Enzyme inhibitor

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Top: enzyme (E) accelerates conversion of substrates (S) to products (P). Bottom: by binding to enzyme, inhibitor (I) blocks binding of substrate. Binding site shown in blue checkerboard, substrate as black rectangle, and inhibitor as green rounded rectangle.

An enzyme inhibitor is a molecule that binds to an enzyme and blocks its activity. Enzymes are proteins that speed up chemical reactions necessary for life, in which substrate molecules are converted into products. An enzyme facilitates a specific chemical reaction by binding the substrate to its active site, a specialized area on the enzyme that accelerates the most difficult step of the reaction.

An enzyme inhibitor hinders ("inhibits") this process, either by binding to the enzyme's active site (thus preventing the substrate itself from binding) or by binding to another site on the enzyme such that the enzyme's catalysis of the reaction is blocked. Enzyme inhibitors may bind reversibly or irreversibly. Irreversible inhibitors form a chemical bond with the enzyme such that the enzyme is inhibited until the chemical bond is broken. By contrast, reversible inhibitors bind non-covalently and may spontaneously leave the enzyme, allowing the enzyme to resume its function. Reversible inhibitors produce different types of inhibition depending on whether they bind to the enzyme, the enzyme-substrate complex, or both.

Enzyme inhibitors play an important role in all cells, since they are generally specific to one enzyme and serve to control that enzyme's activity. For example, enzymes in a metabolic pathway may be inhibited by molecules produced later in the pathway, thus curtailing the production of molecules that are no longer needed. This type of negative feedback is an important way to maintain balance in a cell. Enzyme inhibitors also control essential enzymes such as proteases or nucleases that, if left unchecked, may damage a cell. Many poisons produced by animals or plants are enzyme inhibitors that block the activity of crucial enzymes in prey or predators.

Many drug molecules are enzyme inhibitors that inhibit an aberrant human enzyme or an enzyme critical for the survival of a pathogen such as a virus, bacterium or parasite. Examples include methotrexate (used in chemotherapy and in treating rheumatic arthritis) and the protease inhibitors used to treat HIV/AIDS. Since anti-pathogen inhibitors generally target only one enzyme, such drugs are highly specific and generally produce few side effects in humans, provided that no analogous enzyme is found in humans. (This is often the case, since such pathogens and humans are genetically distant.) Medicinal enzyme inhibitors often have low dissociation constants, meaning that only a minute amount of the inhibitor is required to inhibit the enzyme. A low concentration of the enzyme inhibitor reduces the risk for liver and kidney damage and other adverse drug reactions in humans. Hence the discovery and refinement of enzyme inhibitors is an active area of research in biochemistry and pharmacology.

Structural classes

Enzyme inhibitors are a chemically diverse set of substances that range in size from organic small molecules to macromolecular proteins.

Small molecule inhibitors include essential primary metabolites that inhibit upstream enzymes that produce those metabolites. This provides a negative feedback loop that prevents over production of metabolites and thus maintains cellular homeostasis (steady internal conditions). Small molecule enzyme inhibitors also include secondary metabolites, which are not essential to the organism that produces them, but provide the organism with a evolutionary advantage, in that they can be used to repel predators or competing organisms or immobilize prey. In addition, many drugs are small molecule enzyme inhibitors that target either disease-modifying enzymes in the patient or enzymes in pathogens which are required for the growth and reproduction of the pathogen.

In addition to small molecules, some proteins act as enzyme inhibitors. The most prominent example are serpins (serine protease inhibitors) which are produced by animals to protect against inappropriate enzyme activation and by plants to prevent predation. Another class of inhibitor proteins is the ribonuclease inhibitors, which bind to ribonucleases in one of the tightest known protein–protein interactions. A special case of protein enzyme inhibitors are zymogens that contain an autoinhibitory N-terminal peptide that binds to the active site of enzyme that intramolecularly blocks its activity as a protective mechanism against uncontrolled catalysis. The N-terminal peptide is cleaved (split) from the zymogen enzyme precursor by another enzyme to release an active enzyme.

The binding site of inhibitors on enzymes is most commonly the same site that binds the substrate of the enzyme. These active site inhibitors are known as orthosteric ("regular" orientation) inhibitors. The mechanism of orthosteric inhibition is simply to prevent substrate binding to the enzyme through direct competition which in turn prevents the enzyme from catalysing the conversion of substrates into products. Alternatively, the inhibitor can bind to a site remote from the enzyme active site. These are known as allosteric ("alternative" orientation) inhibitors. The mechanism of allosteric inhibition are varied and include changing the conformation (shape) of the enzyme such that it can no longer bind substrate (kinetically indistinguishable from competitive orthosteric inhibition) or alternatively stabilise binding of substrate to the enzyme but lock the enzyme in a conformation which is no longer catalytically active.

Reversible inhibitors

Inhibition mechanism schematic

Kinetic mechanisms for reversible inhibition. Substrate (S) binding to enzyme (E) in blue, catalysis releasing product (P) in red, inhibitor (I) binding to enzyme in green.

 

Schematics for reversible inhibition. Binding site in blue, substrate in black, inhibitor in green, and allosteric site in light green.

 

Competitive inhibitors usually bind to the active site. Non-competitive bind to a remote (allosteric) site. Uncompetitive inhibitors only bind once the substrate is bound, fully disrupting catalysis, and mixed inhibition is similar but with only partial disruption of catalysis.

Reversible inhibitors attach to enzymes with non-covalent interactions such as hydrogen bonds, hydrophobic interactions and ionic bonds. Multiple weak bonds between the inhibitor and the enzyme active site combine to produce strong and specific binding.

In contrast to irreversible inhibitors, reversible inhibitors generally do not undergo chemical reactions when bound to the enzyme and can be easily removed by dilution or dialysis. A special case are covalent reversible inhibitors that form a chemical bond with the enzyme, but the bond can be cleaved so the inhibition is fully reversible.

Reversible inhibitors are generally categorized into four types, as introduced by Cleland in 1963. They are classified according to the effect of the inhibitor on the V_max (maximum reaction rate catalysed by the enzyme) and K_m (the concentration of substrate resulting in half maximal enzyme activity) as the concentration of the enzyme's substrate is varied.

Competitive

In competitive inhibition, the substrate and inhibitor cannot bind to the enzyme at the same time. This usually results from the inhibitor having an affinity for the active site of an enzyme where the substrate also binds; the substrate and inhibitor compete for access to the enzyme's active site. This type of inhibition can be overcome by sufficiently high concentrations of substrate (V_max remains constant), i.e., by out-competing the inhibitor. However, the apparent K_m will increase as it takes a higher concentration of the substrate to reach the K_m point, or half the V_max. Competitive inhibitors are often similar in structure to the real substrate (see for example the "methotrexate versus folate" figure in the "Drugs" section).

Uncompetitive

In uncompetitive inhibition, the inhibitor binds only to the enzyme-substrate complex. This type of inhibition causes V_max to decrease (maximum velocity decreases as a result of removing activated complex) and K_m to decrease (due to better binding efficiency as a result of Le Chatelier's principle and the effective elimination of the ES complex thus decreasing the K_m which indicates a higher binding affinity). Uncompetitive inhibition is rare.

Non-competitive

In non-competitive inhibition, the binding of the inhibitor to the enzyme reduces its activity but does not affect the binding of substrate. As a result, the extent of inhibition depends only on the concentration of the inhibitor. V_max will decrease due to the inability for the reaction to proceed as efficiently, but K_m will remain the same as the actual binding of the substrate, by definition, will still function properly.

Mixed

In mixed inhibition, the inhibitor may bind to the enzyme whether or not the substrate has already bound. Hence mixed inhibition is a combination of competitive and noncompetitive inhibition. Furthermore, the affinity of the inhibitor for the free enzyme and the enzyme-substrate complex may differ. By increasing concentrations of substrate [S], this type of inhibition can be reduced (due to the competitive contribution), but not entirely overcome (due to the noncompetitive component). Although it is possible for mixed-type inhibitors to bind in the active site, this type of inhibition generally results from an allosteric effect where the inhibitor binds to a different site on an enzyme. Inhibitor binding to this allosteric site changes the conformation (that is, the tertiary structure or three-dimensional shape) of the enzyme so that the affinity of the substrate for the active site is reduced.

These four types of inhibition can also be distinguished by the effect of increasing the substrate concentration [S] on the degree of inhibition caused by a given amount of inhibitor. For competitive inhibition the degree of inhibition is reduced by increasing [S], for noncompetitive inhibition the degree of inhibition is unchanged, and for uncompetitive (also called anticompetitive) inhibition the degree of inhibition increases with [S].

Quantitative description

Reversible inhibition can be described quantitatively in terms of the inhibitor's binding to the enzyme and to the enzyme-substrate complex, and its effects on the kinetic constants of the enzyme. In the classic Michaelis-Menten scheme (shown in the "inhibition mechanism schematic" diagram), an enzyme (E) binds to its substrate (S) to form the enzyme–substrate complex ES. Upon catalysis, this complex breaks down to release product P and free enzyme. The inhibitor (I) can bind to either E or ES with the dissociation constants K_i or K_i', respectively.

• Competitive inhibitors can bind to E, but not to ES. Competitive inhibition increases K_m (i.e., the inhibitor interferes with substrate binding), but does not affect V_max (the inhibitor does not hamper catalysis in ES because it cannot bind to ES).
• Uncompetitive inhibitors bind to ES. Uncompetitive inhibition decreases both K_m and V_max. The inhibitor affects substrate binding by increasing the enzyme's affinity for the substrate (decreasing K_m) as well as hampering catalysis (decreases V_max).
• Non-competitive inhibitors have identical affinities for E and ES (K_i = K_i'). Non-competitive inhibition does not change K_m (i.e., it does not affect substrate binding) but decreases V_max (i.e., inhibitor binding hampers catalysis).
• Mixed-type inhibitors bind to both E and ES, but their affinities for these two forms of the enzyme are different (K_i ≠ K_i'). Thus, mixed-type inhibitors affect substrate binding (increase or decrease K_m) and hamper catalysis in the ES complex (decrease V_max).

