WO2025072446A1 - Cell specific activation - Google Patents

Abstract

Disclosed herein are compositions, systems and methods for the cell specific activation of biochemical activities imported into in vitro or in vivo cell populations. Through practice of the disclosure herein, one may introduce into a heterogeneous cell population a molecule or set of molecules capable of providing a novel activity or novel substrate for a native activity in the cells, and to gate this activity such that it is only active in a subset of the heterogeneous population harboring a target cell marker. Upon identification of the target cell marker, the molecule or set of molecules is capable of providing any one of a broad range of activities specifically to the subset of the cell populations, from expression of novel proteins or catalytic activities to selectively killing cells harboring the target marker.

Description

CELL SPECIFIC ACTIVATION CROSS-REFERENCE TO RELATED APPLICATIONS [0001] This document claims priority to US Prov Ser No 63/585,679, filed September 27, 2023, which is hereby incorporated by reference in its entirety. BACKGROUND [0002] Importing biochemical activities into cells remains a challenging process. Cell transformation remains difficult and in some cases dangerous for many cell types and in particular for cells in vivo. Furthermore, the risk of off target transformation raises the possibility that nontargeted cells may be harmed by the process. Thus, the promise of using cell transformation to import biological activities into specific in vivo cell populations remains distant, despite the tremendous promise of these techniques. SUMMARY [0003] Disclosed herein are compositions, systems and methods for the cell specific activation of biochemical activities imported into in vitro or in vivo cell populations. Through practice of the disclosure herein, one may introduce into a heterogeneous cell population a molecule or set of molecules capable of providing a novel activity or novel substrate for a native activity in the cells, and to gate this activity such that it is only active in a subset of the heterogeneous population harboring a target cell marker. Upon identification of the target cell marker, the molecule or set of molecules is capable of providing any one of a broad range of activities specifically to the subset of the cell populations, from expression of novel proteins or catalytic activities to selectively killing cells harboring the target marker. [0004] Accordingly, disclosed herein are methods of targeting an activity to a subset of a population of cells. Some such methods comprise one or more of transfecting the population of cells using a detection agent, the detection agent being triggered by a component of the subset of the population of cells to activate a moiety capable of performing the activity in the cell population. [0005] The present invention provides methods for cell-specific activation of bacterial immune defense systems to achieve targeted cell depletion in non bacterial cells. The method comprises one or more of a) obtaining a biological sample from a subject; b) processing the sample to isolate cells of interest; c) extracting RNA from the isolated cells; d) performing RNA sequencing and analysis to identify cell-specific RNA molecules; e) designing guide RNAs targeting the identified cell-specific transcripts; f) engineering proteins for optimal activity; g) manufacturing the designed guide RNAs and engineered proteins; h) formulating the manufactured components for delivery; i) administering the formulated components to the subject; and j) measuring outcomes related to target cell depletion. [0006] Also disclosed herein are bipartite target gated in vivo expression systems. Some such systems comprise one or more of: 1) a first constituent activator moiety, the activator moiety comprising a target recognition component and a signaling component, and 2) a second constituent effector moiety comprising signaling detection component and an effector component. [0007] Also disclosed herein are single protein target gated in vivo expression systems. Some such systems comprise one or more of a single protein moiety comprising a target recognition component, often comprising a gRNA directed target recognition functionality, and an effector moiety. [0008] Also disclosed herein are populations of cells, the population comprising a cell such as a cancer cell comprising a foreign nucleic acid binding protein complex that is at least partially base paired to a cancer cell specific transcript in the cancer cell, and wherein the population comprises a non-cancer cell comprising the foreign nucleic acid binding protein complex. [0009] Also disclosed are methods of selectively depleting cancer cell cytoplasmic ATP. Some such methods comprise one or more of treating a patient cell population such that at least one cell such as a patient cancer cell and at least one patient non-cancer cell express a cancer-cell specific transcript binding moiety; and binding the cancer-cell specific transcript binding moiety to the cancer cell specific transcript; wherein the cancer-cell specific transcript binding moiety is activated by binding to the cancer-cell specific transcript to degrade ATP. [0010] Consistent with the above, disclosed herein are methods of ameliorating a symptom of a disorder comprising administering to a patient a composition that is activated upon contact to a cell responsible for the disorder. [0011] Also consistent with the above are methods of targeting senescent cells in a cell population in an individual, comprising contacting the population to a synthesis inducing moiety, wherein the synthesis inducing moiety gates activity of a cell activity synthesizing moiety such as a toxicity synthesizing moiety, wherein the synthesis inducing moiety is gated by a metabolite such as a nucleic acid that is differentially present in senescent cells, and wherein the cell toxicity synthesizing moiety directs cell death in senescent cells. [0012] Similarly disclosed herein are methods of reprogramming a cell population such as senescent cells in a heterogeneous cell population in an individual, said method comprising one or more of contacting the population to a synthesis inducing moiety, wherein the synthesis inducing moiety gates activity of a cell reprogramming synthesizing moiety, wherein the synthesis inducing moiety is gated by a metabolite that is differentially present in senescent cells, and wherein the cell reprogramming synthesizing moiety directs cell reprogramming in senescent cells. [0013] Similarly, disclosed herein are methods of targeting cancer cells in a cell population in an individual, comprising contacting the population to a synthesis inducing moiety, wherein the synthesis inducing moiety gates activity of the cell toxicity synthesizing moiety, wherein the synthesis inducing moiety is gated by a metabolite that is differentially present in cancer cells, and wherein the cell toxicity synthesizing moiety directs cell death in cancer cells. [0014] Also disclosed herein are methods of targeting a cell population in an organism in an individual, comprising contacting the population to a synthesis inducing moiety, wherein the synthesis inducing moiety gates activity of a cell toxicity synthesizing moiety, wherein the synthesis inducing moiety is gated by a metabolite that is differentially present in the cell population, and wherein the cell toxicity synthesizing moiety directs cell death in the cell population. [0015] Also disclosed herein are methods of expressing a tag in a subset of a heterogeneous cell population, comprising contacting the population to a synthesis inducing moiety and a tag synthesizing moiety, wherein the synthesis inducing moiety gates activity of the tag synthesizing moiety, and wherein the synthesis inducing moiety is gated by a metabolite that is differentially present in the subset of the heterogeneous cell population, and wherein the tag synthesizing moiety directs accumulation of a tag. [0016] Consistent with the mechanism of some of the above, disclosed herein are expression systems comprising a nucleic acid sensor such as an RNA or DNA sensor, a secondary messenger such as cOA, and an effector such as an expression cassette comprising a coding region and a secondary-messenger gated functionality governing the expression cassette. [0017] Though some specific examples are cited, it is understood that the disclosure herein may in various embodiments relate to a broad range of heterogeneous cell populations and a broad range of imported gated activities mediated by a first component or a first component and a second component, ranging from co-opting native defense mechanisms to kill target cells, to starving cells of ATP, to using cOA or other messenger to induce secondary biochemical activity or protein expression so as to effect any number of cellular outcomes, from tag expression to chromatin remodeling to disease complementation to cell surface protein expression to inducing cell death or tagging a cell for death. INCORPORATION BY REFERENCE [0018] All publications, patents, and patent applications mentioned in this specification are herein incorporated by reference to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference. BRIEF DESCRIPTION OF THE DRAWINGS [0019] Fig. 1 shows an activation system expressed in a cell population comprising a nontarget cell, top, and a target cell, bottom. [0020] Fig. 2 shows a system for RNA expression-gated cell death. [0021] Fig. 3 shows a range of systems and effects that may be mediated by a secondary messenger such as cOA generated via ATP depletion. DETAILED DESCRIPTION [0022] Disclosed herein are compositions, systems and methods related to cell-specific activation of foreign signaling, catalytic or enzymatic activity delivered to the cell. Through practice of the disclosure herein, a composition comprising a signaling, catalytic or enzymatic activity may be delivered to a target cell or cells, and optionally also delivered to a nontarget cell or cells, but the composition is differentially active in the target cell or cells. [0023] Differential activity is gated by the recognition of a target-cell specific marker such as a nucleic acid present in the target cells but absent in nontarget cells. Alternately, the differential activity may be gated by accumulation of the cell specific marker at above a threshold necessary to activate or otherwise mediate the differential activity. [0024] Gating the differential activity variously comprises any number of changes to the differential activity. Most often the gating is a qualitative ‘yes/no’ or ‘on/off’ gate such that identification of the marker turns on the differential activity. However, in alternative embodiments, identification of the marker leads to a quantitative increase in differential activity, or alternately leads to a quantitative decrease in differential activity or to a qualitative deactivation of differential activity. A common feature of many of these case is that the change in differential activity is gated by identification of a marker such as a target cell specific marker. [0025] Differential activity is in some cases harbored in a single component such as a single protein complex or a single nucleic acid protein complex. In these cases, identification of the target specific marker by the single component such as a single protein complex or a single nucleic acid protein complex gates the differential activity which is mediated by the single component such as a single protein complex or a single nucleic acid protein complex. [0026] A number of single protein component systems are consistent with the disclosure herein. A representative subset are presented below, but one understands that a broad range are consistent with the disclosure. [0027] RNA-guided proteins containing a death domain. Upon target recognition, the activated death domain recruits and interacts with other death domain-containing proteins, forming a larger signaling complex. This is similar to how the Fas-associated death domain (FADD) protein recruits other proteins to form the death-inducing signaling complex (DISC). This signaling complex may activate caspases and initiate an apoptotic cascade. An exemplary protein of this system is as follows: MDILLITLILGAVGALANKEVCVSGKFTTTGECCRQCEPGQGVLKPCGATQTVCTPC LDSETFSENYSHTDTCRPCTRCEGILRMRSPCTDSEDAVCICDYGYYLNEISNRCESCT KCPLGQGMLFACEHERDTVCEECIRDTYSDQESSREPCLPCTICDEDGDMEIQPCNPS KDTVCQGEILAENSPPTENSQPCSRCVGLACSESNDVCICDDEYYLDKNTNRCESCTK CPLGQGMLFACENERDTVCEECIRDTYSDQESSREPCLPCTICDEDGDMEIQPCNPSK DTVCPDLNSSLPSFTNDDRFHYISTEITTTTPTSATTSSIRFIGPGLNENLIPIYCSILAAV VVGLVAFIIFKRWNSCKQNKQGANNCTANQNQTPSPEAEKLHSDSGISVDSQSLQEQ HGQGQTLAQTVVTVDEDPCLLLPLHTREEVEKLLYRGKDMEGCHHSTDSDWCSLA GLLGYQEERIASFCQEDHPVCALLSDWANQECASVDTLCTALRKINREDIAQTLTLSP AAVKPTATSTV . [0028] RNA-guided proteins containing a hemolysin domain. Upon target recognition, the protein undergoes conformation change, activating the hemolysin function, which forms pores in the cell membrane leading to osmotic imbalance, energy imbalance, and eventual cell lysis. This is the primary mechanism of bacterial infection symptoms. An exemplary protein of this system is as follows: MKNARMNRGEEMGWAKQKGKQPENRLYLTRMVPLPLDHYLPLLKPPMLAGTKIW NSCVWESREARKNNEKYPTESELKSRFKHYGSWKSLHSQSAQAVVEEYFEAVRSYI KHRENGHEEMRPPGLKNKNLLRTITWKRQGFEYREGTITLKLSRKLNDIRVPLPEGA DSLKLPDGTVLVGTPIEVKVKAVYRKRKIAGLEIHVTWDFGVVPLIAGNRVSAYDLN TALIARASTTGGQQLIVCRELLSLIQYRNKTIAEFQQKISRLKEGSRKWKALLKAKRK ELKKLERRIKQLTNAVTKLMAEIDAAENIAVSVLGDLGDLRRKARTNDKNKKASQKI NQLPYAQIEQQHKYKSLLKQICPDKWSEKYSSQTCCICGTRNKSFRVHRGLWRCRSC GAIMHADLNGANGILKNYLIGHCDMKQLFPLKSPEVYRWDKRWNRFVKVSPRAAA . [0029] RNA-guided proteins containing a SIVA apoptosis signaling domain. Upon target recognition, the protein is activated and initiates apoptotic signaling, such as by interacting with death receptors such as CD27, inhibiting anti-apoptotic proteins such as BCL-XL, and promoting caspase activation. An exemplary protein of this system is as follows: MFTPTPTRKSTTSIRKRSRPTFTSLSLAPLNGHNDDAAALSSNRDGAGGAVEFSMEDN PVGGGAYAEGTQPSWGGALNGAGWGCCAGESGGNANNGYSPFSPTIGFQTATLAP ATNTGAAGANNGTTNTVSPFFDKNYQSQQQQLNATAANTNNVPSPPDAVTTHRFNA QNNTNSHLQQNDALMLSQTSTTSSLTFASNNATDSSSVLMDLESNHSGFERDFRSTA NSNTTNPNFSFSFHMNSDGQSSESMDSPMRCYHYCLSPPPKRARLDYGRRQEEGGA AVAMQQPMPTCKTILPSDITTSGDNGCCCHVCGAPPLGGGNVNTTMYAVSNPRPDA ASEVNAFAVHNNNDINAQPCSKTRKSKSQSLLSFFPRSATSNKKQSAVESIAPMMMS QTSIETTNNAGTSSSINPPTNTTTNATNNNIISCRYCDKPTCIQSCSRQCEQCSNRFCTF CSKVDYGEVVERIVCFECEELLVGEDVDMMDM . [0030] RNA-guided proteins containing tumor necrosis factor receptor domains. Upon target recognition, the protein undergoes a conformational change resulting in active binding sites of the TNF receptors, initiating the apoptosis signaling cascade. This recruits adaptor proteins such as TRADD or FADD, form the death inducing signaling complex DISC, and lead to the activation of caspases. An exemplary protein of this system is as follows: MDTLTWTLLCAAVSIGTLAAFAMRTMGCSESVSPPQAAEYDSITEFNDNGQVAVVC GSTLELPLEEECESGRFTRSGECCIECPPGEGVITPCGVTQTECGQCLDSETYSDTYSL TDKCQTCTECTGLMRMETPCTDSNNAVCVCDYGYYMSTETGGCEPCTVCPRGHGV YIRCEPEHDTICEPCEEDTYSDQESSLDPCMPCTICNDGSEELETLRECSSTADALCYD PLAPTMASPSSPPELPWDELRTPGPDEDSTTTKPSTPRFIGSGLNENLIPIYCSTLAAVLI GLLAYIVFKRWNSCKQNKQAANNRAATANQTSPSPEGEKLHSDSGISVDSQSLQEQQ QLQTQAEAHTQTQTQLHVPEQIVVRVDGGAQSDSPPSQA . [0031] RNA-guided proteins containing a trypsin like serine protease. Upon target recognition, the protein undergoes a conformational change resulting in an active binding site of the serine protease. Trypsin like enzymes have a negatively charged residue in the S1 pocket to bind and cleave positively charged substrates. These trypsin like serine proteases have broad substrate specificity. An exemplary protein of this system is as follows: MSGAKRREGVIAKWHADAPPLVKKLHQCPTYKTASTEVLLSRVAWIVPTLRRALA WHMHEKPFRRVRHRAYVSRERAITQLAEQLRAPRGMTTVVGVGNWSAQDRGGIMR GTPPGPWIRFLRRLRRVCRVVVVDEHRSSKLCCACHATLHAHQYVRVRNDEEKLVD VWDTKRCPTYKTASTEVLLSRVAKIVPDLREGLAWHRDKKPFRKLRHQAYVGRER AINRLAEQLRAPRGMTTVVGVGNWSAQDRGGIMRGTPPGPWIRFLRRLRRVCRVVV VDEHRSSKLCCACHATLHAHQYVRVRNDEEKLVDVWDTKRCTEQRLQSQRQDKSI VYRLFTAPSCAIDSTCAPEFDFLQHAVVQITNPMTSNFCTGTLLKGPGDKIYVLSAYH CLAFMGKRFMYPWSTFSIIFDYKLPCNASYVEDVPRTFDRYLTGLAVVFQDVYSDVG VFELLQDIPPEWGVVLAGWEAANLGSNFTYTCISQPAGDVQKIAYGKVYNQIPSVIL DAVNEEVDVYNVSCSTHACNFYATHVQHGSMTHGSSGAGMFADELGKIMGVLSTG RGSVCPGTVNKDDPRPSRVVFGSLGGAWEHGLHRIFNRSVEDEGGAEFEEYTRALPT ITVGNIVPEVNPRKGSTSFSIALQQEPDKDTTISLTPTQTDLVSVTPQTLTFTRSNWRTP QFVSVTAGRAHPEATLQFDVALTWPVVSEAGGWSSRTKTISGVVWAERKGNSFFNP QEVRVPFRHVMDLERYNPQIPLITEHNGPFIPAKYFVYTAQKTEVTRKGWAYYFVAH PRTQVTIPGQSKSLNGKASMTIASMPLAEAVTESLNPTRLRIPAVPSHAVLPITIAPVL AWLDLEEDHTLNITTCSNKTDVGAEITVMDDQLEVIRTTGLARDNACVSIPSVVVEG GRRYFISITPVQYQFSLGKKTHQVDIHILDA . [0032] RNA-guided proteins containing a metallopeptidase. Upon target recognition, the protein undergoes a conformational change resulting in an active binding site of the metallopeptidase. The metal ion in the active site activates a water molecule to perform a nucleophilic attack on the peptide bond, forming a tetrahedral intermediate that gets broken down to cleave the peptide bond. These proteases prefer hydrophobic residues at P1 for cleavage. An exemplary protein of this system is as follows: RREDVVAREELNKVTDFTVVKTTLNQFCKSKARALLWDEVLADMNKGVLEAYLLA NVHVLRLCKAGLIPPLNSTFFNQCLSLVMEMSGARGPKNGELLLSRDVYNSFRDPTV PRASRQFIHRGWVHNAANQMATMAQNAVSLNFYRRFHKFLKRKYGVDGRDAYSLL ERILDNAYDGQDAVVLEWRAQIPRTATGAPKTATHLLVPLTYRFLQDIEERNWISQG DHEFRQVRTFTVLPTKRGFECSHMKMCKLGLRSLLQRAGIRVPPEGPKWSAVERAY WRRLFNIKKFETANRKFAGQIVTDGKAVSIVMRKPKRESSPYLFVATNQLDETVSCS TKEFYEEARYTKAKQKIKGWQDRSPRVLEAIRNMPTKKSASLETLGYYIRFMTKRM DLLLGFARHKPFRRLRLRSFIFMKRKLRQLCLMLAREGERTVVGFGDWSNQDVAGV IKKSSAGPVKRFERELARYCTVISIAEFRTSKVHFDCECELKNQYSQRLCWDGEIRTQ KVHSVLHCSSNGCRGITVNRDVNASRNMLRLLQCKLNGIDRPVAYTLTNLRENEKL AFPLVLVEGTVDNVRSANLSDVGLYVQAIAHEVKQGETQSNSWVGSVCWPVVRDS GHFKAYVHLPRTGAFHIRLRIATTTSTLTLRFVPRRTKWILRFHYQKPRESHHAFDGT SGVGNADSDACERLKFNALLLQTAVAELFHRAGLSRKTFALELDGDGFPIVSLLRSK YSSTYARRMSDPQLLSLLHRDVKGDEQQEKRDSEPTRRRRIKHVVIMGDSQLDPRTG KAPRFKALLGGDVVASSACNMYTWPRGLEEFTACCINSELVAPGLSVPHCAVRRSF WANYSGGLSVLLQLLGLSFGLRYRTNGVMHKSFREFTRLFTVFEPRSGMQQSAASSR PIGDGRFARLQLRTLKPVGLAPEGAHLDDLSIGELALQCRWINPNTTKRVHAAMATA AVAA [0033] RNA-guided proteins containing a papain like cysteine protease. Upon target recognition, the protein undergoes a conformational change resulting in an active binding site of the papain like cysteine protease. Upon substrate binding, the cysteine thiol attacks the carbonyl carbon of the peptide bond to be cleaved. This forms a tetrahedral intermediate stabilized by an oxyanion hole. The peptide bond breaks, and the c-terminal portion of the substrate is released while the n-terminal is fused to the protease as an acyl-enzyme intermediate. A water molecule is used to hydrolyze this intermediate. Papain like cysteine proteases have broad substrate specificity. An exemplary protein of this system is as follows: MAQFAHGISALDVTPSAALSAPVWLLGKRYDDVAAADFDAYKRSFESILWFTYRRD YPAMTPYEHTSDAGWGCMLRSAQMLLGQALQRRLLGRDWRLPALFETDMDARLPE TYVQLLRWFADSPDIACRYSIHHMVKLGVQYDKLPGEWYGPTTAAQVLRDLVNLH RREFGGELAMYVPQEGVVYSDDVAKLCVSHIEQETVEKEVKDEGAPEFFDPLLHPPT SEDKSDWSTALLILIPLRLGLDQVNERYVPAIQKTFAFPQSVGIIGGKKGHSVYFVGT QQDQLHLLDPHDVHPAPELNAAFPTATHLRTVHSSRPLVMNVTTIDPSLALGFLCEH RADYEDFERRVRTLHDEVKEEGGMCPFSVAARRPDYAASGGDLLMADCLSGDDMN EDELASASGAGTGEDDEDDYNEDCEARYWDRDVNAAINMLELLKSEVQGRGRMEP FRRS . [0034] RNA-guided protein containing an MFS transporter. Upon target recognition, the protein undergoes a conformational change resulting in the activation of the MFS transporter domain that facilitates the transport of small solutes across membranes. This domain in some cases exports essential metabolites and ions outside the cell resulting in membrane destabilization and disrupting cellular homeostasis. An exemplary protein of this system is as follows: MGVVLQNVEFRALWFAEAQSAAGDQLAKVALAIMVYQRTGSALWAAGVYALTFL PALIGGLGLSQLADRYPRRALLTTCALIQAALVALMAVPGMPLVALCALVVAVQLV VAPANAAQNAVTREVFTDDDLYLRSQDLRGITTNTVMLLGLAGGGLLVTLVGTSW ALACNAVTFAISALVVRLWVRARPAAGKKSDSWFGGARWVFGQRRLRLLLALSWL VGLAVVPEGLAAPLADQIGAPQEAVGWLLAADPLGFVLGAYLLSKYASAQSRLRLM GVLAVASCGVLIGFAVQPNLGLALALLALAGAAGAYIITVGATFNTWVPNEMRGAA GGLYRTGLRVAQGVGVALGGAVAELIGSVPNTIALAGVLGVVLAAPVALSWSRVH KDQQAPRVDEAG . For each of the proteins herein, the sequence is given as an example of broader categories rather than as individual examples. Accordingly, contemplated herein are proteins having a sequence similarity or identity of at least 70%, 750%, 80%, 85%, 90%, 95% or greater than 95% to the listed proteins, as well as proteins differing in no more than 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 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, 100 or more than 100 residues from a protein listed herein. Similarly, some proteins that differ from the listed proteins as indicated herein preserve activity of the unmodified proteins, or exhibit a change in activity such as target binding or activation of 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29%, 30%, 31%, 32%, 33%, 34%, 35%, 36%, 37%, 38%, 39%, 40%, 41%, 42%, 43%, 44%, 45%, 46%, 47%, 48%, 49%, 50%, 51%, 52%, 53%, 54%, 55%, 56%, 57%, 58%, 59%, 60%, 61%, 62%, 63%, 64%, 65%, 66%, 67%, 68%, 69%, 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%, 100%, or more than 100%, [0035] Table 1 presents a list of single component proteins as well as source organism. Table 1

