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Combinatorial chemistry

Combinatorial chemistry comprises chemical synthetic methods that make it possible to prepare a large number (tens to thousands or even millions) of compounds in a single process. These compound libraries can be made as mixtures, sets of individual compounds or chemical structures generated by computer software. Combinatorial chemistry can be used for the synthesis of small molecules and for peptides.

Strategies that allow identification of useful components of the libraries are also part of combinatorial chemistry. The methods used in combinatorial chemistry are applied outside chemistry, too.

History
Combinatorial chemistry was invented by Furka Á (from Eötvös Loránd University in Budapest, Hungary) who described the principle of it, the combinatorial synthesis and a deconvolution procedure in a document that was notarized in 1982. The principle of the combinatorial method is: synthesize a multi-component compound mixture (combinatorial library) in a single stepwise procedure and screen it to find drug candidates or other kinds of useful compounds also in a single process. The most important innovation of the combinatorial method is to use mixtures in the synthesis and screening that ensures the high productivity of the process. Motivations that led to the invention had been published in 2002.

Introduction
Synthesis of molecules in a combinatorial fashion can quickly lead to large numbers of molecules. For example, a molecule with three points of diversity (R1, R2, and R3) can generate $$N_{R_1} \times N_{R_2} \times N_{R_3}$$ possible structures, where $$N_{R_1}$$, $$N_{R_2}$$, and $$N_{R_3}$$ are the numbers of different substituents utilized.

The basic principle of combinatorial chemistry is to prepare libraries of a very large number of compounds then identify the useful components of the libraries.

Although combinatorial chemistry has only really been taken up by industry since the 1990s, its roots can be seen as far back as the 1960s when a researcher at Rockefeller University, Bruce Merrifield, started investigating the solid-phase synthesis of peptides.

In its modern form, combinatorial chemistry has probably had its biggest impact in the pharmaceutical industry. Researchers attempting to optimize the activity profile of a compound create a 'library' of many different but related compounds. Advances in robotics have led to an industrial approach to combinatorial synthesis, enabling companies to routinely produce over 100,000 new and unique compounds per year.

In order to handle the vast number of structural possibilities, researchers often create a 'virtual library', a computational enumeration of all possible structures of a given pharmacophore with all available reactants. Such a library can consist of thousands to millions of 'virtual' compounds. The researcher will select a subset of the 'virtual library' for actual synthesis, based upon various calculations and criteria (see ADME, computational chemistry, and QSAR).

Combinatorial split-mix (split and pool) synthesis
Combinatorial split-mix (split and pool) synthesis is based on the solid-phase synthesis developed by Merrifield. If a combinatorial peptide library is synthesized using 20 amino acids (or other kinds of building blocks) the bead form solid support is divided into 20 equal portions. This is followed by coupling a different amino acid to each portion. The third step is the mixing of all portions. These three steps comprise a cycle. Elongation of the peptide chains can be realized by simply repeating the steps of the cycle.

The procedure is illustrated by the synthesis of a dipeptide library using the same three amino acids as building blocks in both cycles. Each component of this library contains two amino acids arranged in different orders. The amino acids used in couplings are represented by yellow, blue and red circles in the figure. Divergent arrows show dividing solid support resin (green circles) into equal portions, vertical arrows mean coupling and convergent arrows represent mixing and homogenizing the portions of the support.

The figure shows that in the two synthetic cycles 9 dipeptides are formed. In the third and fourth cycles, 27 tripeptides and 81 tetrapeptides would form, respectively.

The "split-mix synthesis" has several outstanding features:

 * It is highly efficient. As the figure demonstrates the number of peptides formed in the synthetic process (3, 9, 27, 81) increases exponentially with the number of executed cycles. Using 20 amino acids in each synthetic cycle the number of formed peptides are: 400, 8,000, 160,000 and 3,200,000, respectively. This means that the number of peptides increases exponentially with the number of the executed cycles.
 * All peptide sequences are formed in the process that can be deduced by a combination of the amino acids used in the cycles.
 * Portioning of the support into equal samples assures formation of the components of the library in nearly equal molar quantities.
 * Only a single peptide forms on each bead of the support. This is the consequence of using only one amino acid in the coupling steps. It is completely unknown, however, which is the peptide that occupies a selected bead.
 * The split-mix method can be used for the synthesis of organic or any other kind of library that can be prepared from its building blocks in a stepwise process.

In 1990 three groups described methods for preparing peptide libraries by biological methods  and one year later Fodor et al. published a remarkable method for synthesis of peptide arrays on small glass slides.

A "parallel synthesis" method was developed by Mario Geysen and his colleagues for preparation of peptide arrays. They synthesized 96 peptides on plastic rods (pins) coated at their ends with the solid support. The pins were immersed into the solution of reagents placed in the wells of a microtiter plate. The method is widely applied particularly by using automatic parallel synthesizers. Although the parallel method is much slower than the real combinatorial one, its advantage is that it is exactly known which peptide or other compound forms on each pin.

Further procedures were developed to combine the advantages of both split-mix and parallel synthesis. In the method described by two groups the solid support was enclosed into permeable plastic capsules together with a radiofrequency tag that carried the code of the compound to be formed in the capsule. The procedure was carried out similar to the split-mix method. In the split step, however, the capsules were distributed among the reaction vessels according to the codes read from the radiofrequency tags of the capsules. A different method for the same purpose was developed by Furka et al. is named "string synthesis". In this method, the capsules carried no code. They are strung like the pearls in a necklace and placed into the reaction vessels in stringed form. The identity of the capsules, as well as their contents, are stored by their position occupied on the strings. After each coupling step, the capsules are redistributed among new strings according to definite rules.