When an enzyme has multiple substrates, inhibitors can show different types of inhibition depending on which substrate is considered. This results from the active site containing two different binding sites within the active site, one for each substrate. For example, an inhibitor might compete with substrate A for the first binding site, but be a non-competitive inhibitor with respect to substrate B in the second binding site.

Traditionally reversible enzyme inhibitors have been classified as competitive, uncompetitive, or non-competitive, according to their effects on K_m and V_max. These three types of inhibition result respectively from the inhibitor binding only to the enzyme E in the absence of substrate S, to the enzyme–substrate complex ES, or to both. The division of these classes arises from a problem in their derivation and results in the need to use two different binding constants for one binding event. It is further assumed that binding of the inhibitor to the enzyme results in 100% inhibition and fails to consider the possibility of partial inhibition. The common form of the inhibitory term also obscures the relationship between the inhibitor binding to the enzyme and its relationship to any other binding term be it the Michaelis–Menten equation or a dose response curve associated with ligand receptor binding. To demonstrate the relationship the following rearrangement can be made:

${\displaystyle {\begin{aligned}{\cfrac {V_{\max }}{1+{\cfrac {\ce {[I]}}{K_{i}}}}}&={V_{\max }}\left({\cfrac {K_{i}}{K_{i}+[{\ce {I}}]}}\right)&&{\text{multiply by }}{\cfrac {K_{i}}{K_{i}}}=1\\&={V_{\max }}\left({\cfrac {K_{i}+[{\ce {I}}]-[{\ce {I}}]}{K_{i}+[{\ce {I}}]}}\right)&&{\text{add }}[{\ce {I}}]-[{\ce {I}}]=0{\text{ to numerator}}\\&={V_{\max }}\left(1-{\cfrac {[{\ce {I}}]}{K_{i}+[{\ce {I}}]}}\right)&&{\text{simplify }}{\cfrac {K_{i}+[{\ce {I}}]}{K_{i}+[{\ce {I}}]}}=1\\&=V_{\max }-V_{\max }{\cfrac {\ce {[I]}}{K_{i}+[{\ce {I}}]}}&&{\text{multiply out by }}V_{\max }\end{aligned}}}$

This rearrangement demonstrates that similar to the Michaelis–Menten equation, the maximal rate of reaction depends on the proportion of the enzyme population interacting with its substrate.

fraction of the enzyme population bound by substrate

${\displaystyle {\cfrac {\ce {[S]}}{[{\ce {S}}]+K_{m}}}}$

fraction of the enzyme population bound by inhibitor

${\displaystyle {\cfrac {\ce {[I]}}{[{\ce {I}}]+K_{i}}}}$

the effect of the inhibitor is a result of the percent of the enzyme population interacting with inhibitor. The only problem with this equation in its present form is that it assumes absolute inhibition of the enzyme with inhibitor binding, when in fact there can be a wide range of effects anywhere from 100% inhibition of substrate turn over to no inhibition. To account for this the equation can be easily modified to allow for different degrees of inhibition by including a delta V_max term.

${\displaystyle V_{\max }-\Delta V_{\max }{\cfrac {\ce {[I]}}{[{\ce {I}}]+K_{i}}}}$

or

${\displaystyle V_{\max 1}-(V_{\max 1}-V_{\max 2}){\cfrac {\ce {[I]}}{[{\ce {I}}]+K_{i}}}}$

This term can then define the residual enzymatic activity present when the inhibitor is interacting with individual enzymes in the population. However the inclusion of this term has the added value of allowing for the possibility of activation if the secondary V_max term turns out to be higher than the initial term. To account for the possibly of activation as well the notation can then be rewritten replacing the inhibitor "I" with a modifier term (stimulator or inhibitor) denoted here as "X".

${\displaystyle V_{\max 1}-(V_{\max 1}-V_{\max 2}){\cfrac {\ce {[X]}}{[{\ce {X}}]+K_{x}}}}$

While this terminology results in a simplified way of dealing with kinetic effects relating to the maximum velocity of the Michaelis–Menten equation, it highlights potential problems with the term used to describe effects relating to the K_m. The K_m relating to the affinity of the enzyme for the substrate should in most cases relate to potential changes in the binding site of the enzyme which would directly result from enzyme inhibitor interactions. As such a term similar to the delta V_max term proposed above to modulate V_max should be appropriate in most situations:

${\displaystyle K_{m1}-(K_{m1}-K_{m2}){\cfrac {\ce {[X]}}{[{\ce {X}}]+K_{x}}}}$

Dissociation constants

Lineweaver–Burk diagrams of different types of reversible enzyme inhibitors. The arrow shows the effect of increasing concentrations of inhibitor.

An enzyme inhibitor is characterised by its dissociation constant K_i, the concentration at which the inhibitor half occupies the enzyme. In non-competitive inhibition, the inhibitor can also bind to the enzyme-substrate complex, and the presence of bound substrate can change the affinity of the inhibitor for the enzyme, resulting in a second dissociation constant K_i'. Hence K_i and K_i' are the dissociation constants of the inhibitor for the enzyme and to the enzyme-substrate complex, respectively. The enzyme-inhibitor constant K_i can be measured directly by various methods; one especially accurate method is isothermal titration calorimetry, in which the inhibitor is titrated into a solution of enzyme and the heat released or absorbed is measured. However, the other dissociation constant K_i' is difficult to measure directly, since the enzyme-substrate complex is short-lived and undergoing a chemical reaction to form the product. Hence, K_i' is usually measured indirectly, by observing the enzyme activity under various substrate and inhibitor concentrations, and fitting the data via nonlinear regression to a modified Michaelis–Menten equation.

${\displaystyle V={\frac {V_{max}[S]}{\alpha K_{m}+\alpha ^{\prime }[S]}}={\frac {(1/\alpha ^{\prime })V_{max}[S]}{(\alpha /\alpha ^{\prime })K_{m}+[S]}}}$

where the modifying factors α and α' are defined by the inhibitor concentration and its two dissociation constants

${\displaystyle \alpha =1+{\frac {[I]}{K_{i}}}}$

${\displaystyle \alpha ^{\prime }=1+{\frac {[I]}{K_{i}^{\prime }}}.}$

Thus, in the presence of the inhibitor, the enzyme's effective K_m and V_max become (α/α')K_m and (1/α')V_max, respectively. However, the modified Michaelis-Menten equation assumes that binding of the inhibitor to the enzyme has reached equilibrium, which may be a very slow process for inhibitors with sub-nanomolar dissociation constants. In these cases, the inhibition becomes effectively irreversible, hence it is more practical to treat such tight-binding inhibitors as irreversible (see below).

The effects of different types of reversible enzyme inhibitors on enzymatic activity can be visualised using graphical representations of the Michaelis–Menten equation, such as Lineweaver–Burk, Eadie-Hofstee or Hanes-Woolf plots. An illustration is provided by the three Lineweaver–Burk plots depicted in the Lineweaver–Burk diagrams figure. In the top diagram, the competitive inhibition lines intersect on the y-axis, illustrating that such inhibitors do not affect V_max. In the bottom diagram, the non-competitive inhibition lines intersect on the x-axis, showing these inhibitors do not affect K_m. However, since it can be difficult to estimate K_i and K_i' accurately from such plots, it is advisable to estimate these constants using more reliable nonlinear regression methods.

Special cases

Partially competitive

The mechanism of partially competitive inhibition is similar to that of non-competitive, except that the EIS complex has catalytic activity, which may be lower or even higher (partially competitive activation) than that of the enzyme–substrate (ES) complex. This inhibition typically displays a lower V_max, but an unaffected K_m value.

Substrate or product

Substrate or product inhibition is where either an enzymes substrate or product also act as an inhibitor. This inhibition may follow the competitive, uncompetitive or mixed patterns. In substrate inhibition there is a progressive decrease in activity at high substrate concentrations, potentially from an enzyme having two competing substrate-binding sites. At low substrate, the high-affinity site is occupied and normal kinetics are followed. However, at higher concentrations, the second inhibitory site becomes occupied, inhibiting the enzyme. Product inhibition (either the enzyme's own product, or a product to an enzyme downstream in its metabolic pathway) is often a regulatory feature in metabolism and can be a form of negative feedback.

Slow-tight

Slow-tight inhibition occurs when the initial enzyme–inhibitor complex EI undergoes conformational isomerism (a change in shape) to a second more tightly held complex, EI*, but the overall inhibition process is reversible. This manifests itself as slowly increasing enzyme inhibition. Under these conditions, traditional Michaelis–Menten kinetics give a false value for K_i, which is time–dependent. The true value of K_i can be obtained through more complex analysis of the on (k_on) and off (k_off) rate constants for inhibitor association with kinetics similar to irreversible inhibition.

Multi-substrate analogues

TGDDF/GDDF multi-substrate adduct inhibitor. Substrate analogue in black, cofactor analogue in blue, non-cleavable linker in red.

 

Peptide-based HIV-1 protease inhibitor ritonavir with substrate binding sites located in enzyme labelled as S2, S1, S1', and S2'.