[0036] Differential activity is in some cases directed to manipulate the target cell, such as by triggering death of the target cell. Alternately or in combination, differential activity may comprise generation of a signal, such as a signal that may activate one or more effectors co- delivered to the target cell. In these cases, the component harboring the differential activity serves as a sensor for the target specific marker, while the signal generated by the differential activity may serve to gate activity of the one or more effectors. [0037] Differential activity acting on the target cell and differential activity serving to gate the one or more effectors are in some cases not mutually exclusive. That is, some differential activities both act on the target cell and gate activity of one or more effectors, while in some cases differential activity serves exclusively to act on the target cell or exclusively to gate effector activity. For example, differential activity converting ATP to cOA may 1) act on the target cell to deplete ATP, as may lead to cell growth inhibition or cell death, may 2) generate cOA to gate activity of one or more effectors, or may 3) both deplete ATP to lead to cell growth inhibition or cell death and also generate cOA to gate activity of one or more effectors. [0038] Consistent with the above, some compositions, systems or methods comprise a single component or component population comprising a uniform single protein complex or a single nucleic acid protein complex. Alternately, some compositions, systems or methods comprise a multicomponent system comprising a first component such as the single component above having a differential activity gated by identification of a target cell marker, and a second component having an effector activity that is gated by the differential activity of the first component. [0039] In some embodiments, the cell-specific activation system comprises a single-part system capable of recognizing a foreign RNA molecule within a cell and selectively killing that specific cell only if it contains the foreign or cell type-specific RNA. Such single-part systems offer the advantage of simplified delivery and reduced complexity compared to multi-component systems. [0040] One exemplary single-part system comprises a CRISPR-Cas13 nuclease programmed with a guide RNA (gRNA) targeting a specific RNA sequence. Upon recognition of the target RNA, Cas13 exhibits collateral RNase activity, cleaving nearby RNA molecules non- specifically. This collateral activity can lead to cell death in cells containing the target RNA. The Cas13 protein may be engineered for enhanced specificity or activity, such as by incorporating mutations in the HEPN catalytic domain or optimizing nuclear localization signals. [0041] Another embodiment utilizes engineered small conditional RNAs (scRNAs) that can trigger cell death pathways when they detect their target RNA sequence. These scRNAs may be designed to activate apoptotic or other cell death mechanisms only in the presence of a specific cellular RNA. The scRNAs may incorporate ribozyme domains, aptamer sequences, or other structural elements that undergo conformational changes upon target binding, leading to the exposure or activation of cell death-inducing motifs. [0042] In yet another embodiment, the single-part system may comprise an RNA-targeting Type III CRISPR system (e.g., Csm/Cmr complexes) programmed to recognize a specific RNA sequence and trigger downstream signaling leading to cell death or other desired cellular outcomes. These systems may be engineered to have enhanced specificity for their target RNA or to produce secondary messengers such as cyclic oligoadenylates (cOA) with greater efficiency. [0043] The single-part system may also be an engineered RNA-sensing system comprising a riboswitch or other RNA-based sensor coupled to a cell death effector. Such a system could be designed to change conformation upon binding to a specific target RNA, thereby activating an associated ribozyme or other RNA-based effector that induces cell death. The riboswitch may be designed to respond to metabolites or small molecules produced as a result of target RNA presence, providing an additional layer of specificity. [0044] In some embodiments, the single-part system may utilize an RNA-binding protein domain fused to a cell death effector domain. The RNA-binding domain would be engineered to specifically recognize the target RNA sequence, while the effector domain would induce cell death upon target recognition. This fusion protein could incorporate modular domains allowing for easy swapping of RNA-binding specificities or effector functions. [0045] These single-part systems may be delivered to cells using various methods, including but not limited to viral vectors, lipid nanoparticles, cell-penetrating peptides, or electroporation. The systems may be expressed from DNA constructs within the cell or directly delivered as RNA or ribonucleoprotein complexes. Delivery methods may be optimized for specific cell types or tissues, such as using tissue-specific promoters or engineered viral capsids with enhanced tropism for target cells. [0046] The single-part systems described herein may be used alone or in combination with the multi-component systems described earlier in this specification. They may also be used in conjunction with other therapeutic approaches, such as chemotherapy or immunotherapy, to enhance overall efficacy in treating diseases or modifying cell populations. Combination therapies may be designed to target multiple cellular pathways or to overcome potential resistance mechanisms. [0047] In some embodiments, the single-part system may incorporate feedback mechanisms to enhance specificity or amplify the response in target cells. For example, the system may include positive feedback loops where initial target recognition leads to increased expression of the RNA-sensing components, thereby amplifying the response specifically in cells containing the target RNA. [0048] The single-part systems may be designed with tunable sensitivity and specificity. This could be achieved through the use of multiple target recognition domains, threshold- dependent activation mechanisms, or incorporation of logic gates that require the presence of multiple RNA targets for activation. [0049] In certain embodiments, the single-part system may be designed to have reversible effects, allowing for temporal control of the cell-specific activation. This could be achieved through the use of inducible promoters, degradable protein domains, or RNA aptamers responsive to small molecule ligands. [0050] The systems described herein may also be adapted for multiplexed targeting of different cell types within a heterogeneous population. This could involve the use of orthogonal RNA-sensing systems, each programmed to recognize a different target RNA and trigger a distinct cellular response. [0051] In some embodiments, the single-part system may be engineered to not only induce cell death but also to mark the targeted cells for immune recognition and clearance. This could involve the induced expression of immunogenic proteins or the release of danger- associated molecular patterns (DAMPs) upon target cell recognition. [0052] The RNA-sensing components of these systems may be further optimized for enhanced stability, reduced immunogenicity, or improved pharmacokinetics. This could involve chemical modifications of the RNA components, use of non-natural nucleotides, or encapsulation in protective nanoparticles. [0053] In certain applications, the single-part system may be designed to induce cellular phenotypes other than cell death, such as cell cycle arrest, differentiation, or transdifferentiation. This could be achieved by coupling the RNA-sensing mechanism to the expression or activation of appropriate cellular factors. [0054] The systems described herein may also incorporate safety mechanisms to prevent unintended activation. This could include the use of split protein systems that require assembly in target cells, or the incorporation of cellular constraints that prevent activation in healthy cells. [0055] In some embodiments, the single-part system comprises a CRISPR-Cas13 nuclease programmed with a guide RNA (gRNA) targeting a specific RNA sequence. Upon recognition of the target RNA, the Cas13 protein exhibits collateral RNase activity, leading to cell death in cells containing the target RNA. The Cas13 protein may be engineered for enhanced specificity or activity through mutations in its HEPN catalytic domain or by optimizing its nuclear localization signals. [0056] For example, a Cas13d protein may be engineered with mutations D1278A and E1280A in its HEPN domain to reduce off-target effects while maintaining on-target activity. The gRNA may be designed with a 28-nucleotide spacer sequence fully complementary to the target RNA, and may include 2'-O-methyl modifications at positions 1-3 to enhance stability. [0057] In another embodiment, the single-part system utilizes engineered small conditional RNAs (scRNAs) that can trigger cell death pathways when they detect their target RNA sequence. These scRNAs may incorporate ribozyme domains, aptamer sequences, or other structural elements that undergo conformational changes upon target binding, leading to the exposure or activation of cell death-inducing motifs. [0058] For instance, an scRNA may be designed with a hammerhead ribozyme domain that is initially inactive due to base-pairing with a target-complementary sequence. Upon binding to the target RNA, the scRNA undergoes a conformational change that activates the ribozyme, leading to self-cleavage and exposure of a poly(A) tail that triggers rapid degradation of essential cellular mRNAs. [0059] In yet another embodiment, the single-part system may comprise an RNA-targeting Type III CRISPR system (e.g., Csm/Cmr complexes) programmed to recognize a specific RNA sequence and trigger downstream signaling leading to cell death. These systems may be engineered to have enhanced specificity for their target RNA or to produce secondary messengers such as cyclic oligoadenylates (cOA) with greater efficiency. [0060] For example, a Csm complex may be engineered with mutations in its Cas10 subunit (D586A and D587A) to enhance its cOA synthesis activity while reducing its DNase activity. The complex may be programmed with a 40-nucleotide crRNA targeting a cancer-specific fusion transcript, triggering robust cOA production only in cells expressing the target RNA. [0061] The single-part system may also be an engineered RNA-sensing system comprising a riboswitch or other RNA-based sensor coupled to a cell death effector. Such a system could be designed to change conformation upon binding to a specific target RNA, thereby activating an associated ribozyme or other RNA-based effector that induces cell death. [0062] As an example, a synthetic riboswitch may be designed to recognize a specific microRNA (miRNA) upregulated in cancer cells. The riboswitch is coupled to a self-cleaving ribozyme that, when activated by miRNA binding, releases a highly stable RNA aptamer capable of binding and inhibiting anti-apoptotic proteins, thereby inducing cell death specifically in cancer cells. [0063] In some embodiments, the single-part system may utilize an RNA-binding protein domain fused to a cell death effector domain. The RNA-binding domain would be engineered to specifically recognize the target RNA sequence, while the effector domain would induce cell death upon target recognition. [0064] For instance, a PUF (Pumilio and FBF homology) domain may be engineered to specifically bind a 16-nucleotide sequence unique to a viral RNA. This PUF domain is fused to a truncated form of the pro-apoptotic protein Bax. Upon binding to the target viral RNA, the fusion protein undergoes a conformational change that activates Bax, triggering apoptosis in infected cells. [0065] These single-part systems may be delivered to cells using various methods, including but not limited to viral vectors, lipid nanoparticles, cell-penetrating peptides, or electroporation. The systems may be expressed from DNA constructs within the cell or directly delivered as RNA or ribonucleoprotein complexes. [0066] For example, a Cas13-based system may be packaged into adeno-associated virus (AAV) particles with tissue-specific promoters for targeted delivery to specific cell types in vivo. Alternatively, chemically modified mRNA encoding the Cas13 protein, along with its guide RNA, may be formulated into lipid nanoparticles for systemic delivery and transient expression. [0067] The single-part systems described herein may be used alone or in combination with the multi-component systems described earlier in this specification. They may also be used in conjunction with other therapeutic approaches, such as chemotherapy or immunotherapy, to enhance overall efficacy in treating diseases or modifying cell populations. [0068] For instance, a Cas13-based system targeting a cancer-specific RNA may be combined with immune checkpoint inhibitors to enhance T cell responses against tumors. The Cas13 system may be designed to not only induce cancer cell death but also to stimulate the release of damage-associated molecular patterns (DAMPs) that further activate the immune system. [0069] Consistent with this core target mediated differential activity, a wide range of biochemical outcomes may be effected within a target cell. Target cells, in isolation or in heterogeneous populations comprising both target and nontarget cells, may be selectively acted on by the differential activity or the differential activity mediated effector activity, so as to for example kill target cells, degrade a biomolecule in target cells, trigger differentiation or de-differentiation in target cells, express or activate a protein or other marker in target cells, protect target cells from a challenge or otherwise selectively perturb the target cells, as discussed below. [0070] A number of components are discussed below, with the understanding that components may be used in combination with one another consistent with the disclosure above. [0071] Target marker. A target marker may be any component of a target cell that distinguishes the target cell from a nontarget cell. Generally, target markers are present in a target cell but absent from a nontarget cell or present in a nontarget cell below a threshold sufficient for identification by a component exhibiting differential activity. [0072] Exemplary target markers are nucleic acids, such as target cell specific or differentially expressed target cell nucleic acids. Some such nucleic acids are RNA molecules such as mRNA molecules or other RNA molecules, or one or more target cell specific DNA molecules or molecular segments such as an allele at a genomic DNA locus. [0073] Often, such nucleic acid target molecules are associated with a disease such as cancer. A number of cancer associated nucleic acids are known in the art, such as point mutations (Kandoth et al. “Mutational landscape and significance across 12 major cancer types,” Nature volume 502, pages333–339 (2013)), alternative splice variant RNA molecule (see, for example, El Mabarabti and Younis, “The Cancer Spliceome: Reprograming of Alternative Splicing in Cancer” Front. Mol. Biosci., 07 September 2018), insertions, deletions, duplications or translocations. In particular, translocations are often associated with cancer cells, and are readily used as target molecules. Such translocations may be used as target molecule DNA loci or as target molecule mRNA transcripts. A partial list of nucleic acid target molecules includes AML-TEL fusions, NTRK fusion genes, MYB-NFIB, NFIB- HMGA2, ETV6-NTRK3, FGFR3-AFF3, FGFR2-CASP7, FGFR2-CCDC6, ERLIN2- FGFR1, EWSR1-FLI1, BCOR-CCNB3, SS18-SSX1, SS18-SSX2, FGFR3-TACC3, FGFR3- TACC1, KIAA1967-BRAF, EML4-ALK, FGFR3-TACC3, FGFR3-KIAA1967, BAG4- FGFR1, SFPQ-TFE3, TFG-GPR128, FGFR3-TACC3, FGFR3-BAIAP2L1, TMPRSS2- ERG/ETV1/ETV4, SLC45A3-FGFR2, ESSRA-C11orf20, PTPRK-RSPO3, EIF3E-RSPO2. See, for an early review, “Fusion genes in solid tumors: an emerging target for cancer diagnosis and treatment” Brittany C. Parker and Wei Zhang, Chin J Cancer. 2013 Nov; 32(11): 594–603. A more recent yet still likely incomplete list includes ACBD6_ENST00000367595-RRP15, ACSL3-ETV1, ACTB-GLI1, AGPAT5-MCPH1, AGTRAP-BRAF, AKAP9-BRAF, ARFIP1_ENST00000353617- FHDC1_ENST00000260008, ARID1A-MAST2, ASPSCR1_ENST00000306739-TFE3, ATG4C_ENST00000371120-FBXO38_ENST00000340253, ATIC-ALK, BBS9-PKD1L1, BCR-ABL1_ENST00000318560, BCR-JAK2, BRD3-NUTM1_ENST00000333756, BRD4- NUTM1_ENST00000333756, CANT1_ENST00000392446-ETV4, CARS_ENST00000397111-ALK, CBFA2T3-GLIS2, CCDC6-RET, CD74-NRG1, CD74- ROS1, CDH11-USP6_ENST00000250066, CDKN2D_ENST00000335766-WDFY2, CENPK-KMT2A, CEP89-BRAF, CHCHD7_ENST00000355315-PLAG1, CIC_ENST00000160740-DUX4, CIC_ENST00000160740-FOXO4, CLCN6-BRAF, CLIP1_ENST00000358808-ROS1, CLTC_ENST00000269122-ALK, CLTC_ENST00000269122-TFE3, CNBP_ENST00000422453-USP6_ENST00000250066, COL1A1-PDGFB, COL1A1-USP6_ENST00000250066, COL1A2-PLAG1, CRTC1_ENST00000321949-MAML2, CRTC3-MAML2, CTNNB1_ENST00000349496- PLAG1, DCTN1-ALK, DDX5-ETV4, DHH-RHEBL1, DNAJB1-PRKACA, EIF3E-RSPO2, EIF3K-CYP39A1, EML4-ALK, EPC1-PHF1, ERC1_ENST00000360905-RET, ERC1_ENST00000360905-ROS1, ERO1A-FERMT2_ENST00000395631, ESRP1_ENST00000358397-RAF1, ETV6-ABL1_ENST00000318560, ETV6-ITPR2, ETV6-JAK2, ETV6-NTRK3_ENST00000394480, ETV6-PDGFRB, ETV6-RUNX1, EWSR1_ENST00000397938-ATF1, EWSR1_ENST00000397938-CREB1, EWSR1_ENST00000397938-DDIT3_ENST00000547303, EWSR1_ENST00000397938- ERG_ENST00000442448, EWSR1_ENST00000397938-ETV1, EWSR1_ENST00000397938-ETV4, EWSR1_ENST00000397938-FEV, EWSR1_ENST00000397938-FLI1, EWSR1_ENST00000397938-MYB, EWSR1_ENST00000397938-NFATC1_ENST00000329101, EWSR1_ENST00000397938- NFATC2, EWSR1_ENST00000397938-NR4A3_ENST00000395097, EWSR1_ENST00000397938-PATZ1_ENST00000215919, EWSR1_ENST00000397938- PBX1, EWSR1_ENST00000397938-POU5F1, EWSR1_ENST00000397938-SMARCA5, EWSR1_ENST00000397938-SP3, EWSR1_ENST00000397938-WT1, EWSR1_ENST00000397938-YY1, EWSR1_ENST00000397938- ZNF384_ENST00000319770, EWSR1_ENST00000397938-ZNF444, EZR-ERBB4, EZR- ROS1, FAM131B-BRAF, FBXL18-RNF216, FCHSD1-BRAF, FGFR1_ENST00000447712- PLAG1, FGFR1_ENST00000447712-TACC1, FGFR1_ENST00000447712-ZNF703, FGFR3_ENST00000440486-BAIAP2L1, FGFR3_ENST00000440486-TACC3, FN1_ENST00000336916-ALK, FUS-ATF1, FUS-CREB3L1, FUS-CREB3L2, FUS- DDIT3_ENST00000547303, FUS-ERG_ENST00000442448, FUS-FEV, GATM-BRAF, GMDS-PDE8B, GNAI1-BRAF, GOLGA5-RET, GOPC-ROS1, GPBP1L1_ENST00000290795-MAST2, HACL1-RAF1, HAS2-PLAG1, HERPUD1_ENST00000300302-BRAF, HEY1_ENST00000354724-NCOA2, HIP1-ALK, HLA-A-ROS1, HMGA2_ENST00000403681-ALDH2, HMGA2_ENST00000403681- CCNB1IP1_ENST00000358932, HMGA2_ENST00000403681- COX6C_ENST00000297564, HMGA2_ENST00000403681-EBF1, HMGA2_ENST00000403681-FHIT_ENST00000476844, HMGA2_ENST00000403681- LHFPL6, HMGA2_ENST00000403681-LPP, HMGA2_ENST00000403681- NFIB_ENST00000397581, HMGA2_ENST00000403681-RAD51B_ENST00000487270, HMGA2_ENST00000403681-WIF1, HNRNPA2B1_ENST00000356674-ETV1, HOOK3- RET, IL6R-ATP8B2, INTS4-GAB2, IRF2BP2-CDX1, JAZF1-PHF1, JAZF1-SUZ12, JPT1- USH1G, KIAA1549_ENST00000440172-BRAF, KIF5B-ALK, KIF5B-RET, KLC1_ENST00000389744-ALK, KLK2-ETV1, KLK2-ETV4, KMT2A-ABI1, KMT2A- ABI2_ENST00000261017, KMT2A-ACTN4, KMT2A-AFDN_ENST00000392108, KMT2A-AFF1_ENST00000307808, KMT2A-AFF3, KMT2A-AFF4, KMT2A-ARHGAP26, KMT2A-ARHGEF12, KMT2A-BTBD18, KMT2A-CASP8AP2, KMT2A-CBL, KMT2A- CEP170B, KMT2A-CIP2A, KMT2A-CREBBP, KMT2A-CT45A2_ENST00000612907, KMT2A-DAB2IP_ENST00000309989, KMT2A-EEFSEC, KMT2A-ELL, KMT2A-EP300, KMT2A-EPS15, KMT2A-FOXO3_ENST00000343882, KMT2A-FOXO4, KMT2A-FRYL, KMT2A-GAS7, KMT2A-GMPS, KMT2A-GPHN, KMT2A-KNL1, KMT2A-LASP1, KMT2A-LPP, KMT2A-MAPRE1, KMT2A-MLLT1, KMT2A- MLLT10_ENST00000377072, KMT2A-MLLT11, KMT2A-MLLT3, KMT2A-MLLT6, KMT2A-MYO1F, KMT2A-NCKIPSD, KMT2A-NRIP3, KMT2A-PDS5A, KMT2A- PICALM, KMT2A-PRRC1_ENST00000296666, KMT2A-SARNP, KMT2A- SEPT2_ENST00000360051, KMT2A-SEPT5, KMT2A-SEPT6, KMT2A-SEPT9, KMT2A- SH3GL1, KMT2A-SORBS2_ENST00000284776, KMT2A-TET1, KMT2A- TOP3A_ENST00000321105, KMT2A-ZFYVE19, KTN1-RET, LIFR-PLAG1, LMNA- NTRK1_ENST00000392302, LRIG3-ROS1, LSM14A-BRAF, MBOAT2-PRKCE, MBTD1- CXorf67, MEAF6-PHF1, MIA2_ENST00000280083-GEMIN2, MKRN1-BRAF, MN1- ETV6, MSN-ALK, MYB-NFIB_ENST00000397581, MYO5A-ROS1, NAB2-STAT6, NACC2_ENST00000371753-NTRK2_ENST00000376214, NCOA4-RET, NDRG1_ENST00000323851-ERG_ENST00000442448, NF1-ASIC2, NFIA_ENST00000485903-EHF_ENST00000257831, NFIX_ENST00000360105-MAST1, NONO-TFE3, NOTCH1-GABBR2, NPM1_ENST00000517671-ALK, NTN1-ACLY, NUP107-LGR5, NUP214-ABL1_ENST00000318560, NUP98-KDM5A, OMD- USP6_ENST00000250066, PAX3-FOXO1, PAX3-NCOA1, PAX3-NCOA2, PAX5-JAK2, PAX7-FOXO1, PAX8_ENST00000429538-PPARG, PCM1-JAK2, PCM1-RET, PLA2R1- RBMS1, PLXND1-TMCC1, PML-RARA, PPFIBP1_ENST00000228425-ALK, PPFIBP1_ENST00000228425-ROS1, PRCC-TFE3, PRKAR1A_ENST00000358598-RET, PTPRK_ENST00000368226-RSPO3, PWWP2A_ENST00000456329-ROS1, QKI- NTRK2_ENST00000376214, RAF1-DAZL_ENST00000399444, RANBP2-ALK, RBM14- PACS1, RELCH-RET, RGS22-SYCP1_ENST00000369518, RNF130-BRAF, RUNX1- RUNX1T1_ENST00000360348, SDC4-ROS1, SEC16A-NOTCH1, SEC31A_ENST00000348405-ALK, SEC31A_ENST00000348405-JAK2, SEPT8_ENST00000296873-AFF4, SET_ENST00000322030-NUP214, SFPQ-TFE3, SHTN1_ENST00000615301-ROS1, SLC22A1-CUTA_ENST00000440279, SLC26A6- PRKAR2A, SLC34A2-ROS1, SLC3A2-NRG1, SLC45A3-BRAF, SLC45A3-ELK4, SLC45A3-ERG_ENST00000442448, SLC45A3-ETV1, SLC45A3-ETV5, SND1-BRAF, SQSTM1-ALK, SRGAP3-RAF1, SS18-SSX1, SS18-SSX2, SS18-SSX4B, SS18- USP6_ENST00000250066, SS18L1-SSX1, SSBP2_ENST00000320672-JAK2, SSH2_ENST00000269033-SUZ12, STIL_ENST00000360380-TAL1_ENST00000371884, STRN-ALK, SUSD1_ENST00000374270-PTBP3_ENST00000374255, TADA2A-MAST1, TAF15_ENST00000604841-NR4A3_ENST00000395097, TBL1XR1-TP63, TCEA1- PLAG1, TCF12-NR4A3_ENST00000395097, TCF3-PBX1, TECTA- TBCEL_ENST00000529397, TFG-ALK, TFG-NR4A3_ENST00000395097, TFG- NTRK1_ENST00000392302, THRAP3-USP6_ENST00000250066, TMPRSS2_ENST00000332149-ERG_ENST00000442448, TMPRSS2_ENST00000332149- ETV1, TMPRSS2_ENST00000332149-ETV4, TMPRSS2_ENST00000332149-ETV5, TP53-NTRK1_ENST00000392302, TPM3-ROS1, TPM3_ENST00000368533-ALK, TPM3_ENST00000368533-NTRK1_ENST00000392302, TPM3_ENST00000368533- ROS1, TPM4_ENST00000300933-ALK, TPR-ALK, TPR-NTRK1_ENST00000392302, TRIM24-BRAF, TRIM24-RET, TRIM27-RET, TRIM33-RET, UBE2L3_ENST00000342192-KRAS_ENST00000311936, VCL-ALK, VTI1A- TCF7L2_ENST00000369397, WDCP-ALK, YWHAE-NUTM2A, YWHAE-NUTM2B, ZC3H7B-BCOR, ZCCHC8-ROS1, ZNF700_ENST00000254321-MAST1, ZSCAN30_ENST00000333206-BRAF. [0074] Non-nucleic acid target molecules are also consistent with the disclosure herein, such as proteins, for example cell surface proteins. [0075] Alternately, some target markers such as nucleic acid target markers are associated with a non-cancer genetic disease, with an infectious disease, with an autoimmune disease, or with any other disease or non-disease cell type or cell differentiation state. Such target markers may include viral nucleic acids, viral proteins, cellular pathogen cell surface markers or nucleic acids, cell differentiation markers, cell health markers, senescence markers, differential cell aging markers such as HERVK or an HERVK regulated transcript, or a spurious intergenic transcript. See Sen et al. “Spurious intragenic transcription is a feature of mammalian cellular senescence and tissue aging” Nature Aging volume 3, pages 402–417 (2023) as a source for senescent associated markers. [0076] A number of nucleic acid targets are consistent