Small molecules
In the drug discovery process, the synthesis and biological evaluation of small molecules of interest have typically been a long and laborious process. Combinatorial chemistry has emerged in recent decades as an approach to quickly and efficiently synthesize large numbers of potential small molecule drug candidates. In a typical synthesis, only a single target molecule is produced at the end of a synthetic scheme, with each step in a synthesis producing only a single product. In a combinatorial synthesis, when using only single starting material, it is possible to synthesize a large library of molecules using identical reaction conditions that can then be screened for their biological activity. This pool of products is then split into three equal portions containing each of the three products, and then each of the three individual pools is then reacted with another unit of reagent B, C, or D, producing 9 unique compounds from the previous 3. This process is then repeated until the desired number of building blocks is added, generating many compounds. When synthesizing a library of compounds by a multi-step synthesis, efficient reaction methods must be employed, and if traditional purification methods are used after each reaction step, yields and efficiency will suffer.

Solid-phase synthesis offers potential solutions to obviate the need for typical quenching and purification steps often used in synthetic chemistry. In general, a starting molecule is adhered to a solid support (typically an insoluble polymer), then additional reactions are performed, and the final product is purified and then cleaved from the solid support. Since the molecules of interest are attached to a solid support, it is possible to reduce the purification after each reaction to a single filtration/wash step, eliminating the need for tedious liquid-liquid extraction and solvent evaporation steps that most synthetic chemistry involves. Furthermore, by using heterogeneous reactants, excess reagents can be used to drive sluggish reactions to completion, which can further improve yields. Excess reagents can simply be washed away without the need for additional purification steps such as chromatography. Over the years, a variety of methods have been developed to refine the use of solid-phase organic synthesis in combinatorial chemistry, including efforts to increase the ease of synthesis and purification, as well as non-traditional methods to characterize intermediate products. Although the majority of the examples described here will employ heterogeneous reaction media in every reaction step, Booth and Hodges provide an early example of using solid-supported reagents only during the purification step of traditional solution-phase syntheses. In their view, solution-phase chemistry offers the advantages of avoiding attachment and cleavage reactions necessary to anchor and remove molecules to resins as well as eliminating the need to recreate solid-phase analogues of established solution-phase reactions.

The single purification step at the end of a synthesis allows one or more impurities to be removed, assuming the chemical structure of the offending impurity is known. While the use of solid-supported reagents greatly simplifies the synthesis of compounds, many combinatorial syntheses require multiple steps, each of which still requires some form of purification. Armstrong, et al. describe a one-pot method for generating combinatorial libraries, called multiple-component condensations (MCCs). In this scheme, three or more reagents react such that each reagent is incorporated into the final product in a single step, eliminating the need for a multi-step synthesis that involves many purification steps. In MCCs, there is no deconvolution required to determine which compounds are biologically active because each synthesis in an array has only a single product, thus the identity of the compound should be unequivocally known. In another array synthesis, Still generated a large library of oligopeptides by split synthesis. The drawback to making many thousands of compounds is that it is difficult to determine the structure of the formed compounds. Their solution is to use molecular tags, where a tiny amount (1 pmol/bead) of a dye is attached to the beads, and the identity of a certain bead can be determined by analyzing which tags are present on the bead. Despite how easy attaching tags makes identification of receptors, it would be quite impossible to individually screen each compound for its receptor binding ability, so a dye was attached to each receptor, such that only those receptors that bind to their substrate produce a color change.

When many reactions need to be run in an array (such as the 96 reactions described in one of Armstrong's MCC arrays), some of the more tedious aspects of synthesis can be automated to improve efficiency. This work, the "DIVERSOMER method" was pioneered at Parke-Davis in the early 1990s to run up to 40 chemical reactions in parallel. These efforts led to the first commercially available equipment for combinatorial chemistry (Diversomer synthesizer which was sold by Chemglass) and the first use of liquid handling robotics within a chemistry labortory. This method uses a device that automates the resin loading and wash cycles, as well as the reaction cycle monitoring and purification, and demonstrates the feasibility of their method and apparatus by using it to synthesize a variety of molecule classes, such as hydantoins and benzodiazepines, running 8 or 40 individual reactions in parallel. This and several other pioneering efforts in combinatorial chemistry were featured as "classical" papers in the field in 1999.

Oftentimes, it is not possible to use expensive equipment, and Schwabacher, et al. describe a simple method of combining parallel synthesis of library members and evaluation of entire libraries of compounds. In their method, a thread that is partitioned into different regions is wrapped around a cylinder, where a different reagent is then coupled to each region which bears only a single species. The thread is then re-divided and wrapped around a cylinder of a different size, and this process is then repeated. The beauty of this method is that the identity of each product can be known simply by its location along the thread, and the corresponding biological activity is identified by Fourier transformation of fluorescence signals. In most of the syntheses described here, it is necessary to attach and remove the starting reagent to/from a solid support. This can lead to the generation of a hydroxyl group, which can potentially affect the biological activity of a target compound. Ellman uses solid phase supports in a multi-step synthesis scheme to obtain 192 individual 1,4-benzodiazepine derivatives, which are well-known therapeutic agents. To eliminate the possibility of potential hydroxyl group interference, a novel method using silyl-aryl chemistry is used to link the molecules to the solid support which cleaves from the support and leaves no trace of the linker. When anchoring a molecule to a solid support, intermediates cannot be isolated from one another without cleaving the molecule from the resin. Since many of the traditional characterization techniques used to track reaction progress and confirm product structure are solution-based, different techniques must be used. Gel-phase 13 C NMR spectroscopy, MALDI mass spectrometry, and IR spectroscopy have been used to confirm structure and monitor the progress of solid-phase reactions. Gordon et al., describe several case studies that utilize imines and peptidyl phosphonates to generate combinatorial libraries of small molecules. To generate the imine library, an amino acid tethered to a resin is reacted in the presence of an aldehyde. The authors demonstrate the use of fast 13 C gel phase NMR spectroscopy and magic angle spinning 1 H NMR spectroscopy to monitor the progress of reactions and showed that most imines could be formed in as little as 10 minutes at room temperature when trimethyl orthoformate was used as the solvent. The formed imines were then derivatized to generate 4-thiazolidinones, B-lactams, and pyrrolidines.