 

Nonpeptidic HIV-1 protease inhibitor tipranavir

Multi-substrate analogue inhibitors are high affinity selective inhibitors that can be prepared for enzymes that catalyse reactions with more than one substrate by capturing the binding energy of each of those substrate into one molecule. For example, in the formyl transfer reactions of purine biosynthesis, a potent Multi-substrate Adduct Inhibitor (MAI) to glycinamide ribonucleotide (GAR) TFase was prepared synthetically by linking analogues of the GAR substrate and the N-10-formyl tetrahydrofolate cofactor together to produce thioglycinamide ribonucleotide dideazafolate (TGDDF), or enzymatically from the natural GAR substrate to yield GDDF. Here the subnanomolar dissociation constant (KD) of TGDDF was greater than predicted presumably due to entropic advantages gained and/or positive interactions acquired through the atoms linking the components. MAIs have also been observed to be produced in cells by reactions of pro-drugs such as isoniazid or enzyme inhibitor ligands (for example, PTC124) with cellular cofactors such as nicotinamide adenine dinucleotide (NADH) and adenosine triphosphate (ATP) respectively.

Examples

As enzymes have evolved to bind their substrates tightly, and most reversible inhibitors bind in the active site of enzymes, it is unsurprising that some of these inhibitors are strikingly similar in structure to the substrates of their targets. Inhibitors of dihydrofolate reductase (DHFR) are prominent examples.^[46] Other examples of these substrate mimics are the protease inhibitors, a therapeutically effective class of antiretroviral drugs used to treat HIV/AIDS. The structure of ritonavir, a peptidomimetic (peptide mimic) protease inhibitor containing three peptide bonds, as shown in the "competitive inhibitor examples" figure. As this drug resembles the peptide that is the substrate of the HIV protease, it competes with the substrate in the enzyme's active site.

Enzyme inhibitors are often designed to mimic the transition state or intermediate of an enzyme-catalysed reaction. This ensures that the inhibitor exploits the transition state stabilising effect of the enzyme, resulting in a better binding affinity (lower K_i) than substrate-based designs. An example of such a transition state inhibitor is the antiviral drug oseltamivir; this drug mimics the planar nature of the ring oxonium ion in the reaction of the viral enzyme neuraminidase.

However, not all inhibitors are based on the structures of substrates. For example, the structure of another HIV protease inhibitor tipranavir is not based on a peptide and has no obvious structural similarity to a protein substrate. These non-peptide inhibitors can be more stable than inhibitors containing peptide bonds, because they will not be substrates for peptidases and are less likely to be degraded.

In drug design it is important to consider the concentrations of substrates to which the target enzymes are exposed. For example, some protein kinase inhibitors have chemical structures that are similar to ATP, one of the substrates of these enzymes. However, drugs that are simple competitive inhibitors will have to compete with the high concentrations of ATP in the cell. Protein kinases can also be inhibited by competition at the binding sites where the kinases interact with their substrate proteins, and most proteins are present inside cells at concentrations much lower than the concentration of ATP. As a consequence, if two protein kinase inhibitors both bind in the active site with similar affinity, but only one has to compete with ATP, then the competitive inhibitor at the protein-binding site will inhibit the enzyme more effectively.

Irreversible inhibitors

Types

DFP reaction

Reaction of the irreversible inhibitor diisopropylfluorophosphate (DFP) with a serine protease

 

Irreversible inhibitors bind to the enzyme's binding site then undergo a chemical reaction to form a covalent enzyme-inhibitor complex (EI*). Binding site in blue, inhibitor in green.

Irreversible inhibitors covalently bind to an enzyme, and this type of inhibition can therefore not be readily reversed. Irreversible inhibitors often contain reactive functional groups such as nitrogen mustards, aldehydes, haloalkanes, alkenes, Michael acceptors, phenyl sulfonates, or fluorophosphonates. These electrophilic groups react with amino acid side chains to form covalent adducts. The residues modified are those with side chains containing nucleophiles such as hydroxyl or sulfhydryl groups; these include the amino acids serine (that reacts with DFP, see the "DFP reaction" diagram), and also cysteine, threonine, or tyrosine.

Irreversible inhibition is different from irreversible enzyme inactivation. Irreversible inhibitors are generally specific for one class of enzyme and do not inactivate all proteins; they do not function by destroying protein structure but by specifically altering the active site of their target. For example, extremes of pH or temperature usually cause denaturation of all protein structure, but this is a non-specific effect. Similarly, some non-specific chemical treatments destroy protein structure: for example, heating in concentrated hydrochloric acid will hydrolyse the peptide bonds holding proteins together, releasing free amino acids.

Irreversible inhibitors display time-dependent inhibition and their potency therefore cannot be characterised by an IC₅₀ value. This is because the amount of active enzyme at a given concentration of irreversible inhibitor will be different depending on how long the inhibitor is pre-incubated with the enzyme. Instead, k_obs/[I] values are used, where k_obs is the observed pseudo-first order rate of inactivation (obtained by plotting the log of % activity versus time) and [I] is the concentration of inhibitor. The k_obs/[I] parameter is valid as long as the inhibitor does not saturate binding with the enzyme (in which case k_obs = k_inact) where k_inact is the rate of inactivation.

Measuring

Irreversible inhibition mechanism

Kinetic mechanism for irreversible inhibition. Substrate binding in blue, catalysis in red, inhibitor binding in green, inactivation reaction in dark green.

Irreversible inhibitors first form a reversible non-covalent complex with the enzyme (EI or ESI). Subsequently a chemical reaction occurs between the enzyme and inhibitor to produce the covalently modified "dead-end complex" EI* (an irreversible covalent complex). The rate at which EI* is formed is called the inactivation rate or k_inact. Since formation of EI may compete with ES, binding of irreversible inhibitors can be prevented by competition either with substrate or with a second, reversible inhibitor. This protection effect is good evidence of a specific reaction of the irreversible inhibitor with the active site.

The binding and inactivation steps of this reaction are investigated by incubating the enzyme with inhibitor and assaying the amount of activity remaining over time. The activity will be decreased in a time-dependent manner, usually following exponential decay. Fitting these data to a rate equation gives the rate of inactivation at this concentration of inhibitor. This is done at several different concentrations of inhibitor. If a reversible EI complex is involved the inactivation rate will be saturable and fitting this curve will give k_inact and K_i.

Another method that is widely used in these analyses is mass spectrometry. Here, accurate measurement of the mass of the unmodified native enzyme and the inactivated enzyme gives the increase in mass caused by reaction with the inhibitor and shows the stoichiometry of the reaction. This is usually done using a MALDI-TOF mass spectrometer. In a complementary technique, peptide mass fingerprinting involves digestion of the native and modified protein with a protease such as trypsin. This will produce a set of peptides that can be analysed using a mass spectrometer. The peptide that changes in mass after reaction with the inhibitor will be the one that contains the site of modification.

Slow binding

DFMO inhibitor mechanism

Chemical mechanism for irreversible inhibition of ornithine decarboxylase by DFMO. Pyridoxal 5'-phosphate (Py) and enzyme (E) are not shown. Adapted from Poulin et al, 1992.

Not all irreversible inhibitors form covalent adducts with their enzyme targets. Some reversible inhibitors bind so tightly to their target enzyme that they are essentially irreversible. These tight-binding inhibitors may show kinetics similar to covalent irreversible inhibitors. In these cases, some of these inhibitors rapidly bind to the enzyme in a low-affinity EI complex and this then undergoes a slower rearrangement to a very tightly bound EI* complex (see the "irreversible inhibition mechanism" diagram). This kinetic behaviour is called slow-binding. This slow rearrangement after binding often involves a conformational change as the enzyme "clamps down" around the inhibitor molecule. Examples of slow-binding inhibitors include some important drugs, such methotrexate, allopurinol, and the activated form of acyclovir.

Some examples

Trypanothione reductase with the lower molecule of an inhibitor bound irreversibly and the upper one reversibly. Created from Bond, et al, 2004. (PDB: 1GXF​)

Diisopropylfluorophosphate (DFP) is an example of an irreversible protease inhibitor (see the "DFP reaction" diagram). The enzyme hydrolyses the phosphorus–fluorine bond, but the phosphate residue remains bound to the serine in the active site, deactivating it. Similarly, DFP also reacts with the active site of acetylcholine esterase in the synapses of neurons, and consequently is a potent neurotoxin, with a lethal dose of less than 100 mg.

Suicide inhibition is an unusual type of irreversible inhibition where the enzyme converts the inhibitor into a reactive form in its active site. An example is the inhibitor of polyamine biosynthesis, α-difluoromethylornithine (DFMO), which is an analogue of the amino acid ornithine, and is used to treat African trypanosomiasis (sleeping sickness). Ornithine decarboxylase can catalyse the decarboxylation of DFMO instead of ornithine (see the "DFMO inhibitor mechanism" diagram). However, this decarboxylation reaction is followed by the elimination of a fluorine atom, which converts this catalytic intermediate into a conjugated imine, a highly electrophilic species. This reactive form of DFMO then reacts with either a cysteine or lysine residue in the active site to irreversibly inactivate the enzyme.

Since irreversible inhibition often involves the initial formation of a non-covalent enzyme inhibitor (EI) complex, it is sometimes possible for an inhibitor to bind to an enzyme in more than one way. For example, in the figure showing trypanothione reductase from the human protozoan parasite Trypanosoma cruzi, two molecules of an inhibitor called quinacrine mustard are bound in its active site. The top molecule is bound reversibly, but the lower one is bound covalently as it has reacted with an amino acid residue through its nitrogen mustard group.

Applications

Enzyme inhibitors are found in nature and also produced artificially in the laboratory. Naturally occurring enzyme inhibitors regulate many metabolic processes and are essential for life. In addition, naturally produced poisons are often enzyme inhibitors that have evolved for use as toxic agents against predators, prey, and competing organisms. These natural toxins include some of the most poisonous substances known. Artificial inhibitors are often used as drugs, but can also be insecticides such as malathion, herbicides such as glyphosate, or disinfectants such as triclosan. Other artificial enzyme inhibitors block acetylcholinesterase, an enzyme which breaks down acetylcholine, and are used as nerve agents in chemical warfare.