with the disclosure herein. Targets are in some cases not present, or comprise a point mutation or segment that is not present in off- target cells such that their detection is sufficient to indicate that the cell in which they are detected is a target for system activation, so as to trigger system activity, for example cell death induction, chromatin remodeling, ATP diversion or other activity. [0077] Alternately, in some cases targets are present in off-target cells but at an accumulation level insufficient to indicate that the cell in which they are detected is a target for system activation, or at levels insufficient to be detected by the system. In target cells, the nucleic acid targets are present at levels sufficient to be detected by the system or to indicate that the cell in which they are detected is a target for system activation. In some cases system sensitivity or activity or both sensitivity and activity are tailored so as to tune system activation to cells in which a target nucleic acid is present at a particular or threshold accumulation level so as to distinguish target cells from cells in which the target nucleic acid is present at a level below that sufficient for activation, or a level at which the target nucleic acid does not indicate their cells to be target cells. [0078] As mentioned elsewhere, one category of targets comprises cancer-specific or cancer- indicative gene fusions. Such gene fusions comprise portions of two transcripts that are separate in healthy or nontarget cells but fused in cancer or target cells, in some cases conveying cell growth or cell cycle dysregulation implicated in cancer. [0079] Such targets may be detected due to the accumulation of one or both segments of the fusion, which may be independently present in nontarget or healthy cells but at differing or lower accumulation levels. Alternately or in combination, such targets may be detected by assaying for sequence at or associated with the fusion or junction between the segments, particularly when such sequence is not present in unfused constituents of the fusion. [0080] That is, some targets may be detected by assaying for sequence at the fusion, which may comprise a portion of one or both of the fused segments, alone or in combination with novel sequence linking the fused segments, or may exclusively comprise novel sequence linking the fused segments. [0081] Some exemplary targets, among those listed elsewhere herein, comprise the BCR- ABL fusion in chronic myeloid leukemia, the ML4-ALK fusion in non-small cell lung cancer, the TMPRSS2-ERG fusion in prostate cancer, the EWS-FLI1 or EWSR-FLI1 fusion in Ewing's sarcoma, among others. [0082] Systems are in some cases designed to recognize the unique RNA transcripts produced by these fusions and selectively trigger cell death or other effect in cancer or other target cells expressing them. [0083] A second category comprises transcripts associated with viral infections or viral proliferation in host cells. [0084] For any of a broad range of viral infections like influenza or SARS-CoV-2, the system could target viral RNA sequences that are highly conserved across strains, such as: the Influenza nucleoprotein (NP) gene, or the SARS-CoV-2 RNA-dependent RNA polymerase gene, though other viral encoded transcripts are suitable as targets. [0085] Detection of one or more of these targets allows selective destruction of infected cells while sparing healthy tissue. present as a fusion in healthy or nontarget cells. [0086] A third category includes native transcripts or nutated native transcripts that accumulate at higher levels in diseased or target cells, such as cancer related transcript overaccumulation. For example, glioblastoma often exhibits amplification or mutation of the EGFR gene. A system targeting EGFR variant III (EGFRvIII) transcripts, which are specific to glioblastoma cells, is disclosed that may selectively kill tumor cells in which EGFRvIII transcripts are present or accumulate above a threshold. [0087] A fourth category comprises target cells arising from somatic mutations that are manifest in accumulated transcripts. In Clonal hematopoiesis of indeterminate potential (CHIP), for example, one sees somatic mutations in blood cells, often in genes DNMT3A, TET2, or ASXL1. Targeting mutant transcripts with of one or more of these gene mutations allows for selective removal of pre-malignant or malignant cells associated with this disorder. [0088] A fifth category comprises cells which accumulate a target at an elevated level. Senescent cells, for example, often express p16INK4a at high levels. A system targeting p16INK4a transcripts accumulating above a threshold may selectively eliminate senescent cells from blood or tissues, even if in some cases p16INK4a is present in nontarget cells. [0089] Similarly, in Autoimmune diseases such as rheumatoid arthritis, synovial fibroblasts become hyperactive and express high levels of cadherin-11. Targeting cadherin-11 transcripts accumulating above a threshold could selectively eliminate these pathogenic cells. [0090] For dominant negative genetic disorders like some forms of osteogenesis imperfecta, the system may target mutant collagen transcripts to eliminate cells producing defective collagen. [0091] Much like viral infections, above, for parasitic infections such as malaria, the system may target Plasmodium falciparum-specific transcripts in infected red blood cells or extracellular pathogen cells. For bacterial pathogenic infections, one may target, for example antibiotic-resistant bacteria by recognizing resistance gene transcripts, such as mecA transcripts or genomic loci as targets in MRSA. [0092] Another exemplary set of targets includes cells implicated in or causative of Metabolic disorders. For example, in type 2 diabetes, pancreatic beta cells can become dysfunctional. A system targeting transcripts associated with beta cell stress or dysfunction may eliminate unhealthy beta cells, and in some cases promote regeneration [0093] For many conditions, diseases or target cell types, especially cancer, there are unique or over-accumulating RNA sequences of unknown function, that are only present in that disease or cell type or accumulate at substantially greater levels in that disease or cell type. These are often non-coding, passive sequences may convey a function or may be artefacts of cell type specific transcription. RNA degradation or RNA processing defects. These transcripts are often only detected using non-standard computational pipelines that look at raw sequencing reads without searching for open reading frames, coding capacity or alignment. Some such RNA sequences are passively different in the disease. Some of these arise from genetic mutations and structural variants but some also arise from alternative spliced isoforms or differential chromatin access to transcription start sites or defects in RNA degradation. Due to the diversity and in some cases the cell specificity of these transcripts, they represent a large and attractive pool of target candidates or targets. [0094] Target molecules are used to identify target cells, often to the exclusion of one or more nontarget cells in a common heterogeneous population. Exemplary target cells comprise cancer cells, virally, bacterially or eukaryotically infected cells such as HIV infected cells, malarially infected cells or other infected cells. Some target cells comprise pathogen cells themselves, such as tuberculosis cells, E. coli cells, Plasmodium cells or other disease causing cells. [0095] Target cells need not be disease cells in all cases. Some target cells may comprise, for example, cells of a particular differentiation state, senescent cells, differentially aged cells or other cells distinctly differentiated cells in a homogeneous or heterogeneous population. Examples include T-cells, stem cells, differentiated cells, white or red blood cells. In particular cases, the target cells are senescent or aged cells, independent of whether they differ genetically from other cells in a heterogeneous population. [0096] Some target cells differ morphologically from other cells within a population, as is the case with a particular bacterial target cell line or population, such as may be found in a microbiome peripheral or internal to an individual, such as a skin, oral, gut or gastrointestinal, nasal, or vaginal microbiome. Alternately, some cells are not morphologically distinct from other cells in a heterogeneous population but are nonetheless distinguishable by their target molecule status. [0097] A common feature of target cells is that they possess a target molecule at a level sufficient to be identified by and to gate differential activity of a differential activity component introduced into the target cell. [0098] Nontarget cells may be characterized by an absence of the target molecule, or presence of the target molecule below a threshold or at an inaccessible location, such that a differential activity component introduced into the target cell does not undergo a change in its differential activity. As mentioned above, a nontarget cell may or may not differ morphologically from a target cell in a heterogeneous population. The nontarget cell may be conspecific or distinct from the target cell, and may be of the same temporal age or a different temporal age from the target cell. [0099] A broad range of first components are consistent with the disclosure herein. First components share the features of having a differential activity that is gated by identification of a target molecule, for example in a cell or extracellular medium. [0100] In some cases, the first component comprises both native and exogenously provided constituents. For example, some first components comprise an exogenously provided guide nucleic acid, such as a sgRNA or crRNA, that may target a particular cellular component, bound to a native CRISPR protein, as occur in many eubacterial systems. In these systems the sgRNA or other nucleic acid is exogenously provided, but the complex is not assembled until the sgRNA or other nucleic acid is localized into the cell. [0101] Independent of target or indication, some systems share common components. For example, components may comprise a guide RNA (gRNA) designed to recognize the specific target RNA sequence; protein engineered to bind the gRNA and target RNA, often without cleaving it, such as a TnpB-like or Cas protein; and a secondary effector mechanism, such as a nuclease to destroy genomic DNA (e.g. Cas9 or Fokl) or RNA, an apoptosis-inducing protein (e.g. caspase-9), a protein to disrupt cellular membranes, a protein to perturb or block translation, transcription, autophagy or cell metabolite recycling, a mitochondrial regulator, a chromatin or DNA methylation remodeling effector, or other mechanism for cell perturbation or impacting cell viability. [0102] The guide RNA (gRNA) may be designed according to one or more of the following principles, and in various compositions guide RNAs exhibit one or more of the characteristics resulting from employing one or more of the following characteristics. [0103] Length: Exemplary gRNA length is typically 17-23 nucleotides, such as 17, 18, 19, 20, 21, 22, or 23 nucleic acids, with 20 nucleotides being a common choice. Longer and shorter gRNA, such as 22-30 bases or longer, are also contemplated herein. [0104] Complementarity: The gRNA is often fully complementary to the target sequence, or comprises a contiguous segment that is fully complementary (sometimes referred to as reverse complementary), with some exceptions for specific applications. Exceptions variously result in a segment that differs from total reverse complementarity with a target a t 1, 2, 3, 4 or more than four positions. [0105] GC content: gDNA often exhibit a GC content between 40-60% for optimal binding efficiency, particularly in human transcripts. Exceptions are contemplated, for example to target transcripts in aberrant GC content organisms such as plasmodium, which is globally about 20% GC, or for aberrantly high GC content. [0106] No self-complementarity: gDNA are often selected so as to avoid or not exhibit self- dimerization or hairpin formation under the conditions in which they are to be expressed in target cells or potential target cells. [0107] Minimize off-target effects: gDNA are often assessed computationally or experimentally to predict and avoid potential off-target binding or binding sites in a target cell or potential target cell, or among transcripts of a target organism. [0108] Target nucleotide selection for accessibility: gDNA are often selected so as to target regions of RNA or DNA that are likely to be accessible rather than tightly bound in secondary structures. [0109] Stabilizing modifications: in some cases gRNA is modified, for example so as to increase stability. One exemplary modification comprises adding 2'-O-methyl modifications at positions 1-3 (that is, positions 1, 1 and 2, 1 and 3, 2, 2 and 3, or 1, 2, and 3) of the gRNA to enhance stability. [0110] PAM considerations: For CRISPR-based systems, gRNA are constructed or selected to ensure the presence of an appropriate PAM sequence adjacent to the target site. For other systems, gRNA are in some cases analogously constructed or selected to ensure the presence of an appropriate TAM sequence, such as a sequence adjacent to the target site. [0111] Target identification is effected through a number of approaches herein. In the case of nucleic acids such as RNA or DNA, target identification is often effected through structure specific or sequence specific nucleic acid binding, as effected through guide nucleic acid base pairing, ring finger, talon or other sequence specific binding. Non-nucleic acid or nucleic acid target identification is alternately effected through binding by an antibody, antibody binding domain, receptor domain, aptamer or other moiety capable of binding to a target molecule with specificity sufficient to distinguish it from nontarget molecules in the target cell. [0112] Alternate target recognition approaches, for example using talon, zinc finger or other nucleic acid recognition proteins, are also consistent with the disclosure herein. [0113] Target identification gates a change in a differential activity of the first component. As mentioned above, the first component differential activity may increase, decrease, be turned on or turned off in response to gating by target identification. [0114] A number of differential activities are consistent with the disclosure herein. As mentioned above, some differential activities act directly on the target cell. Alternately or in combination, some differential activities serve to generate one or more signals or signaling molecules within the cell, such as an intermediate signaling molecule. That is, some differential activities act on the cell directly, while others additionally or alternately serve to activate a second component effector. [0115] Examples of differential activities consistent with the disclosure herein comprise catabolic or degradation activity that is activated, upregulated, downregulated or deactivated in response to target molecule detection. As mentioned above, this activity may act upon cellular components to deplete or degrade a cellular component. Similarly, this activity may alter a cellular component so as to generate a novel secondary signal. In some cases the differential activity comprises a nuclease activity, such as DNase activity or RNase activity. The nuclease activity may in some cases reduce or deplete nucleic acids generally or a specific nucleic acid population from the cell, so as to impact, for example, cellular metabolism, cell function, cell differential state or cell viability. Exemplary nuclease activities include mRNA degradation activity, so as to in some cases deplete a cell of messenger RNA necessary to encode ongoing protein synthesis, tRNA degradation activity, so as to in some cases impair or deplete delivery of amino acids to positions specified by mRNA codons, or rRNA degradation activity, so as to deplete the cell of ribosomal RNA components that may be necessary for protein synthesis. A partial list of first component activities comprises DNase, RNAse, protease, kinase or phosphatase, or ATPase activity, as examples. Some activities are exogenously provided, while in alternate cases an activity native to the cell is co-opted by addition of a guide nucleic acid so as to signal in response to detection of a target molecule. [0116] Alternately or in combination, one may employ specific nuclease activity so as to target a specific nucleic acid substrate in response to target molecule detection. The specific nucleic acid substrate may comprise a riboswitch, such that its degradation, binding, activation or inactivation may constitute or be a part of transmission of a signal. Exemplary molecules include ribozymes or aptamers, or even any RNA/DNA molecule with catalytic/conformational activity that is triggered upon binding to a small molecule. Exemplary molecules include RNA toeholds. [0117] The riboswitch is in some cases a specific cellular component. Alternately, a riboswitch is in some cases exogenously delivered to the cell. Degradation, binding, activation or inactivation or modification of a riboswitch may be specific in that it is the primary, predominant, specific or exclusive substrate of the nuclease activity. Alternately, in some cases degradation, binding, activation or inactivation or modification of a riboswitch is effected pursuant to a nonspecific or nonexclusive activity such as an mRNA binding or degradation activity, rRNA binding or degradation activity, tRNA binding or degradation activity, or other RNA binding or degradation activity, or other RNA or DNA activity. [0118] In some cases the first component differential activity is not a nuclease activity, or is not a nuclease activity that has a native cellular component as a primary, predominant, specific or exclusive substrate. That is, some nuclease activities may act primarily or solely on an exogenous nucleic acid. In some such cases, native cellular nucleic acids are not affected or not substantially effected by the first component differential activity, or are effected only peripherally pursuant to first component differential activity. [0119] Some first component differential activities do not act on nucleic acids. Some such differential activities act to degrade, modify, inactivate or otherwise act upon a cellular component to effect a cellular impact or transmit a signal. As a representative example, some differential activities degrade nucleotide triphosphates such as adenosine triphosphate (ATP). ATP is a major energy currency for the cell, such that permutation to its accumulation levels, for example through its degradation, may impact the cell directly, or alternately or in combination may effect cell signaling or serve as a signaling mechanism. Similarly, degradation of a cellular component such as ATP may yield a degradation product that may also serve as a signaling component. [0120] That is, some first component differential activities may act to deplete a cell component that is necessary for cell viability, proliferation, metabolic function, or other activity. In these cases, identification of a target molecule in the cell activates a differential activity to effect the depletion of such a cellular component, thereby impacting the cell. For example, a first component that identifies an oncogenic gene fusion or an RNA molecule transcribed therefrom may selectively deplete ATP in cells in which the target gene fusion transcript accumulates. The depletion of ATP in these cells, particularly in cancer cells which are intensive consumers of ATP, may result in the selective starvation of ATP or the energy delivered by ATP from these cells. This starvation of energy in some cases leads directly or indirectly to the death of some or all of these cells, thereby depleting an individual of some cells harboring the oncogene such as the gene fusion. [0121] Alternately or in combination, the depletion of a cellular component such as ATP in cells, particularly in cancer cells which are intensive consumers of ATP, may result in the induction of a signaling response to the dearth of energy or of ATP molecules, leading for example to quiescence, dormancy, or autophagy in these cells, thereby ameliorating the impact of these cells on an individual, facilitating killing or clearing of these cells pursuant to a concurrently administered therapy, or otherwise ameliorating a condition arising from the presence or active proliferation of these cells. This starvation of energy in some cases leads directly or indirectly to the death of some or all of these cells, thereby depleting an individual of some cells harboring the oncogene such as the gene fusion. [0122] Alternately or in combination, the depletion of a cellular component such as ATP in cells serves as a signal to be detected by a second component, so as to activate a second component differential activity. As an example, a second component may exhibit as a second differential activity an ATP-inhibited catabolic, nuclease, lipase, protease or other activity that may impact a cell, such as by leading to cell quiescence, differentiation, dedifferentiation, or death. In these cases, the absence of the cellular metabolite such as ATP may serve as a signal to activate, for example by de-repressing, a second component differential activity, so as to impact a cellular population harboring a target molecule. [0123] Alternately or in combination, the depletion of a cellular component such as ATP in cells may lead to accumulation of a degradation product. Such a degradation product may act on cellular metabolism directly or may serve as a signal to be detected by a second component, so as to activate a second component differential activity. As an example, a second component may exhibit as a second differential activity an ATP degradation product- induced catabolic, nuclease, lipase, protease or other activity that may impact a cell, such as by leading to cell quiescence, differentiation, dedifferentiation, or death. In these cases, the absence of the cellular metabolite such as ATP may serve as a signal to activate, for example by de-repressing, a second component differential activity, so as to impact a cellular population harboring a target molecule. [0124] A partial list of first component constituents comprises Csm such as wild type or RNase dead Csm, Cmr, dCas9, an RNase dead protein, Csx29, Csx30, a Type III Crispr protein, CasX, Cas13, Cas13b, Cas12a2, Cas12g, an Argonaut protein, siAGO, SPARTA, SPARSA, Cas13d, CBASS, Pycar, Cas7-11, a retron complex, Type I-F CRISPR complex, an omega complex such as Fanzor, Theoris, TnsB, TnpB, IsrB, IscB, a complex such as Hachiman, Shedu, Gabija, Septu, Lamassu, Zorya, Kiwa and Druantia, PARIS, AVAST, DRT, Zorya, Detocs, Mokosh, Eleos, GIMAP, or other protein that may complex with a nucleic acid or otherwise specifically bind a cellular target nucleic acid or other molecule, and to exhibit a gated activity in response to such binding. [0125] As mentioned above, first component constituents often also comprise sgRNA or other guide nucleic acid or crRNA. Such a constituent may be delivered in parallel or in complex with one or more of the protein constituents recited above. Alternately, such a constituent may be delivered alone or without a protein binding constituent, in particular when it is intended to complex with a native protein to form a native RNA-protein complex