introduced. Suitably the plasmid is selected which is suitable for the cell or organism into which plasmid is to be introduced. Suitable plasmids for bacterial expression may include: pQE80L, pACYC-Duet, pSEVA series for example. Suitable plasmids for mammalian expression may include pcDNA3.1+. Suitably the or each vector is for introducing the Cas proteins and guide RNA into a cell such that the methods of the invention can take place within the cell. Suitably therefore the methods may comprise a step of introducing a vector comprising one or more nucleic acids encoding the Cas proteins or modified Cas proteins, and one or more nucleic acids encoding the guide RNAs into a cell, wherein the cell comprises the target nucleic acid sequence. Suitable means of introducing vectors into cells are the same as the means for introducing nucleic acids into cells as described hereinabove. For example, methods of non-viral delivery of nucleic acids may include lipofection, microinjection, biolistics, virosomes, liposomes, immunoliposomes, polycation or lipid:nucleic acid conjugates, naked DNA, artificial virions, conjugation, and agent-enhanced uptake of DNA. Suitably after introduction of the or each vector into the cell, the Cas proteins and the guide RNA are expressed in the cell. Suitably expression of the Cas proteins and the guide RNA may be induced, suitably induced from the or each vector. Suitably therefore the or each vector comprises an inducible promoter operably linked to the or each nucleic acid sequence encoding the Cas proteins and/or the guide RNA. Suitably the cell may be contacted with an inducer to induce said expression. Suitably the inducer may induce expression of the Cas proteins and/or the guide RNA from the or each vector. Suitably upon expression of the Cas proteins and the guide RNA, the components automatically assemble into the type I-D CRISPR-Cas complex of the invention. Cells The methods of the present invention may be carried out in a cell. Therefore there is provided a cell comprising a type I-D complex of the invention, or a modified type I-D complex of the invention, comprising a vector of the invention, or comprising a nucleic acid encoding any part of the type I-D complex of the invention. Suitably therefore the cell may be regarded as a host cell. Suitably the cell may be ex vivo, in vitro, or in vivo. Suitably the cell may be eukaryotic or prokaryotic. Suitably the cell my be from a bacterium, archaeon, plant, animal, insect, fungi. Suitably the cell is a cyanobacterial cell. Suitably the cell is an animal cell. Suitably the cell is a mammalian cell. Suitably the cell may be a human or a non-human cell. Suitably the cell may be a non-human mammalian cells. Suitably the cell may be a non-human primate cell. Suitably the cell may be part of an organism. Suitably the cell may be located within an organism. Suitably the organism may be a prokaryote or a eukaryote. Suitably the organism is a bacterium, a virus, an archaeon, a fungus, plant, or an animal. Suitably the organism may be a host organism. Thus, the invention includes any animal or cell, produced by the present methods, or a progeny thereof. The progeny may be a clone of the produced plant or animal or may result from sexual reproduction by crossing with other individuals of the same species to introgress further desirable traits into their offspring. Suitably the methods of the invention may not include methods of prevention or treatment of disease when performed on the human or animal body. The invention may however include the modification of cells or tissue obtained from a human or animal which is then modified ex vivo in accordance with methods of the invention. The modified tissue or cells may then be returned to the human or animal body, whether the same as from which the tissue or cells were removed, or different. In one aspect, the invention provides therapeutic methods for organisms (humans or animals), whereby a single cell or a population of cells is sampled or cultured from an organism, and then that cell or cells are modified ex vivo, as described by the methods herein, and re-introduced into the organism. Accordingly, the invention includes any type I-D CRISPR complex as described herein, for use as a medicament, for the prevention or treatment of human or animal disease. For example, where gene silencing is known or suspected to offer a mode of treatment for a particular human or animal disease, then the aspects of the present invention relating to inhibiting expression of a target nucleic acid may be used. Similarly, where changes to a nucleic acid sequence offer a mode of treatment for a particular human or animal disease, then again the aspects of the present invention relating to modification of a target nucleic acid may be used. FIGURES The invention will now be described by way of reference to the accompanying figures in which: Figure 1 shows: dsDNA binding. A, Schematic of I-D Cascade (grey box protein and interior sequence crRNA) binding to complementary target sequence of dsDNA. B. Gel shifts with increasing concentrations of I-D Cascade with dsDNA containing various PAMs: 5′-GTT-3′ -- perfect PAM 5′-CGT-3′ -- scrambled PAM 5′-AAC-3′ -- bases from CRISPR repeat NS is a non-specific probe. Figure 2 shows: ssRNA binding. A. Schematic of I-D Cascade binding to complementary target sequence of ssRNA. B. Gel shifts with increasing concentrations of I-D Cascade with ssRNA containing various PFSs: 5′-AAC-3′ -- complementary to GTT PAM 5′-ACG-3′ -- complementary to CGT PAM 5′-GUU-3′ -- complementary to repeat NS is a non-specific probe. Figure 3 shows: ssDNA binding. A. Schematic of I-D Cascade binding to complementary target sequence of ssDNA. B. Gel shifts with increasing concentrations of I-D Cascade with ssDNA containing various PFSs: 5′-AAC-3′ -- complementary to GTT PAM 5′-ACG-3′ -- complementary to CGT PAM 5′-GTT-3′ -- complementary to repeat NS is a non-specific probe. Figure 4 shows: deltaCas11d complex does not bind dsDNA. A) The cas10d gene, including the translational start site of Cas11d. Lines show The N-terminal peptides from MS analysis after trypsin and chymotrypsin digests are shown. B) Translation-reporter assay of cas11d RBS and start codon, with respective mutants. C) SDS-PAGE gel of purified wild-type type I-D Cascade (WT), deltaCas11d complex (ΔCas11d), and ΔCas11d co-expressed with a complementary cas11d-containing plasmid (+Cas11d). The asterisks indicate the mutated cas11d RBS and ATG within cas10d. ΔCas11d complex made from attenuation of cas11d internal translation initiation by mutations shown as RBS1-CTG in (B) and creates a M830L mutation to protein. Figure 5 shows: deltaCas11d complex binds ssDNA. Gel shift with increasing concentrations of either wild type or deltaCas11d type I-D Cascade with ssDNA. Figure 6 shows: PAM recognition by Cas10d.a, Residues responsible for stabilizing and recognizing PAM nucleotides. Residues shown were found to be within 3.5 Å of the phospho-diester backbone of the dsDNA target. b, Lysine 326 of Cas10d hydrogen bonds with target strand and non- target strand of the PAM. Figure 7 shows: PAM recognition by Cas5d. a, Residues responsible for stabilizing and recognizing PAM nucleotides. b, Glutamine 110 of Cas5d hydrogen bonds with A-1 of the target strand PAM. Figure 8 shows: I-D Cascade represses gene expression. Top, The crRNAs direct I-D Cascade to bind locations along the promoter and gene of ZsGreen, which encodes the green fluorescent protein. Lines represent crRNAs complementary to the non-template (NT) strand and template (T) strand, respectively. Circles within guides show the position of the PAM relative to the target DNA. The NT targets will also target the mRNA transcript. Bottom, ZsGreen fluorescence of cells expressing I-D Cascade targeted to locations in the reporter plasmid. Error bars show the mean and SEM of 6 biological replicates. NPAM control (control guide that did not target a PAM) was significantly different to all other groups. ns not significant; * P < 0.05, ** P < 0.005, **** P < 0.0001. Figure 9 shows: I-D Cascade repression of a gene operon. Gene operon containing for example ZsGreen and mCherry genes, which encode Green and Red fluorescent proteins, respectively. The single mRNA transcript is the template for translation of both proteins. I-D Cascade can be programmed to differentially turn off protein expression of genes in an operon. Figure 10 shows: I-D Cascade represses gene expression. Top, The crRNAs direct I-D Cascade to ZsGreen reporter. Lines represent crRNAs complementary to the non-template (NT) strand and template (T) strand, respectively. Both guides only have partial complementarity to DNA. Guide SJNT has full binding to mRNA and SJT will not bind mRNA. Bottom, ZsGreen fluorescence of cells expressing I-D Cascade targeted to locations in the reporter plasmid and transcript. Error bars show the mean and SEM of 6 biological replicates. NPAM control (control guide that did not target a PAM) was significantly different to all other groups. ns not significant; * P < 0.05. Figure 11 shows: I-D Cascade Cleavage. Top, ssDNA sequence and the first observed cleavage (dark) and expected (light). Left, initial cleavage result of ssDNA, M refers to markers. Middle, recent cleavage of ssDNA and RNA with wild-type and Cas7(E101A) mutant complexes. Figure 12 shows: Structure of I-D Cascade structure bound to RNA target (ribbon). The proposed cut site, base 34, is highlighted (dark grey). Cas7 residue E101 is in close proximity to base 34, and D119 is close to E101. Figure 13 shows: The ΔCas3′ type I-D CRISPRi complex represses transcription when targeted to either strand of DNA. Different crRNAs were used to direct the I-D CRISPRi complex to target different locations along the non-template strand (lines with squares) or template strand (lines with diamonds) of zsgreen DNA. The location of squares and diamonds represent the position of the PAM for each crRNA. RBS, ribosome binding site. The y-axis shows the level of ZsGreen fluorescence relative to a non- targeting control crRNA. Error bars depict the SEM of 6 replicates. Figure 14 shows: Proposed model of how the 3′ – 5′ of helicase activity of the Cas3 subunit (maroon) could enhance CRISPRi-mediated gene repression by colliding with RNA polymerase and preventing transcription. RBS, ribosome binding site. I-D Cascade proteins are Cas6d, Cas7d, Cas11d, Cas10d, Cas5d, Cas3′. Figure 15 shows: The addition of Cas3′ to the type I-D CRISPRi complex introduces strand- biased targeting