Metabolic regulation

Enzyme inhibition is a common feature of metabolic pathway control in cells. Metabolic flux through a pathway is often regulated by a pathway's metabolites acting as inhibitors and enhancers for the enzymes in that same pathway. The glycolytic pathway is a classic example. This catabolic pathway consumes glucose and produces ATP, NADH and pyruvate. A key step for the regulation of glycolysis is an early reaction in the pathway catalysed by phosphofructokinase-1 (PFK1). When ATP levels rise, ATP binds an allosteric site in PFK1 to decrease the rate of the enzyme reaction; glycolysis is inhibited and ATP production falls. This negative feedback control helps maintain a steady concentration of ATP in the cell. However, metabolic pathways are not just regulated through inhibition since enzyme activation is equally important. With respect to PFK1, fructose 2,6-bisphosphate and ADP are examples of metabolites that are allosteric activators.

Physiological enzyme inhibition can also be produced by specific protein inhibitors. This mechanism occurs in the pancreas, which synthesises many digestive precursor enzymes known as zymogens. Many of these are activated by the trypsin protease, so it is important to inhibit the activity of trypsin in the pancreas to prevent the organ from digesting itself. One way in which the activity of trypsin is controlled is the production of a specific and potent trypsin inhibitor protein in the pancreas. This inhibitor binds tightly to trypsin, preventing the trypsin activity that would otherwise be detrimental to the organ. Although the trypsin inhibitor is a protein, it avoids being hydrolysed as a substrate by the protease by excluding water from trypsin's active site and destabilising the transition state. Other examples of physiological enzyme inhibitor proteins include the barstar inhibitor of the bacterial ribonuclease barnase.

Natural poisons

To discourage seed predation, legumes contain trypsin inhibitors that interfere with digestion.

Animals and plants have evolved to synthesise a vast array of poisonous products including secondary metabolites, peptides and proteins that can act as inhibitors. Natural toxins are usually small organic molecules and are so diverse that there are probably natural inhibitors for most metabolic processes. The metabolic processes targeted by natural poisons encompass more than enzymes in metabolic pathways and can also include the inhibition of receptor, channel and structural protein functions in a cell. For example, paclitaxel (taxol), an organic molecule found in the Pacific yew tree, binds tightly to tubulin dimers and inhibits their assembly into microtubules in the cytoskeleton.

Many natural poisons act as neurotoxins that can cause paralysis leading to death and function for defence against predators or in hunting and capturing prey. Some of these natural inhibitors, despite their toxic attributes, are valuable for therapeutic uses at lower doses. An example of a neurotoxin are the glycoalkaloids, from the plant species in the family Solanaceae (includes potato, tomato and eggplant), that are acetylcholinesterase inhibitors. Inhibition of this enzyme causes an uncontrolled increase in the acetylcholine neurotransmitter, muscular paralysis and then death. Neurotoxicity can also result from the inhibition of receptors; for example, atropine from deadly nightshade (Atropa belladonna) that functions as a competitive antagonist of the muscarinic acetylcholine receptors.

Although many natural toxins are secondary metabolites, these poisons also include peptides and proteins. An example of a toxic peptide is alpha-amanitin, which is found in relatives of the death cap mushroom. This is a potent enzyme inhibitor, in this case preventing the RNA polymerase II enzyme from transcribing DNA. The algal toxin microcystin is also a peptide and is an inhibitor of protein phosphatases. This toxin can contaminate water supplies after algal blooms and is a known carcinogen that can also cause acute liver haemorrhage and death at higher doses.

Proteins can also be natural poisons or antinutrients, such as the trypsin inhibitors (discussed in the "metabolic regulation" section above) that are found in some legumes. A less common class of toxins are toxic enzymes: these act as irreversible inhibitors of their target enzymes and work by chemically modifying their substrate enzymes. An example is ricin, an extremely potent protein toxin found in castor oil beans. This enzyme is a glycosidase that inactivates ribosomes. Since ricin is a catalytic irreversible inhibitor, this allows just a single molecule of ricin to kill a cell.

Drugs

Methotrexate versus folate

The coenzyme folic acid (top) compared to the anti-cancer drug methotrexate (bottom)

 

The structure of sildenafil (Viagra)

The most common uses for enzyme inhibitors are as drugs to treat disease. Many of these inhibitors target a human enzyme and aim to correct a pathological condition. For instance, aspirin is a widely used drug that acts as a suicide inhibitor of the cyclooxygenase enzyme. This inhibition in turn suppresses the production of proinflammatory prostaglandins and thus aspirin may be used to reduce pain, fever, and inflammation.

As of 2017, an estimated 29% of approved drugs are enzyme inhibitors of which approximately one-fifth are kinase inhibitors. A notable class of kinase drug targets is the receptor tyrosine kinases which are essential enzymes that regulate cell growth; their over-activation may result in cancer. Hence kinase inhibitors such as imatinib are frequently used to treat malignancies. Janus kinases are another notable example of drug enzyme targets. Inhibitors of Janus kinases block the production of inflammatory cytokines and hence these inhibitors are used to treat a variety of inflammatory diseases in including arthritis, asthma, and Crohn's disease.

An example of the structural similarity of some inhibitors to the substrates of the enzymes they target is seen in the figure comparing the drug methotrexate to folic acid. Folic acid is the oxidised form of the substrate of dihydrofolate reductase, an enzyme that is potently inhibited by methotrexate. Methotrexate blocks the action of dihydrofolate reductase and thereby halts thymidine biosynthesis. This block of nucleotide biosynthesis is selectively toxic to rapidly growing cells, therefore methotrexate is often used in cancer chemotherapy.

A common treatment for erectile dysfunction is sildenafil (Viagra). This compound is a potent inhibitor of cGMP specific phosphodiesterase type 5, the enzyme that degrades the signalling molecule cyclic guanosine monophosphate. This signalling molecule triggers smooth muscle relaxation and allows blood flow into the corpus cavernosum, which causes an erection. Since the drug decreases the activity of the enzyme that halts the signal, it makes this signal last for a longer period of time.

Antibiotics

The structure of a complex between penicillin G and the Streptomyces transpeptidase. (PDB: 1PWC​)

Drugs are also used to inhibit enzymes needed for the survival of pathogens. For example, bacteria are surrounded by a thick cell wall made of a net-like polymer called peptidoglycan. Many antibiotics such as penicillin and vancomycin inhibit the enzymes that produce and then cross-link the strands of this polymer together. This causes the cell wall to lose strength and the bacteria to burst. In the figure, a molecule of penicillin (shown in a ball-and-stick form) is shown bound to its target, the transpeptidase from the bacteria Streptomyces R61 (the protein is shown as a ribbon diagram).

Antibiotic drug design is facilitated when an enzyme that is essential to the pathogen's survival is absent or very different in humans. Humans do not make peptidoglycan, therefore antibiotics that inhibit this process are selectively toxic to bacteria. Selective toxicity is also produced in antibiotics by exploiting differences in the structure of the ribosomes in bacteria, or how they make fatty acids.

Antivirals

Drugs that inhibit enzymes needed for the replication of viruses are effective in treating viral infections. Antiviral drugs include protease inhibitors used to treat HIV/AIDS and Hepatitis C, reverse-transcriptase inhibitors targeting HIV/AIDS, neuraminidase inhibitors targeting influenza, and terminase inhibitors targeting human cytomegalovirus.

Pesticides

Many pesticides are enzyme inhibitors. Acetylcholinesterase (AChE) is an enzyme found in animals, from insects to humans. It is essential to nerve cell function through its mechanism of breaking down the neurotransmitter acetylcholine into its constituents, acetate and choline. This is somewhat unusual among neurotransmitters as most, including serotonin, dopamine, and norepinephrine, are absorbed from the synaptic cleft rather than cleaved. A large number of AChE inhibitors are used in both medicine and agriculture. Reversible competitive inhibitors, such as edrophonium, physostigmine, and neostigmine, are used in the treatment of myasthenia gravis and in anaesthesia to reverse muscle blockade. The carbamate pesticides are also examples of reversible AChE inhibitors. The organophosphate pesticides such as malathion, parathion, and chlorpyrifos irreversibly inhibit acetylcholinesterase.

Herbicides

The herbicide glyphosate is an inhibitor of 3-phosphoshikimate 1-carboxyvinyltransferase, other herbicides, such as the sulfonylureas inhibit the enzyme acetolactate synthase. Both enzymes are needed for plants to make branched-chain amino acids. Many other enzymes are inhibited by herbicides, including enzymes needed for the biosynthesis of lipids and carotenoids and the processes of photosynthesis and oxidative phosphorylation.

Discovery and design of inhibitors

Robots used for the high-throughput screening of chemical libraries to discover new enzyme inhibitors

New drugs are the products of a long drug development process, the first step of which is often the discovery of a new enzyme inhibitor. There are two principle approaches of discovering these inhibitors.

The first general method is rational drug design based on mimicking the transition state of the chemical reaction catalysed by the enzyme. The designed inhibitor often closely resembles the substrate, except that the portion of the substrate that undergoes chemical reaction is replaced a chemically stable functional group that resembles the transition state. Since the enzyme has evolved to stabilise the transition state, transition state analogues generally possess higher affinity for the enzyme compared to the substrate, and therefore are effective inhibitors.

The second way of discovering new enzyme inhibitors is high-throughput screening of large libraries of structurally diverse compounds to identify hit molecules that bind to the enzyme. This method has been extended to include virtual screening of databases of diverse molecules using computers, which are then followed by experimental confirmation of binding of the virtual screening hits. Complementary approaches that can provide new starting points for inhibitors include fragment-based lead discovery and screening of DNA-encoded chemical libraries.

Hits from any of the above approaches can be optimised to high affinity binders that efficiently inhibit the enzyme. Computer-based methods for predicting the binding orientation and affinity of an inhibitor for an enzyme such as molecular docking and molecular mechanics can be used to assist in the optimisation process. New inhibitors are used to obtain crystallographic structures of the enzyme in an inhibitor/enzyme complex to show how the molecule is binding to the active site, allowing changes to be made to the inhibitor to optimise binding in a process known as structure-based drug design. This test and improve cycle is repeated until a sufficiently potent inhibitor is produced.