The use of solid-phase supports greatly simplifies the synthesis of large combinatorial libraries of compounds. This is done by anchoring a starting material to a solid support and then running subsequent reactions until a sufficiently large library is built, after which the products are cleaved from the support. The use of solid-phase purification has also been demonstrated for use in solution-phase synthesis schemes in conjunction with standard liquid-liquid extraction purification techniques.

Combinatorial libraries
Combinatorial libraries are special multi-component mixtures of small-molecule chemical compounds that are synthesized in a single stepwise process. They differ from collection of individual compounds as well as from series of compounds prepared by parallel synthesis. It is an important feature that mixtures are used in their synthesis. The use of mixtures ensures the very high efficiency of the process. Both reactants can be mixtures and in this case the procedure would be even more efficient. For practical reasons however, it is advisable to use the split-mix method in which one of two mixtures is replaced by single building blocks (BBs). The mixtures are so important that there are no combinatorial libraries without using mixture in the synthesis, and if a mixture is used in a process inevitably combinatorial library forms. The split-mix synthesis is usually realized using solid support but it is possible to apply it in solution, too. Since he structures the components are unknown deconvolution methods need to be used in screening. One of the most important features of combinatorial libraries is that the whole mixture can be screened in a single process. This makes these libraries very useful in pharmaceutical research. Partial libraries of full combinatorial libraries can also be synthesized. Some of them can be used in deconvolution

Deconvolution of libraries cleaved from the solid support
If the synthesized molecules of a combinatorial library are cleaved from the solid support a soluble mixture forms. In such solution, millions of different compounds may be found. When this synthetic method was developed, it first seemed impossible to identify the molecules, and to find molecules with useful properties. Strategies for identification of the useful components had been developed, however, to solve the problem. All these strategies are based on synthesis and testing of partial libraries. The earliest iterative strategy is described in the above-mentioned document of Furka notarized in 1982 and. The method was later independently published by Erb et al. under the name "Recursive deconvolution"

Recursive deconvolution
The method is made understandable by the figure. A 27-member peptide library is synthesized from three amino acids. After the first (A) and second (B) cycles samples were set aside before mixing them. The products of the third cycle (C) are cleaved down before mixing then are tested for activity. Suppose the group labeled by + sign is active. All members have the red amino acid at the last coupling position (CP). Consequently, the active member also has the red amino acid at the last CP. Then the red amino acid is coupled to the three samples set aside after the second cycle (B) to get samples D. After cleaving, the three E samples are formed. If after testing the sample marked by + is the active one it shows that the blue amino acid occupies the second CP in the active component. Then to the three A samples first the blue then the red amino acid is coupled (F) then tested again after cleaving (G). If the + component proves to be active, the sequence of the active component is determined and shown in H.

Positional scanning
Positional scanning was introduced independently by Furka et al. and Pinilla et al. The method is based on the synthesis and testing of series of sublibraries. in which a certain sequence position is occupied by the same amino acid. The figure shows the nine sublibraries (B1-D3) of a full peptide trimer library (A) made from three amino acids. In sublibraries there is a position which is occupied by the same amino acid in all components. In the synthesis of a sublibrary the support is not divided and only one amino acid is coupled to the whole sample. As a result, one position is really occupied by the same amino acid in all components. For example, in the B2 sublibrary position 2 is occupied by the "yellow" amino acid in all the nine components. If in a screening test this sublibrary gives positive answer it means that position 2 in the active peptide is also occupied by the "yellow" amino acid. The amino acid sequence can be determined by testing all the nine (or sometime less) sublibraries.

Omission libraries
In omission libraries a certain amino acid is missing from all peptides of the mixture. The figure shows the full library and the three omission libraries. At the top the omitted amino acids are shown. If the omission library gives a negative test the omitted amino acid is present in the active component.

Deconvolution of tethered combinatorial libraries
If the peptides are not cleaved from the solid support we deal with a mixture of beads, each bead containing a single peptide. Smith and his colleagues showed earlier that peptides could be tested in tethered form, too. This approach was also used in screening peptide libraries. The tethered peptide library was tested with a dissolved target protein. The beads to which the protein was attached were picked out, removed the protein from the bead then the tethered peptide was identified by sequencing. A somewhat different approach was followed by Taylor and Morken. They used infrared thermography to identify catalysts in non-peptide tethered libraries. The method is based on the heat that is evolved in the beads that contain a catalyst when the tethered library immersed into a solution of a substrate. When the beads are examined through an infrared microscope the catalyst containing beads appear as bright spots and can be picked out.