such as Type III native CRISPR protein complex. In some cases first constituent components are fused to effectors or second components to form single protein systems. [0126] Intermediate signaling molecules or signaling activities are in some cases generated by first constituent components in response to detection of a target molecule. Representative signaling molecules are in some cases degradation products of substrates acted on by gated first constituent metabolic activity. Exemplary signaling molecules include cOA, nucleic acid cleavage products such as RNA or DNA cleavage products, phosphorylation or dephosphorylation of a substrate such as a protein substrate, or other molecule targeted by first constituent activity. In some embodiments the signaling molecule is cOA, produced by an active Csm protein. Exemplary signaling activities include RNase activity, DNase activity, protease activity, kinase or phosphatase activity, in particular an activity leading to activation or modulation of a second constituent component. [0127] Second component constituents show broad flexibility as to composition and activity, and are not in all cases essential parts of the systems herein. In particular, some Csm cOA systems herein act by starving the target cells of ATP through synthesis of cOA by the first component, thereby slowing, altering growth patterns, or starving the target cell of energy, in some cases killing the target cell or target cell population. These systems rely upon cOA not as an intermediate signaling molecule but as a by-product of ATP degradation. In these and other systems herein, effects are achieved without the use of a second component. . In some cases first constituent components are fused to effectors or second components to form single protein systems. [0128] Other systems employ second components, often to effect biochemical activities not available or less conveniently achieved by first components. [0129] . A common feature of some second components when they are present is that they are modulated by first constituent activity rather than by direct detection of a native cell target molecule. Indirectly they are mediated by presence of the target molecule and its detection by the first component, but their role is in many cases not to interact with the target molecule directly. [0130] Beyond this constraint of many second components, there is a broad chemical diversity available. Some second components, like first components, comprise a nucleic acid guide and a protein constituent. In these cases, the guide may bind to a cleavage product generated by an active first component, so as to activate an activity within the cell. [0131] Alternate second components include, for example, an mRNA molecule having a 5’ signaling molecule binding motif such as a cOA binding motif. The 5’ binding motif may exhibit differential stability, such that it triggers degradation or suppresses translation of the mRNA coding region in the absence of the binding substrate. In the presence of the binding substrate such as cOA, the coding region of the mRNA is available for translation, resulting in expression of an effector protein. [0132] In exemplary configurations, the 5’ binding motif comprises a degradation motif that may recruit, for example, a 5’-3’ exonuclease to degrade the molecule in the absence of signal molecule binding. Alternately or in combination, the 5’ binding motif may comprise an internal autocleavage site that is masked or autocleavage activity that is inactivated by signaling molecule binding, or a translation inhibitor that is displaced by signal molecule binding, or a translation factor or ribosomal recruitment factor that is recruited upon signal molecule binding. [0133] Similarly, a second component may comprise an mRNA coding region bounded by a translation inhibitory motif or binding site having an endonuclease target site that is vulnerable to an RNase or DNase activity activated by the first component, such that activation of the first component leads to degradation of the translation inhibitory moiety and access of the mRNA coding region to translation. [0134] The coding region of the second component may encode any number of effectors, such as a cell killing enzyme such as a DNase, RNase, protease, kinase or phosphatase, a translation inhibitor, a toxin such as ricin, a chromatin modifier, a transcription factor, a cell differentiation or de-differentiation moiety, mitosis promoter or inhibitor, a protein to compensate for or mask a defective protein in the target cell, an immunoregulator such as IL2, IFNy, CCL20, CXCL16, or a cell surface molecule such as one that may target the cell for degradation. [0135] A benefit of the disclosure herein is that various secondary effector mechanisms can be called upon to achieve desired cellular outcomes, from cell death to gain of metabolic function in target cells. [0136] Some examples of secondary effector functionalities and embodiments are listed below. [0137] An effective mechanism of clearing target cells is apoptosis induction, which can be effected through, for example, caspase-9 fusion for rapid and efficient cell death. [0138] Epigenetic modulation of gene expression is an approach for long-lasting effects without permanent genetic changes. As an example, DNMT3A fusions may be used to effect epigenetic modulation through targeted DNA methylation and gene silencing to modulate gene expression. [0139] Protein degradation, either directly or through induction of ubiquitin-mediated protein degradation, can be used to target non-genetic or post-translational cellular components. For example, PROTAC fusions may be used to induce ubiquitin-mediated protein degradation. [0140] Cellular reprogramming is another attractive outcome, as it can alter cell fate without introducing exogenous genes. MyoD fusions, for example, may be used to induce muscle cell differentiation. [0141] Genome editing may be induced, so as to enable correction of genetic defects. Secondary effectors can prime editing fusion for precise DNA modifications. [0142] Accordingly, second components may possess any number of effector activities. Examples range from enzymatic activity to transcription or translation modulators to structural protein synthesis. Second component effector activities may comprise synthesis of cell surface proteins to target antibodies to the cell, for degradation or cell sorting, for example; synthesis of a transcription factor or chromatin remodeling moiety to modulate transcription or cellular differentiation state; cell progression or cell growth modulators such as TOR kinase or other growth modulator substrates, or constituently active or inactive mutants thereof; proteins that convey resistance to a pathogen or disease; enzymes that perturb metabolism or a molecule equilibrium, so as to disrupt metabolism or trigger cell death; enzymes that redundantly generate cOA or otherwise deplete ATP or other energy sources in the cell, as well as in some cases generating a positive feedback loop for second component activation; or enzymes that nonspecifically or specifically target transcripts or DNA molecules for degradation or sequester them. Other activities are consistent with the disclosure herein, and indeed a benefit of the disclosure herein is the versatility of the effector activities enabled by the disclosure herein. [0143] . In some cases first constituent components are fused to effectors or second components to form single protein systems. [0144] Delivery mechanism. A number of delivery systems are consistent with the disclosure herein. Features common to many of the delivery mechanisms herein is that they have a minimal impact on cells through their delivery. [0145] In the most streamlined embodiments, such as those where a guide nucleic acid such as a sgRNA is delivered to a bacterium to redirect the bacterium or other cell’s own CRISPR protein to trigger an anti-self response, a delivery mechanism comprises a medium through which the nucleic acid such as a sgRNA is presented for uptake by the bacterium. In these systems only a first component is used, and it comprises both exogenous guide and native protein constituents. [0146] Consistent with these embodiments, a delivery mechanism may comprise a carrier that is biocompatible with the target cell’s nucleic acid uptake mechanism. Examples comprise an emulsion, a suspension, a solution, a salve or lotion, or other carrier suitable for delivery of nucleic acids to a cellular target capable of importing the nucleic acids. In these systems, a broad range of nucleic acid concentrations are compatible with the disclosure. In some cases, nucleic acids are present at a concentration at or near the highest concentration permissible by the carrier. [0147] Some two-component systems comprise a delivery system such as that disclosed above, alone or in combination with a microcapsule or vesicle system. In particular, a first component nucleic acid guide complexed to a protein effector may be encapsulated in a microcapsule or vesicle, while a second component mRNA / regulator nucleic acid may be delivered through a mechanism such as that described above for guide nucleic acid delivery. Alternately, both parts of a two component system may be delivered through microcapsules or microvesicles. Suitable carriers include, for example viral-like particles, lipid microvesicles, exosome like particles or other microcarriers. Generally, the delivery mechanisms share the feature that their delivery to or uptake by the cell population is minimally disruptive to the cell population, such that non-target cells that take up the compositions are not substantially impacted in the absence of target molecule recognition. [0148] In various delivery configurations, the first and second components are either delivered in common microcapsules, delivered concurrently in separate microcapsules, or delivered as unassembled components in distinct or common microcapsules. . In some cases first constituent components are fused to effectors or second components to form single protein systems. [0149] A number of system delivery vector systems are consistent with the disclosure herein. Some vector delivery systems are selected so as to tailor delivery to a particular organ or tissue of interest. Some exemplary delivery systems comprise lipid nanoparticles, viral vectors, or cell-penetrating peptides. [0150] Some delivery strategies optimized for different tissue types include the following. For liver, one may use Lipid nanoparticles with N-acetylgalactosamine targeting ligands, which convey, high specificity for hepatocytes via ASGPR receptor. [0151] For brain, one may use Exosomes engineered to express, for example, rabies virus glycoprotein, so as to effect efficient crossing of the blood-brain barrier. [0152] For muscle, one may use adeno-associated virus serotype 9 (AAV9) vectors, so as to make use of strong tropism for skeletal and cardiac muscle. [0153] For lungs, one may use Inhalable nanoparticles coated with pulmonary surfactant, so as to make use of enhanced mucus penetration and cellular uptake [0154] For various tumors, one may use Cell-penetrating peptide-functionalized gold nanoparticles, so as to make use of Accumulation in tumors via EPR effect and improved cellular entry. [0155] A composition comprising a first component, alone or in combination with a second component, is in some cases formulated for delivery to a cell or cell population. Formulation for delivery may comprise encapsulation into nanoparticles such as lipid nanoparticles, viroid capsules, or other delivery capsules sufficient to allow delivery to or uptake by the cell or cell population. The delivery mechanisms may variously facilitate uptake into the cell cytoplasm, cell nucleus, an organelle such as the mitochondria or plastids, proteosomes, endoplasmic reticulum or other subcellular space. In some cases the formulation comprises lipid nanoparticles. [0156] Consistent with the disclosure above, the first component is in some cases delivered alone or in a composition that does not comprise a second component. The composition may uniformly comprise first components encapsulated microcapsules, or maybe heterogeneous, for example by also comprising any combination of empty microcapsules, microcapsules harboring therapeutics such as cytotoxic small molecule or antibody therapeutics, cell viability enhancers or toxins, cell differentiation promoters or repressors, transcription or translation inhibitors, antibiotics, antivirals, nucleic acid vaccines, or other small molecule suitable for delivery via microencapsulation. [0157] Similarly, a second component is in some cases delivered alone or in a composition that does not comprise a first component, and that may be homogeneous or may comprise one or more of the constituents mentioned above. [0158] Alternately, the first component is in some cases delivered in a composition further comprising a second component, such as a second component encapsulated in a microcapsule. Such a composition may in some cases comprise one or more of the constituents mentioned above. . In some cases first constituent components are fused to effectors or second components to form single protein systems. [0159] Uptake by the cell of one or more of these delivery compositions is variously effected by coincubation, electroporation, co-contacting or other uptake approaches in the art through which microcapsules or viroid particles, for example, may be taken up by a cell population. In some cases the delivery mechanism comprises a surface protein ligand or receptor that facilitates microcapsule uptake. In some systems a guide nucleic acid is taken up directly by a bacterial target cell, for complexing with native CRISPR proteins to mediate targeting of the native CRISPR system to the host cell. [0160] Compositions are in some cases formulated immediately prior to administration or are not packaged or stored prior to administration to a cell population. Alternately, some compositions are prepared well in advance of administration, and may be frozen or stored at a temperature where the microcapsules are suspended in a liquid carrier. Storage is variously at a temperature of or about -80 C, -20 C, -4C, 4C, room temperature, 25 C or any temperature spanned by or outside of this range of values. In some cases, formulations are stored as packaged therapeutics or reagents such that they may be sold in bulk or individual unit aliquots of a bulk pre-prepared reservoir of reagents. [0161] Compositions are in some cases formulated from a combination of exogenous and native components. Eubacteria, such as Staphylococcus aureus, often comprise a native nucleic acid binding signaling molecule such as a Type III CRISPR protein sufficient for activity in first complexes herein. Accordingly, some first complexes comprise a native nucleic acid binding protein such as a Cas or Csm protein, to which is added an exogenous guide nucleic acid molecule such as an sgRNA that may identify a common target-specific marker in the target cell. [0162] The first complex constituent is delivered using an approach or composition consistent with the disclosure above. Alternately, some sgRNA delivery relies upon native uptake of nucleic acids such as RNA by some target cells, for example some eubacterial cells. In these systems, the nucleic acid component, alone or with other components, is delivered directly to the target cell population, and the target cell population native nucleic acid uptake mechanism is relied upon to import the constituent into the cell where first nucleic acid- protein complexes sufficient to detect the target-specific marker are formed. In these systems a second complex is optionally delivered concurrently through the same mechanism or through an approach discussed above. [0163] Compositions as disclosed herein are used to practice methods comprising delivery to a heterogeneous cell population and selective activation or activity in cells harboring a common target-specific marker. [0164] Delivery of some compositions is effected through topical administration, such as in a salve. This is particularly useful when target cells are present on a patient exterior, such as skin cells or target bacterial cells. [0165] Populations of cells. Accordingly, disclosed herein are Populations of cells harboring differentially active first component. In these cell populations, cells comprising a common target-specific marker exhibit or harbor active first component activity, while cells lacking the common target-specific marker do not exhibit first component activity. [0166] Exemplary cell populations may be in vitro or in vivo, and may include tumor cells and their adjacent healthy or nontumor cells, senescent and non-senescent cell populations, such as may be circulating in blood, virally or pathogen infected and noninfected cells in vitro or in vivo in an individual, bacterial or other disease inducing cells and host cells in an individual, gut flora population constituents or other heterogeneous populations. [0167] Populations of cells are variously in vivo constituents of a patient or other individual, ex vivo cell populations extracted from a patient or other individual, or cultured populations. In many cases, cell populations are removed from a patient or other individual, subjected to a composition as disclosed herein, and the population or populations are returned to the individual in the populations’ entirety or in part, such as a surviving part of the population. Through such an approach, a cell population may be culled of target cells such as cancer cells, infected cells, pathogens, senescent cells, differentiated or undifferentiated cells or other target cells, and the remaining cells or nontarget cells alone or in combination with products of a targeted cell modification may be returned to an individual such as a patient. Exemplary cell populations comprise circulating populations, such as those obtained from blood. [0168] A Partial List of Applications. A number of applications are consistent with the present disclosure. The list is not exhaustive, such that a number of applications not listed herein but consistent with the disclosure of cell specific activation approaches as disclosed herein are also encompassed by the scope of the disclosure herein. [0169] The disclosure herein conveys a broad range of benefits in cell-targeted therapeutic treatment. In particular, systems accomplish high specificity due to reliance on nucleic acid base pairing to effect target cell recognition, while also having broad versatility, in that any target cell for which a suitable target nucleic acid segment is available may be targeted. Cell specificity reduces the likelihood of side effects as those otherwise arising from off target cell impacts. Additionally, cell targeting does rely upon cell surface proteins, facilitating a substantially broader range of target cell selection. [0170] Molecular Biology Tools. The disclosure herein finds use in the development or deployment of molecular technology tools relating to selective removal of particular cell types from heterogeneous cell populations in vitro or in vivo. That is, any cell type or group of cell types having a common target-specific marker may be selectively manipulated within a larger cell population. [0171] A broad number of selective removal methods benefit from the disclosure herein. For example, in vivo removal of a specific cell type or cell types allows determination of disease causality mechanisms. By comparing cell ablation induced phenotypes to those associated with a disease, one can identify the cells whose disruption correlates to the disease phenotype or to an exacerbation or alleviation of the phenotype, which may then suggest disease mechanisms that may serve as therapeutic targets. [0172] Disorders conducive to analysis enabled herein comprise any number of disorders occurring in tissues of varying degrees of differentiation, for example, retinal disorders, immune disorders such as those relating to cell differentiation, neural disorders, liver diseases, diseases of the digestive tract, and any number of additional examples. [0173] Cell sorting is another molecular biology approach that benefits from the disclosure herein. Cell types can generally be purified with FACS. However, cell states cannot easily be purified because the proteins are a continuum of expression. Any cell that differentiates such as stem cells and immune cells can be sorted using our approach. A composition herein is added to the cells to be sorted. When a cell enters a certain state it turns on a fluorescent reporter or a tag or cell surface protein, such as a FLAG tag, delivered through a composition herein and can be sorted. [0174] Cellular processes such as splicing may be assayed using the approaches herein. Using a splice variant retention region as a target, and a reporter as the downstream effector moiety or effector product, one may visualize splicing events in a cell population. This approach may find use in, for example, organoid or embryogenesis. [0175] Combination Therapies. The disclosure herein finds use in the development or deployment of therapies, individually or as part of combination therapies. [0176] As an example, some tumor resistance to chemotherapy such as gemcitabine is mediated by intratumor bacterial populations. Selective induction of cell death pathways or activities in the bacteria effects clearance from the bacteria from the tumor, thereby facilitating chemotherapy efficacy. That is, a tumor identified or suspected of being protected by intratumor or peripheral bacteria from chemotherapy or other therapy is identified and the associated bacteria are characterized. [0177] A target specific marker in the bacteria is identified and used to develop a marker- gated cytotoxic system that is delivered to the tumor. The system induces cell death in the bacteria but not in adjacent tumor cells, tumor fighting immune cells or adjacent healthy tissue. Concurrently with or subsequent to administration of the bacterial clearing system, the tumor is treated using a chemotherapeutic that ameliorates a symptom of the tumor, up to in some cases killing some or all of the tumor cells. It is observed that chemotherapeutic treatment subsequent to bacterial clearance exhibits substantially higher efficacy than a chemotherapeutic treatment prior to bacterial clearance. In some cases it is observed that tumor cell death, tumor dormancy, or cancer remission is achieved, using a treatment regimen comprising doses that are variously 100%, 50%, 20%, 10% or less than 10% of those used prior to bacterial treatment, such that in some cases side effects of chemotherapy are substantially reduced in patients receiving the bacterial clearance treatment. [0178] Novel Therapies. Alternate therapies comprise delivery of a system that provides an activity or component absent from a cell or cells leading to a disorder. [0179] For example, a patient suffering from sickle cell anemia is administered a system that uses the sickle cell hemoglobin allele transcript as a target specific marker for a system that induces expression of a wild-type hemoglobin allele, thereby alleviating the sickle cell anemia condition. Such a system may be delivered continuously or in response to an acute sickle cell anemia episode, and may be injected, inhaled, delivered through dialysis, or delivered through any approach in the art suitable for application to the target cells. [0180] Similarly, any disorder where a cell type having