Zero tolerance policies in schools

From Wikipedia, the free encyclopedia

https://en.wikipedia.org/wiki/Zero_tolerance_policies_in_schools

A zero-tolerance policy in schools is a strict enforcement of regulations and bans against behaviors or the possession of items deemed undesirable by said schools. Public criticism against the enforcement of such policies has arisen due to potential negative consequences when acts deemed intolerable are done in ignorance, by accident, or under extenuating circumstances, in addition to its connection to educational inequality in the United States. In schools, common zero-tolerance policies concern possession or use of illicit drugs or weapons. Students, and sometimes staff, parents, and other visitors, who possess a banned item for any reason are always (if the policy is followed) to be punished.

In the United States and Canada, zero-tolerance policies have been adopted in various schools and other education venues. Zero-tolerance policies in the United States became widespread in 1994, after federal legislation required states to expel for one year any student who brought a firearm to school, or lose all federal funding.

These policies are promoted as preventing drug abuse and violence in schools. Critics say zero-tolerance policies in schools have resulted in punishments that have been criticized as egregiously unfair against students and teachers, especially in schools with poorly written policies. Consequently, critics describe these policies as "zero-logic policies" because they treat juveniles the way that adults would be treated — or more harshly, given that children are seldom granted full permission to speak up in their own defense to adults with authority over them. Many people have been critical of zero-tolerance policies, claiming that they are draconian, provide little if any benefit to anyone, contribute to overcrowding of the criminal justice system, and/or disproportionately target people of color, particularly people of African-American and Hispanic descent.

Research

There is no concrete evidence that zero-tolerance reduces violence or drug abuse by students. Furthermore, school suspension and expulsion result in a number of negative outcomes for both schools and students. The American Bar Association finds that the evidence indicates that minority children are the most likely to suffer the negative consequences of zero-tolerance policies. Analysis of the suspension rate of students shows that black females and other racial minorities are suspended at a greater rate. The American Psychological Association concluded that the available evidence does not support the use of zero-tolerance policies as defined and implemented, that there is a clear need to modify such policies, and that the policies create a number of unintended negative consequences, including making schools "less safe".

In 2014, a study of school discipline figures was conducted. It was found that suspensions and expulsions as a result of zero-tolerance policies have not reduced school disruptions. The study's author stated that "zero-tolerance approaches to school discipline are not the best way to create a safe climate for learning". Zero-tolerance policies are sometimes viewed as a quick fix solution for student problems. While this seems like a simple action-reaction type of situation, it often leaves out the mitigating circumstances that are often the important details in student incidents. Even civilian judges consider mitigating circumstances before passing judgment or sentencing. If zero-tolerance policies were applied in adult courtroom scenarios, they would be fundamentally unjust and unconstitutional due to neglecting the laws involving due process, along with cruel and unusual punishments.

History

The label of zero-tolerance began with the Gun-Free Schools Act of 1994, when Congress authorized public-school funding subject to the adoption of zero-tolerance policies. Similar policies of intolerance coupled with expulsions for less serious behaviors than bringing a weapon to school had long been a part of private, and particularly religious schools. The use of zero-tolerance policies in public schools increased dramatically after the Columbine High School massacre, with principals declaring that safety concerns made them want zero-tolerance for weapons. These have led to a large number of disproportionate responses to minor, or technical transgressions, many of that have attracted the attention of the international media. These cases include students being suspended or expelled for such offenses as possession of ibuprofen or Midol (both legal, non-prescription drugs commonly used to treat headaches and menstrual cramps respectively) with permission of the students' parents, keeping pocketknives (small utility knife) in cars, and carrying sharp tools outside of a woodshop classroom (where they are often required materials). In Seal v. Morgan, a student was expelled for having a knife in his car on school property, despite his protestations that he was unaware of the knife's presence. In some jurisdictions, zero-tolerance policies have come into conflict with freedom of religion rules already in place allowing students to carry, for example, kirpans.

In the "kids for cash" scandal, judge Mark Ciavarella, who promoted a platform of zero-tolerance, received kickbacks for constructing a private prison that housed juvenile offenders, and then proceeded to fill the prison by sentencing children to extended stays in juvenile detention for offenses as minimal as mocking a principal on Myspace, scuffles in hallways, trespassing in a vacant building, and shoplifting DVDs from Wal-Mart. Critics of zero-tolerance policies argue that harsh punishments for minor offenses are normalized. The documentary Kids for Cash interviews experts on adolescent behavior, who argue that the zero-tolerance model has become a dominant approach to policing juvenile offenses after the Columbine shooting.

In New York City, Carmen Fariña, head of the New York City Department of Education, restricted school suspension by principals in 2015. The Los Angeles Unified school board, responsible for educating 700,000 students, voted in 2013 to ban suspensions for "willful defiance", which had mostly been used against students from racial minorities. A year later, the same school district decided to decriminalize school discipline so that minor offenses would be referred to school staff rather than prosecuted—the previous approach had resulted in black students being six times more likely to be arrested or given a ticket than white students. The district saw suspensions drop by 53%, and graduation rates rise by 12%.

Media attention

Media attention has proven embarrassing to school officials, resulting in changes to state laws as well as to local school policies. One school board member gave this reason for changes his district made to their rigid policy: "We are doing this because we got egg on our face."

• A student at Sandusky High School in Sandusky, Ohio, was suspended for 90 days and failed, after school authorities searched him for drugs in September 1999, and found a broken pocketknife. He had used the knife to clean his golfing cleats.
• The Christina School District in Newark, Delaware, has experienced multiple highly publicized cases of zero-tolerance:
  • After bringing a Cub Scouts dinner knife to school to eat his lunch, a six-year-old boy was ordered to attend an alternative school for students with behavioral problems for nine weeks. After a media uproar, the school board voted unanimously to reduce punishments for kindergartners and first-graders who take weapons to school to a 3-5 day mandatory suspension, retaining the original definition of "weapons".
  • Kasia Haughton, running for fifth-grade mayor at the Leasure Elementary School in Newark, Delaware was suspended and faced possible expulsion after coming to school with a knife to cut the cake. School officials were called in to investigate the incident, and referred to the knife as a "deadly weapon."
  • Other cases include a straight-A student who was ordered to attend "reform school" after a classmate dropped a pocket knife in his lap, and in 2007, when a girl was expelled for using a utility knife to cut paper for a project.
• Earlier in 2009, an Eagle Scout in New York was suspended for 20 days for having an emergency supply kit in his car that included a pocket knife.
• A kindergartner in Grand Rapids, Michigan, was suspended in March 2010 for making a finger gun.
• Another kindergartner, in Pennsylvania, was suspended for 10 days in January 2013 for referring to "shooting" a friend with a Hello Kitty bubble making gun. The suspension was reduced to two days after the parent met with school officials.
• A second-grader in Baltimore, Maryland, was suspended in March 2013 for biting a Pop-Tart into the shape of a mountain, which school officials mistook for a gun.
• 6-year-old Hunter Yelton in Colorado was suspended in 2013 for alleged repeated sexual harassment of a 6-year-old schoolmate, a charge the boy's family disputed. Following widespread negative media coverage and public disapproval, the school agreed to downgrade the suspension caused by "misconduct".
• A freshman at MacArthur High School in Irving, Texas, was suspended for a week in September 2015 after he put a digital alarm clock in a pencil box, and took it to his school to show a teacher. When the device beeped while in one class, the student was suspended and detained on suspicion of creating a hoax bomb.
• In the Escondido school knives case, Brian Capalletti and another student in San Diego were suspended from school for between 2 and 3 weeks and faced criminal charges and possible expulsion after knives were found in their vehicles parked outside their Escondido high school.

Promotion

Proponents of punishment- and exclusion-based philosophy of school discipline policies claim that such policies are required to create an appropriate environment for learning. This rests on the assumption that strong enforcement can act as a psychological deterrent to other potentially disruptive students.

The policy assumption is that inflexibility is a deterrent because, no matter how or why the rule was broken, the fact that the rule was broken is the basis for the imposition of the penalty. This is intended as a behavior modification strategy: since those at risk know that it may operate unfairly, they may be induced to take even unreasonable steps to avoid breaking the rule. This is a standard policy in rule- and law-based systems around the world on "offenses" as minor as traffic violations to major health and safety legislation for the protection of employees and the environment.

Disciplinarian parents view zero-tolerance policies as a tool to fight corruption. Under this argument, if subjective judgment is not allowed, most attempts by the authorised person to encourage bribes or other favors in exchange for leniency are clearly visible.

Criticism

Critics of zero-tolerance policies in schools say they are part of a school-to-prison pipeline that over-polices children with behavioral problems, treating their problems as criminal justice issues rather than educational and behavioral problems. Students that may previously have been given short school suspensions before the implementation of policies are now sent to juvenile courts.

Critics of zero-tolerance policies frequently refer to cases where minor offenses have resulted in severe punishments. Typical examples include the honor-roll student being expelled from school under a "no weapons" policy while in possession of nail clippers, or for possessing "drugs" like cough drops and dental mouthwash or "weapons" like rubber bands.

A related criticism is that zero-tolerance policies make schools feel like a jail or a prison. Furthermore zero-tolerance policies have been struck down by U.S. courts and by departments of education.

Another criticism is that the zero-tolerance policies have actually caused schools to turn a blind eye to bullying, resulting in them refusing to solve individual cases in an attempt to make their image look better. The zero-tolerance policy also punishes both the attacker and the defender in a fight, even when the attacker was the one who started the fight unprovoked. In 2017, the Georgia Supreme Court ruled that public schools within Georgia could not have a zero-tolerance policy for violence that does not allow for self-defense.