that favoured the template strand of DNA at the promoter. Different crRNAs were used to direct the I-D CRISPRi complexes to target different locations along the non-template strand (lines with squares) or template strand (lines with diamonds) of zsgreen DNA. The location of squares and diamonds represent the position of the PAM for each crRNA. RBS, ribosome binding site. The y-axis shows the level of ZsGreen fluorescence relative to a non-targeting control crRNA. Error bars depict the SEM of 6 replicates. Experiment was conducted at 30°C. (A) Shows the CRISPRi activity of the ΔCas3′ complex. (B) Shows the CRISPRi activity of the +Cas3′ complex. Figure 16 shows: Type I-D CRISPRi (ΔCas3′) targeting of operonic genes. Different crRNAs were used to direct the I-D CRISPRi complex to target different locations along the non-template strand (lines with squares) or template strand (lines with diamonds) of DNA, and to mRNA (+ssRNA) transcripts (lines with circles). The lines with triangles represent negative control guides that target antisense to the mRNA. The location of the squares, diamonds, circles and triangles, represent the position of the PAM for each crRNA. (A) Shows the fold-change of ZsGreen fluorescence relative to a non-targeting control crRNA. (B) Shows the fold-change of mCherry2 fluorescence relative to the non-targeting crRNA. RBS, ribosome binding site. Error bars depict the SEM of 6 biological replicates. Experiment was conducted at 30°C. Figure 17 shows: Type I-D CRISPRi (+Cas3′) targeting of operonic genes at 30°C – Technical replicate #1. Different crRNAs were used to direct the I-D CRISPRi complex to target different locations along the non-template strand (lines with squares) or template strand (lines with diamonds) of DNA, and to mRNA (+ssRNA) transcripts (lines with circles). The lines with triangles represent negative control guides that target antisense to the mRNA. The location of the squares, diamonds, circles and triangles, represent the position of the PAM for each crRNA. (A) Shows the fold-change of ZsGreen fluorescence relative to a non-targeting control crRNA. (B) Shows the fold-change of mCherry2 fluorescence relative to the non-targeting crRNA. RBS, ribosome binding site. Error bars depict the SEM of 6 biological replicates. Figure 18 shows: Type I-D CRISPRi (+Cas3′) targeting of operonic genes at 30°C – Technical replicate #2. Different crRNAs were used to direct the I-D CRISPRi complex to target different locations along the non-template strand (lines with squares) or template strand (lines with diamonds) of DNA, and to mRNA (+ssRNA) transcripts (lines with circles). The lines with triangles represent negative control guides that target antisense to the mRNA. The location of the squares, diamonds, circles and triangles, represent the position of the PAM for each crRNA. (A) Shows the fold-change of ZsGreen fluorescence relative to a non-targeting control crRNA. (B) Shows the fold-change of mCherry2 fluorescence relative to the non-targeting crRNA. RBS, ribosome binding site. Error bars depict the SEM of 6 biological replicates. Figure 19 shows: Type I-D CRISPRi (+Cas3′) targeting of operonic genes at 37°C – Technical replicate #1. Different crRNAs were used to direct the I-D CRISPRi complex to target different locations along the non-template strand (lines with squares) or template strand (lines with diamonds) of DNA, and to mRNA (+ssRNA) transcripts (lines with circles). The lines with triangles represent negative control guides that target antisense to the mRNA. The location of the squares, diamonds, circles and triangles, represent the position of the PAM for each crRNA. (A) Shows the fold-change of ZsGreen fluorescence relative to a non-targeting control crRNA. (B) Shows the fold-change of mCherry2 fluorescence relative to the non-targeting crRNA. RBS, ribosome binding site. Error bars depict the SEM of 6 biological replicates. Figure 20 shows: Type I-D CRISPRi (+Cas3′) targeting of operonic genes at 37°C – Technical replicate #2. Different crRNAs were used to direct the I-D CRISPRi complex to target different locations along the non-template strand (lines with squares) or template strand (lines with diamonds) of DNA, and to mRNA (+ssRNA) transcripts (lines with circles). The lines with triangles represent negative control guides that target antisense to the mRNA. The location of the squares, diamonds, circles and triangles, represent the position of the PAM for each crRNA. (A) Shows the fold-change of ZsGreen fluorescence relative to a non-targeting control crRNA. (B) Shows the fold-change of mCherry2 fluorescence relative to the non-targeting crRNA. RBS, ribosome binding site. Error bars depict the SEM of 6 biological replicates. Figure 21 shows: Cas11 is required to optimal gene repression. Different crRNAs were used to direct the I-D CRISPRi complex lacking the Cas11 subunits to target different locations along the non- template strand (lines with squares) or template strand (lines with diamonds) of DNA, and to mRNA (+ssRNA) transcripts (lines with circles). The lines with triangles represent negative control guides that target antisense to the mRNA. The position of the squares, diamonds, circles and triangles, represent the position of the PAM for each crRNA. (A) Shows the fold-change of ZsGreen fluorescence relative to a non-targeting control crRNA. (B) Shows the fold-change of mCherry2 fluorescence relative to the non- targeting crRNA. RBS, ribosome binding site. Error bars depict the SEM of 6 biological replicates. Experiment was conducted at 30°C. Figure 22 shows: The heterologous, plasmid-based expression platform for I-D Cascade in an E. coli host. The spacer expression plasmid contains a CRISPR array with a spacer encoding the crRNA guide. The pCas expression plasmid encodes the I-D Cas proteins. The co-expression of pSpacer and pCas results in the assembly of I-D Cascade. Different spacers are used to target I-D Cascade to different sites along the fluorescent reporter gene zsgreen on the target plasmid. Figure 23 shows: Type I-D Cascade represses gene transcription in HEK293 cells. A Confocal images at 100x magnification of HEK293 cells transfected with a type I-D expression vector codon optimized for human cells (pPF3609). Transfected cells that show red fluorescent protein (RFP) fluorescence are indicated by arrows. B Flow cytometry data of HEK293 cells that have been co- transfected with a plasmid expressing Venus (pPF3328) and type I-D vectors with either a control spacer or spacers targeting the non-template strand (NTS) and template strand (TS) of the kozak (protein translation initiation site) and CDS (coding sequence) of Venus (yellow fluorescent protein). Data in (i) shows median fluorescent intensity (MFI) of Venus in RFP positive cells. Statistics were calculated using one-way ANOVA relative to MFI of Venus in cells transfected with a control spacer, stars represent a significant difference p<0.0001. MFI of Venus in RFP+ cells is then plotted as normalized repression in (ii), data is normalized to the mean MFI for the control spacer and plotted as a percentage. C Confocal images at 40x magnification of HEK293 cells co-transfected with a plasmid expressing Venus (pPF3328) and type I-D vector with a spacer for the TS of the CDS of Venus. Panel (i) shows total cell population, with cells stained with a Hoechst DNA stain; panel (ii) shows RFP positive cells, indicative of cells expressing type I-D Cascade, indicated by black arrows; panel (iii) shows Venus positive cells indicated by grey arrows. The circle indicated a co-transfected cell that expressed RFP and Venus. D Flow cytometry data for HEK293 cells transfected with a ^cas3 ^ vector (pPF3658) with a control spacer and spacers targeting the Kozak and CDS of venus is shown in (i), with MFI presented for Venus in the RFP+ cells. Data was analyzed using one-way ANOVA relative to the MFI of the control spacer, stars represent a significant difference with p<0.0001. MFI for each condition was then normalized to the average MFI found for the control spacer and is presented as a percentage of normalized repression in (ii). Figure 24 shows: Electrophoretic mobility shift assay of fluorescently labeled dsDNA or ssDNA (right) incubated with wild-type I-D Cascade (WT; top) or mutated complex containing Cas5 (Q110A) (bottom). The concentration of complex in dsDNA experiments ranged from 400 nM to 12.5 nM in two- fold increments, and in ssDNA experiments complex ranged from 200 nM to 6 nM in two-fold increments. Figure 25 shows: Gene editing in bacteria using nickase activity from a modified I-D complex. (A) Diagram representing recombination that occurs between pPF1117 and the gene-editing plasmid. The +Cas3(helicase mutant) I-D complex is directed by guides from spacer 1 and 2 (or 3) to nick a single DNA strand in sacB of pPF1117. Recombination between pPF1117 and the gene-editing plasmid may occur at the 500 bp homology arms either side of the mutation site. (B) Recombination efficiency of different gene-editing plasmids. Efficiency measures the number of colonies that grew in the presence of sucrose compared to total colonies grown in the absence of sucrose. Escape control is represented by the gene-editing plasmid having a control guide but no sacB homology arms. Recombination control is represented by the gene-editing plasmid having a control guide and sacB homology arms. (C) PCR screen of colonies and control plasmids to test for recombination. A PCR amplicon will only occur in the presence of recombination between pPF1117 and the gene-editing plasmid. The invention will now be described with reference to the following non-limiting examples. Examples Example 1: Proof of Concept/Preliminary Data Materials and Methods Type I-D systems The type I-D system used in the examples is from Synechocystis sp. PCC 6803. Plasmids used in the examples are either listed in Table 1, otherwise reference to the source is given in the text. Oligonucleotides used to make constructs or used in binding and cleavage studies in the examples are listed in Table 2. I-D Cascade for biochemical assays were prepared either according to McBride et al. (2020), or as explained herein Construction of expression plasmids The following expression plasmids were used: pPF2455 for expression of Cas10d and Cas7d, and pPF2453 for the expression of Cas5d, Cas6d, Cas11d and the guide crRNA from the CRISPR-Cas type I-D array in Synechocystis. Plasmid pPF2453 included sequence for a His10 tag and a TEV protease recognition sequence on the N-terminus of