a target specific marker and a deficiency in a signaling, metabolic or other pathway resulting in a challenge to the patient may be treated using the technology herein. Single locus disorders are particularly suitable for supplementation as disclosed herein, such as various muscular dystrophy loci, among others. [0181] Selective targeting of a cell population or subset of cells within a heterogeneous cell population, such as an infective cell population or infective cells within a population obtained from circulating cells, for induced dormancy or cell death. Some such therapies target a type of cell generally, such as trypanosomes or Plasmodium pathogens, or a type of infected cell, such as a cell harboring the HIV virus. Using either a native transcript or a viral transcript as a target specific marker, the cells are induced to undergo cell death, cell arrest or to otherwise perturb the target cell population using a system consistent with the disclosure herein. [0182] Alternate embodiments allow more specific cell population targeting, such as targeting of cells harboring antibiotic resistance, for example MRSA (methicillin resistant Staphylococcus aureus) cells. In these systems, a first component complex is assembled in the cell that identifies as a target a nucleic acid molecule specific to the multiple resistance phenotype of MSRA bacteria. [0183] The first component complex may in some cases comprise an exogenously provided crRNA and the cell’s native Type III CRISPR protein, such that upon identification of the cell’s native MRSA related transcript, the cell’s own cell-death inducing pathway is induced. [0184] This approach allows the selective killing of MRSA bacteria without subjecting the bacterial population as a whole to a selective pressure to develop resistance. In addition, this approach allows use of a very efficient delivery system for the exogenous first component, namely a composition comprising the specific sgRNA, such as a salve or emulsion. [0185] Delivery in these examples may be through a salve or lotion administered to a patient skin surface, or through injection or other administration route. [0186] An additional cell population that may be selectively targeted for removal is the human senescent cell population. Human senescent cells express HERVK, an endogenous retrovirus dormant in healthy cells. HERVK expression results in the production of 4 distinct mRNA molecules and 4 proteins. Without being bound by theory, by using HERVK as a target specific marker one may effect targeted activity in senescent cells, such as targeted cell death in these cells, or targeted expression of a moiety to suppress HERVK expression or to induce these cells to revert to a de-differentiated or de-senescent state, such as an RNA silencing moiety, an HERVK target silencing or inactivating moiety, a chromatin remodeling moiety or a cell death inducing moiety. Some examples of each of these moieties are known in the art, use of which is contemplated herein as well as specific examples disclosed or recited herein. [0187] Accordingly, an application disclosed herein is aging therapy. Blood is removed and incubated with our therapy, which selectively targets and removes cells with the aging RNA signature, such as senescence. Blood that is depleted for senescent cells is put back into the patient, having an effect of reducing the overall proportion of circulating senescent cells in the patient’s blood. [0188] As discussed elsewhere herein, cancer cell populations are exemplary targets of systems disclosed herein. Many cancers exhibit one or more cancer specific signatures that may each act as a target specific marker one may use to effect targeted activity. Signatures that may exhibit sufficient specificity for use as target specific markers include in various cancer types include some alternative splicing events, oncogenic gene fusions or translocations, mutations harbored either in the canonical genome or in extrachromosomal DNA molecules, or aberrant transposable element activity. [0189] Cancer cell populations, and other target cell populations, may be targeted through a number of approaches. As mentioned above, cells may be targeted by the target specific marker gated conversion of ATP to cOA, so as to starve the target cells of ATP. Cells may be targeted by activation of a nuclease, protease or other metabolic activity at the first complex, or through an intermediate signal, at the second complex. Alternately, cells may be targeted for degradation through the target specific marker gated expression of a cell surface marker, such as a cell surface marker that is recognized by the immune system or otherwise tags the cell for degradation. [0190] A benefit of the technology disclosed herein is that cells such as cancer cells may be distinguished from noncancer cells in a heterogeneous population without reliance upon cell surface proteins as cell population identifiers. Instead, internal markers such as a DNA allele or an mRNA transcript that is present in the cancer cell but not in the noncancer cells in the population, or present at distinguishably different concentrations, levels, cell localizations, or specific or unique to the cancer cells, may be used as target markers. In some cases these target markers encode known cell surface proteins, while in other cases the target markers are unrelated to previously characterized cancer cell markers. [0191] In addition to treatment of circulating cells, compositions may be delivered to particular areas. [0192] As a non-cancer alternative example, the disclosure herein relates to tissue repair for example in heart scarring. Fibrotic cells in the heart build up after injury and lead to cardiac diseases. By targeting scar cells, one may use the disclosure herein as a therapy to remove the scarred and useless cells. [0193] In addition to cell removal, the disclosure herein is relevant to selective removal of cells in development, so as to dictate a developmental outcome. A key step of development is cell death and necrosis. During embryogenesis or organogenesis key cell types die at certain time points. Using the disclosure herein, one may target certain cells that begin organoid development, so as to cause certain target cell types to die, for example by giving the cells a guide RNA specific to that type. At each time point one can remove certain cell types of interest. This finds application, for example, in synthetic meat generation so as to remove the tendon like scaffolding cells or to remove a certain percent of fat cells in order to adjust the fat content. [0194] Selective cell removal, of pathogen cells, infected cells, cancer cells, senescent cells or other target cells results in a population enriched for non-target cells. This enrichment is accomplished such that target cells constitute no more than 90%, 80%, 70%, 60%, 50%, 40%, 30%, 205%, 20%, 15%, 10%, 5%, 1% or less than 1% of their number prior to treatment. Similarly, Enrichment is accomplished such that target cells constitute no more than 90%, 80%, 70%, 60%, 50%, 40%, 30%, 25%, 20%, 15%, 10%, 5%, 1% or less than 1% of the total cell population. At the whole patient level, cell removal, treatment and return to the patient may result in a reduction of target cells throughout the patient which is no more than 90%, 80%, 70%, 60%, 50%, 40%, 30%, 25%, 20%, 15%, 10%, 5%, 1% or less than 1% of their number prior to treatment. [0195] Gain of function cell generation. The disclosure herein also relates to adding additional functions to cells, which may then be returned to the patient. This finds use, for example, in immunotherapy. In some set of examples, T cells are extracted from blood in the same process as CAR-T cell therapy. In addition to giving the cells the CAR construct, they are given our therapy, which selectively removes the subtypes of T cells that do not correlate with tumor clearance and a strong clinical response. [0196] In another set of examples, all T cells are extracted from patient blood, given our therapy and put back into the patient. When the T cells interact with the tumor they activate turning on a slew of unique RNA transcripts, which activates our system, and releases immune cytokines that attract macrophages and dendritic cells to the tumor. [0197] This also finds use, for example in stem cell therapy. Cells are removed from a patient and induced into a stem cell like state or the stem cells are isolated from a patient specimen. The cells are given our therapy which remains dormant. When the stem cells become oncogenic and begin to form a tumor our therapy will turn on and kill the cells. Therapy acts as a kill switch. [0198] In vitro fertilization selection also benefits from the disclosure herein. Either the fertilized eggs, or the eggs or sperm alone are incubated with our therapy that targets for RNA markers of early death such as spinal muscular atrophy (41% of infant deaths are genetic). Cells harboring genetic defects such as those that lead to stillbirth, early fetal death or failure to carry to term may be targeted. Our therapy is transient which means it will be cleared in days and thus no effect on development of the healthy cells. [0199] Compositions. A broad range of compositions are consistent with the disclosure herein. Two embodiments are provided below, with the understanding that functional alternatives and alternatives consistent with the activator moieties and effector moieties disclosed herein are also contemplated herein. [0200] One set of compositions relates to CRISPR complexes, such as type III complexes. RNAse dead Type III CRISPR complex with a guide binds and recognizes the RNA target. The secondary component is activated and intracellular ATP is converted into cyclic oligoadenylate (cOA). The RNA target remains bound due to the RNAse inactivity and the amount of cOA is amplified. In various embodiments, the cOA molecule selectively activates a nuclease enzyme that indiscriminately cleaves dsDNA in the nucleus of the cell, or the cOA molecule selectively activates one or many ribozymes that release mRNA encoding for proteins of interest, or the cOA molecule selectively activates one or many ribozymes that release pre-miRNA that bind and inhibit the translation of genes of interest. [0201] A distinct set of compositions relate to Cas complexes, such as Cas13 and Cas12a2 Complexes. Cas13 with a crRNA binds and recognizes the RNA target. The secondary component is activated and Cas13 indiscriminately cleaves single stranded RNA in the cell. An siRNA construct is delivered to the cells harboring the universal cell death k-mer that activates the DICE/DISE complex. The antisense strand is circularized and hybridized to the linear sense strand. The secondary RNAse activity of Cas13 cleaves the circularized siRNA, enabling binding and activation with the RISC/Ago complex leading to the knock down of essential genes and eventual cell death. [0202] Delivery. Delivery of payload may targeted to effect transient or stable payload expression capabilities. Transient payload expression may be effected through a broad range of expression or payload introduction approaches, such as virus like particle packaging or other appropriate delivery approach, so as for example to use VLP to deliver a composition to a tumor area. Cells with cancer specific signature or other target signature may be targeted, either for cell death or for expression, of a marker, such as an antigen on the cell surface that is already recognized by the patient immune system, or particularly marked cells may be targeted such as senescent cells. Generally, many of the cells and conditions mentioned throughout the disclosure herein may be targeted through transient approaches disclosed herein or known in the art. This approach can be general or tailored to a specific cancer therapy, based on tumor biopsy and sequencing. Delivery using VLPs is well known in the art, as for example disclosed in Banskota et al. (2022) “Engineered virus-like particles for efficient in vivo delivery of therapeutic proteins” Cell Volume 185, Issue 2, pages 250- 265.e16, which is hereby incorporated by reference in its entirety. Similarly, delivery of CRISPR moieties using lipid-nanoparticles is disclosed in, for example, Kazemian et al. (2022) “Lipid-Nanoparticle-Based Delivery of CRISPR/Cas9 Genome-Editing Components” Mol. Pharmaceutics 19, 6, 1669–1686, which is hereby incorporated by reference in its entirety. Alternate delivery approaches, such as PEG10 packaging, is disclosed in Segel et al. (2021) “Mammalian retrovirus-like protein PEG10 packages its own mRNA and can be pseudotyped for mRNA delivery” Science Vol 373 Issue 6557, pages 882-889, which is hereby incorporated by reference in its entirety. Additionally, compositions may be delivered is salves or ointments to the surface of an individual, or may be suspended in solution, particularly when a population of cells is treated in solution ex vivo. Delivery is in some cases mediated by antigen fusion to particle surface such as VLP surface or extracellular vesicle (EV) surface so as to interact with a cell surface receptor on a particular target cell type. See, e.g., Strebinger et al. (2023) “Cell type-specific delivery by modular envelope design” Nature Communications volume 14: 5141, which is hereby incorporated by reference in its entirety, and Hamilton et al. (2024) “In vivo human T cell engineering with enveloped delivery vehicles” Nature Biotechnology, published January 11, 2024, which is hereby incorporated by reference in its entirety. [0203] Similarly, stable or transient transformation may be effected through a broad range of transformation approaches known in the art, such as electroporation, cell bombardment, agrobacterium mediated plant cell transformation, or standard or modified lentiviral RNA based transduction delivery. Cells with cancer specific signature or other target signature may be targeted, either for cell death or for expression, of a marker, such as an antigen on the cell surface that is already recognized by the patient immune system, or particularly marked cells may be targeted such as senescent cells. Generally, many of the cells and conditions mentioned throughout the disclosure herein may be targeted through transient approaches disclosed herein or known in the art. Such a delivery approach may be used to effect immune cell engineering, stem cell therapy, and blood based removal of aging and senescent cells. [0204] Combination therapies with existing treatments. Compositions systems and methods herein are suitable for combination therapy treatment regimens in addition to their utility as stand alone treatments. [0205] Cancer-directed compositions herein may be used alone or in combination with, for example, immune checkpoint inhibitors (such as anti-PD-1 antibodies) to enhance T cell responses, or in conjunction with CAR-T cell therapy to improve tumor targeting specificity. Similarly, in some cases a system herein employs as an effector an expression system so as to express an epitope that renders target cells more likely to be identified by a cell targeting therapy such as a CAR-T cell therapy or an anti-PD-1 antibody treatment. [0206] For genetic disorders arising from nonsense mutations, systems, compositions and methods herein may be paired with small molecule read-through agents so as to ameliorate the impact of one or more nonsense mutations, or may have as effectors translational modifiers that increase readthrough or a tRNA that targets the nonsense codon so as to facilitate readthrough to effect translation of a wild-type or near wild-type protein. [0207] Some systems, compositions and methods herein may be combined with antisense oligonucleotides for synergistic splicing modulation, so as to impact relative accumulation of one or more splice variants in a target cell. [0208] For infectious diseases, systems, compositions and methods herein may be combined with conventional antibiotics to target antibiotic-resistant subpopulations, or may be combined with broadly neutralizing antibodies for multi-pronged antiviral approach. [0209] For neurodegenerative diseases, systems, compositions and methods herein may be combined with small molecule aggregation inhibitors to enhance protein clearance. [0210] As an additional example, systems, compositions and methods herein may be combined with stem cell therapies for improved cellular replacement. [0211] System modifications. Some compositions, systems and methods herein comprise use of wild type or engineered components, in particular protein components. Some exemplary improvements or modifications comprise the following. [0212] For improved DNA binding without cleavage, exemplary modifications comprise the following: mutation of catalytic residues (e.g. D10A, H840A for SpCas9) to create catalytically inactive or "dead" versions; fusion to a transcriptional repression domain such as a KRAB repressor domains for enhanced transcriptional repression; engineering of smaller versions (e.g. "mini-TnpB") for improved delivery or expression in cell; incorporation of positive charges in the PAM-interacting domain to enhance DNA affinity. [0213] To modify PAM specificity, one may adopt any of a number of approaches herein or consistent with the disclosure herein. For example, one may use structure-guided design to modify PAM-interacting residues. One may apply directed evolution to select for variants recognizing novel PAM sequences. One may create chimeric proteins fusing PAM- interacting domains from different orthologs. One may incorporate non-natural amino acids to create novel DNA recognition properties. [0214] Safety mechanisms. Alternately or in combination, with the disclosure herein, disclosed herein are methods comprising modifying system so as to modulate stringency or otherwise affect off-target effects. Similarly, disclosed herein are compositions, systems and methods incorporating modifications as disclosed below or otherwise consistent with improvements in safety or modulation of specificity or reduction of off-target effects. [0215] Split systems: some systems comprise separate DNA-binding and effector domains, such that activity requires or is increased by reassembly of the binding and effector domains for activity. An advantage of these approaches in reduced activity at off-target sites. [0216] Photocaged nucleotides: some systems incorporate light-sensitive nucleotides into gRNAs for spatial control. An advantage of these approaches is that they allow precise activation in specific tissues/regions. [0217] Small molecule-regulated systems: some systems comprise engineered or native proteins that require a small molecule for activation (e.g. rapamycin-inducible), for example by mediating proximity of constituents. An advantage of these approaches is that they provide temporal control and dose-dependent activity. [0218] Self-inactivating systems: some systems comprise designing gRNAs to target the coding sequence of the effector protein after initial activity, so as to trigger a negative feedback or self-inactivation activity. An advantage of these approaches is that they limit the duration of activity to reduce the risk of long-term off-target effects. [0219] Tissue-specific promoters: some systems comprise expression of components under the control of tissue specific or tissue-upregulated promoters, for example as an approach for targeting systems to target cells or to tissues in which target cells are suspected to be found. An advantage of these approaches is that they restrict activity to desired cell types. [0220] Manufacturing and formulation. The components of the invention can be manufactured using standard molecular biology and protein production techniques. For RNA components, in vitro transcription or chemical synthesis methods can be employed. Proteins can be produced in bacterial, yeast, insect, or mammalian expression systems, depending on the specific requirements for post-translational modifications and scale. [0221] Formulation of the components will depend on the intended delivery method and target tissue. Common formulations include the following. [0222] For Lipid nanoparticles, one may encapsulate RNA and protein components in a lipid bilayer, optionally including targeting ligands. [0223] For Viral vectors one may package genetic constructs encoding the system components into adeno-associated virus (AAV) or lentiviral particles. [0224] For Exosomes, one may load components into engineered exosomes derived from appropriate cell types. [0225] For polymeric nanoparticles, one may encapsulate components in biodegradable polymers such as PLGA. [0226] For Cell-penetrating peptide conjugates one may attach cell-penetrating peptides to protein components to enhance cellular uptake. [0227] To ensure consistency and efficacy of the manufactured products, the following quality control measures are available to be implemented. [0228] Nucleic acid purity and integrity may be assessed using spectrophotometry, gel electrophoresis, and bioanalyzer techniques. [0229] Protein purity and activity may be evaluated using SDS-PAGE, Western blotting, and functional assays specific to each protein's intended activity. [0230] Nanoparticle characterization may be accomplished by measuring one or more of size distribution, zeta potential, and encapsulation efficiency using dynamic light scattering and other appropriate techniques. [0231] Sterility and endotoxin testing may be performed to ensure products are free from microbial contamination and have acceptably low endotoxin levels. [0232] In vitro efficacy testing may be used to validate the activity of each batch using cell- based assays that recapitulate the intended therapeutic effect. [0233] Dosing and administration. The optimal dosing and administration route will vary depending on the specific application, target tissue, and patient characteristics. General considerations include the following. [0234] Dose-finding studies may be performed by conducting careful dose-escalation studies to determine the minimum effective dose and maximum tolerated dose. [0235] Administration frequency may be assessed by determining whether single or repeated administrations are necessary based on the durability of the effect and turnover of target cells. [0236] Route of administration may be selected by choosing the most appropriate route based on one or more of target tissue and patient convenience (e.g., intravenous, subcutaneous, intramuscular, inhaled, or topical). [0237] Monitoring may be accomplished by developing appropriate biomarkers or imaging techniques to assess target engagement and therapeutic effect. [0238] Personalization may be accomplished by considering patient-specific factors such as body weight, organ function, and genetic background in dosing decisions. [0239] Reagent development workflow. Some compositions are developed and provided in a standard from to individuals having known ailments or having target cells addressable using known targets. In alternate cases, guide RNA sequences are selected denovo and in some cases proteins are developed de novo through a workflow along the lines of the following. [0240] Sample Obtainment and Processing: Some guide RNAs are developed in some cases de novo for a cell target or individual. One example of how to generate guide RNA is as follows. Guide RNA development may begin with obtaining a biological sample from a subject. This sample may be a tissue biopsy, blood sample, or other relevant biological material. The sample is then processed to isolate the cells of