A particularly dismaying hypothesis about zero-tolerance policies is that they may actually discourage some people from reporting criminal and illegal behavior, for fear of losing relationships, and for many other reasons. That is, ironically, zero-tolerance policies may be ineffective in the very purpose for which they were originally designed.

As schools develop responses to online bullying, schools that have overly harsh approaches to zero-tolerance policies may increasingly police speech of students in their own time that would normally be protected by free speech laws.

The American Bar Association opposes "zero-tolerance policies that mandate either expulsion or referral of students to juvenile or criminal court, without regard to the circumstances or nature of the offense or the students [sic] history."

Critics of zero-tolerance policies also argue that the large numbers of students who are suspended and expelled from school experience negative effects, which can prohibit them from finishing high school. Students who experience suspension, expulsion and arrests pay higher psychological and social costs: such as depression, suicidal thoughts, academic failure, and run the risk of being incarcerated as adults. In a study by Forrest et al., (2000), psychologists identified that a third of youths in juvenile detention centers were diagnosed with depression shortly after being incarcerated. In addition to being diagnosed with depression many youths found themselves having suicidal thoughts (Gnau et al. 1997).

Research found that black, Latino, and white adults with low educational attainment risked a higher propensity of being incarcerated in their lifetime (Pettit & Western 2010). The same study found that the incarceration rate in 2008 was 37% and had risen since the 1980s. That showed that incarceration rates of people with low levels of education were continuing to rise and that students were not completing their high school requirements.

According to kidsdata.org, 21,638 students were suspended and 592 students were expelled from San Diego County schools in 2012. A total of 10.1% of students did not complete their high school diploma.

Despite a decrease in juvenile arrest, suspensions, expulsions, and drop out rates, many still argue that these disciplinary policies have helped contribute to students not completing their high school curriculum. Schools are struggling to keep students within the walls of the educational system rather than the walls of a juvenile detention center.

Reforms to zero-tolerance policies

The American Psychological Association (APA) assembled a Zero-Tolerance Task Force in 2008 that reviewed data and extensive literature on zero-tolerance policies and their effect on student behavior. After synthesizing the evidence, the APA found that zero-tolerance policies do not support child development nor improve school climate or school safety. The APA made several recommendations to reform zero-tolerance policies for serious infractions.

• One reform introduced by the APA was for school staff to consider teacher expertise and allow for greater flexibility when applying zero-tolerance policies. According to the APA, professional school staff need greater discretion when applying zero-tolerance policies because they are often the best mediators when evaluating infractions.
• Similarly, the APA recommended that all offenses be defined and that school officials be adequately trained to handle each offense. The APA affirmed that adequate teacher training will (1) protect teachers from being wrongfully accused of how they applied their school policy and (2) protect students from unfair repercussions.
• Another reform presented by the APA was for schools to evaluate their disciplinary prevention strategies. The APA maintained that schools, after evaluating their existing interventions and programs, would have strategies that have a positive effect on student behavior and school climate.

Alternatives to zero-tolerance policies

For less severe infractions, the American Psychological Association (APA) provided alternatives to zero-tolerance policies to ensure that students are not denied their opportunity to learn.

• The APA encouraged schools to implement preventive strategies that foster student support and a sense of community as an alternative to zero-tolerance policies. In particular, the APA asserted that research-supported preventive strategies improve the school climate and sense of community in schools, whereas zero-tolerance policies result in immediate punishment.
• For students who consistently engage in disruptive behavior, the APA recommended that schools design a list of effective alternatives they can use with students. The APA discussed various options that schools can implement to decrease disruptive behavior, including restorative justice, alternative programs, and community service.
• The APA also promoted increasing culturally relevant training available to teachers. According to the APA, this strategy is important for teachers to integrate culturally responsive management and instruction in their classrooms and, therefore, reduce the disproportionate amount of disciplinary referrals to maximize student learning.

Escondido school knives case

The Escondido school knives case was a collection of school suspensions, possible expulsions, and protests surrounding knives that were found in the cars of two students at San Pasqual High School in Escondido, California.

Discovery and arrests

Brandon Cappeletti, an 18-year-old student at the school, had been on a fishing trip in early January, 2016. He says he had used the knives to cut line and would have used them to prepare fish. After the fishing trip, he left the knives in his truck. Another 16-year-old student had a pocket knife in his glove compartment.

On January 27, police dogs were sniffing vehicles in the school's parking lot. Each student had Advil in the truck. In each case, the dogs alerted on the Advil. Cappeletti was called out of class to unlock the truck. The police found the Advil and the knives. In the case of the 16-year-old, the alert led to the police finding the pocket knife.

Both boys were arrested. Cappeletti was later released to his mother. The 16-year-old's case was referred to the California's juvenile diversion program. Both boys were charged with a misdemeanor for having a knife on school property with a blade longer than two-and-a-half inches. Both were also immediately suspended from classes.

Impact and protests

Cappeletti had already joined the U.S. Marine Corps. Had he been convicted of the misdemeanor, he might not have been able to remain. His mother Amy Cappelletti said, “He's the most patriotic student. He never gets into trouble. These weren't Crocodile Dundee knives.” At a School Board meeting on February 9, 2016, hundreds of people asked the Board not to expel the two students. Tony Coreley, the high school's football coach said that “There are rules and laws that the district has to follow, but this (situation) is unfortunate.” School District spokeswoman Karyl O’Brien said that the rules were the result of California's zero-tolerance policy.

Resolution

On February 11, 2016, the superintendent of the Escondido Union School District stated that the students would not be expelled and that they were expected to be allowed to return to school the following week. Both boys have since been exonerated from misdemeanor citations and juvenile diversion programs.

School-to-prison pipeline

From Wikipedia, the free encyclopedia

https://en.wikipedia.org/wiki/School-to-prison_pipeline 

In the United States, the school-to-prison pipeline (SPP), also known as the school-to-prison link, school-prison nexus, or schoolhouse-to-jailhouse track, is the disproportionate tendency of minors and young adults from disadvantaged backgrounds to become incarcerated because of increasingly harsh school and municipal policies. Additionally, this is due to educational inequality in the United States. Many experts have credited factors such as school disturbance laws, zero tolerance policies and practices, and an increase in police in schools in creating the "pipeline". This has become a hot topic of debate in discussions surrounding educational disciplinary policies as media coverage of youth violence and mass incarceration has grown during the early 21st century.

In recent years, many have started using the term school-prison nexus in place of school-to-prison pipeline to challenge the idea of a unidirectional pipeline that begins in schools in order to show that schools work within a web of institutions, policies, and practices that funnel youth into prisons. Moreover, it may no longer operate as a "pathway" to prison, but instead as a de facto prison.

The current climate of mass incarceration in the United States increases the contact the incarceration system has with the United States education system. More specifically, these patterns of criminalization translate into the school context. Specific practices implemented in United States schools over the past ten years to reduce violence in schools, including zero-tolerance policies and an increase in School Resource Officers have created the environment for criminalization of youth in schools. This results from patterns of discipline in schools mirroring law-enforcement models.

The disciplinary policies and practices that create an environment for the United States school-to-prison link to occur disproportionately affect disabled, Latino and Black students, which is later reflected in the rates of incarceration. Between 1999 and 2007, the percentage of black students being suspended has increased by twelve percent, while the percentage of white students being suspended has declined since the implementation of zero-tolerance policies. Of the total incarcerated population in the United States, 61% are Black or Latino.

History

A graph of the incarceration rate under state and federal jurisdiction per 100,000 population 1925–2008 (omits local jail inmates). The male incarceration rate (top line) is roughly 15 times the female rate (bottom line).

For the half-century prior to 1975 the incarceration rate in the U.S. was fairly constant at roughly 0.1 percent of the population, as indicated in the accompanying figure. The overall incarceration rate in the United States has grown rapidly and steadily since 1972, rising by 6 to 8 percent per year until 2000. Growth rates declined in the first decade of the 2000s and peaked at 506 per 100,000 in 2007 and 2008. From its peak in 2009 and 2010, the population of state and federal prisoners decreased slightly in 2011 and 2012. However, the incarceration rate, including those in jail, in 2012 was 707 per 100,000 people, which was more than four times the rate in 1972.

Causes

See also: Zero tolerance (schools)

Exclusionary disciplinary policies, specifically zero tolerance policies, that remove students from the school environment increase the probability of a youth coming into contact with the incarceration system. Zero tolerance policies have led to the mistreatment of students' situations and strict disciplinary action which greatly impact the students' future, causing them to go to juvenile detention centers or prison.

Approximately 3.3 million suspensions and over 100,000 expulsions occur each year. This number has nearly doubled since 1974, with rates escalating in the mid-1990s as zero tolerance policies began to be widely adopted. Rising rates of the use of expulsion and suspension are not connected to higher rates of misbehaviors. Risky behaviors is something suspended students will most likely engage in. Zero tolerance disciplinary policies have been adopted across the country. Zero tolerance policies are discussed in more detail later in the article, in the Current policies maintaining the link section.

Research is increasingly examining the connections between school failure and later contact with the criminal justice system for minorities. Once a child drops out, they are eight times more likely to be incarcerated than youth who graduate from high school. Studies have found that 68% of all males in state and federal prison do not have a high school diploma. Suspensions and expulsions have been shown to correlate with a young person's probability of dropping out and becoming involved with the criminal justice system. According to the American Civil Liberties Union, "Students suspended or expelled for a discretionary violation are nearly 3 times more likely to be in contact with the juvenile justice system the following year." However, it is unclear if the factors determining the risk of dropping out are not wholly or partially the same as the factors determining the risk of incarceration as an individual likely to enter the criminal justice system is also likely to encounter difficulties within the education system.