Encoded combinatorial libraries
If we deal with a non-peptide organic libraries library it is not as simple to determine the identity of the content of a bead as in the case of a peptide one. In order to circumvent this difficulty methods had been developed to attach to the beads, in parallel with the synthesis of the library, molecules that encode the structure of the compound formed in the bead. Ohlmeyer and his colleagues published a binary encoding method They used mixtures of 18 tagging molecules that after cleaving them from the beads could be identified by Electron Capture Gas Chromatography. Sarkar et al. described chiral oligomers of pentenoic amides (COPAs) that can be used to construct mass encoded OBOC libraries. Kerr et al. introduced an innovative encoding method An orthogonally protected removable bifunctional linker was attached to the beads. One end of the linker was used to attach the non-natural building blocks of the library while to the other end encoding amino acid triplets were linked. The building blocks were non-natural amino acids and the series of their encoding amino acid triplets could be determined by Edman degradation. The important aspect of this kind of encoding was the possibility to cleave down from the beads the library members together with their attached encoding tags forming a soluble library. The same approach was used by Nikolajev et al. for encoding with peptides. In 1992 by Brenner and Lerner introduced DNA sequences to encode the beads of the solid support that proved to be the most successful encoding method. Nielsen, Brenner and Janda also used the Kerr approach for implementing the DNA encoding In the latest period of time there were important advancements in DNA sequencing. The next generation techniques make it possible to sequence large number of samples in parallel that is very important in screening of DNA encoded libraries. There was another innovation that contributed to the success of DNA encoding. In 2000 Halpin and Harbury omitted the solid support in the split-mix synthesis of the DNA encoded combinatorial libraries and replaced it by the encoding DNA oligomers. In solid phase split and pool synthesis the number of components of libraries can't exceed the number of the beads of the support. By the novel approach of the authors, this restraint was eliminated and made it possible to prepare new compounds in practically unlimited number. The Danish company Nuevolution for example synthesized a DNA encoded library containing 40 trillion! components The DNA encoded libraries are soluble that makes possible to apply the efficient affinity binding in screening. Some authors apply the DEL for acromim of DNA encoded combinatorial libraries others are using DECL. The latter seems better since in this name the combinatorial nature of these libraries is clearly expressed. Several types of DNA encoded combinatorial libraries had been introduced and described in the first decade of the present millennium. These libraries are very successfully applied in drug research. Details are found about their synthesis and application in the page DNA-encoded chemical library. The DNA encoded soluble combinatorial libraries have drawbacks, too. First of all the advantage coming from the use of solid support is completely lost. In addition, the polyionic character of DNA encoding chains limits the utility of non-aqueous solvents in the synthesis. For this reason many laboratories choose to develop DNA compatible reactions for use in the synthesis of DECLs. Quite a few of available ones are already described
 * DNA templated synthesis of combinatorial libraries described in 2001 by Gartner et al.
 * Dual pharmacophore DNA encoded combinatorial libraries invented in 2004 by Mlecco et al.
 * Sequence encoded routing published by Harbury Halpin and Harbury in 2004.
 * Single pharmacophore DNA encoded combinatorial libraries introduced in 2008 by Manocci et al.
 * DNA encoded combinatorial libraries formed by using yoctoliter-scale reactor published by Hansen et al. in 2009

Materials science
Materials science has applied the techniques of combinatorial chemistry to the discovery of new materials. This work was pioneered by P.G. Schultz et al. in the mid-nineties in the context of luminescent materials obtained by co-deposition of elements on a silicon substrate. His work was preceded by J. J. Hanak in 1970 but the computer and robotics tools were not available for the method to spread at the time. Work has been continued by several academic groups   as well as companies with large research and development programs (Symyx Technologies, GE, Dow Chemical etc.). The technique has been used extensively for catalysis, coatings, electronics, and many other fields. The application of appropriate informatics tools is critical to handle, administer, and store the vast volumes of data produced. New types of design of experiments methods have also been developed to efficiently address the large experimental spaces that can be tackled using combinatorial methods.

Diversity-oriented libraries
Even though combinatorial chemistry has been an essential part of early drug discovery for more than two decades, so far only one de novo combinatorial chemistry-synthesized chemical has been approved for clinical use by FDA (sorafenib, a multikinase inhibitor indicated for advanced renal cancer). The analysis of the poor success rate of the approach has been suggested to connect with the rather limited chemical space covered by products of combinatorial chemistry. When comparing the properties of compounds in combinatorial chemistry libraries to those of approved drugs and natural products, Feher and Schmidt noted that combinatorial chemistry libraries suffer particularly from the lack of chirality, as well as structure rigidity, both of which are widely regarded as drug-like properties. Even though natural product drug discovery has not probably been the most fashionable trend in the pharmaceutical industry in recent times, a large proportion of new chemical entities still are nature-derived compounds,     and thus, it has been suggested that effectiveness of combinatorial chemistry could be improved by enhancing the chemical diversity of screening libraries. As chirality and rigidity are the two most important features distinguishing approved drugs and natural products from compounds in combinatorial chemistry libraries, these are the two issues emphasized in so-called diversity oriented libraries, i.e. compound collections that aim at coverage of the chemical space, instead of just huge numbers of compounds.