interest using appropriate techniques such as density gradient centrifugation or magnetic-activated cell sorting. [0241] RNA Extraction and Sequencing: Total RNA is extracted from the isolated cells using standard methods, such as commercially available RNA extraction kits. The extracted RNA is then used to prepare sequencing libraries, which are subjected to high-throughput sequencing using platforms such as Illumina, Ion Torrent, or Oxford Nanopore. [0242] RNA Analysis and Target Identification: Sequencing data is analyzed using bioinformatics tools to identify cell-specific RNA molecules. This may involve differential expression analysis, fusion transcript detection, or variant calling, viral or pathogen transcript identification depending on the specific cell population being targeted. [0243] Guide RNA Design: Based on the identified cell-specific transcripts, guide RNAs (gRNAs) are designed to target these molecules. The gRNAs are typically 22-30 nucleotides in length and are designed to maximize specificity and minimize off-target effects. [0244] Protein Engineering: Proteins are in some cases engineered for improves, tailored or optimal activity in the target cell type. This may involve modifications to enhance specificity, improve nuclear localization, or alter protein size for more efficient delivery. [0245] Component Manufacturing: The designed gRNAs and engineered proteins are manufactured using appropriate methods. For Cas13 proteins, this may involve recombinant protein expression in cell lines such as Expi293F or HEK293T, followed by purification using affinity chromatography and size exclusion chromatography. gRNAs may be produced by in vitro transcription or chemical synthesis. [0246] Delivery Formulation: The manufactured components are formulated into an appropriate delivery vehicle, such as lipid nanoparticles or viral vectors. The choice of delivery system depends on the target cell type and route of administration. [0247] Administration to Subject: The formulated components are administered to the subject via an appropriate route, such as intravenous injection, intratumoral injection, or inhalation. The dosage and administration schedule are determined based on preclinical studies and may be adjusted according to patient response. [0248] Outcome Measurement: Following administration, outcomes related to target cell depletion are measured. This may include monitoring blood counts, performing follow-up biopsies, analyzing biomarkers, or assessing clinical symptoms. Off-target effects are also evaluated to ensure the specificity of the treatment. [0249] Turning to the figures, one sees the following. [0250] At Fig. 1, one sees an activation system acting on a heterogeneous population comprising a nontarget cell, top, and a target cell, bottom. [0251] At top, one sees that the initiator, or activator moiety, does not detect the RNA marker indicative of a target cell. Subsequently, the effector, or effector moiety, is not activated. The activator moiety and effector moiety are degraded without triggering their effect, and the nontarget cell is unharmed. [0252] At bottom, one sees a target cell having an RNA target, indicated by the grey segment of RNA. The target RNA is bound by the initiator, or activator moiety. This event gates activity of the effector moiety, which triggers cell death in the target cell. [0253] The result of the treatment is that the nontarget cells become enriched, and the target cells depleted, in the heterogeneous population. [0254] At Fig. 2, one sees an activation system acting within a target cell. A Cas13-RNA complex serves as an activator moiety. Ubon biding to target RNA, the Cas13 trans-cleavage activity is activated, which indiscriminately cleaves RNA in the cell, including a circular RNA molecule comprising an siRNA. The siRNA, once liberated from the circular molecule, serves as a guide for a RISC complex, which activates a DICE complex which in turn binds to a number of mRNA molecules encoding proteins essential for cellular viability. Inhibiting translation of these mRNA molecules leads to cell death. [0255] At Fig. 3, one sees a diversity of activation systems driven by a common activator moiety and signaling intermediate. An RNAse dead Type III CRISPR complex serves as the activator moiety. Alternate target binding or target identifying moieties, such as alternate CRISPR complexes or alternate RNA, DNA or protein biding moieties disclosed herein or otherwise known in the art similarly serve as activation moieties in activation systems herein. [0256] Upon binding to a target RNA, the activator moiety is activated to convert ATP to cOA. The cOA conversion is amplified such that the overall ATP level in the cell is depleted. [0257] The cOA serves as an intermediate signaling molecule. In alternate embodiments, ATP depletion may serve as a signal, or may act mechanistically to effect an outcome in the cell, such as by starving the cell of energy. This is particularly relevant for energy-hungry cells such as some cancer cells. [0258] The secondary messenger cOA may gate any number of downstream effector moieties, such as activating an enzyme, thereby accessing an enzyme activity as an effector, such as a protease, RNAse, DNAse, ATPase, kinase, phosphatase, lipidase or any number of other catalytic activities. [0259] Alternately, a secondary messenger such as cOA may impact gene or protein expression, so as to lead to expression of a structural protein, signaling protein or an enzyme such as an enzyme having a enzymatic activity of any of those above. Alternately, a secondary messenger such as cOA may impact gene or protein expression, so as to lead to inhibition of expression of a structural protein, signaling protein or an enzyme such as an enzyme having a enzymatic activity of any of those above. [0260] Any number of a broad range of effects may arise from the activation system. Target cells may be induced to undergo cell death or senescence. A gene network may be modulated so as to upregulate or downregulate a signaling pathway or other network. Cell differentiation or cell state may be impacted, leading to a cell state conversion. A reporter or other tag may be expressed so as to facilitate cell identification or sorting. A cell surface protein may be expressed or induced to accumulate, so as to facilitate cell surface mediated signaling or activity. Additional effects are also contemplated herein and consistent with the disclosure herein. [0261] The disclosure is further understood in light of the following partial list of numbered embodiments. 1. A population of cells, the population comprising a cancer cell comprising a foreign nucleic acid binding protein complex that is at least partially base paired to a cancer cell specific transcript in the cancer cell, and wherein the population comprises a non-cancer cell comprising the foreign nucleic acid binding protein complex. 2. The population of cells of any previous embodiment, such as number 1, wherein the foreign nucleic acid binding protein complex of the non-cancer cell is not bound to a transcript. 3. The population of cells of any previous embodiment, such as number 1, wherein the foreign nucleic acid binding protein complex of the non-cancer cell is not bound to a nucleic acid target. 4. The population of cells of any previous embodiment, such as number 1, wherein the foreign nucleic acid binding protein complex of the non-cancer cell is bound to a nucleic acid target but not active. 5. The cancer cell of any previous embodiment, such as number 1, wherein the nucleic acid binding protein complex comprises a guide RNA. 6. The cancer cell of any previous embodiment, such as number 5, wherein the guide RNA exhibits incomplete reverse complementarity to the cancer cell specific transcript. 7. The cancer cell of any previous embodiment, such as number 5, wherein the guide RNA exhibits complete reverse complementarity to the cancer cell specific transcript. 8. The cancer cell of any previous embodiment, such as number 1, wherein the nucleic acid binding protein complex exhibits binding-gated ATPase activity. 9. The cancer cell of any previous embodiment, such as number 1, wherein the nucleic acid binding protein complex exhibits binding-gated cOA synthetase activity. 10. The cancer cell of any previous embodiment, such as number 9, wherein the binding-gated cOA synthetase activity is ATPase-driven. 11. The cancer cell of any previous embodiment, such as number 1, wherein the nucleic acid binding protein complex is expressed from at least one transgene. 12. The cancer cell of any previous embodiment, such as number 1, wherein the nucleic acid binding protein complex is expressed from at least one viral template. 13. The cancer cell of any previous embodiment, such as number 1, wherein the nucleic acid binding protein complex is delivered via at least one exosome. 14. The cancer cell of any previous embodiment, such as number 1, wherein the nucleic acid binding protein complex is delivered via at least one Virus like particle. 15. The cancer cell of any previous embodiment, such as number 1, wherein the nucleic acid binding protein complex is partially base paired to a cancer cell specific transcript in the cancer cell. 16. The cancer cell of any previous embodiment, such as number 15, when being partially base paired comprises base pairing of no more than 80% of the cancer cell specific transcript to the nucleic acid binding protein complex. 17. The cancer cell of any previous embodiment, such as number 15, when being partially base paired comprises base pairing of no more than 60% of the cancer cell specific transcript to the nucleic acid binding protein complex. 18. The cancer cell of any previous embodiment, such as number 6, wherein the incomplete reverse complementarity comprises base pairing of no more than 80% of the guide nucleic acid. 19. The cancer cell of any previous embodiment, such as number 6, wherein the incomplete reverse complementarity comprises base pairing of no more than 60% of the guide nucleic acid. 20. The cancer cell of any previous embodiment, such as number 1, wherein the cancer cell is depleted for ATP. 21. The cancer cell of any previous embodiment, such as number 20, wherein the cancer cell is enriched for cOA. 22. The population of any previous embodiment, such as number 1 - 20, wherein the cancer cell and the non-cancer cell further comprise a cOA-activated effector. 23. The population of any previous embodiment, such as number 22, wherein the effector is active in the cancer cell. 24. The population of any previous embodiment, such as number 22, wherein the effector is inactive in the non-cancer cell. 25. The population of any previous embodiment, such as number 22, wherein the effector exhibits RNase activity when active. 26. The population of any previous embodiment, such as number 22, wherein the effector exhibits DNase activity when active. 27. The population of any previous embodiment, such as number 22, wherein the effector exhibits specific gene knockdown activity when active. 28. The population of any previous embodiment, such as number 22, wherein the effector exhibits multiple gene knockdown activity when active. 29. The population of any previous embodiment, such as number 22, wherein the effector comprises NucC. 30. The population of any previous embodiment, such as number 22, wherein the effector comprises a cOA activated effector. 31. The population of any previous embodiment, such as number 22, wherein the effector comprises a riboswitch. 32. The population of any previous embodiment, such as number 22, wherein the effector comprises a ribozyme. 33. The population of any previous embodiment, such as number 22, wherein the effector comprises an adapter. 34. The population of any previous embodiment, such as number 22, wherein the effector comprises an RNA/DNA hybrid having catalytic activity activated by binding to a small molecule. 35. The population of any previous embodiment, such as number 31, wherein the riboswitch regulates ADAR1 expression. 36. A method of selectively depleting cancer cell cytoplasmic ATP, the method comprising treating a patient such that at least one patient cancer cell and at least one patient non-cancer cell express a cancer-cell specific transcript binding moiety; and binding the cancer-cell specific transcript binding moiety to the cancer cell specific transcript; wherein the cancer-cell specific transcript binding moiety is activated by binding to the cancer-cell specific transcript to degrade ATP. 37. The method of any previous embodiment, such as number 36, wherein the cancer-cell specific transcript binding moiety is activated by binding to the cancer-cell specific transcript to degrade ATP so as to convert it into cOA. 38. The method of any previous embodiment, such as number 36, wherein the cancer cell exhibits reduced ATP levels subsequent to binding the cancer-cell specific transcript binding moiety to the cancer cell specific transcript. 39. The method of any previous embodiment, such as number 38, wherein the reduced ATP levels are no more than 80% of level prior to binding the cancer-cell specific transcript binding moiety to the cancer cell specific transcript. 40. The method of any previous embodiment, such as number 38, wherein the reduced ATP levels are no more than 50% of level prior to binding the cancer-cell specific transcript binding moiety to the cancer cell specific transcript. 41. The method of any previous embodiment, such as number 38, wherein the reduced ATP levels are no more than 25% of level prior to binding the cancer-cell specific transcript binding moiety to the cancer cell specific transcript. 42. The method of any previous embodiment, such as number 38, wherein the reduced ATP levels are no more than 10% of level prior to binding the cancer-cell specific transcript binding moiety to the cancer cell specific transcript. 43. The method of any previous embodiment, such as number 38, wherein the reduced ATP levels are no more than 5% of level prior to binding the cancer-cell specific transcript binding moiety to the cancer cell specific transcript. 44. The method of any previous embodiment, such as number 38, wherein the reduced ATP levels are no more than 2% of level prior to binding the cancer-cell specific transcript binding moiety to the cancer cell specific transcript. 45. The method of any previous embodiment, such as number 38, wherein the reduced ATP levels are no more than 1% of level prior to binding the cancer-cell specific transcript binding moiety to the cancer cell specific transcript. 46. The method of any previous embodiment, such as number 38, wherein the reduced ATP levels are no more than 80% of level of ATP levels in the patient non cancer cell. 47. The method of any previous embodiment, such as number 38, wherein the reduced ATP levels are no more than 50% of level of ATP levels in the patient non cancer cell. 48. The method of any previous embodiment, such as number 38, wherein the reduced ATP levels are no more than 25% of level of ATP levels in the patient non cancer cell. 49. The method of any previous embodiment, such as number 38, wherein the reduced ATP levels are no more than 10% of level of ATP levels in the patient non cancer cell. 50. The method of any previous embodiment, such as number 38, wherein the reduced ATP levels are no more than 5% of level of ATP levels in the patient non cancer cell. 51. The method of any previous embodiment, such as number 38, wherein the reduced ATP levels are no more than 2% of level of ATP levels in the patient non cancer cell. 52. The method of any previous embodiment, such as number 38, wherein the reduced ATP levels are no more than 1% of level of ATP levels in the patient non cancer cell. 53. The method of any previous embodiment, such as number 36, wherein the cancer-cell specific transcript binding moiety comprises a protein. 54. The method of any previous embodiment, such as number 53, wherein the protein comprises Csm. 55. The method of any previous embodiment, such as number 54, wherein the Csm is a multicomponent complex. 56. The method of any previous embodiment, such as number 54, wherein the Csm is an RNase dead Csm. 57. The method of any previous embodiment, such as number 36, wherein the cancer-cell specific transcript binding moiety comprises a guide RNA. 58. The method of any previous embodiment, such as number 57, wherein the guide RNA is reverse-complementary to a cancer cell specific nucleic acid. 59. The method of any previous embodiment, such as number 58, wherein the cancer cell specific nucleic acid comprises a gene translocation. 60. The method of any previous embodiment, such as number 59, wherein the gene translocation comprises a gene fusion. 61. The method of any previous embodiment, such as number 58, wherein the cancer cell specific nucleic acid comprises an alternatively spliced transcript. 62. The method of any previous embodiment, such as number 61, wherein the alternatively spliced transcript comprises a retained intron. 63. The method of any previous embodiment, such as number 58, wherein the cancer cell specific nucleic acid comprises a transposable element junction. 64. The method of any previous embodiment, such as number 58, wherein the cancer cell specific nucleic acid comprises a mutation indicative of an extrachromosomal DNA. 65. The method of any previous embodiment, such as number 36, wherein treating the patient cell expressing the cancer-cell specific transcript binding moiety comprises delivering the cancer-cell specific transcript binding moiety in a microvesicle. 66. The method of any previous embodiment, such as number 36, wherein treating the patient cell expressing the cancer-cell specific transcript binding moiety comprises delivering the cancer-cell specific transcript binding moiety in a viral nanoparticle. 67. The method of any previous embodiment, such as number 36, wherein patient non-cancer cell ATP levels are not substantially affected by transfection. 68. The method of any previous embodiment, such as number 36 - 67, comprising administering a chemotherapeutic agent to the patient. 69. The method of any previous embodiment, such as number 36 - 67, comprising administering a radiotherapy regimen to the patient.70. Method of targeting an activity to a subset of a population of cells, comprising transfecting the population of cells using a detection agent, the detection agent being triggered by a component of the subset of the population of cells to activate the moiety capable of performing the activity in the cell population. 71. The method of any previous embodiment, such as number 70, wherein the moiety capable of performing the activity in the cell population is endogenous. 72. The method of any previous embodiment, such as number 70, wherein the moiety capable of performing the activity in the cell population is transfected. 73. The method of any previous embodiment, such as number 70, comprising introducing the population of cells using a delivery agent to introduce a moiety capable of performing the activity in the cell population. 74. The method of any previous embodiment, such as number 70, wherein the population of cells comprises in vivo human cells. 75. The method of any previous embodiment, such as number 70, wherein the population of cells comprises ex vivo cultured cells. 76. The method of any previous embodiment, such as number 70, wherein the subset comprises cancer cells. 77. The method of any previous embodiment, such as number 70, wherein the subset comprises senescent cells. 78. The method of any previous embodiment, such as number 70, wherein the subset comprises healthy cell. 79. The method of any previous embodiment, such as number 70, wherein the subset comprises bacterial cells. 80. The method of any previous embodiment, such as number 70, wherein the subset comprises cells in a tumor microenvironment. 81. The method of any previous embodiment, such as number 70, wherein the subset comprises cells on a skin surface. 82. The method of any previous embodiment, such as number 75, wherein the subset comprises cancer cells. 83. The method of any previous embodiment, such as number 75, wherein the subset comprises senescent cells. 84. The method of any previous embodiment, such as number 75, wherein the subset comprises healthy cells. 85. The method of any previous embodiment, such as number 75, wherein the subset comprises bacterial cells. 86. The method of any previous embodiment, such as number 75, wherein the moiety capable of performing the activity in the cell population comprises a DNase. 87. The method of any previous embodiment, such as number 75, wherein the moiety capable of performing the activity in the cell population comprises a cell pore forming agent. 88. The method of any previous embodiment, such as number 75, wherein the moiety capable of performing the activity in the cell population comprises a transcription inhibitor. 89. The method of any previous embodiment, such as number 75, wherein the moiety capable of performing the activity in the cell population comprises a translation inhibitor. 90. The method of any previous embodiment, such as number 75, wherein the moiety capable of performing the activity in the cell population comprises a respiration inhibitor. 91. The method of any previous embodiment, such as number 75, wherein the moiety capable of performing the activity in the cell population comprises a mitochondrial electron transport inhibitor. 92. The method of any previous embodiment, such as number 75, wherein the moiety capable of performing the activity in the cell population comprises a DNA polymerase inhibitor. 93. The method of any previous embodiment, such as number 75, wherein the moiety capable of performing the activity in the cell population comprises a cell surface localized protein. 94. The method of any previous embodiment, such as number 75, wherein the moiety capable of performing the activity in the cell population comprises a fluorophore. 95. The method of any previous embodiment, such as number 75, wherein the moiety capable of performing the activity in the cell population comprises Csm1. 96. The method of any previous embodiment, such as number 75, wherein the moiety capable of performing the activity in the cell population comprises Cmr. 97. The method of any previous embodiment, such as number 75, wherein the moiety capable of performing the activity in the cell population comprises Csx29. 98. The method of any previous embodiment, such as number 75, wherein the moiety capable of performing the activity in the cell population comprises a Type III Crispr protein. 99. The method of any previous embodiment, such as number 75, wherein the moiety capable of performing the activity in the cell population comprises Cas 13. 100. The method of any previous embodiment, such as number 75, wherein the moiety capable of performing the activity in the cell population comprises Cas13b. 101. The method of any previous embodiment, such as number 75, wherein the moiety capable of performing the activity in the cell population comprises Cas12a2. 102. The method of any previous embodiment, such as number 75, wherein the moiety capable of performing the activity in the cell population comprises Cas12g. 103. The method of any previous embodiment, such as number 75, wherein the moiety capable of performing the activity in the cell population comprises an Argonaut protein. 104. The method of any previous embodiment, such as number 75, wherein the moiety capable of performing the activity in the cell population comprises siAGO. 