Cas5d. Plasmid pPF2455 was constructed by PCR-amplifying cas10d and cas7d (primers PF4991+PF4992) from Synechocystis genomic DNA and Gibson cloning the product into pPF1719 via SphI and KpnI restriction sites. Plasmid pPF1719 was constructed by ligating the AraC-pBAD promoter fragment resulting from digestion of pSEVA1810 with KpnI and PstI with a similarly digested plasmid pSEVA251. Plasmid pPF2917 is for expression of Cas10d and Cas7d(E101A). Plasmid pPF2917 was constructed by amplifying plasmid pPF2455 with primers PF5852 and PF5853 for site-directed mutagenesis, treating with DpnI to remove PCR template, and Gibson assembly to ligate the PCR product into the mutated plasmid. Construction of plasmid pPF2453 involved three steps. First, a new entry plasmid (pPF2451) that encoded a His10 tag and a TEV protease recognition sequence was constructed by annealing and extending two oligonucleotides (primers PF3653+PF3654) by PCR and cloning the product into pACYCDuet-1 via NcoI and BamHI restriction sites. Second, genes cas5d and cas6d (primers PF4980+PF4981) and the region that encodes Cas11d within cas10d (primers PF4982+PF4983) were PCR-amplified from Synechocystis genomic DNA and using Gibson assembly cloned into plasmid pPF2451 via BamHI and HindIII restriction sites (making pPF2452). Third, sequence encoding the repeat-spacer1-repeat sequence from the type I-D CRISPR array in Synechocystis was PCR amplified (primers PF2937+PF2938) and cloned into pPF2452 via NdeI and KpnI restriction sites. The spacer is comprised of sequence 5'-GATTGTTGTGCCCCTGGCGGTCGCTTTCAATGCCT-3' (SEQ ID NO:25) and the flanking repeat sequences are comprised of sequence 5'- CTTTCCTTCTACTAATCCCGGCGATCGGGACTGAAAC-3' (SEQ ID NO:26). Expression and Purification of I-D Cascade Type I-D Cascade was expressed in LOBSTR cells containing plasmids pPF2453 and pPF2455 grown in LB media supplemented with chloramphenicol (25 μg/mL) and kanamycin (50 μg/mL). Cultures were grown by shaking at 37˚C until OD ₆₀₀ = 0.6, then cells were induced with 1 mM IPTG and 0.2% arabinose and grown overnight at 18°C. Cells were harvested at 10,000 x g for 15 min. The cell pellet was resuspended in 20 mL of lysis buffer (50 mM HEPES-NaOH, pH 7.5, 300 mM KCl, 5% Glycerol, 1 mM DTT, 10 mM imidazole, 0.02 mg/mL DNaseI, cOmplete EDTA free protease (Roche), 0.1 mM of PMSF). Cells were lysed by French press at 10,000 psi and the lysate was clarified by centrifugation at 15,000 x g for 15 min. The clarified lysate was applied to a HisTrap Nickel-affinity column equilibrated in binding buffer (10 mM HEPES-NaOH, pH 7.5, 300 mM KCl, 5% Glycerol, 1 mM DTT, 10 mM imidazole) and eluted using a gradient against binding buffer containing 500 mM imidazole. The His10 tag on Cas5d was removed by cleavage with TEV protease during overnight dialysis at 4°C in SEC buffer. The liberated His ₁₀ tag and non-specific E. coli proteins were removed using a second HisTrap affinity column and the flow through was collected. The sample was further purified from free Cas5d by size exclusion chromatography (SEC) on a HiLoad 16/600 Superdex 200 column (GE Healthcare) equilibrated in SEC Buffer (10 mM HEPES-NaOH, pH 7.5, 100 mM KCl, 5% Glycerol, 1 mM DTT). Purified complexes were typically concentrated to 1.5 mg/mL using a centrifugal concentrator (Amicon; 100 kDa molecular weight cut off (MWCO)), aliquoted, and stored at -80˚C. Gel Shift assays A plasmid (pPF1609) carrying the protospacer of the type I-D CRISPR array spacer 1, flanked by a 5′-GTT-3′ PAM was constructed by ligating annealed oligonucleotides PF3089 and PF3090 into pPF1590 via SpeI and XhoI restriction sites. A plasmid (pPF1610) carrying the protospacer of the type I-D CRISPR array spacer 1, flanked by a 5′-AAC-3 PAM was constructed by ligating annealed oligonucleotides PF3091 and PF3092 into pPF1590 via SpeI and XhoI restriction sites. The 153-bp IRD700 fluorescently labeled dsDNA probes that contained the protospacer sequence complementary to the crRNA spacer with flanking PAM sequence 5′-GTT-3′ or 5′-AAC-3′ were amplified by PCR using primers PF3158 and PF3160 from template plasmids pPF1609 or pPF1610, respectively. The complementary protospacer with a 5′-CGT-3 PAM was amplified from a gene fragment (PF5590) with PF4095 and PF4096. The non-specific probe was amplified from pPF1590 using primers PF3158 and PF3160. Binding assays with dsDNA assays were performed with or without 400 nM type I-D Cascade (purified via His10-Cas5 method). Cascade was incubated with 2.5 nM fluorescently labelled probes at 30°C for 60 min in a total volume of 10 μL (final conditions: 10 mM HEPES-NaOH, pH 7.5, 100 mM KCl, 5% v/v glycerol, 1 mM DTT, 0.01% v/v triton X-100, 1 µg BSA, and 0.1 µg poly(dI.dC)). Final reactions were separated on 4% polyacrylamide (19:1 acrylamide:bisacrylamide) native gel containing 0.5x TBE at 4˚C. The fluorescent probe was imaged using the Odyssey Fc imaging system (LICOR) and results were analyzed with Image Studio Lite software. The ssRNA probes were 60-nucleotides with 5′ IRD800 fluorescent labels. The probes contained the protospacer sequence complementary to the crRNA spacer with the protospacer flanking sequence 5′-AAC-3′ (primer PF3167), 5′-ACG-3′ (primer PF5591), or 5′-GUU-3′ (primer PF3322). The non- specific probe (primer PF3079) had no complementarity to the crRNA. RNA binding assays were performed with increasing concentrations (0, 3, 4, 6, 8, 10, 14, 18, 24, 33 nM) of type I-D Cascade. I- D Cascade was incubated with 5 nM fluorescently labelled probes at 30°C for 60 min in a total volume of 10 μL (final conditions: 10 mM HEPES-NaOH, pH 7.5, 100 mM KCl, 5% v/v glycerol, 1 mM DTT, 0.01% v/v triton X-100, 1 µg BSA, and 0.26 µg E. coli tRNA). Final reactions were separated on 4% polyacrylamide (19:1 acrylamide:bisacrylamide) native gel containing 0.5x TBE at 4˚C. The fluorescent probe was imaged using the Odyssey Fc imaging system (LICOR) and results were analyzed with Image Studio Lite software. The signals from bound and unbound ssRNA were quantified using Image Studio. Data were plotted on GraphPad Prism (version 8.0.1) and curve fitting was carried out by non-linear regression using one site specific binding with Hill slope. The apparent binding dissociation constants for type I-D Cascade for ssRNA were determined from three independent experiments. The ssDNA probes were 60-nucleotides with 5′ IRD700 fluorescent labels. The probes contained the protospacer sequence complementary to the crRNA spacer with the protospacer flanking sequence 5′-AAC-3′ (primer PF3271), 5′-ACG-3′ (primer PF5589), and 5′-GTT-3′ (primer PF3272). The non- specific probe (primer PF3149) had no complementarity to the crRNA. DNA Binding assays were performed with or without 20 nM purified type I-D Cascade. Cascade was incubated with 5 nM fluorescently labeled probes at 30°C for 60 min in a total volume of 10 μL. Conditions, electrophoresis, visualization, and analysis as per dsDNA. DNA degradation assays Reactions containing 3 µL of 1 mg/mL type I-D Cascade (purified via His10-Cas5 method), 1 µL of 4 µM fluorescent-labeled ssDNA (PF3167) or ssRNA (PF3167) and 1 µL cleavage buffer (50 mM MgCl ₂ and 5 mM DTT; MgCl ₂ was omitted for -MgCl ₂ control) were incubated at 37˚C overnight. Reactions were stopped with 1 µL of 6 M guanidinium thiocyanate. An equal volume of 2× RNA loading buffer was added, tubes were incubated at 95˚C for 20 min and then immediately on ice for 2 min. Samples were separated by urea denaturing electrophoresis (8M urea, 0.5× TBE buffer, 22.5% formamide). Fluorescence was visualized using the Odyssey Fc imaging system (LICOR). CRISPRi cloning A plasmid (pPF2790) was constructed for expression of the core cas genes required for I-D Cascade formation in CRISPRi assays (cas10d(HD), cas7d, cas5d, and cas6d; the DNase HD domain of Cas10d was inactivated by D123A mutation). The cas operon was PCR amplified in two fragments from Synechocystis genomic DNA. The first fragment was PCR amplified with primers PF4171+PF3321 and then again with PF4168 +PF3321.) The second fragment was PCR amplified with primers PF3320+PF4170. The PCR products were cloned into pPF1719 via KpnI and PstI restriction sites using Gibson assembly. Plasmid pPF1719 was constructed by ligating the AraC-pBAD promoter fragment resulting from digestion of pSEVA1810 (Silva-Rocha et al., 2013) with KpnI and PstI with a similarly digested plasmid pSEVA251 (Silva-Rocha et al., 2013). An entry plasmid (pPF2800) was constructed to express crRNA guides for I-D Cascade. This plasmid contained a T5 promoter upstream of a mini CRISPR array, which was composed of Synechocystis type I-D repeat sequences flanking the gene lacZ. Spacer fragments were formed by annealing oligonucleotides (Table 2) and these were inserted into pPF2800 at BsaI restriction sites positioned inside of the repeat boundaries and replaced the lacz gene. A zsGreen reporter plasmid (pPF2828) was constructed to express the fluorescent gene zsGreen from a constitutive promoter (Bba_J23100; from iGEM2006_Berkeley collection by John Anderson) (sequence in Table 3). A derivative of plasmid pPF1854 (Rey Campa et al. 2021), which had the Gm ^R gene cassette replaced with Cm ^R , was modified to place a T7 promoter in control of the zsGreen reporter by ligation of PCR product (primers PF4837+PF4838) from pACYC-Duet (Novagen) into restriction sites SpeI and BamHI (creating pPF2431). The promoter was replaced with the constitutive promoter by whole-plasmid amplification of pPF2431 with primers PF5165 and PF5166, and using Gibson assembly (creating pPF2537). An extension to the 5’-UTR upstream of the promoter was constructed by amplifying plasmid pPF2537 with primers PF5587 and PF5588, DpnI treatment and Gibson assembly on the PCR product (creating pPF2827). Plasmid pPF2828 was formed by Gibson assembly of PCR amplified pPF2827 (primers PF5603+PF5604) with gene fragment PF5602 to extend the 3’-UTR. A zsGreen reporter plasmid with an intron (pPF2609) was constructed with the zsGreen gene interrupted with a group I self-splicing intron from Tetrahymena thermophila ribosomal DNA (sequence in Table 3). The intron self-splices from the mRNA transcript, which is translated into a functional zsGreen protein. Plasmid pPF2537 with zsGreen was amplified with PF5300+PF5238 and gene fragment PF5236 was cloned into this using Gibson assembly. CRISPRi E. coli DH5α cells contained a plasmid for cas operon expression (pPF2790), a plasmid for the desired guide RNA (derivatives of pPF2800), and a plasmid containing the ZsGreen fluorescent reporter system (pPF2828 or pPF2609). Strains were grown in 1 mL LB media supplemented with chloramphenicol (25 μg/mL), kanamycin (50 μg/mL), tetracycline (10 μg/mL) and D-glucose (0.05%) in 96-well deep well plates overnight at 37˚C and 120 rpm. An appropriate volume of overnight culture was added to fresh 1 mL LB media supplemented with chloramphenicol (25 μg/mL), kanamycin (50 μg/mL), tetracycline (10 μg/mL), 0.2% arabinose and 0.1 mM IPTG, for an initial OD ₆₀₀ of 0.1. The arabinose and IPTG induce expression of the Cas proteins and guide RNA, respectively. The cultures were incubated for 16 h at 37̊C and 120 rpm, at which point cell density (OD ₆₀₀ ) and ZsGreen fluorescence (excitation of 496 nm, emission of 506 nm, measurement time of 100 ms) of each culture was determined using a VarioskanTM LUX Multimode Microplate Reader (Thermo Fisher Scientific). Fluroesence was normalised by the OD600. In Figure 8, the data was log transformed using natural log and normalised against NPAM guide. Table 1: Plasmids used in the examples