Patent classification subclass
In the 8th edition of the International Patent Classification (IPC), which entered into force on January 1, 2006, a special subclass has been created for patent applications and patents related to inventions in the domain of combinatorial chemistry: "C40B".

title: Combinatorial chemistry


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Brave New World

Brave New World is a dystopian novel by English author Aldous Huxley, written in 1931 and published in 1932. Largely set in a futuristic World State, whose citizens are environmentally engineered into an intelligence-based social hierarchy, the novel anticipates huge scientific advancements in reproductive technology, sleep-learning, psychological manipulation and classical conditioning that are combined to make a dystopian society which is challenged by the story's protagonist. Huxley followed this book with a reassessment in essay form, Brave New World Revisited (1958), and with his final novel, Island (1962), the utopian counterpart. This novel is often compared as an inversion counterpart to George Orwell's 1984 (1949).

In 1999, the Modern Library ranked Brave New World at number 5 on its list of the 100 best English-language novels of the 20th century. In 2003, Robert McCrum, writing for The Observer, included Brave New World chronologically at number 53 in "the top 100 greatest novels of all time", and the novel was listed at number 87 on The Big Read survey by the BBC. Brave New World has frequently been banned and challenged since its original publication. It has landed on the American Library Association list of top 100 banned and challenged books of the decade since the association began the list in 1990.

Title
The title Brave New World derives from Miranda's speech in William Shakespeare's The Tempest, Act V, Scene I: O wonder! How many goodly creatures are there here! How beauteous mankind is! O brave new world, That has such people in 't.

— William Shakespeare The Tempest, Act V, Scene I, ll. 203–206 Shakespeare's use of the phrase is intended ironically, as the speaker is failing to recognise the evil nature of the island's visitors because of her innocence. Indeed, the next speaker—Miranda's father Prospero—replies to her innocent observation with the statement Tis new to thee."

Translations of the title often allude to similar expressions used in domestic works of literature: the French edition of the work is entitled Le Meilleur des mondes (The Best of All Worlds), an allusion to an expression used by the philosopher Gottfried Leibniz and satirised in Candide, Ou l'Optimisme by Voltaire (1759). The first Standard Chinese translation, done by novelist Lily Hsueh and Aaron Jen-wang Hsueh in 1974, is entitled "美麗新世界" (Pinyin: Měilì Xīn Shìjiè, literally "Beautiful New World").

History
Huxley wrote Brave New World whilst living in Sanary-sur-Mer, France, in the four months from May to August 1931. By this time, Huxley had established himself as a writer and social satirist. He was a contributor to Vanity Fair and Vogue magazines and had published a collection of his poetry (The Burning Wheel, 1916) and four satirical novels, Crome Yellow (1921), Antic Hay (1923), Those Barren Leaves (1925) and Point Counter Point (1928). Brave New World was Huxley's fifth novel and first dystopian work.

A short passage in Crome Yellow foreshadows Brave New World, showing that Huxley had such a future in mind already in 1921. Mr. Scogan, one of the earlier book's characters, describes an "impersonal generation" of the future that will "take the place of Nature's hideous system. In vast state incubators, rows upon rows of gravid bottles will supply the world with the population it requires. The family system will disappear; society, sapped at its very base, will have to find new foundations; and Eros, beautifully and irresponsibly free, will flit like a gay butterfly from flower to flower through a sunlit world".

Huxley said that Brave New World was inspired by the utopian novels of H. G. Wells, including A Modern Utopia (1905), and as a parody of Men Like Gods (1923). Wells' hopeful vision of the future gave Huxley the idea to begin writing a parody of the novels, which became Brave New World. He wrote in a letter to Mrs. Arthur Goldsmith, an American acquaintance, that he had "been having a little fun pulling the leg of H. G. Wells" but then he "got caught up in the excitement of [his] own ideas". Unlike the most popular optimistic utopian novels of the time, Huxley sought to provide a frightening vision of the future. Huxley referred to Brave New World as a "negative utopia", somewhat influenced by Wells's own The Sleeper Awakes (dealing with subjects like corporate tyranny and behavioural conditioning) and the works of D. H. Lawrence.

For his part Wells published, two years after Brave New World, his Utopian Shape of Things to Come. Seeking to rebut the argument of Huxley's Mustapha Mond—that moronic underclasses were a necessary "social gyroscope" and that a society composed solely of intelligent, assertive "Alphas" would inevitably disintegrate in internecine struggle—Wells depicted a stable egalitarian society emerging after several generations of a reforming elite having complete control of education throughout the world. In the future depicted in Wells' book, posterity remembers Huxley as "a reactionary writer". The scientific futurism in Brave New World is believed to be appropriated from Daedalus by J. B. S. Haldane.

The events of the Great Depression in Britain in 1931, with its mass unemployment and the abandonment of the gold standard, persuaded Huxley to assert that stability was the "primal and ultimate need" if civilisation was to survive the present crisis. The Brave New World character Mustapha Mond, Resident World Controller of Western Europe, is named after Sir Alfred Mond. Shortly before writing the novel, Huxley visited the Billingham Manufacturing Plant, Mond's technologically advanced factory near Billingham, north-east England, and it made a great impression on him.

Huxley used the setting and characters in his science fiction novel to express widely felt anxieties, particularly the fear of losing individual identity in the fast-paced world of the future. An early trip to the United States gave Brave New World much of its character. Huxley was outraged by the culture of youth, commercial cheeriness, sexual promiscuity and the inward-looking nature of many Americans; he had also found the book My Life and Work by Henry Ford on the boat to America and he saw the book's principles applied in everything he encountered after leaving San Francisco.