105. The method of any previous embodiment, such as number 75, wherein the moiety capable of performing the activity in the cell population comprises SPARTA. 106. The method of any previous embodiment, such as number 75, wherein the moiety capable of performing the activity in the cell population comprises SPARSA. 107. The method of any previous embodiment, such as number 70, wherein the component of the subset of the population of cells comprises a transcript. 108. The method of any previous embodiment, such as number 107, wherein the transcript comprises a translocation junction. 109. The method of any previous embodiment, such as number 107, wherein the transcript comprises a retained intron. 110. The method of any previous embodiment, such as number 107, wherein the transcript is cell-type specific. 111. The method of any previous embodiment, such as number 107, wherein the transcript is differentially expressed in the population. 112. The method of any previous embodiment, such as number 70, wherein the detection agent comprises a protein. 113. The method of any previous embodiment, such as number 70, wherein the detection agent comprises a guide RNA. 114. The method of any previous embodiment, such as number 70, wherein the detection agent generates a signal upon being triggered by the component. 115. The method of any previous embodiment, such as number 114, wherein the signal comprises ATP degradation. 116. The method of any previous embodiment, such as number 114, wherein the signal comprises cOA generation. 117. The method of any previous embodiment, such as number 70 - 116, wherein the subset comprises cancer cells. 118. The method of any previous embodiment, such as number 70 - 116, wherein the subset comprises stem cells. 119. The method of any previous embodiment, such as number 70 - 116, wherein the subset comprises immune cells. 120. A bipartite target gated in vivo expression system, the system comprising: 1) a first constituent activator moiety, the activator moiety comprising a target recognition component and an signaling component, and 2) a second constituent effector moiety comprising signaling detection component and an effector component. 121. The system of any previous embodiment, such as number 120, wherein the second constituent is exogenously applied. 122. The system of any previous embodiment, such as number 120, wherein the second constituent is endogenous to a system target. 123. The system of any previous embodiment, such as number 120, wherein the first constituent comprises an RNA binding complex. 124. The system of any previous embodiment, such as number 123, wherein the RNA binding complex comprises a Csm1-guide RNA riboprotein complex. 125. The system of any previous embodiment, such as number 123, wherein the target recognition component comprises a guide RNA. 126. The system of any previous embodiment, such as number 123, wherein the target recognition component comprises a talon RNA recognition polypeptide. 127. The system of any previous embodiment, such as number 123, wherein the target recognition component comprises a zinc finger RNA recognition polypeptide. 128. The system of any previous embodiment, such as number 123, wherein the effector signaling component comprises an ATPase. 129. The system of any previous embodiment, such as number 123, wherein the effector signaling component comprises a cOA synthase. 130. The system of any previous embodiment, such as number 120, wherein the system is packaged in at least one exosome. 131. The system of any previous embodiment, such as number 120, wherein the system is delivered using SEND. 132. The system of any previous embodiment, such as number 120, wherein the system is delivered using endogenous viral-like particles. 133. The system of any previous embodiment, such as number 120, wherein the effector moiety is cytotoxic upon activation. 134. The system of any previous embodiment, such as number 120, wherein the signaling detection component detects elevated cOA levels. 135. The system of any previous embodiment, such as number 120, wherein the signaling detection component detects reduced ATP levels. 136. The system of any previous embodiment, such as number 120, wherein the effector component directs expression of a DNase. 137. The system of any previous embodiment, such as number 120, wherein the effector component directs expression of an RNase. 138. The system of any previous embodiment, such as number 120, wherein the effector component directs expression of a DNA polymerase inhibitor. 139. The system of any previous embodiment, such as number 120, wherein the effector component directs expression of a respiration inhibitor. 140. The system of any previous embodiment, such as number 120, wherein the effector component directs expression of a mitochondrial inhibitor. 141. The system of any previous embodiment, such as number 120, wherein the effector component directs expression of a pore. 142. The system of any previous embodiment, such as number 120, wherein the effector component directs expression of a pore synthetase activity. 143. The system of any previous embodiment, such as number 120, wherein the effector component directs expression of a reporter. 144. The system of any previous embodiment, such as number 120, wherein the effector component directs expression of an epitope. 145. The system of any previous embodiment, such as number 120, wherein the effector component directs expression of a fluorescent protein. 146. The system of any previous embodiment, such as number 120, wherein the effector component directs expression of Csm1. 147. The system of any previous embodiment, such as number 120, wherein the effector component directs expression of Cmr. 148. The system of any previous embodiment, such as number 120, wherein the effector component directs expression of Csx29. 149. The system of any previous embodiment, such as number 120, wherein the effector component directs expression of a Type III Crispr protein. 150. The system of any previous embodiment, such as number 120, wherein the effector component directs expression of Cas 13. 151. The system of any previous embodiment, such as number 120, wherein the effector component directs expression of Cas13b. 152. The system of any previous embodiment, such as number 120, wherein the effector component directs expression of Cas12a2. 153. The system of any previous embodiment, such as number 120, wherein the effector component directs expression of Cas12g. 154. The system of any previous embodiment, such as number 120, wherein the effector component directs expression of an Argonaut protein. 155. The system of any previous embodiment, such as number 120, wherein the effector component directs expression of siAGO. 156. The system of any previous embodiment, such as number 120, wherein the effector component directs expression of SPARTA. 157. The system of any previous embodiment, such as number 120, wherein the effector component directs expression of SPARSA. 158. The system of any previous embodiment, such as number 120, wherein the activator moiety binds an mRNA target pursuant to activation. 159. The system of any previous embodiment, such as number 158, wherein the mRNA target accumulates in a target cell type. 160. The system of any previous embodiment, such as number 159, wherein the mRNA target does not accumulate in a nontarget cell type. 161. The system of any previous embodiment, such as number 120, wherein the activator moiety binds a polypeptide target pursuant to activation. 162. The system of any previous embodiment, such as number 161, wherein the polypeptide target accumulates in a target cell type. 163. The system of any previous embodiment, such as number 162, wherein the polypeptide target does not accumulate in a nontarget cell type. 164. The system of any previous embodiment, such as number 120, wherein the activator moiety binds a small molecule target pursuant to activation. 165. The system of any previous embodiment, such as number 164, wherein the small molecule target accumulates in a target cell type. 166. The system of any previous embodiment, such as number 165, wherein the small molecule target does not accumulate in a nontarget cell type. 167. The system of any previous embodiment, such as number 120, wherein the system is packaged such that a first population of exosomes encapsulates at least one activator moiety, and a second population of exosomes encapsulates at least one effector moiety. 168. The system of any previous embodiment, such as number 120, wherein the system is encoded in at least one viral delivery vector. 169. The system of any previous embodiment, such as number 168, wherein a first population of viral delivery vectors encodes at least one activator moiety, and a second population of viral delivery vectors encodes at least one effector moiety. 170. Method of ameliorating a symptom of a disorder comprising administering to a patient a composition that is activated upon contact to a cell responsible for the disorder. 171. The method of any previous embodiment, such as number 172, comprising coadministration of a standard of care treatment. 172. A method of targeting senescent cells in a cell population in an individual, comprising contacting the population to a synthesis inducing moiety, wherein the synthesis inducing moiety gates activity of a cell toxicity synthesizing moiety, wherein the synthesis inducing moiety is gated by a metabolite that is differentially present in senescent cells, and wherein the cell toxicity synthesizing moiety directs cell death in senescent cells. 173. A method of reprogramming senescent cells in a heterogeneous cell population in an individual, comprising contacting the population to a synthesis inducing moiety, wherein the synthesis inducing moiety gates activity of a cell reprogramming synthesizing moiety, wherein the synthesis inducing moiety is gated by a metabolite that is differentially present in senescent cells, and wherein the cell reprogramming synthesizing moiety directs cell reprogramming in senescent cells. 174. A method of targeting cancer cells in a cell population in an individual, comprising contacting the population to a synthesis inducing moiety, wherein the synthesis inducing moiety gates activity of the cell toxicity synthesizing moiety, wherein the synthesis inducing moiety is gated by a metabolite that is differentially present in cancer cells, and wherein the cell toxicity synthesizing moiety directs cell death in cancer cells. 175. A method of targeting a cell population in an organism in an individual, comprising contacting the population to a synthesis inducing moiety, wherein the synthesis inducing moiety gates activity of a cell toxicity synthesizing moiety, wherein the synthesis inducing moiety is gated by a metabolite that is differentially present in the cell population, and wherein the cell toxicity synthesizing moiety directs cell death in the cell population. 176. The method of any previous embodiment, such as number 175, comprising performing a subsequent experiment on the individual. 177. A method of expressing a tag in a subset of a heterogeneous cell population, comprising contacting the population to a synthesis inducing moiety and a tag synthesizing moiety, wherein the synthesis inducing moiety gates activity of the tag synthesizing moiety, and wherein the synthesis inducing moiety is gated by a metabolite that is differentially present in the subset of the heterogeneous cell population, and wherein the tag synthesizing moiety directs accumulation of a tag. 178. The method of any previous embodiment, such as number 177, wherein the tag comprises an epitope. 179. The method of any previous embodiment, such as number 177, wherein the tag comprises a cell surface protein. 180. The method of any previous embodiment, such as number 177, wherein the tag comprises a fluorescent protein. 181. The method of any previous embodiment, such as number 177, wherein the tag comprises an antibiotic resistance marker. 182. The method of any previous embodiment, such as number 177, comprising sorting the heterogeneous cell population so as to enrich for cells expressing the tag. 183. An expression system comprising an RNA sensor, a secondary messenger, and an expression cassette. 184. The system of any previous embodiment, such as number 183, wherein the RNA sensor comprises an RNA- protein complex. 185. The system of any previous embodiment, such as number 184, wherein the RNA-protein complex comprises a guide RNA. 186. The system of any previous embodiment, such as number 184, wherein the RNA-protein complex comprises a Csm1 protein. 187. The system of any previous embodiment, such as number 183, wherein the RNA sensor detects an RNA that marks a cell type. 188. The system of any previous embodiment, such as number 187, wherein the cell type is a cancer cell type. 189. The system of any previous embodiment, such as number 187, wherein the cell type is a senescent cell type. 190. The system of any previous embodiment, such as number 187, wherein the cell type is an undifferentiated cell type. 191. The system of any previous embodiment, such as number 187, wherein the cell type is an experimental ablation target cell type. 192. The system of any previous embodiment, such as number 183, wherein the secondary messenger comprises ATP levels. 193. The system of any previous embodiment, such as number 183, wherein the secondary messenger comprises cOA. 194. The system of any previous embodiment, such as number 183, wherein the expression cassette encodes a cell death protein. 195. The system of any previous embodiment, such as number 183, wherein the expression cassette encodes a cell surface protein. 196. The system of any previous embodiment, such as number 183, wherein the expression cassette encodes a fluorescent protein. 197. The system of any previous embodiment, such as number 183, wherein the expression cassette encodes a chromatin remodeling protein. 198. The system of any previous embodiment, such as number 183, wherein the expression cassette encodes a chromatin remodeling RNA. 199. The system of any previous embodiment, such as number 183, wherein the expression cassette encodes Cmr. 200. The system of any previous embodiment, such as number 183, wherein the expression cassette encodes Csx29. 201. The system of any previous embodiment, such as number 183, wherein the expression cassette encodes a Type III Crispr protein. 202. The system of any previous embodiment, such as number 183, wherein the expression cassette encodes Cas 13. 203. The system of any previous embodiment, such as number 183, wherein the expression cassette encodes Cas13b. 204. The system of any previous embodiment, such as number 183, wherein the expression cassette encodes Cas12a2. 205. The system of any previous embodiment, such as number 183, wherein the expression cassette encodes Cas12g. 206. The system of any previous embodiment, such as number 183, wherein the expression cassette encodes an Argonaut protein. 207. The system of any previous embodiment, such as number 183, wherein the expression cassette encodes siAGO. 208. The system of any previous embodiment, such as number 183, wherein the expression cassette encodes SPARTA. 209. The system of any previous embodiment, such as number 183, wherein the expression cassette encodes SPARSA. EXAMPLES [0262] Example 1. A patient suffering from a MRSA bacterial infection is contacted with a salve comprising an sgRNA directed to an MRSA mediating nucleic acid. The sgRNA is taken up by the bacteria and assembled with the native bacterial type III CRISPR protein. The resulting complex is activated by the MRSA mediated nucleic acid target molecule to trigger cytotoxic RNase activity. [0263] Non MRSA bacteria adjacent to the MRSA bacteria at the wound site are not affected by the salve, such that selection pressure for resistance to the system is reduced, while the MRSA bacteria are targeted. [0264] Example 2. A patient suffers from a chemotherapy-resistant tumor. The tumor is biopsied and observed to harbor intratumor bacteria that harbor a native type III CRISPR system. [0265] A guide sgRNA directed to the intratumor bacteria is designed and delivered in a suspension in combination with a chemotherapeutic. The cotreatment is observed to respond to the chemotherapeutic. [0266] Example 3. A patient suffers from a chemotherapy-resistant tumor. The tumor is biopsied and observed to harbor intratumor bacteria. [0267] A guide RNA directed to the intratumor bacteria is designed and delivered in a microvesicle system with a second component cell death factor in combination with a chemotherapeutic. The cotreatment is observed to respond to the chemotherapeutic. [0268] Example 4. A patient region comprising a tumor and healthy cells is treated with a microvesicle system comprising a tumor specific guide targeting an oncogenic gene fusion transcript, complexed to a Csm protein. The microvesicles are delivered to the region of the tumor and taken up by both healthy and tumor cells. [0269] The guide RNA binds the target transcripts in the tumor only, activating Csm protein in those cells only. Specifically in the tumor cells, ATP is converted to cOA, depleting the cancer cells of ATP as an intracellular energy source. [0270] Example 5. A patient region comprising a tumor and healthy cells is treated with a microvesicle system comprising a first component comprising a tumor specific guide targeting an oncogenic gene fusion transcript, complexed to a Csm protein, and a second component comprising a cOA derepressed mRNA construct encoding a surface protein recognized by the patient’s immune system. The microvesicles are delivered to the region of the tumor and taken up by both healthy and tumor cells. [0271] The guide RNA binds the target transcripts in the tumor only, activating Csm protein in those cells only. Specifically in the tumor cells, ATP is converted to cOA, which serves as a messenger molecule. The cOA is bound by the cOA derepressed mRNA construct encoding a surface protein, resulting in the mRNA being recruited to the ribosome and its encoded surface protein being expressed. [0272] The cancer cells expressing the surface protein are attacked by the patient’s immune system. Adjacent cells comprise the first component and second component but do not exhibit activity, and are not attacked by the patient’s immune system. [0273] Example 6. A portion of an individual’s blood is removed and contacted to a composition disclosed herein. The composition comprises a first component having a guide RNA complexed to a Csm protein and targeting the senescence marker HERVK. The composition also comprises a second component comprising a cOA activated Can1 DNase. [0274] Cells expressing HERVK and not expressing HERVK are both induced to take up the composition, but the first component sgRNA/Csm complex is only activated in the cells expressing the HERVK marker. In cells where the first complex is activated, ATP is converted to cOA, which induces activity in the Can1 DNase. The DNase destroys cellular DNA, leading to death in HERVK expressing cells. [0275] The resulting cell population is enriched for cells that do not express the senescent marker HERVK, and is returned to the individual. [0276] Example 7. A portion of an individual’s blood is removed and contacted to a composition disclosed herein. The composition comprises a first component having a guide RNA complexed to a Csm protein and targeting a senescence associated resurrected transposable element. The composition also comprises a second component comprising a cOA activated Can1 DNase. [0277] Cells expressing the resurrected transposable element and not expressing the resurrected transposable element are both induced to take up the composition, but the first component sgRNA/Csm complex is only activated in the cells expressing the resurrected transposable element marker. In cells where the first complex is activated, ATP is converted to cOA, which induces activity in the Can1 DNase. The DNase destroys cellular DNA, leading to death in HERVK expressing cells. [0278] The resulting cell population is enriched for cells that do not express the senescent resurrected transposable element marker, and is returned to the individual. [0279] Example 8. A portion of an individual’s skin is contacted to a composition disclosed herein. The composition comprises a first component having a guide RNA complexed to a Csm protein and targeting transcripts encoding antibodies that misdirect the individual’s immune system to the individual’s skin cells, causing aberrantly differentiated skin patches. The composition also comprises a second component comprising a cOA activated mutant transcription factor having DNA binding but lacking transcription activity, and targeting the promoter region of the targeted transcripts. [0280] Cells expressing the transcripts encoding antibodies that misdirect the individual’s immune system to the individual’s skin cells and not expressing the transcripts encoding antibodies that misdirect the individual’s immune system to the individual’s skin cells are both induced to take up the composition, but the first component sgRNA/Csm complex is only activated in the cells expressing the transcripts encoding antibodies that misdirect the individual’s immune system to the individual’s skin cells. In cells where the first complex is activated, ATP is converted to cOA, which induces mutant transcription factor having DNA binding but lacking transcription activity, and targeting the promoter region of the targeted transcripts. The mutant transcription factor blocks expression of the target transcript. [0281] The skin disorder in the patient is alleviated. [0282] Example 8. Targeting senescent cells in aging: A composition comprising a guide RNA targeting the p16INK4a transcript and a TnpB-like protein fused to a caspase-9 domain is delivered to a patient's tissues using lipid nanoparticles. Upon binding to the p16INK4a transcript in senescent cells, the system activates caspase-9, leading to selective apoptosis of senescent cells. [0283] Example 9. Treating chronic myeloid leukemia: A system targeting the BCR-ABL fusion transcript is designed, comprising a guide RNA complementary to the fusion junction and a Cas13d protein fused to a KRAB repressor domain. This system is delivered to a patient's bone marrow using engineered exosomes, resulting in specific repression of the BCR-ABL oncogene in leukemic cells. [0284] Example 10. Combating antibiotic-resistant infections: For MRSA infections, a guide RNA targeting the mecA gene (responsible for methicillin resistance) is combined with a Cas12a2 protein engineered to induce cell death upon target binding. This composition is applied topically to infected wounds, selectively eliminating antibiotic-resistant bacteria while sparing normal flora. [0285] Example 11. Correcting genetic disorders: To treat cystic fibrosis, a guide RNA targeting the most common CFTR mutation (AF508) is designed, along with a TnpB- like protein fused to a prime editing domain. This system is delivered to lung epithelial cells using inhalable nanoparticles, enabling precise correction of the genetic defect. [0286] Example 12. Modulating the tumor microenvironment: A dual-guide RNA system is developed to target both PD-L1 expressing tumor cells and regulatory T cells in the tumor microenvironment. The system uses a Cas12g protein fused to a LIGHT (TNFSF14) domain, which upon activation, enhances T cell infiltration and anti-tumor immunity.