Table 2: Oligonucleotides used in the examples

Table 3: Reporter plasmid Sequences. Sequence encoding zsGreen (bold) and intron (underlined) are identified. Table 4: Other plasmid Sequence Results I-D Cascade binds dsDNA and ssRNA with different flanking sequence requirements We previously demonstated wild-type I-D Cascade specifically bound dsDNA carrying a complementary protospacer and 5’-GTT-3’ PAM (protospacer adjacent motif) with an apparent K _D of 35 ± 3 nM (McBride et al. 2020). The PAM for DNA binding is 5’-GTN-3’, where N is any base (Shah et al. 2013; Kieper et al. 2018; Vink et al. 2021). Here we confirm I-D Cascade binding to target dsDNA with a 5’-GTT-3’ PAM (Figure 1). We further show that type I-D Cascade had no detectable binding to a 5′-AAC-3′ PAM-protospacer (the last three bases of the CRISPR array repeat and therefore not expected to bind) and minimal binding to a scrambled 5′-CGT-3′ PAM-protospacer. This binding data supports that type I-D Cascade binds dsDNA in a PAM-specific manner. The type I-D system is a genetic hybrid of type I and III systems and structurally has an overall architecture and crRNA geometry that most closely resembles a type III-A complex (McBride et al., 2020). Effector complexes from type III systems specifically bind ssRNA; therefore, we speculated whether type I-D could also bind ssRNA. To investigate, we bound type I-D to a ssRNA target containing a protospacer that matched the crRNA spacer (Figure 2). Indeed, binding of a ssRNA substrate that contained either a 5′-AAC-3′ PFS (protospacer flanking sequence; corresponding to the complement of the GTT PAM) or a scrambled 5′-ACG-3′ PFS (corresponding to the complement of the CGT PAM) showed nearly identical binding with an apparent affinity of 11.0 ± 0.9 nM. We observed minimal binding to 5′-GUU-3′ PFS (corresponding to the complement of the AAC repeat) and no binding to a non-specific control. Additionally, I-D Cascade was previously demonstrated to bind ssDNA (Lin et al. 2020), and we confirm ssDNA binding by I-D Cascade and demonstrated that binding occured similarly to ssRNA binding requirements (Figure 3). Together, these results show I-D Cascade binding to ssRNA and ssDNA is less restrictive than binding to dsDNA, and that the first two positions in the PFS are less important than the third position. Specifically, our binding results reveal I-D Cascade does not bind dsDNA with a divergent PAM (5’- CGT-3’) but will bind to the corresponding ssDNA/RNA sequence. This shows I-D Cascade can be programmed to bind only an RNA or ssDNA transcript and not the corresponding dsDNA template. I-D Cascade without Cas11d binds ssDNA but not dsDNA We previously showed that mutation within the cas10d gene inhibited protein expression of the Cas11d subunit, and this deltaCas11d complex did not bind dsDNA (McBride et al. 2020). Figure 4b shows this prior work in which different DNA modifications we have tested to the Cas11d RBS (ribosomal binding site) and start codon (ATG) regions inhibited expression of a translation-coupled reporter assay. Figure 4c shows mutations to the RBS and start codon of Cas11d inhibited expression of Cas11d when the whole complex was expressed and purified. Cas11d expressed in trans from a separate plasmid was able to associate with the I-D complex. The modified I-D complex with complemented Cas11d had restored dsDNA binding ability, showing Cas11d is essential for dsDNA binding function and this subunit can be supplied in trans. Since this work conducted in McBride 2020, we have now shown the deltaCas11d complex can surprisingly still bind ssDNA (Figure 5) – we expect on this basis that the ΔCas11d complex will also bind ssRNA. This result implies we can direct I-D Cascade to exclusively bind ssDNA/RNA and not dsDNA by mutations that inhibit translation of Cas11d from within the cas10d transcript. Mutating residues within the PAM-binding pocket may provide I-D Cascade differential binding abilities To obtain mechanistic insight into dsDNA targeting, we employed cryo-electron microscopy to directly visualize type I-D Cascade bound to dsDNA with a protospacer sequence complementary to the crRNA and flanked by a GTT PAM. This yielded a structure of the dsDNA-bound type I-D Cascade at a global resolution of 2.9 Å and enabled de novo atomic modeling of the entire complex. We also employed cryo-electron microscopy to directly visualize type I-D Cascade bound to ssRNA with a protospacer sequence complementary to the crRNA and flanked by a 5’-AAC-3’ PFS. This yielded a structure of the ssRNA-bound complex at 3.1 Å resolution. Overall, the structures are strikingly similar. However, in the single-stranded target-bound complex, we lose recognizable density for the PAM recognition domain, likely due to the flexibility of the complex in the presence of a single- stranded nucleic acid. To understand the molecular basis for PAM recognition by type I-D Cascade, we analyzed specific interactions between Cas10d and the PAM duplex (5′-GTT-protospacer-3′ on the NTS (non- target strand) and its complement on the TS (target strand)) of the target dsDNA. The K326 residue in Cas10d recognizes the C (-3 position) on the TS, the T (-2 position) on the NTS, and the G (-3 position) on the NTS via hydrogen bonding (Figure 6). These results are consistent with previous bioinformatic and in vivo studies on type I-D PAM selection that showed these -3 and -2 PAM positions were the most important (Kieper et al. 2018; Shah et al. 2013; Vink et al. 2021). This interaction suggests a process where the K326 finger scans for a GTN PAM. We predict that mutation of Cas10d residue K326 will also reduce DNA binding specificity, but will have minimal effect on RNA binding as the -2 and -3 positions do not appear important for ssDNA/RNA binding (Figures 2,3,5). This could be used to programme I-D Cascade by mutation of Cas10:K326 to bind ssDNA/RNA and not DNA. We observed a well resolved glutamine (Q110) of Cas5d that intercalated into the dsDNA major groove of the PAM and close enough to interact with the A (-1 position) on the TS (Figure 7). This residue likely only plays a role in non-specifically stabilizing the -1 position of the PAM, aiding PAM sliding. The role of Cas5:Q110 could not be inferred from the I-D Cascade:ssRNA structure because of missing density. We predict mutation of this residue will not significantly affect dsDNA binding (base in the -1 positon is not important for specificity), but will impede ssDNA and RNA binding (base in the -1 position appears important for specificity). This could be used to programme I-D Cascade by mutation of Cas5:Q110 to bind dsDNA and not ssDNA/RNA. The I-D Cascade CRISPRi system can repress transcriptional gene expression. Gene silencing can be performed by deactivated CRISPR enzymes in a process called CRISPR interference (CRISPRi). The most common mechanism of gene repression is by DNA targeting and inhibiting gene transcription, as shown with dCas9, dCas12 and I-E Cascade (Bikard et al. 2013; Qi et al. 2013; Luo et al. 2015; Kim et al. 2017). These prior studies demonstrated that CRISPRi complexes directed to promoter regions repressed gene expression by >100-fold in a strand independent manner, but when complexes were directed to the coding DNA sequence (CDS) there was approximately 10-fold repression with a strand bias, where a certain DNA strand must be targeted. Very recent work has shown RNA-specific complex dCas13 can act post-transcriptionally at the ribosomal binding site (RBS) through RNA binding (Charles et al. 2021). Given that I-D Cascade has the dual function of binding DNA and RNA, we proposed I-D Cascade could inhibit gene expression both transcriptionally and post-transcriptionally. To investigate, we created a CRISPRi system with deactivated I-D Cascade containing guides that targeted a fluorescent reporter gene. The CRISPRi system involved three plasmids in Escherichia coli DH5alpha. One plasmid (pPF2790) involved arabinose inducible expression of Cas proteins (Cas10d(∆HD mutant), Cas5d, Cas7d, Cas6d and Cas11d (from the cas10d gene)). One plasmid, a derivative of plasmid pPF2800 (Table 1), contained IPTG inducible expression of a crRNA guide. The third plasmid (pPF2828) contained the ZsGreen reporter under constitutive expression. First, we investigated the activity of I-D Cascade targeting the constitutive promoter region of our ZsGreen reporter. Guides T1 (template strand 1) and NT1 (non-template strand 1) were used to direct I-D Cascade to bind the -10 element of the promoter on the template and non-template strands, respectively, and caused >170-fold reduction in ZsGreen fluorescence relative to a control guide that did not target a PAM (NPAM) – non target PAM control, irrespective of the strand targeted (Figure 8). These findings demonstrate that I-D Cascade could be expressed in the E .coli host and could be programmed to bind DNA targets to repress transcription in vivo. We next analysed the effect of directing I-D Cascade to different positions along the ZsGreen gene. When I-D Cascade was directed to the RBS of ZsGreen we observed 100-fold repression when the NTS was targeted (guide NT2) and 60-fold repression when the TS was targeted (guide T2) (Figure 8). This result is particularly interesting as the NTS sequence is identical to the expressed mRNA transcript. Therefore, it is possible the increased levels of repression observed when targeting the NTS could be from transcriptional and also post-transcriptional repression. When I-D Cascade was