Plot
The novel opens in the World State city of London in AF (After Ford) 632 (AD 2540 in the Gregorian calendar), where citizens are engineered through artificial wombs and childhood indoctrination programmes into predetermined classes (or castes) based on intelligence and labour. Lenina Crowne, a hatchery worker, is popular and sexually desirable, but Bernard Marx, a psychologist, is not. He is shorter in stature than the average member of his high caste, which gives him an inferiority complex. His work with sleep-learning allows him to understand, and disapprove of, his society's methods of keeping its citizens peaceful, which includes their constant consumption of a soothing, happiness-producing drug called "soma". Courting disaster, Bernard is vocal and arrogant about his criticisms, and his boss contemplates exiling him to Iceland because of his nonconformity. His only friend is Helmholtz Watson, a gifted writer who finds it difficult to use his talents creatively in their pain-free society.

Bernard takes a holiday with Lenina outside the World State to a Savage Reservation in New Mexico, in which the two observe natural-born people, disease, the ageing process, other languages, and religious lifestyles for the first time. The culture of the village folk resembles the contemporary Native American groups of the region, descendants of the Anasazi, including the Puebloan peoples of Hopi and Zuni. Bernard and Lenina witness a violent public ritual and then encounter Linda, a woman originally from the World State who is living on the reservation with her son John, now a young man. She, too, visited the reservation on a holiday many years ago, but became separated from her group and was left behind. She had meanwhile become pregnant by a fellow holidaymaker (who is revealed to be Bernard's boss, the Director of Hatcheries and Conditioning). She did not try to return to the World State, because of her shame at her pregnancy. Despite spending his whole life in the reservation, John has never been accepted by the villagers, and his and Linda's lives have been hard and unpleasant. Linda has taught John to read, although from the only book in her possession—a scientific manual—and another book John found: the complete works of Shakespeare. Ostracised by the villagers, John is able to articulate his feelings only in terms of Shakespearean drama, quoting often from The Tempest, King Lear, Othello, Romeo and Juliet and Hamlet. Linda now wants to return to London, and John, too, wants to see this "brave new world" that his mother so often praised. Bernard sees an opportunity to thwart plans to exile him, and gets permission to take Linda and John back. On their return to London, John meets the Director and calls him his "father", a vulgarity which causes a roar of laughter. The humiliated Director resigns in shame before he can follow through with exiling Bernard.

Bernard, as "custodian" of the "savage" John who is now treated as a celebrity, is fawned on by the highest members of society and revels in attention he once scorned. Bernard's popularity is fleeting, though, and he becomes envious that John only really bonds with the literary-minded Helmholtz. Considered hideous and friendless, Linda spends all her time using soma, which she craved for so long, while John refuses to attend social events organised by Bernard, appalled by what he perceives to be an empty society. Lenina and John are physically attracted to each other, but John's view of courtship and romance, based on Shakespeare's writings, is utterly incompatible with Lenina's freewheeling attitude to sex. She tries to seduce him, but he attacks her, before suddenly being informed that his mother is on her deathbed. He rushes to Linda's bedside, causing a scandal, as this is not the "correct" attitude to death. Some children who enter the ward for "death-conditioning" come across as disrespectful to John, and he attacks one physically. He then tries to break up a distribution of soma to a lower-caste group, telling them that he is freeing them. Helmholtz and Bernard rush in to stop the ensuing riot, which the police quell by spraying soma vapor into the crowd.

Bernard, Helmholtz, and John are all brought before Mustapha Mond, the "Resident World Controller for Western Europe", who tells Bernard and Helmholtz that they are to be exiled to islands for antisocial activity. Bernard pleads for a second chance, but Helmholtz welcomes the opportunity to be a true individual, and chooses the Falkland Islands as his destination, believing that their bad weather will inspire his writing. Mond tells Helmholtz that exile is actually a reward. The islands are full of the most interesting people in the world, individuals who did not fit into the social model of the World State. Mond outlines for John the events that led to the present society and his arguments for a caste system and social control. John rejects Mond's arguments, and Mond sums up John's views by claiming that John demands "the right to be unhappy". John asks if he may go to the islands as well, but Mond refuses, saying he wishes to see what happens to John next.

Jaded with his new life, John moves to an abandoned hilltop lighthouse, near the village of Puttenham, where he intends to adopt a solitary ascetic lifestyle in order to purify himself of civilization, practising self-flagellation. This draws reporters and eventually hundreds of amazed sightseers, hoping to witness his bizarre behaviour.

For a while it seems that John might be left alone, after the public's attention is drawn to other diversions, but a documentary maker has secretly filmed John's self-flagellation from a distance, and when released the documentary causes an international sensation. Helicopters arrive with more journalists. Crowds of people descend on John's retreat, demanding that he perform his whipping ritual for them. From one helicopter a young woman emerges who is implied to be Lenina. John, at the sight of a woman he both adores and loathes, whips at her in a fury and then turns the whip on himself, exciting the crowd, whose wild behaviour transforms into a soma-fuelled orgy. The next morning John awakes on the ground and is consumed by remorse over his participation in the night's events.

That evening, a swarm of helicopters appears on the horizon, the story of last night's orgy having been in all the papers. The first onlookers and reporters to arrive find that John is dead, having hanged himself.

Characters
Bernard Marx, a sleep-learning specialist at the Central London Hatchery and Conditioning Centre. Although Bernard is an Alpha-Plus (the upper class of the society), he is a misfit. He is unusually short for an Alpha; an alleged accident with alcohol in Bernard's blood-surrogate before his decanting has left him slightly stunted. Unlike his fellow utopians, Bernard is often angry, resentful, and jealous. At times, he is also cowardly and hypocritical. His conditioning is clearly incomplete. He does not enjoy communal sports, solidarity services, or promiscuous sex. He does not particularly enjoy soma. Bernard is in love with Lenina and does not like her sleeping with other men, even though "everyone belongs to everyone else". Bernard's triumphant return to utopian civilisation with John the Savage from the Reservation precipitates the downfall of the Director, who had been planning to exile him. Bernard's triumph is short-lived; he is ultimately banished to an island for his non-conformist behaviour.