Claims

CLAIMS We claim: 1. A population of cells, the population comprising a cancer cell comprising a foreign nucleic acid binding protein complex that is at least partially base paired to a cancer cell specific transcript in the cancer cell, and wherein the population comprises a non- cancer cell comprising the foreign nucleic acid binding protein complex.

2. The population of cells of claim 1, wherein the foreign nucleic acid binding protein complex of the non-cancer cell is not bound to a transcript.

3. The population of cells of claim 1, wherein the foreign nucleic acid binding protein complex of the non-cancer cell is not bound to a nucleic acid target.

4. The population of cells of claim 1, wherein the foreign nucleic acid binding protein complex of the non-cancer cell is bound to a nucleic acid target but not active.

5. The cancer cell of claim 1, wherein the nucleic acid binding protein complex comprises a guide RNA.

6. The cancer cell of claim 5, wherein the guide RNA exhibits incomplete reverse complementarity to the cancer cell specific transcript.

7. The cancer cell of claim 5, wherein the guide RNA exhibits complete reverse complementarity to the cancer cell specific transcript.

8. The cancer cell of claim 1, wherein the nucleic acid binding protein complex exhibits binding-gated ATPase activity.

9. The cancer cell of claim 1, wherein the nucleic acid binding protein complex exhibits binding-gated cOA synthetase activity.

10. The cancer cell of claim 9, wherein the binding-gated cOA synthetase activity is ATPase-driven.

11. The cancer cell of claim 1, wherein the nucleic acid binding protein complex is expressed from at least one transgene.

12. The cancer cell of claim 1, wherein the nucleic acid binding protein complex is expressed from at least one viral template.

13. The cancer cell of claim 1, wherein the nucleic acid binding protein complex is delivered via at least one exosome.

14. The cancer cell of claim 1, wherein the nucleic acid binding protein complex is delivered via at least one Virus like particle.

15. The cancer cell of claim 1, wherein the nucleic acid binding protein complex is partially base paired to a cancer cell specific transcript in the cancer cell.

16. The cancer cell of claim 15, when being partially base paired comprises base pairing of no more than 80% of the cancer cell specific transcript to the nucleic acid binding protein complex.

17. The cancer cell of claim 15, when being partially base paired comprises base pairing of no more than 60% of the cancer cell specific transcript to the nucleic acid binding protein complex.

18. The cancer cell of claim 6, wherein the incomplete reverse complementarity comprises base pairing of no more than 80% of the guide nucleic acid.

19. The cancer cell of claim 6, wherein the incomplete reverse complementarity comprises base pairing of no more than 60% of the guide nucleic acid.

20. The cancer cell of claim 1, wherein the cancer cell is depleted for ATP.

21. The cancer cell of claim 20, wherein the cancer cell is enriched for cOA.

22. The population of any one of claims 1 - 20, wherein the cancer cell and the non- cancer cell further comprise a cOA-activated effector.

23. The population of claim 22, wherein the effector is active in the cancer cell.

24. The population of claim 22, wherein the effector is inactive in the non-cancer cell.

25. The population of claim 22, wherein the effector exhibits RNase activity when active.

26. The population of claim 22, wherein the effector exhibits DNase activity when active.

27. The population of claim 22, wherein the effector exhibits specific gene knockdown activity when active.

28. The population of claim 22, wherein the effector exhibits multiple gene knockdown activity when active.

29. The population of claim 22, wherein the effector comprises NucC.

30. The population of claim 22, wherein the effector comprises a cOA activated effector.

31. The population of claim 22, wherein the effector comprises a riboswitch.

32. The population of claim 22, wherein the effector comprises a ribozyme.

33. The population of claim 22, wherein the effector comprises an adapter.

34. The population of claim 22, wherein the effector comprises an RNA/DNA hybrid having catalytic activity activated by binding to a small molecule.

35. The population of claim 31, wherein the riboswitch regulates ADAR1 expression.

36. A method of selectively depleting cancer cell cytoplasmic ATP, the method comprising treating a patient such that at least one patient cancer cell and at least one patient non-cancer cell express a cancer-cell specific transcript binding moiety; and binding the cancer-cell specific transcript binding moiety to the cancer cell specific transcript; wherein the cancer-cell specific transcript binding moiety is activated by binding to the cancer-cell specific transcript to degrade ATP.

37. The method of claim 36, wherein the cancer-cell specific transcript binding moiety is activated by binding to the cancer-cell specific transcript to degrade ATP so as to convert it into cOA.

38. The method of claim 36, wherein the cancer cell exhibits reduced ATP levels subsequent to binding the cancer-cell specific transcript binding moiety to the cancer cell specific transcript.

39. The method of claim 38, wherein the reduced ATP levels are no more than 80% of level prior to binding the cancer-cell specific transcript binding moiety to the cancer cell specific transcript.

40. The method of claim 38, wherein the reduced ATP levels are no more than 50% of level prior to binding the cancer-cell specific transcript binding moiety to the cancer cell specific transcript.

41. The method of claim 38, wherein the reduced ATP levels are no more than 25% of level prior to binding the cancer-cell specific transcript binding moiety to the cancer cell specific transcript.

42. The method of claim 38, wherein the reduced ATP levels are no more than 10% of level prior to binding the cancer-cell specific transcript binding moiety to the cancer cell specific transcript.

43. The method of claim 38, wherein the reduced ATP levels are no more than 5% of level prior to binding the cancer-cell specific transcript binding moiety to the cancer cell specific transcript.

44. The method of claim 38, wherein the reduced ATP levels are no more than 2% of level prior to binding the cancer-cell specific transcript binding moiety to the cancer cell specific transcript.

45. The method of claim 38, wherein the reduced ATP levels are no more than 1% of level prior to binding the cancer-cell specific transcript binding moiety to the cancer cell specific transcript.

46. The method of claim 38, wherein the reduced ATP levels are no more than 80% of level of ATP levels in the patient non cancer cell.

47. The method of claim 38, wherein the reduced ATP levels are no more than 50% of level of ATP levels in the patient non cancer cell.

48. The method of claim 38, wherein the reduced ATP levels are no more than 25% of level of ATP levels in the patient non cancer cell.

49. The method of claim 38, wherein the reduced ATP levels are no more than 10% of level of ATP levels in the patient non cancer cell.

50. The method of claim 38, wherein the reduced ATP levels are no more than 5% of level of ATP levels in the patient non cancer cell.

51. The method of claim 38, wherein the reduced ATP levels are no more than 2% of level of ATP levels in the patient non cancer cell.

52. The method of claim 38, wherein the reduced ATP levels are no more than 1% of level of ATP levels in the patient non cancer cell.

53. The method of claim 36, wherein the cancer-cell specific transcript binding moiety comprises a protein.

54. The method of claim 53, wherein the protein comprises Csm.

55. The method of claim 54, wherein the Csm is a multicomponent complex.

56. The method of claim 54, wherein the Csm is an RNase dead Csm.

57. The method of claim 36, wherein the cancer-cell specific transcript binding moiety comprises a guide RNA.

58. The method of claim 57, wherein the guide RNA is reverse-complementary to a cancer cell specific nucleic acid.

59. The method of claim 58, wherein the cancer cell specific nucleic acid comprises a gene translocation.

60. The method of claim 59, wherein the gene translocation comprises a gene fusion.

61. The method of claim 58, wherein the cancer cell specific nucleic acid comprises an alternatively spliced transcript.

62. The method of claim 61, wherein the alternatively spliced transcript comprises a retained intron.

63. The method of claim 58, wherein the cancer cell specific nucleic acid comprises a transposable element junction.

64. The method of claim 58, wherein the cancer cell specific nucleic acid comprises a mutation indicative of an extrachromosomal DNA.

65. The method of claim 36, wherein treating the patient cell expressing the cancer-cell specific transcript binding moiety comprises delivering the cancer-cell specific transcript binding moiety in a microvesicle.

66. The method of claim 36, wherein treating the patient cell expressing the cancer-cell specific transcript binding moiety comprises delivering the cancer-cell specific transcript binding moiety in a viral nanoparticle.

67. The method of claim 36, wherein patient non-cancer cell ATP levels are not substantially affected by transfection.

68. The method of any one of claims 36 - 67, comprising administering a chemotherapeutic agent to the patient.

69. The method of any one of claims 36 - 67, comprising administering a radiotherapy regimen to the patient.

70. Method of targeting an activity to a subset of a population of cells, comprising transfecting the population of cells using a detection agent, the detection agent being triggered by a component of the subset of the population of cells to activate the moiety capable of performing the activity in the cell population.

71. The method of claim 70, wherein the moiety capable of performing the activity in the cell population is endogenous.

72. The method of claim 70, wherein the moiety capable of performing the activity in the cell population is transfected.

73. The method of claim 70, comprising introducing the population of cells using a delivery agent to introduce a moiety capable of performing the activity in the cell population.

74. The method of claim 70, wherein the population of cells comprises in vivo human cells.

75. The method of claim 70, wherein the population of cells comprises ex vivo cultured cells.

76. The method of claim 70, wherein the subset comprises cancer cells.

77. The method of claim 70, wherein the subset comprises senescent cells.

78. The method of claim 70, wherein the subset comprises healthy cell.

79. The method of claim 70, wherein the subset comprises bacterial cells.

80. The method of claim 70, wherein the subset comprises cells in a tumor microenvironment.

81. The method of claim 70, wherein the subset comprises cells on a skin surface.

82. The method of claim 75, wherein the subset comprises cancer cells.

83. The method of claim 75, wherein the subset comprises senescent cells.

84. The method of claim 75, wherein the subset comprises healthy cells.

85. The method of claim 75, wherein the subset comprises bacterial cells.

86. The method of claim 75, wherein the moiety capable of performing the activity in the cell population comprises a DNase.

87. The method of claim 75, wherein the moiety capable of performing the activity in the cell population comprises a cell pore forming agent.

88. The method of claim 75, wherein the moiety capable of performing the activity in the cell population comprises a transcription inhibitor.

89. The method of claim 75, wherein the moiety capable of performing the activity in the cell population comprises a translation inhibitor.

90. The method of claim 75, wherein the moiety capable of performing the activity in the cell population comprises a respiration inhibitor.

91. The method of claim 75, wherein the moiety capable of performing the activity in the cell population comprises a mitochondrial electron transport inhibitor.

92. The method of claim 75, wherein the moiety capable of performing the activity in the cell population comprises a DNA polymerase inhibitor.

93. The method of claim 75, wherein the moiety capable of performing the activity in the cell population comprises a cell surface localized protein.

94. The method of claim 75, wherein the moiety capable of performing the activity in the cell population comprises a fluorophore.

95. The method of claim 75, wherein the moiety capable of performing the activity in the cell population comprises Csml.

96. The method of claim 75, wherein the moiety capable of performing the activity in the cell population comprises Cmr.

97. The method of claim 75, wherein the moiety capable of performing the activity in the cell population comprises Csx29.

98. The method of claim 75, wherein the moiety capable of performing the activity in the cell population comprises a Type III Crispr protein.

99. The method of claim 75, wherein the moiety capable of performing the activity in the cell population comprises Cas 13.

100. The method of claim 75, wherein the moiety capable of performing the activity in the cell population comprises Casl3b.

101. The method of claim 75, wherein the moiety capable of performing the activity in the cell population comprises Casl2a2.

102. The method of claim 75, wherein the moiety capable of performing the activity in the cell population comprises Cas12g.

103. The method of claim 75, wherein the moiety capable of performing the activity in the cell population comprises an Argonaut protein.

104. The method of claim 75, wherein the moiety capable of performing the activity in the cell population comprises siAGO.

105. The method of claim 75, wherein the moiety capable of performing the activity in the cell population comprises SPARTA.

106. The method of claim 75, wherein the moiety capable of performing the activity in the cell population comprises SPARSA.

107. The method of claim 70, wherein the component of the subset of the population of cells comprises a transcript.

108. The method of claim 107, wherein the transcript comprises a translocation junction.

109. The method of claim 107, wherein the transcript comprises a retained intron.

110. The method of claim 107, wherein the transcript is cell-type specific.

111. The method of claim 107, wherein the transcript is differentially expressed in the population.

112. The method of claim 70, wherein the detection agent comprises a protein.

113. The method of claim 70, wherein the detection agent comprises a guide RNA.

114. The method of claim 70, wherein the detection agent generates a signal upon being triggered by the component.

115. The method of claim 114, wherein the signal comprises ATP degradation.

116. The method of claim 114, wherein the signal comprises cOA generation.

117. The method of any one of claims 70 - 116, wherein the subset comprises cancer cells.

118. The method of any one of claims 70 - 116, wherein the subset comprises stem cells.

119. The method of any one of claims 70 - 116, wherein the subset comprises immune cells.

120. A bipartite target gated in vivo expression system, the system comprising: 1) a first constituent activator moiety, the activator moiety comprising a target recognition component and an signaling component, and 2) a second constituent effector moiety comprising signaling detection component and an effector component.

121. The system of claim 120, wherein the second constituent is exogenously applied.

122. The system of claim 120, wherein the second constituent is endogenous to a system target.

123. The system of claim 120, wherein the first constituent comprises an RNA binding complex.

124. The system of claim 123, wherein the RNA binding complex comprises a Csm1-guide RNA riboprotein complex.

125. The system of claim 123, wherein the target recognition component comprises a guide RNA.

126. The system of claim 123, wherein the target recognition component comprises a talon RNA recognition polypeptide.

127. The system of claim 123, wherein the target recognition component comprises a zinc finger RNA recognition polypeptide.

128. The system of claim 123, wherein the effector signaling component comprises an ATPase.

129. The system of claim 123, wherein the effector signaling component comprises a cOA synthase.

130. The system of claim 120, wherein the system is packaged in at least one exosome.

131. The system of claim 120, wherein the system is delivered using SEND.

132. The system of claim 120, wherein the system is delivered using endogenous viral-like particles.

133. The system of claim 120, wherein the effector moiety is cytotoxic upon activation.

134. The system of claim 120, wherein the signaling detection component detects elevated cOA levels.

135. The system of claim 120, wherein the signaling detection component detects reduced ATP levels.

136. The system of claim 120, wherein the effector component directs expression of a DNase.

137. The system of claim 120, wherein the effector component directs expression of an RNase.

138. The system of claim 120, wherein the effector component directs expression of a DNA polymerase inhibitor.

139. The system of claim 120, wherein the effector component directs expression of a respiration inhibitor.

140. The system of claim 120, wherein the effector component directs expression of a mitochondrial inhibitor.

141. The system of claim 120, wherein the effector component directs expression of a pore.

142. The system of claim 120, wherein the effector component directs expression of a pore synthetase activity.

143. The system of claim 120, wherein the effector component directs expression of a reporter.

144. The system of claim 120, wherein the effector component directs expression of an epitope.

145. The system of claim 120, wherein the effector component directs expression of a fluorescent protein.

146. The system of claim 120, wherein the effector component directs expression of Csm1.

147. The system of claim 120, wherein the effector component directs expression of Cmr.

148. The system of claim 120, wherein the effector component directs expression of Csx29.

149. The system of claim 120, wherein the effector component directs expression of a Type III Crispr protein.

150. The system of claim 120, wherein the effector component directs expression of Cas 13.

151. The system of claim 120, wherein the effector component directs expression of Cas13b.

152. The system of claim 120, wherein the effector component directs expression of Cas12a2.

153. The system of claim 120, wherein the effector component directs expression of Cas12g.

154. The system of claim 120, wherein the effector component directs expression of an Argonaut protein.

155. The system of claim 120, wherein the effector component directs expression of siAGO.

156. The system of claim 120, wherein the effector component directs expression of SPARTA.

157. The system of claim 120, wherein the effector component directs expression of SPARSA.

158. The system of claim 120, wherein the activator moiety binds an mRNA target pursuant to activation.

159. The system of claim 158, wherein the mRNA target accumulates in a target cell type.

160. The system of claim 159, wherein the mRNA target does not accumulate in a nontarget cell type.

161. The system of claim 120, wherein the activator moiety binds a polypeptide target pursuant to activation.

162. The system of claim 161, wherein the polypeptide target accumulates in a target cell type.

163. The system of claim 162, wherein the polypeptide target does not accumulate in a nontarget cell type.

164. The system of claim 120, wherein the activator moiety binds a small molecule target pursuant to activation.

165. The system of claim 164, wherein the small molecule target accumulates in a target cell type.

166. The system of claim 165, wherein the small molecule target does not accumulate in a nontarget cell type.

167. The system of claim 120, wherein the system is packaged such that a first population of exosomes encapsulates at least one activator moiety, and a second population of exosomes encapsulates at least one effector moiety.

168. The system of claim 120, wherein the system is encoded in at least one viral delivery vector.

169. The system of claim 168, wherein a first population of viral delivery vectors encodes at least one activator moiety, and a second population of viral delivery vectors encodes at least one effector moiety.

170. Method of ameliorating a symptom of a disorder comprising administering to a patient a composition that is activated upon contact to a cell responsible for the disorder.

171. The method of claim 172, comprising coadministration of a standard of care treatment.

172. A method of targeting senescent cells in a cell population in an individual, comprising contacting the population to a synthesis inducing moiety, wherein the synthesis inducing moiety gates activity of a cell toxicity synthesizing moiety, wherein the synthesis inducing moiety is gated by a metabolite that is differentially present in senescent cells, and wherein the cell toxicity synthesizing moiety directs cell death in senescent cells.

173. A method of reprogramming senescent cells in a heterogeneous cell population in an individual, comprising contacting the population to a synthesis inducing moiety, wherein the synthesis inducing moiety gates activity of a cell reprogramming synthesizing moiety, wherein the synthesis inducing moiety is gated by a metabolite that is differentially present in senescent cells, and wherein the cell reprogramming synthesizing moiety directs cell reprogramming in senescent cells.

174. A method of targeting cancer cells in a cell population in an individual, comprising contacting the population to a synthesis inducing moiety, wherein the synthesis inducing moiety gates activity of the cell toxicity synthesizing moiety, wherein the synthesis inducing moiety is gated by a metabolite that is differentially present in cancer cells, and wherein the cell toxicity synthesizing moiety directs cell death in cancer cells.

175. A method of targeting a cell population in an organism in an individual, comprising contacting the population to a synthesis inducing moiety, wherein the synthesis inducing moiety gates activity of a cell toxicity synthesizing moiety, wherein the synthesis inducing moiety is gated by a metabolite that is differentially present in the cell population, and wherein the cell toxicity synthesizing moiety directs cell death in the cell population.

176. The method of claim 175, comprising performing a subsequent experiment on the individual.

177. A method of expressing a tag in a subset of a heterogeneous cell population, comprising contacting the population to a synthesis inducing moiety and a tag synthesizing moiety, wherein the synthesis inducing moiety gates activity of the tag synthesizing moiety, and wherein the synthesis inducing moiety is gated by a metabolite that is differentially present in the subset of the heterogeneous cell population, and wherein the tag synthesizing moiety directs accumulation of a tag.

178. The method of claim 177, wherein the tag comprises an epitope.

179. The method of claim 177, wherein the tag comprises a cell surface protein.

180. The method of claim 177, wherein the tag comprises a fluorescent protein.

181. The method of claim 177, wherein the tag comprises an antibiotic resistance marker.

182. The method of claim 177, comprising sorting the heterogeneous cell population so as to enrich for cells expressing the tag.

183. An expression system comprising an RNA sensor, a secondary messenger, and an expression cassette.

184. The system of claim 183, wherein the RNA sensor comprises an RNA-protein complex.

185. The system of claim 184, wherein the RNA-protein complex comprises a guide RNA.

186. The system of claim 184, wherein the RNA-protein complex comprises a Csm1 protein.

187. The system of claim 183, wherein the RNA sensor detects an RNA that marks a cell type.

188. The system of claim 187, wherein the cell type is a cancer cell type.

189. The system of claim 187, wherein the cell type is a senescent cell type.

190. The system of claim 187, wherein the cell type is an undifferentiated cell type.

191. The system of claim 187, wherein the cell type is an experimental ablation target cell type.

192. The system of claim 183, wherein the secondary messenger comprises ATP levels.

193. The system of claim 183, wherein the secondary messenger comprises cOA.

194. The system of claim 183, wherein the expression cassette encodes a cell death protein.

195. The system of claim 183, wherein the expression cassette encodes a cell surface protein.

196. The system of claim 183, wherein the expression cassette encodes a fluorescent protein.

197. The system of claim 183, wherein the expression cassette encodes a chromatin remodeling protein.

198. The system of claim 183, wherein the expression cassette encodes a chromatin remodeling RNA.

199. The system of claim 183, wherein the expression cassette encodes Cmr.

200. The system of claim 183, wherein the expression cassette encodes Csx29.

201. The system of claim 183, wherein the expression cassette encodes a Type III Crispr protein.

202. The system of claim 183, wherein the expression cassette encodes Cas 13.

203. The system of claim 183, wherein the expression cassette encodes Cas13b.

204. The system of claim 183, wherein the expression cassette encodes Cas12a2.

205. The system of claim 183, wherein the expression cassette encodes Cas12g.

206. The system of claim 183, wherein the expression cassette encodes an Argonaut protein.

207. The system of claim 183, wherein the expression cassette encodes siAGO.

208. The system of claim 183, wherein the expression cassette encodes SPARTA.

209. The system of claim 183, wherein the expression cassette encodes SPARSA.