From 1980 to 2008, the number of people incarcerated in the United States quadrupled from roughly 500,000 to 2.3 million people. The graphic to the right shows the uniqueness of this practice in comparison to other countries across the globe, with the United States incarcerating a larger portion of its population than any other country in 2008. The United States holds 25% of the world's prisoners, but only has 5% of the world's population.

Disparities

See also: Youth incarceration in the United States

School disciplinary policies disproportionately affect Black and Latino youth in the education system. Ultimately, this means that they are more likely to be suspended, expelled or arrested; a practice known as the discipline gap. This discipline gap is also connected to the achievement gap. The U.S. Department of Education Office for Civil Rights issued a brief in 2014 outlining the current disparities. Black students are suspended and expelled at a rate three times greater than white students. The Advancement Project found that "In the 2006-2007 school year, there was no state in which African-American students were not suspended more often than white students." On average, 5% of white students are suspended, compared to 16% of black students. Black students represent 16% of student enrollment, and represent 27% of students referred to law enforcement and 31% of students subjected to a school-related arrest. Combined, 70% of students involved in "In-School arrests or referred to law enforcement are Black or Latino." The majority of these arrests are under zero tolerance policies.

Disparities were found in the implementation of zero tolerance policies (ZTPs) in relation to minor offenses. In 2010, in North Carolina black students were punished for the same minor offenses, specifically cell phone, dress code, disruptive behavior and display of affection by more than 15 percent for each category of offense than white students. According to the American Civil Liberties Union, "'Zero-tolerance' policies criminalize minor infractions of school rules, while cops in school lead to students being criminalized for behavior that should be handled inside the school. Students of color are especially vulnerable to push-out trends and the discriminatory application of discipline." Additionally, "The Council of State Governments Report found that black students were more likely to be disciplined for less serious 'discretionary' offenses, and that when other factors were controlled for, higher percentages of White students were disciplined on more serious non-discretionary grounds, such as possessing drugs or carrying a weapon."

A 2009 study reported that the racial disparity in rates of school suspensions could not be explained solely by racial differences in rates of delinquent behavior, and that this disparity in turn was "strongly associated with similar levels of disproportion in juvenile court referrals". Similarly, a 2010 study found that black students were more likely to be referred to the office than students of other races, and that this disparity could be partly, but not completely, explained by student behavior and school-level factors. According to Fordham Law Review Online, "In the juvenile justice system, black girls are the fastest growing demographic when it comes to arrest and incarceration." A 2014 study found that although black students were more likely to be suspended, this disparity "was completely accounted for by a measure of the prior problem behavior of the student", and concluded that "the use of suspensions by teachers and administrators may not have been as racially biased as some scholars have argued." Another 2015 study using a national high school dataset concluded that "misconduct and deviant attitudes were important factors in predicting the receipt of out-of-school suspensions though results indicated that Black students did not generally misbehave or endorse deviant attitudes more than White students did".

These interdisciplinary policies and practices disproportionately impact students from historically disadvantaged backgrounds such as, Latino and Black. It also been noted that students of minority groups were vulnerable to expulsions and that black girls are also highly criminalized for being absent from a schooling context. Dorothy E. Hines and Dorinda J. Carter Andrews have argued that increasing rates criminalization of black girls, disciplinary enforcements such as harsh policies and bans against "various student offenses" can be illuminated through (a) ZTPs including various forms of surveillance measures, (b) policing of their bodies as criminals, and (c) penalizing "bad" girl attitudes."

Schools with a higher percentage of black students are more likely to implement zero tolerance policies and to use extremely punitive discipline, supporting the racial threat hypothesis.

In November 2003, at Stratford High School in Goose Creek, South Carolina, police pointed their guns at students even though the students had not done anything wrong. The police also handcuffed the students, and forced them to kneel while facing the wall. The police claimed they were looking for illegal drugs, but did not actually find any. The police were also accused of racial profiling, due to the disproportionate number of African-American students whom they searched.

Current policies maintaining the link

Zero tolerance policies

Zero tolerance policies are school disciplinary policies that set predetermined consequences or punishments for specific offenses. By nature zero tolerance policies, as any policy that is "unreasonable rule or policy that is the same for everyone but has an unfair effect on people who share a particular attribute" often become discriminatory. The zero tolerance approach was first introduced in the 1980s to reduce drug use in schools. The use of zero tolerance policies spread more widely in the 1990s. To reduce gun violence, the Gun Free Schools Act of 1994 (GFSA) required that schools receiving federal funding "must 1) have policies to expel for a calendar year any student who brings a firearm to school or to school zone, and 2) report that student to local law enforcement, thereby blurring any distinction between disciplinary infractions at school and the law." During the 1996-1997 school year, 94% of schools had zero tolerance policies for fire arms, 87% for alcohol, and 79% for violence.

Over the past decade, zero tolerance policies have expanded to predetermined punishments for a wide degree of rule violations. Zero tolerance policies do not distinguish between serious and non-serious offenses. All students who commit a given offense receive the same treatment. Behaviors punished by zero tolerance policies are most often non-serious offense and are punished on the same terms as a student would be for bringing a gun or drugs to school. In 2006, 95% of out-of-school suspensions were for nonviolent, minor disruptions such as tardiness. In 2006-2007, "out-of-school suspensions for non-serious, non-violent offenses accounted for 37.2% of suspensions in Maryland, whereas only 6.7% of suspensions were issued for dangerous behaviors." In Chicago, the widespread adoption of zero tolerance policies in 1994 resulted in a 51% increase in student suspensions for the next four years and a 3,000% increase in expulsions.

The most direct way these policies increase the probability of a youth coming into contact with the incarceration system is through their exclusionary methods. Suspension, expulsion, and an increased risk of dropping out all contribute to a youth's increased chances of becoming involved with the incarceration system. Suspension removes students from the structure and supervision provided through schooling, providing opportunities for youth to engage in criminal activities while not in the school environment. Other factors may include "increased exposure to peers involved in antisocial behavior, as well as effects on school performance and completion and student attitudes toward antisocial behavior." Suspension can lead to feelings of alienation from the school setting that can lead to students to feel rejected, increasing chances of relationships with antisocial peers. Relationships with peers have strong impacts on student behavior, demonstrated through differential association theory. Students are more than twice as likely to be arrested during months in which they are forcibly removed from school. Students who have been suspended are three times more likely to drop out by the 10th grade than students who have never been suspended. Dropping out makes that student three times more likely to be incarcerated.

Policing in schools

Zero tolerance policies increase the number of School Resource Officers (SRO) in schools, which increases the contact a student has with the criminal justice system. Students may be referred by teachers or other administrators but most often zero tolerance policies are directly enforced by police or school resource officers. The practice of increasing the number of police in schools contributes to patterns of criminalization. This increase in SROs has led to contemporary school discipline beginning to mirror approaches used in legal and law enforcement. Zero tolerance policies increase the use of profiling, a very common practice used in law enforcement. This practice is able to identify students who may engage in misbehavior, but the use of profiling is unreliable in ensuring school safety, as this practice over identifies students from minority populations. There were no students involved in the 1990s shootings who were Black or Latino and the 1990s school shootings were the main basis for the increase in presence of police in schools. Data shows that people of color with disabilities are the most affected by the school-to-prison pipeline.

A Justice Policy Institute report (2011) found a 38% increase in the number of SROs between 1997 and 2007 as a result of the growing implementation of zero tolerance policies. In 1999, 54% of students surveyed reported seeing a security guard or police officer in their school, by 2005, this number increased to 68%. The education system has seen a huge increase in the number of students referred to law enforcement. In one city in Georgia, when police officers were introduced into the schools, "school-based referrals to juvenile court in the county increased 600% over a three year period." There was no increase in the number of serious offenses or safety violations during this three-year period. In 2012, forty-one states required schools to report students to law enforcement for various misbehaviors on school grounds. This practice increases the use of law enforcement professionals in handling student behavior and decreases the use of in-classroom (non-exclusionary) management of behaviors.

In 2014, the United Nations Human Rights Committee (HRC) expressed concern with increasing criminalization of students in response to school disciplinary problems, and recommended that the US government "promote the use of alternatives to the application of criminal law" to address such issues. The HRC also noted its concern with the use of corporal punishment in schools in the US. In the second Universal Periodic Review of the United States' human rights record, the government avowed taking "effective measures to help ensure non-discrimination in school discipline policies and practices."

In March 2010, at the Carver Primary School on the Far South Side of Chicago, several first grade students were handcuffed, and told that they were going to prison and would never see their parents again, after they talked in class.

In November 2011, at Orange River Elementary School in Florida, an assistant principal called the police after a girl kissed a boy.^[

In February 2010, the principal of a junior high school in Forest Hills, New York, called police after a 12-year-old student used a green magic marker to write, "I love my friends Abby and Faith. Lex was here 2/1/10 :)" on a desk. A police officer handcuffed the girl, and took her to the police station.

In October 2010, at Southern Lee High School in Lee County, North Carolina, a 12th grade honors student, who was taking college-level classes, was charged with misdemeanor possession of a weapon on school grounds, and suspended for the rest of the school year, after she brought a paring knife to school. The student had mistakenly taken her father's lunch box to school, which looked the same as her own lunch box. The school found the knife while searching the lunch box for illegal drugs, which the student did not have.

In 2014, in Lynchburg, Virginia, an 11 year-old black autistic boy was charged with a misdemeanor disorderly contact for kicking a trash can. A few later, this same kid was walking to join other students, and the same officer that reprimanded him for the trash can grabbed him, pushed him to the floor, and arrested him. As a result, the officer charged him with felony assault on a police officer.

Robbins v. Lower Merion School District

Further information: Robbins v. Lower Merion School District

In Rosemont, Pennsylvania, Harriton High School lent students laptop computers by way of their One-to-One initiative program. Over 2,000 students were given these laptops for school and home usage. Unbeknownst to the students and parents, the school district had webcams installed on each computer that were utilized to take images of students' activities while on the computer. The school district used these photos to attempt to incriminate students. In November 2009, the school's assistant principal falsely accused a student of selling illegal drugs after a school employee saw the student holding Mike and Ike candy while the student was at home.