directed to sites along the CDS and the 3’-UTR, the fluorescent reporter was repressed between 22- fold and 6-fold, regardless of what strand was targeted. In summary, the results show that our I-D Cascade CRISPRi platform can target either strand of a target gene to repress transcription, and the GTN PAM sequence offers an alternative PAM compared to other CRISPRi systems that could be useful for certain target genes and/or organisms. I-D Cascade can act post-transcriptionally to repress expression To confirm whether I-D Cascade can act post-transcriptionally to repress transcription, we took advantage of a reporter system with a self-splicing intron that interrupted the DNA coding sequence but would be spliced from the mature transcript for expression of functional ZsGreen protein (Figure 10). We used two guides that only have partial complementarity to DNA, but guide SJNT (splice junction non-template) had full complementary sequence to the mature mRNA and guide SJT (splice junction template) matched the mRNA sequence and therefore would not bind the transcript. We demonstrated 6x reduction in gene expression with guide SJNT and not SJT. This result provides evidence that I-D Cascade can act via RNA binding to repress translation and supports this platform being used to both transcriptionally and post-transcriptionally to repress gene expression. I-D Cascade targeting gene operons RNA targeting by I-D Cascade opens the oportunity to repress different genes in an operon. Different genes within an operon can have different roles and phenotypes; therefore manipulating expression within an operon is important to discover the function of individual genes. CRISPRi by dCas9 inhibits transcription and therefore all genes in an operon. Operon targeting will require “dead” Cas10d and probably “dead” Cas7 (i.e. no mRNA cleavage). We predict that by targeting the mRNA, we can differentially turn off some genes while others can still be expressed (Figure 9). I-D Cascade cleavage It was previously demostrated that I-D Cascade cleaved ssDNA, although the catalytic residues were not identified (Lin et al. 2020). We have confirmed ssDNA cleavage by our purified I-D Cascade complex (Figure 11). We have preliminary evidence that one cleavage event occurs 14 nucleotides upstream of the 5’-AAC-3’ PFS (left panel) and that processive cleavage occurs after extensive incubation (middle panel). This distance from the PFS is consistent to that observed by Lin et al. 2020. Cleavage is expected to proceed via general acid-base catalysis involving charged amino acids. From our structure determined as explained above, we have identified residue E101 of Cas7 as a potential catalytic residue that is within hydrogen-binding distance to the DNA cleavage point (Figure 11). We investigated a Cas7:E101A mutant complex and it appeared to reduce ssDNA cleavage successfully. RNA cleavage by I-D Cascade was not observed by Lin et al. 2020. However, recently we have obtained preliminary in vitro RNA cleavage data that shows degradation of the RNA probe after digestion with I-D Cascade (Figure 11, right panel). The Cas7:E101A mutant complex also appeared to have decreased some cleavage products, indicating these are from specific nuclease activity of I-D Cascade. This indicates that the Cas7 protein is the component of I-D Cascade that cleaves single stranded nucleic acids including not only ssDNA but also RNA. The Cas7:E101A mutant acts as a catalytically inhibited ‘dead’ Cas7 that can be used to bind to these nucleic acids without cleavage. This may be used in CRISPRi methods described above, specially to inhibit expression of ssDNA and RNA. Example 2: Type I-D CRISPR-Cas Systems for Gene Repression/Editing in Prokaryotes The data which follow further demonstrate that the type I-D CRISPR-Cas systems according to the present invention may be used as a “CRISPRi” tool that represses gene expression. The applicants sought to: 1. further demonstrate that the type I-D CRISPR-Cas system can be used as a CRISPRi tool that represses gene expression; 2. determine whether the addition of Cas3’ to the type I-D complex can improve CRISPRi gene silencing; 3. demonstrate CRISPRi silencing of genes in an operon; 4. determine whether ssRNA targeting can be achieved using a Cas11d deficient mutant; and 5. determine whether the type I-D system can be used for gene editing in prokaryotes. Methods Escherichia coli strains (DH5α, ST18) and Serratia sp. ATCC 39006 were grown at 37°C and 30°C, respectively, in lysogeny broth (LB) or on 1.5% LB agar plates. Media were supplemented as required with the antibiotics: chloramphenicol (Cm; 25 µg/mL), kanamycin (Km; 50 µg/mL), and tetracycline (Tc; 25 µg/mL). When necessary, media were supplemented with alanine (Ala; X mM), L-arabinose (0.5%), D-glucose (0.5%), Isopropyl β-D-1-thiogalactopyranoside (IPTG; 0.1 mM). Construction of type I-D expression plasmids A plasmid (PF2790) for the expression of Cas10d(ΔHD), Cas7d, Cas5d and Cas6d was constructed by restriction digesting pPF2416 with SphI-HF and NaeI-HF. The double digest produced a 10.2 kb fragment that contained the cas genes under the control of an arabinose inducible promoter. A 1.4 kb fragment from pSEVA251 that contained the kanamycin cassette was generated by digestion with SphI- HF and NaeI-HF, and was ligated to the cas gene fragment, creating a 12.6 kb plasmid. A plasmid (pPF2791) for the expression of Cas3′, Cas10d, Cas7d, Cas5d and Cas6d was constructed by PCR-amplification of their respective genes using Synechocystis sp. PCC6803 genomic DNA as the template. The cas operon was amplified in two segments, the first segment, which contained the gene for Cas3′ and part of the Cas10d gene (until the HD nuclease domain), was amplified with primers PF7120 and PF6647. The second fragment, which contained the rest of the gene for Cas10d, Cas7d, Cas5d and Cas6d, was amplified using primers PF6648 and PF4170. The two cas gene fragments were ligated by Gibson assembly into pPF1719 via PstI and KpnI digestion. A plasmid (pPF2792) for the expression of Cas3′, Cas10d(ΔHD), Cas7d, Cas5d and Cas6d was constructed via the same method as described for pPF2791. However, the primer pairs used to amplify the cas genes were PF7120 and PF3221 (Cas3′ and part of Cas10d), and PF3320 and PF4170 (part of Cas10d, Cas7d, Cas5d and Cas6d). The primers PF3320 and PF3321 overlap at the Cas10d HD domain, and introduce a point mutation (D115A) that catalytically inactivates the HD domain. A plasmid (pPF3605) for the expression of Cas3′ (ΔHEL), Cas10d(HD), Cas7d, Cas5d and Cas6d, was generated by PCR mutagenesis of pPF2791 with the primers PF3197 and PF3198. These primers introduce a point mutation (D198A) into Cas3′ that catalytically inactivates the helicase domain. The same method was used to generate a plasmid (pPF3606) for the expression of Cas3′ (ΔHEL), Cas10d(ΔHD), Cas7d, Cas5d and Cas6d, using the plasmid pPF2792 as the template. A plasmid (pPF3224) for the expression of Cas10d(ΔHD), Cas7d, Cas5d and Cas6d, and ΔCas11d was constructed by PCR-amplifying pPF2790 with the mutagenic primers PF6650 and PF6784, which introduced site-directed mutations to cas10d to interrupt the alternative cas11d RBS and start codon. The resulting type I-D Cascade complex should not bind (ΔCas11d) or cleave Cas10d(ΔHD) dsDNA. A plasmid (pPF2913) for the expression of an operon containing zsgreen and mcherry2 was constructed by PCR-amplifying a zsgreen-only reporter plasmid (pPF2828) with the primers PF5884 and PF5604, which generated compatible ends for cloning the gBlock (PF5892) into the backbone via Gibson assembly. Recently, it was reported that mcherry2 contains an alternative translational start site that is recognised by the prokaryotic ribosome (Fages-Lartaud et al., 2021). As my experiment required that mcherry2 have only one RBS, PCR mutagenesis of pPF2913 (with primers PF6275 and PF6276) was used to remove the start codon by introducing an M10L substitution, therefore, generating the dual- reporter plasmid pPF2921 (Fages-Lartaud et al., 2021). The plasmid (pPF2800) was used as the backbone for all crRNA expression plasmids, and contained a mini CRISPR array that consisted of lacZ, flanked by palindromic repeats derived from Synechocystis. The two palindromic repeats contained internal BsaI restriction sites, which enabled BsaI to cleave at the repeat boundary, and excise lacZ from the array. This enabled different dsDNA 35 bp crRNA sequences to be ligated into the I-D array via golden gate cloning. The sequences of all oligonucleotide pairs that were used to generate I-D crRNAs are listed in Table 7. All plasmids used in this study are listed in Table 5. Plasmids were transformed into Escherichia coli DH5a and selected by plating on LBA that contained the appropriate antibiotic(s) and supplement(s). After 24 h of incubation at 37⁰C, colonies were screened via colony PCR and confirmed by Sanger sequencing. All PCR and sequencing primers are listed in Table 6. All gBlock sequences are listed in Table 8. Table 5. Plasmids used in this study

Table 6. Primers used in this study Table 7. Oligonucleotide pairs for crRNAs R PF2923 F PF3066

Table 8. gBlock Sequences