John, the illicit son of the Director and Linda, born and reared on the Savage Reservation ("Malpais") after Linda was unwittingly left behind by her errant lover. John ("the Savage" or "Mr. Savage", as he is often called) is an outsider both on the Reservation—where the natives still practice marriage, natural birth, family life and religion—and the ostensibly civilised World State, based on principles of stability and happiness. He has read nothing but the complete works of William Shakespeare, which he quotes extensively, and, for the most part, aptly, though his allusion to the "Brave New World" (Miranda's words in The Tempest) takes on a darker and bitterly ironic resonance as the novel unfolds. John is intensely moral according to a code that he has been taught by Shakespeare and life in Malpais but is also naïve: his views are as imported into his own consciousness as are the hypnopedic messages of World State citizens. The admonishments of the men of Malpais taught him to regard his mother as a whore; but he cannot grasp that these were the same men who continually sought her out despite their supposedly sacred pledges of monogamy. Because he is unwanted in Malpais, he accepts the invitation to travel back to London and is initially astonished by the comforts of the World State. He remains committed to values that exist only in his poetry. He first spurns Lenina for failing to live up to his Shakespearean ideal and then the entire utopian society: he asserts that its technological wonders and consumerism are poor substitutes for individual freedom, human dignity and personal integrity. After his mother's death, he becomes deeply distressed with grief, surprising onlookers in the hospital. He then withdraws himself from society and attempts to purify himself of "sin" (desire), but is unable to do so. He finds himself gathering a lot of trouble for both his body and mind. He soon does not realise what is real or what is fake, what he does and what he does not do. Soon, everything he thinks about or feels just becomes blurred and unrecognizable. Finally he hangs himself in despair.

Helmholtz Watson, a handsome and successful Alpha-Plus lecturer at the College of Emotional Engineering and a friend of Bernard. He feels unfulfilled writing endless propaganda doggerel, and the stifling conformism and philistinism of the World State make him restive. Helmholtz is ultimately exiled to the Falkland Islands—a cold asylum for disaffected Alpha-Plus non-conformists—after reading a heretical poem to his students on the virtues of solitude and helping John destroy some Deltas' rations of soma following Linda's death. Unlike Bernard, he takes his exile in his stride and comes to view it as an opportunity for inspiration in his writing. His first name derives from the German physicist Hermann von Helmholtz.

Lenina Crowne, a young, beautiful foetus technician at the Central London Hatchery and Conditioning Centre. Lenina Crowne is a Beta who enjoys being a Beta. She is a vaccination worker with beliefs and values that are in line with a citizen of the World State. She is part of the 30% of the female population that are not freemartins (sterile women). Lenina is promiscuous and popular but somewhat quirky in her society: she had a four-month relation with Henry Foster, choosing not to have sex with anyone but him for a period of time. She is basically happy and well-conditioned, using soma to suppress unwelcome emotions, as is expected. Lenina has a date with Bernard, to whom she feels ambivalently attracted, and she goes to the Reservation with him. On returning to civilisation, she tries and fails to seduce John the Savage. John loves and desires Lenina but he is repelled by her forwardness and the prospect of pre-marital sex, rejecting her as an "impudent strumpet". Lenina visits John at the lighthouse but he attacks her with a whip, unwittingly inciting onlookers to do the same. Her exact fate is left unspecified.

Mustapha Mond, Resident World Controller of Western Europe, "His Fordship" Mustapha Mond presides over one of the ten zones of the World State, the global government set up after the cataclysmic Nine Years' War and great Economic Collapse. Sophisticated and good-natured, Mond is an urbane and hyperintelligent advocate of the World State and its ethos of "Community, Identity, Stability". Among the novel's characters, he is uniquely aware of the precise nature of the society he oversees and what it has given up to accomplish its gains. Mond argues that art, literature, and scientific freedom must be sacrificed to secure the ultimate utilitarian goal of maximising societal happiness. He defends the caste system, behavioural conditioning, and the lack of personal freedom in the World State: these, he says, are a price worth paying for achieving social stability, the highest social virtue because it leads to lasting happiness.

Fanny Crowne, Lenina Crowne's friend (they have the same last name because only ten thousand last names are in use in a World State comprising two billion people). Fanny voices the conventional values of her caste and society, particularly the importance of promiscuity: she advises Lenina that she should have more than one man in her life because it is unseemly to concentrate on just one. Fanny then warns Lenina away from a new lover whom she considers undeserving, yet she is ultimately supportive of the young woman's attraction to the savage John.

Henry Foster, one of Lenina's many lovers, is a perfectly conventional Alpha male, casually discussing Lenina's body with his coworkers. His success with Lenina, and his casual attitude about it, infuriate the jealous Bernard. Henry ultimately proves himself every bit the ideal World State citizen, finding no courage to defend Lenina from John's assaults despite having maintained an uncommonly longstanding sexual relationship with her.

Benito Hoover, another of Lenina's lovers. She remembers that he is particularly hairy when he takes his clothes off.

The Director of Hatcheries and Conditioning (DHC), also known as Thomas "Tomakin", is the administrator of the Central London Hatchery and Conditioning Centre, where he is a threatening figure who intends to exile Bernard to Iceland. His plans take an unexpected turn when Bernard returns from the Reservation with Linda (see below) and John, a child they both realise is actually his. This fact, scandalous and obscene in the World State, not because it was extramarital (which all sexual acts are), but because it was procreative, leads the Director to resign his post in shame.