Events affecting school to prison pipeline

1. A large factor of the school to prison pipeline is the disproportionate disciplinary actions taken against students of color. In recent years, the media has reported about some of these experiences.
2. Examples of zero tolerance policies and its role in school-to-prison pipeline statistics.

In Spring 2018, a 14-year-old black boy came to school with a new haircut. The haircut featured a design made with a razor. The student was pulled out of class one day at Tenaya Middle School in Fresno, California, because of his haircut, which the school claimed violated their dress code. The child's mother claimed, "The vice principal told my son that he needed to cut his hair because it was distracting and violated the dress code". The child's mother claims she agreed to get her son a new haircut; she also said she was unable to immediately get an appointment due to a lack of black barbers in her area. When her son arrived at school the next day, according to the child's mother, the school explained to her that he would face in-school suspension after returning with his haircut. The mother claims, "I requested that my son is issued a warning, to allow time to grow out his hair."

In Spring 2018, a black male student at Apache Junction High School in Arizona wore a blue bandana to school, which violated the dress code. His teacher called the police on him for not removing his bandana. He was then arrested and suspended for nine days.

In the summer of 2018, an 11-year-old black girl, Faith Fennidy, was sent home from a private Roman Catholic school in Louisiana because she had hair extensions. The young girl had been wearing extensions to school for two years before a new policy was added. The policy prohibits extensions, clip-ins, and/or weaves. The child would have to adhere to the policy to attend school. The family chose to withdraw the student from the school; the student was not suspended or expelled.

In 2012, at Creekside Elementary School in Milledgeville, Georgia, a six-year-old student, Salecia Johnson, was crying and flailing on the floor of her principal's office. The principal said she was inconsolable, had thrown various items, and had damaged school property during a tantrum. Salecia was handcuffed and transported to a police station. The child was initially charged as a juvenile with simple battery of a school teacher and criminal damage to property, but it was later decided the girl would not be charged because of her age.

Impact of COVID-19 pandemic

On March 11, 2020, the World Health Organization (WHO) declared the COVID-19 disease a global pandemic, resulting in school shut-downs across multiple countries, including the United States. Based on a report by UNICEF, approximately 94% of all countries enacted forms of remote learning to continue education for children in response to government closures caused by the COVID-19 pandemic. Likewise, as a result of the pandemic, in the United States, state and federal legislation either closed public schools and transferred to virtual instruction or offered hybrid learning, a mixture of face-to-face instruction and online learning. As school districts in the US encountered difficulty navigating requirements to provide education in remote settings, disciplinary practices continued to reflect aspects of the school-to-prison pipeline with zero-tolerance policies just as harmful as those before the COVID-19 pandemic. Since the nation's transition to remote learning, punishments including out-of-school suspension, juvenile detention, and police involvement have been enacted for minor infractions that have occurred in virtual learning environments.

• In May 2020, a fifteen-year-old Black female student with ADHD in Michigan was sent to a juvenile detention center for not turning in her online homework. The juvenile court concluded that her failure to submit her homework violated her probation and sentenced her to seventy-eight days in juvenile detention. She was later released after an adverse reaction from the public.

• In August 2020, Isaiah Elliot, a twelve-year-old Black student with ADHD attending virtual school in Colorado was punished after being seen on his computer camera picking up a toy NERF gun. Isaiah was suspended for five days by the school, which later contacted police to conduct a welfare check before notifying his parents.

As before the pandemic, the "virtual" school-to-prison pipeline continues to disproportionately impact racial minorities, predominantly African American and Hispanic students from low-income backgrounds, and students with disabilities. There are more than 48,000 youth confined in facilities in the United States on any given day. According to a report by the NAACP, as of 2020, "African American children represent 32% of children who are arrested, 42% of children who are detained, and 52% of children whose cases are judicially waived to criminal court." Additionally, students with disabilities account for 8.6% of the student population in the United States but represent 36% of incarcerated youth. Because students of color and students with disabilities are disproportionately incarcerated, they represent a large number of youth at risk for contracting COVID-19 and other infectious diseases. On that note, infectious diseases are severely concentrated in both adult and juvenile correctional facilities. The Marshall Project reported that most juvenile prison facilities have more than 80% infection rates. Moreover, approximately "15% of jail inmates and 22% of prisoners – compared to 5% of the general population – are reported having tuberculosis, Hepatitis B and C, HIV/AIDS, or other STDs."

Controversy over efforts to reduce racial disparities

In 2014 the Obama administration issued guidance that urged schools to reduce the number of suspensions and expulsions, especially of minority students, thereby stemming the school-to-prison pipeline. During the Trump administration, in December 2018, Education Secretary Betsy DeVos rescinded these guidelines. In doing so, she cited research by John Paul Wright and four coauthors that purported to show that the disparate rates of suspensions and expulsions were due not to racism, but rather to prior poor behavior by black students.

Lead author John Paul Wright has advocated for the fringe view that black people evolved to be genetically inferior to white people. In the study cited by DeVos, Wright et al. assumed that teachers' reporting of behavior was accurate and unbiased. They concluded that "the racial gap in suspensions was completely accounted for by a measure of the prior problem behavior of the student --- a finding never before reported in the literature." However, other scholars have found implicit bias and racial discrimination in teachers' interpretation of behavior of black students as more threatening than similar behavior by white students.

Education researcher Francis Huang found other methodological flaws in the study by Wright et al., such as sample bias (comparison between a sample of 4,101 students and a reduced sample of 2,737 students who were not representative of the earlier sample) and their use of the Social Skills Rating Scale as a proxy for evaluating prior behavior. Correcting for sample bias in the study by Wright et al. led Huang to conclude that their data confirmed what earlier researchers had found regarding racial disparities in punishment that could not be accounted for by actual differences in behavior.

Alternative approaches

Restorative justice

The use of restorative justice in schools began in the early 1990s with initiatives in Australia. Restorative justice models are used globally and have recently been introduced to school disciplinary policies in the United States as an alternative approach to current punitive models, such as zero tolerance. The focus is on ensuring that students understand and learn from their behavior as well as take responsibility for their actions and participate in steps that aim to repair the harm done to relationships between the student and the school environment. Programs, such as restorative circles, restorative meetings, restorative youth courts, and peer mediation, are being used as alternatives to zero tolerance policies and harsh disciplinary practices. The idea behind these programs is that students should be encouraged to participate in their punishments and school administration should refrain from using suspensions and expulsions for minor offenses. The goal of restorative programs is to keep students in school and to stop the flow of students from schools to the criminal justice system.

Some challenges to the use of restorative justice in schools are lack of time and community support. It requires balancing the time needed for mediation with the other demands of education in one school day. Scholars acknowledge that to achieve proper, unbiased mediation, it will require training, support, and review. It is also crucial that an entire community— students, parents, teachers, staff, coaches, etc. are convinced it is a better alternative and willing to work together.

Steven Teske, a juvenile court judge in Clayton County, Georgia, created the School-Justice Partnership model in 2003, known as the "Clayton County Model" or informally, "The Teske Model", to reduce the arrests of students involving minor offenses by using a collaborative agreement between schools, law enforcement, and the courts. The model has three main components: identifying minor offenses not subject to referral to the court; defining the roles of school police and school administrators to avoid using police as disciplinarians; and creating restorative practices and education programs in lieu of arrests. It took aim at zero tolerance policies which do not consider situational context or individual circumstances. The model's application in his county resulted in a 67 percent decline in referrals to juvenile court. Despite concerns by some that a softer approach would yield school safety issues, the data shows an increase in graduation rates of approximately 20 percent and an 8 percent decline in suspensions. The method has spread across the United States with some notable cities such as Birmingham, Alabama, and Wichita, Kansas, seeing similar improvements.

Editorial policies of major media

See also: United States incarceration rate § Editorial policies of major media

Beginning especially in the 1970s, the mainstream commercial media in the U.S. increased coverage of the police blotter, while reducing coverage of investigative journalism.

Advertising rates are set based on the audience. Because "if it bleeds, it leads", the media were able to accomplish this change without losing its audience.

Beyond this, the growth of private prisons increased the pool of major advertisers who could be offended by honest reporting on incarcerations and the school-to-prison pipeline: It makes financial sense to report on this only to the extent that such reporting is needed to maintain an audience.

Media constructions have contributed to hysteria over youth violence and mass incarcerations. TV overrepresents violent crime and people of color as offenders. This creates a "culture of fear" and "mean world syndrome" that particularly works against black or Latino males.

Mental health relating to the school to prison pipeline

Where there are undetected and untreated child mental health concerns, this can lead to unwanted suspensions and expulsions. When teachers include strategies to address the concerns found in students, it leads to students wanting to pursue their own academic achievement and success.

Students with diagnosable mental health problems suffer under zero tolerance policies. Such policies aim to create safer classrooms by removing potential disruptions, but many in mental health, social services, courts, or other related fields believe they fail in this goal and may result in less safe schools and communities. School is considered a protective factor against "delinquent conduct" and removing students from such an environment harms their ability to succeed.

An American Psychological Association Zero Tolerance Task Force report found that "students with disabilities, especially those with emotional and behavioral disorders, appear to be suspended and expelled at rates disproportionate to the representation in the population."

Zero tolerance policies also fail to account for neurological development in youths. Studies show that the brain is still "under construction" until about age 21. Youth are more likely to take risks, act impulsively, and exercise poor judgment. When these actions result in their involvement with the criminal justice system, they are punished rather than taught how to develop.

One issue in improving mental health services in school and interrupting the school to prison pipeline is that schools are unequipped to identify disorders and provide help for them.