Fluorescent Reporter (CRISPRi) Assays Fluorescent reporter assays were conducted as described previously. A schematic of the 3-plasmid assay is shown in Figure 22. Results The ΔCas3′ CRISPRi complex represses transcription when targeted to either strand of DNA Applicants sought to replicate and confirm the original data presented in Example 2 which was generated using the Cas protein expression plasmid pPF2790, which expressed Cas10d(ΔHD), Cas7d, Cas5d, Cas6d, and Cas11d (expressed from within Cas10d). The Cas3′ helicase was omitted. Applicants designed additional ZsGreen-targeting crRNAs and integrated them into the pre-established plasmid-based expression platform, to gain further insights into the target site preferences of the type I-D complex. The findings of this experiment reaffirmed that type I-D complexes with an inactivated Cas10d HD nuclease domain and no Cas3′ helicase retain dsDNA binding activity, and repress gene expression through CRISPRi. The crRNAs targeting promoter-proximal region (-50 to +85) elicited the strongest repression (50 – 83-fold) of ZsGreen expression, which is consistent with the I-D complex preventing transcriptional initiation (Figure 13). Strong repression was also achieved by targeting the non- template strand at the RBS, this could be due to I-D Cascade preventing transcription initiation/elongation (DNA level) and/or due to I-D Cascade binding ZsGreen mRNA and preventing translation (Figure 13). Consistent with RNA targeting occurring, guides that targeted the non- template strand at the RBS, which would also target the RBS on the mRNA transcript, demonstrated higher levels of repression than guides that targeted the template strand (DNA only). The crRNAs targeting the coding region of ZsGreen showed strand-independent targeting, although generally elicited weaker silencing compared to those targeting the promoter (approx. 0.5 – 43-fold repression) (Figure 13). The addition of Cas3’ to the type I-D CRISPRi complex introduced strand-biased targeting at the promoter that favoured the template strand of DNA Applicants next tested whether the expression of Cas3’ would improve the level of gene-repression achieved by the type I-D CRISPRi complex. The Cas3’ protein of the type I-D system is a Superfamily 2 helicase that is recruited to the type I-D complex after target DNA binding. Cas3’ loads onto the displaced non-target strand and unwinds the dsDNA duplex in the 3′ – 5′ direction. Applicants hypothesised that the addition of Cas3′ to the existing I-D CRISPRi complex could increase the level of gene repression through: A) providing 3′ – 5′ helicase activity that could interfere with the 5′ – 3′ translocation of RNA polymerase during transcription (Figure 14); and B) increasing the dsDNA binding affinity of the I-D CRISPRi complex / adding mass to the complex, which could act as a bigger “roadblock” that would inhibit elongating RNA polymerase. To investigate this hypothesis, a plasmid (pPF2792) was constructed to express the Cas3′, Cas10d(ΔHD), Cas7d, Cas5d, Cas6d, and Cas11d (expressed from within cas10d) proteins. When expressed, these proteins form a catalytically inactive I-D Cascade complex that binds the target sequence and then recruits the Cas3′ helicase. This plasmid can be used as part of the pre-established CRISPRi system, which involves the expression of three plasmids in an Escherichia coli host as described above. Firstly, Applicants observed that the type I-D CRISPRi platform can repress the expression of the ZsGreen reporter when Cas3′ is present in the I-D complex (Figure 15B). Therefore, indicating that Cas3′ helicase activity does not cause excessive levels of translocation that would destroy the ability of the complex to act as a “roadblock” to elongating DNA and RNA polymerases. When directed to target the gene promoter, the +Cas3′ CRISPRi complex improved repression, achieving a 270-fold and 73-fold decrease in ZsGreen expression when bound to the template and non- template strands, respectively (Figure 15B compared to 15A). When directed to target the sites over 400 bp downstream of the promoter, the +Cas3′ CRISPRi complex appeared to have reduced silencing activity compared to -Cas3′ CRISPRi complex (Figures 15–20). Applicants hypothesised that the +Cas3′ CRISPRi complex may prefer the template strand because 1) the core CRISPRi proteins provide a steric block that prevents RNA polymerase from initiating transcription at the promoter, and 2) when the I-D complex targets the template strand, Cas3′ interacts with the non-target strand (the non-template strand) and is in an orientation for the helicase 3′ to 5′ translocation activity to opposes the 5′ to 3′ movement of elongating RNA polymerase along the gene (Figure 14), resulting in a collisions that may terminate transcription. The type I-D CRISPRi complex can be used to silence operonic genes To determine how dsDNA and ssRNA targeting each contribute to type I-D-mediated gene silencing, applicants constructed a plasmid (pPF2921) to express the genes for two fluorescent reporters: ZsGreen and mCherry2. The reporter genes were located within an operon controlled by a constitutive promoter but had separate ribosome binding sites. Applicants also constructed new crRNA expression plasmids (pPF2800 derivatives) that targeted regions with DNA PAMs (5′-GTN-3′) and others with the putative type I-D RNA PAM (5′-CGT-3′). The crRNAs with RNA PAMs should significantly reduce dsDNA binding as only the recognition of a 5′-GTN-3′ PAM by Cas10d licenses I-D Cascade to form an R-loop and elicit full binding of dsDNA targets (Schwartz et al., 2022). First, applicants conducted an assay that tested the ability of the ΔCas3′ CRISPRi complex (encoded by pPF2790) to repress the expression of the operonic fluorophore genes (Figure 16). Applicants observed that efficient gene silencing can be achieved when the ΔCas3′ CRISPRi complex is targeted to promoter-proximal regions, irrespective of the strand of DNA targeted. ZsGreen expression was minimally affected by targeting regions downstream of the ZsGreen gene (Figure 16A). The expression of mCherry2 was repressed effectively when the ΔCas3′ CRISPRi complex was targeted to upstream regions within the promoter and ZsGreen. Silencing of mCherry2 expression was also observed when the CRISPRi complex was directed to bind within the mcherry2 gene and the downstream 3′ UTR (Figure 16B). Applicants subsequently conducted assays that tested whether the addition of Cas3′ to the CRISPRi complex (on plasmid pPF2792) effected the repression of operonic genes (Figures 17 – 20). Applicants conducted these tests at 30°C (Figures 17 and 18), and at 37°C (Figures 19 and 20). In all tests, applicants observed that the +Cas3′ CRISPRi complex demonstrated greater repression of ZsGreen and mCherry2 when targeting the template strand of promoter DNA, compared to the non- template strand. The addition of Cas3′ to the CRISPRi complex resulted in decreased silencing efficiency when the complex was targeted to the non-template strand of promoter DNA. Without Cas3, 26-fold repression of ZsGreen was achieved (Figure 16A), compared to a maximum 1.5-fold-repression of ZsGreen when Cas3′ was present (Figures 17 – 20). Targeting the +Cas3′ complex to regions downstream of ZsGreen had minimal effect on ZsGreen expression, consistent with what was observed when Cas3′ was absent from the complex (Figure 16A). Therefore, Cas3′ helicase activity did not disrupt the transcription of genes upstream of the target site. As observed using the ΔCas3′ complex (Figure 16B), the +Cas3′ CRISPRi complex repressed mCherry2 when targeted to upstream regions (promoter and ZsGreen), within mcherry2 and downstream in the 3′ UTR (Figures 17 – 20). Overall, greater repression of mCherry2 was achieved by using the ΔCas3′ complex. Therefore, the addition of Cas3′ to the I-D CRISPRi platform may attenuate the ability of the I-D complex to repress downstream operonic genes. Applicants observed that the RNA targeting crRNAs elicited little to no repression of ZsGreen or mCherry2 fluorescence with/without Cas3′ present (Fig. 16 – 20). The antisense RNA-targeting guides (which had RNA PAMS but were complementary to the template strand of DNA), elicited some repression of both genes, indicating that the I-D complex can still weakly bind DNA-targets using an RNA PAM. RNA-targeting was not observed in the fluorescent operon reporter system. The type I-D CRISPR-Cas complex has genetic and structural characteristics from both type I and III CRISPR-Cas systems. Previous studies by the applicants have demonstrated that the I-D Cascade complex can bind dsDNA and ssRNA in vitro. The Applicants also demonstrated RNA targeting in vivo by targeting a self-splicing intron (Figure 10). Further, there appears to be a preference in the above CRISPRi results of the I-D complex targeting the template strand at the RBS, which would also target the mRNA transcript. Applicants hypothesised that these dual dsDNA and ssRNA binding may allow the type I-D system to silence genes at both the DNA (transcriptional) and mRNA (translational) levels. To determine how dsDNA and ssRNA targeting each contribute to type I-D-mediated gene silencing, applicants used the dual fluorescent reporter plasmid pPF2921. Applicants predicted that DNA- level targeting by the type I-D complex would cause the silencing of genes at/downstream of the target site due to I-D inhibiting transcription. Secondly, applicants hypothesised that RNA-level targeting would affect only the target gene, as the two reporter genes have separate ribosome binding sites (RBSs). To examine RNA-targeting, applicants constructed another Cas protein expression plasmid (pPF3224) for the expression of Cas10d(ΔHD), Cas7d, Cas5d and Cas6d, and ΔCas11d (this will now be referred to as the “ΔCas11d plasmid”. Applicants prior in vitro studies (McBride et al., 2020) demonstrated that the ΔCas11d mutation dramatically reduced dsDNA binding capability, but did not affect ssRNA binding, therefore, applicants predicted that this construct would allow RNA-level silencing activity of I-D Cascade, independent of the effects of dsDNA targeting. The Applicants had discovered that the I-D complex had a different RNA PAM (CGT) to DNA PAM (GTT) (Figure 1 and 2). Therefore, the complex can to targeted to RNA transcripts by targeting spacers that were adject to the CGT PAM. RNA targeting assays To further test RNA targeting by type I-D, applicants integrated the dual-reporter plasmid (pPF2921), the ΔCas11d plasmid (pPF2921) and different DNA and mRNA targeting guides into the plasmid-targeting assay. Applicants observed that the ΔCas11d CRISPRi complex retained weak dsDNA binding activity as it still repressed gene expression when targeted to the promoter and the template strand sequences which are present in DNA and not in mRNA (Figure 21), making it difficult to distinguish mRNA-mediated repression. Performing CRISPRi with the RNA PAMs did not appear to show repression of ZsGreen or mCherry. The Applicants expected to see no activity with guides that targeted the template strand (does not share sequence identity with the mRNA transcript); however these did show some levels of repression. Therefore, under the context of the operon reporter system, the targeting of RNA transcripts to elicit gene silencing is not apparent. The Applicants speculate that in the context of the above assay that the high-copy number of the plasmid and multiple transcript copies out- competed the numbers of the I-D complex expressed. Conclusions • The ΔCas3′ CRISPRi complex represses transcription when targeted to either strand of DNA. • Adding Cas3′ to the type I-D CRISPRi complex improved repression when targetedto the template strand at the promoter. • Adding Cas3′ to the type I-D CRISPRi complex decreased the level of repression achieved by crRNAs that targeted the non-template strand of DNA at locations >400 bp downstream of the p ^romoter. Cas3′-mediated translocation appears to makes the I-D complex a less effective “roadblock” to transcription. • Type I-D CRISPRi tools can be used to repress the expression of operonic genes. • Under the context of the reporter system, the Applicants observed no direct evidence of gene silencing when targeting the RNA transcript. Example 5: Gene Repression in Mammalian Cells Methods Construction of type I-D Cascade complex plasmids for expression in mammalian cells Vectors used for expression of type I-D Cascade in mammalian cells were synthetically constructed. The cas genes were codon optimized for expression in mammalian cells and ordered as gene-blocks from IDT (Table 10). Gene-blocks were PCR amplified using the oligonucleotides listed in Table 10. Cloning was performed with eight gene fragments combined a Gibson assembly reaction (NEB). The resulting entry vector (pPF3609) was confirmed with Oxford nanopore sequencing. Spacers (annealed oligonucleotides in Table 9) were cloned into the entry vector via a BsaI restriction site. Clones were confirmed by Sanger sequencing. Vector for expression of I-D Cascade ∆cas11 (pPF3657) was constructed by KpnI/SphI digest of vectors pPF3609 and pPF3656 (constructed similar to pPF3609 but with cas11 in a different position), resulting in removal of cas11. Vector for expression of I-D Cascade ∆cas3 ^ (pPF3658) was constructed by site-directed mutagenesis through amplifying vector pPF3609 with primers PF7309+PF7310. Reaction was treated with DpnI to remove PCR template and Gibson assembly was used to ligate the PCR product into the mutated vector. Cell culture Human embryonic kidney cells (HEK293) were cultured in Dulbecco’s modified essential medium (DMEM) supplemented with 10 % foetal calf serum (FCS; Pan Biotech Aidenbach, Germany) and Pen- Strep (100 U/mL penicillin and 100 µg/mL streptomycin; Gibco) at 37 ^C with 5 % CO2. One day prior to transfection HEK293 cells were seeded into either 12 or 6-well plates at ~1.5 x 10 ⁵ cells/mL in 10 %/DMEM without Pen-Strep. HEK293 cells were then transfected with either 1000 or 2500 ng total DNA using Lipofectamine 3000 (Thermofisher Scientific, Waltham, MA, USA) as per the manufacturer’s protocol. The media was replaced 6 – 12 hours post-transfection, with 10 % FCS/DMEM supplemented with Pen-Strep. Cells were then processed for imaging or flow cytometry 24-hours to 48-hours post- transfection. Flow cytometry To quantitate the efficiency of gene knockdown of type I-D system (pPF3609) against Venus (pPF3328) in HEK293 cells flow cytometry was used. After 48-hours transfection cells had media removed and were resuspended in 1 mL wash buffer (PBS pH 7.4), 0.1 % w/v BSA, 2 mM EDTA), then were then centrifuged at 453 xg for 5 min. Cells were washed in this fashion in triplicate and then resuspended in 300 µL wash buffer and measured on a LSRFortessa flow cytometer (BD Biosciences). Cells were threshholded using FSC and SSC to pick the single cell population and then fluorescent intensity of co-transfected cells determined for Venus (from pPF3328) and the microRFP (from pPF3609). For Venus, an excitation wavelength of 488 nm and filter with a bandpass at 530/30 nm was used. For microRFP, a red laser for excitation at 640 nm and a filter with a bandpass at 670/14 nm was used. A total of 50,000 events were recorded for each sample using BD FACSDiva software (v.8, BD Biosciences). Analysis of recorded data was performed using FlowJo software v.10 (BD Bioscienes). Cells were gated on SSC-A vs. FSC-A, FSC-H vs. FSC-A and SSC-H vs. SSC-A was used to identify the singlet population of HEK293 cells. Co-transfected singlet cells that were both microRFP and Venus positive had the median fluorescence intensity (MFI) of Venus fluorescence determined. Determined MFIs were plotted and analysed using Prism v. 9.2.0 (Graphpad). Statistical analysis was performed by t-test, comparing treatment with targeting spacer to the non-targeting spacer. Confocal microscopy To image transfected HEK293 cells, cells were seeded onto glass coverslips in 12-well plates. After 24 or 48-hours of transfection cells were fixed in 4 % paraformaldehyde, then washed twice with PBS pH 7.4 before being stained with Hoechst 33342 (Thermofisher Scientific, Waltham, MA, USA) and washed again in PBS pH 7.4 followed by a final wash in distilled water. Coverslips were then mounted onto microscope slides using Fluorsave (Merckmillipore). Images were acquired using a CFI Plan APO Lambda ×40 or x100 1.49 numerical aperture oil objective (Nikon Corporation) on the multimodal imaging platform Dragonfly v.505 (Oxford Instruments) equipped with 405, 488, 561 and 637 nm lasers built on a Nikon Ti2-E microscope body with Perfect Focus System (Nikon Corporation). Data were collected in Spinning Disk 40 μm pinhole mode on the iXon888 EMCCD camera with x2 optical magnification using the Fusion Studio Software v.1.4 (Andor Oxford Instruments). Z stacks were collected with 0.1 μm increments on the z-axis using an Applied Scientific Instrumentation stage with 500 μm piezo z drive. Images were visualized and cropped using Fiji Software (Windows 64-bit) and processed using the Huygens Essential Deconvolution Wizard (Scientific Volume Imaging). Final composite images and fluorescence plot data were generated using Fiji Software (Windows 64-bit) and graphed using Prism v. 9.2.0 (GraphPad). Table 9: Oligonucleotides used in this study.

Table 10: Gene blocks used to synthesize plasmids

Table 11. Additional plasmids used in mammalian study Results To establish the gene knockdown efficacy of type I-D CRISPR-Cas system in mammalian cells, cas sequences were codon optimized for expression in human cells. Each gene fragment was then ordered as gene-blocks and PCR amplified with suitable primers and fragments were cloned cloning by Gibson assembly. The entry vector (pPF3609) was confirmed with using Oxford Nanopore sequencing. Spacers, after annealing of appropriate oligonucleotides, were cloned into a BsaI restriction site and confirmed with Sanger sequencing. To confirm that the type I-D mammalian expression vectors could be transfected into mammalian cells, HEK293 cells were transfected using lipofectamine and 1 µg of vector DNA. After 48-hours transfection cells were fixed and then visualized using confocal microscopy. Figure 23A(i) shows confocal images of HEK293 cells stained with the DNA nuclei stain Hoechst, while Figure 23A(ii) shows HEK293 cells with red fluorescence. Red fluorescence is indicative of cells transfected with the type I-D expression vector, which has microRFP tagged onto Cas6. This shows that HEK293 cells can be transfected with the type I-D expression vector pPF3609. To quantify the knockdown efficiency of type I-D in mammalian cells, HEK293 cells were co- transfected with a Venus expression plasmid (pPF3328) and type I-D expression vectors with spacers targeting differing parts of the Venus gene at the template (TS) and non-template (NTS) strands. After 48-hours transfection, cells were washed and then run on a flow cytometer measuring forward and side scatter along with yellow (Venus) and red fluorescence (type I-D expression vector). Singlet cells that showed red fluorescence (RFP+) then had the median fluorescent intensity (MFI) of Venus analyzed to determine the effect of type I-D Cascade on gene expression. Results from this analysis are shown in Figure 23B. Relative to the non-targeting control spacer, spacers targeting the NTS and TS of the kozak sequence for Venus showed an average reduction of 44 and 40% in YFP MFI, respectively, while the TS for the CDS of Venus showed a 71% reduction in YFP MFI. In contrast, spacers on the NTS of the CDS of Venus did not show any significant reduction in YFP MFI relative to the control spacer. This data shows that the type I-D Cascade can effectively target and knockdown gene expression in mammalian cells, and in a strand independent manner when targeting the kozak sequence. Visual confirmation of flow cytometry data was achieved by co-transfecting HEK293 cells under similar conditions as stated above, then fixing cells and imaging them with confocal microscopy. Select images from this analysis are shown in Figure 23C. Panel (i) shows Hoechst-stained cells, indicating total cell population in the field of view. Cells transfected with the type I-D expression vector with a spacer targeting the TS of the CDS of Venus showed red fluorescence (Figure 23C(ii)), which is due to the presence of microRFP from the type I-D expression vector being expressed, as indicated by arrows. HEK293 cells transfected with Venus (pPF3328) showed green fluorescence, as indicated by arrows. In the field of view, one cell is observed to contain co-transfection of Venus and the type I-D expression vectors (circled in all panels), and the level of green fluorescence of this cell appears attenuated compared to the other Venus positive cells that do not also contain RFP. This result indicates the presence of type I-D Cascade reduced the levels of Venus expression, consistent with the flow cytometry data. To determine the essentiality of the cas3 helicase for knockdown efficacy of the type I-D system in mammalian cells, the cas3 gene was deleted from the vector pPF3609, to create the derivative vector pPF3658. Control spacers and spacers targeting both strands of the Venus ORF were then cloned into the ^cas3 ^ derivative and used to transfect HEK293 cells. Fluorescence of transfected cells was then measured using flow cytometry, the raw data is presented in Figure 23D(i) and the normalized repression is shown as a percentage in Figure 23C(ii). Targeting the NTS of the Venus Kozak the ^cas3 ^ I-D complex resulted in 21% repression, while targeting the TS in the CDS had 38% repression. Similar to results observed for the the I-D complex with Cas3 ^ (Figure 23B(ii)), there was no decrease in fluorescent intensity observed when targeting the NTS of the CDS of Venus. These results for ^cas3 ^ indicate that Cas3 does indeed play a role in increasing knockdown efficacy of the complex in mammalian cells, where the deletion of cas3 resulted in a ~50% reduction in repression with guides targeted ot the NTS of the Kozak and TS of the CDS of Venus. The data presented here shows that type I-D Cascade can be used as an effective CRISPRi tool for knocking down gene transcription in targeted genes in mammalian cells. We observed approximately 25% knockdown efficiency when targeting either strand of the kozak sequence or the template strand of the CDS. The Applicants speculate that the helicase activity of Cas3 may have a role in improving access of the I-D complex to bind genetic sequences in mammalian cells. Example 6 – Cas5 mutant binding The Applicants had predicted that Cas5 residue Q110 made important interactions for binding single-stranded nucleic acids (ssDNA and RNA), and that modification of this residue would limit single- stranded binding but maintain dsDNA binding. To investigate this, the Applicants modified Cas5 and tested binding by I-D complex with Cas5(Q110A) modification. In support of the prediction, using gel shift assays the Applicants showed both WT and Cas5(Q110A) complex bound dsDNA equally well but Cas5(Q110A) had less affinity for ssDNA (at least 2-fold reduction in binding). Methods: Construction of type I-D (Cas5:Q110A) expression plasmid A plasmid (PF3553) for the expression of Cas10d(ΔHD), Cas7d, Cas5d(Q110A) and Cas6d was constructed by site-directed mutagenesis through amplifying vector pPF1549 (McBride at al.2020) with primers PF5755+PF5756. Reaction was treated with DpnI to remove PCR template and Gibson assembly was used to ligate the PCR product into the mutated vector. Expression and Purification of I-D Cascade Cas5(Q110A) and wild-type I-D complex were purified according to McBride et al. (2020). Gel Shift assays Gel shifts were done as previously described with either a 153-bp IRD700 fluorescently labeled dsDNA containing a 5′-GTT-3′ PAM or a 60-nt IRD700 fluorescently labeled oligonucleotide (primer PF3271). Cascade was incubated with 5 nM fluorescently labeled probes at 30°C for 60 min in a total volume of 10 μL. Conditions, electrophoresis, visualization, and analysis as per previous methods. Table 12: Additional oligonucleotides used in Cas5 binding example (Q ) To investigate the ability of the type I-D system to be used for specific gene-editing, the Applicants exploited the potential nickase activity of the system. The authors predicted the I-D complex could be modified into a nickase by including a modified Cas3 that lacks helicase activity and provide Cas10d with an active nuclease. Gene-editing using a nickase has potential for less off-site targeting compared to CRISPR enzymes that make double stranded DNA cuts ( for example Cas9). The Applicants setup a system where the sacB gene in plasmid pPF1117 would be modified, resulting is removal of sucrose sensitivity for the bacterial cell. Natural sacB escapes were detected using a gene-editing plasmid lacking homology with sacB (no recombination was possible) and the background recombination activity was observed with using a gene-editing plasmid containing sacB homology but with a non-targeting control guide. The Applicants observed an increased number of sucrose tolerant colonies when specific guides targeting sacB were included, especially the combinations of guides 1 and 2 and guides 1 and 3. A PCR screen on the colonies demonstrated that the majority of these colonies were recombinants. Together, this result showed targeting the nickase activity of the I-D complex to a genetic location increased the level of gene-editing. Methods: Construction of type I-D (Cas5:Q110A) expression plasmid A plasmid (PF3588) for the cloning multiple guides was constructed by amplifying plasmid pPF2800 with primers PF7117+PF7118. Reaction was treated with DpnI to remove PCR template and Gibson assembly was used to ligate the PCR product into the mutated vector. A plasmid (PF3662) for adding the modified sacB gene with 500 bp homology was constructed by amplifying two parts of modified sacB from plasmid pPF1117 with primers PF7368+PF7371 and PF7369+PF7370, and digesting plasmid pPF3588 with KpnI/HindIII. PCR reactions were treated with DpnI to remove PCR template and Gibson assembly was used to ligate the PCR products into the pPF3588 backbone. Spacer fragments were formed by annealing oligonucleotides (Table BELOW) and these were inserted into pPF3588 (control only) and pPF3662 at the BsaI restriction site at the CRIPSR repeat boundary. These plasmids were named gene-editing plasmid in the assay. A plasmid (pPF3605) for the expression of I-D complex (with active Cas10d HD nuclease) with inactive Cas3’ (helicase mutant) was constructed by amplifying plasmid pPF2791 with primers PF3197+PF3198. Reaction was treated with DpnI to remove PCR template and Gibson assembly was used to ligate the PCR product into the mutated vector. Gene-editing in bacteria Plasmids for Cas expression (pPF3605), pPF1117 and the appropriate gene-editing plasmid were transformed into Escherichia coli MFDpir recA+ cells, which allow recombination to occur, and cells were plated on LBA supplemented with appropriate antibiotics, diaminopimelic acid (DAP) and 0.5% glucose (repress I-D complex expression). Colonies were grown overnight at 37˚C in LB with antibiotics, DAP and glucose. Cultures were pelleted by centrifugation at 7,000 g for 2 min and resuspended in LB with antibiotics, DAP, 50 µM IPTG (express guides) and 0.2% arabinose (express Cas proteins). After 3 hr, cultures were serially diluted in 10-fold increments and 10 µL of each dilution were spotted onto LBA with chloramphenicol (for pPF1117), DAP and with or without 10% sucrose. Plates were incubated overnight at 37˚C. Colonies were counted and the recombination frequency was determined by divding the number of colonies that grew with sucrose supplemented by those that grew without sucrose. Recombination was measured by amplifying colonies with primers PF4948+PF7372. Only successful recombinant will amplify an amplicon of 1.4 kb. Table 14: Additional oligonucleotides used in gene-editing example Table 14. Additional plasmids used in gene-editing study References Bikard, D., Jiang, W., Samai, P., Hochschild, A., Zhang, F., Marraffini, L.A. (2013). Programmable repression and activation of bacterial gene expression using an engineered CRISPR-Cas system. Nucleic Acids Res. 41, 7429–37. Campa, A.R., ^, Smith, L.M., ^, Hampton, H.G., Sharma, S., Jackson, S.A., Bischler, T., Sharma, C.M., Fineran, P.C. (2021). The Rsm (Csr) post-transcriptional regulatory pathway coordinately controls multiple CRISPR-Cas immune systems. Nucleic Acids Res. 49, 9508-25 Charles, E.J., Kim, S.E., Knott, G.J., Smock, D., Doudna, J., Savage, D.F. (2021). Engineering improved Cas13 effectors for targeted post-transcriptional regulation of gene expression. bioRxiv dio: 10.1101/2021.05.26.445687 Kieper, S.N., Almendros, C., Behler, J., McKenzie, R.E., Nobrega, F.L., Haagsma, A.C., Vink, J.N.A., Hess, W.R., Brouns S.J.J. (2018). Cas4 Facilitates PAM-Compatible Spacer Selection during CRISPR Adaptation. Cell Rep. 22, 3377–84. Kim, S.K., Kim, H., Ahn, W.-C., Park, K.-H., Woo, E.-J., Lee, D.-H., Lee, S.-G. (2017). Efficient Transcriptional Gene Repression by Type V‑A CRISPR-Cpf1 from Eubacterium eligens. ACS Synth Biol. 6, 1273-82. Lin, J., Fuglsang, A., Kjeldsen, A.L., Sun, K., Bhoobalan-Chitty, Y., Peng, X. (2020). DNA targeting by subtype I-D CRISPR–Cas shows type I and type III features. Nucleic Acids Res. 48, 10470–8. Luo, M.L., Mullis, A.S., Leenay, R.T., Beisel, C.L. (2015). Repurposing endogenous type I CRISPR-Cas systems for programmable gene repression. Nucleic Acids Res. 43, 674–81. McBride, T.M., Schwartz, E.A., Kumar, A., Taylor, D.W., Fineran, P.C., Fagerlund, R.D. (2020). Diverse CRISPR-Cas Complexes Require Independent Translation of Small and Large Subunits from a Single Gene. Mol Cell. 80, 971-979.e7. Shah, S.A., Erdmann, S., Mojica, F.J.M., Garrett, R.A. (2013). Protospacer recognition motifs: Mixed identities and functional diversity. RNA Biol. 10, 891–9. Silva-Rocha, R., Martínez-García, E., Calles, B., Chavarría, M., Arce-Rodríguez, A., de Las Heras, A., Páez-Espino, A.D., Durante-Rodríguez, G., Kim, J., Nikel, P.I., Platero R., de Lorenzo V. (2013). The Standard European Vector Architecture (SEVA): a coherent platform for the analysis and deployment of complex prokaryotic phenotypes. Nucleic Acids Res. 41, D666–D675. Vink, J.N.A., Baijens, J.H.L., Brouns, S.J.J. (2021). PAM-repeat associations and spacer selection preferences in single and cooccurring CRISPR-Cas systems. Genome Biology 22, 281 Qi, L.S., Larson, M.H., Gilbert, L.A., Doudna, J.A., Weissman, J.S., Arkin, A.P., et al. (2013). Repurposing CRISPR as an RNA-guided platform for sequence-specific control of gene expression. Cell. 152, 1173–83.

Sequences (5’ to 3’) SEQ ID NO: 2. Cas10d protein sequence (GenBank: BAD01913.1) HD domain is in bold

SEQ ID NO: 3. cas7d DNA sequence (GenBank: BAD01914.1) SEQ ID NO: 4. Cas7d protein sequence (GenBank: BAD01914.1) residues which may be modified are in bold SEQ ID NO: 5. cas5d DNA sequence (GenBank: BAD01915.1) SEQ ID NO: 6. Cas5d protein sequence (GenBank: BAD01915.1) residues which may be modified are in bold SEQ ID NO: 7. cas6d DNA sequence (GenBank: BAD01916.1) SEQ ID NO: 8. Cas6d protein sequence (GenBank: BAD01916.1) N SEQ ID NO: 9. cas3’ DNA sequence (GenBank: BAD01912.1)

SEQ ID NO: 10. Cas3’ protein sequence (GenBank: BAD01912.1) SEQ ID NO: 11. Cas11d DNA sequence (The first A is 2488 bp into cas10d (GenBank: BAD01913.1)): SEQ ID NO: 12. Cas11d protein sequence (The first M is residue 830 of Cas10d (GenBank: BAD01913.1)): Modified Sequences (modified sequence in bold):

SEQ ID NO: 15. PAM-sensing mutant cas10d DNA sequence (BAD01913.1:c.976A>G;977A>C) modified positions are in bold

SEQ ID NO: 16. PAM-sensing mutant Cas10d (BAD01913.1:p.K326A) modified residues are in bold SEQ ID NO: 17. Dead cas7d DNA sequence (BAD01913.1:c.302A>C;356A>C) modified positions are in bold SEQ ID NO: 18. Dead Cas7d (BAD01913.1:p.E101A;D119A) modified positons are in bold SEQ ID NO: 19. PFS-sensing cas5d DNA sequence (BAD01913.1:c.328C>G;329A>C) modified positions are in bold SEQ ID NO: 20. PFS-sensing mutant Cas5d (BAD01913.1:p.Q110A) modified positions are in bold SEQ ID NO: 94. PAM-sensing mutant cas5d DNA sequence (BAD01913.1:c 340A>G;341A>C) modified positions are in bold SEQ ID NO: 95. PAM-sensing mutant Cas5d (BAD01913.1:p.K114A) modified positions are in bold Q Q SEQ ID NO: 21. Example guide RNA (spacer bold) SEQ ID NO:22 dsDNA sequence tested (protospacer bold; PAM underlined): SEQ ID NO:23 RNA sequence tested (protospacer bold; possible PFS underlined) SEQ ID NO:24 ssDNA sequence tested (protospacer bold; possible PFS underlined): SEQ ID NO:25 CRISPR array spacer SEQ ID NO:26 CRISPR array flanking repeat SEQ ID NO: 92. cas3’ (BAD01912.1:c.593A>C;596A>C) modified positions are in bold

SEQ ID NO: 93. Cas3’ (BAD01912.1:p.D198A;E199A) modified positions are in bold