, John's mother, decanted as a Beta-Minus in the World State, originally worked in the DHC's Fertilizing Room, and subsequently lost during a storm while visiting the New Mexico Savage Reservation with the Director many years before the events of the novel. Despite following her usual precautions, Linda became pregnant with the Director's son during their time together and was therefore unable to return to the World State by the time that she found her way to Malpais. Having been conditioned to the promiscuous social norms of the World State, Linda finds herself at once popular with every man in the pueblo (because she is open to all sexual advances) and also reviled for the same reason, seen as a whore by the wives of the men who visit her and by the men themselves (who come to her nonetheless). Her only comforts there are mescal brought by Popé as well as peyotl. Linda is desperate to return to the World State and to soma, wanting nothing more from her remaining life than comfort until death.

The Arch-Community-Songster, the secular equivalent of the Archbishop of Canterbury in the World State society. He takes personal offense when John refuses to attend Bernard's party.

The Director of Crematoria and Phosphorus Reclamation, one of the many disappointed, important figures to attend Bernard's party.

The Warden, an Alpha-Minus, the talkative chief administrator for the New Mexico Savage Reservation. He is blond, short, broad-shouldered, and has a booming voice.

Darwin Bonaparte, a "big game photographer" (i.e. filmmaker) who films John flogging himself. Darwin Bonaparte became known for two works: "feely of the gorillas' wedding", and "Sperm Whale's Love-life". He had already made a name for himself but still seeks more. He renews his fame by filming the savage, John, in his newest release "The Savage of Surrey". His name alludes to Charles Darwin and Napoleon Bonaparte.

Dr. Shaw, Bernard Marx's physician who consequently becomes the physician of both Linda and John. He prescribes a lethal dose of soma to Linda, which will stop her respiratory system from functioning in a span of one to two months, at her own behest but not without protest from John. Ultimately, they all agree that it is for the best, since denying her this request would cause more trouble for Society and Linda herself.

Dr. Gaffney, Provost of Eton, an Upper School for high-caste individuals. He shows Bernard and John around the classrooms, and the Hypnopaedic Control Room (used for behavioural conditioning through sleep learning). John asks if the students read Shakespeare but the Provost says the library contains only reference books because solitary activities, such as reading, are discouraged.

Miss Keate, Head Mistress of Eton Upper School. Bernard fancies her, and arranges an assignation with her.

Others

 * Freemartins, women who have been deliberately made sterile by exposure to male hormones during foetal development but are still physically normal except for "the slightest tendency to grow beards". In the book, government policy requires freemartins to form 70% of the female population.

Of Malpais

 * Popé, a native of Malpais. Although he reinforces the behaviour that causes hatred for Linda in Malpais by sleeping with her and bringing her mescal, he still holds the traditional beliefs of his tribe. In his early years John attempted to kill him, but Popé brushed off his attempt and sent him fleeing. He gave Linda a copy of the Complete Works of Shakespeare. (Historically, Popé or Po'pay was a Tewa religious leader who led the Pueblo Revolt in 1680 against Spanish colonial rule.)
 * Mitsima, an elder tribal shaman who also teaches John survival skills such as rudimentary ceramics (specifically coil pots, which were traditional to Native American tribes) and bow-making.
 * Kiakimé, a native girl whom John fell for, but is instead eventually wed to another boy from Malpais.
 * Kothlu, a native boy with whom Kiakimé is wed.

Background figures
These are non-fictional and factual characters who lived before the events in this book, but are of note in the novel:
 * Henry Ford, who has become a messianic figure to the World State. "Our Ford" is used in place of "Our Lord", as a credit to popularising the use of the assembly line.
 * Sigmund Freud, "Our Freud" is sometimes said in place of "Our Ford" because Freud's psychoanalytic method depends implicitly upon the rules of classical conditioning, and because Freud popularised the idea that sexual activity is essential to human happiness. (It is also strongly implied that citizens of the World State believe Freud and Ford to be the same person.)
 * H. G. Wells, "Dr. Wells", British writer and utopian socialist, whose book Men Like Gods was a motivation for Brave New World. "All's well that ends Wells", wrote Huxley in his letters, criticising Wells for anthropological assumptions Huxley found unrealistic.
 * Ivan Petrovich Pavlov, whose conditioning techniques are used to train infants.
 * William Shakespeare, whose banned works are quoted throughout the novel by John, "the Savage". The plays quoted include Macbeth, The Tempest, Romeo and Juliet, Hamlet, King Lear, Troilus and Cressida, Measure for Measure and Othello. Mustapha Mond also knows them because as a World Controller he has access to a selection of books from throughout history, including the Bible.
 * Thomas Robert Malthus, 19th century British economist, believed the people of the Earth would eventually be threatened by their inability to raise enough food to feed the population. In the novel, the eponymous character devises the contraceptive techniques (Malthusian belt) that are practiced by women of the World State.
 * Reuben Rabinovitch, the Polish-Jew character on whom the effects of sleep-learning, hypnopædia, are first observed.
 * John Henry Newman, 19th century Catholic theologian and educator, believed university education the critical element in advancing post-industrial Western civilization. Mustapha Mond and The Savage discuss a passage from one of Newman's books.
 * Alfred Mond, British industrialist, financier and politician. He is the namesake of Mustapha Mond.
 * Mustafa Kemal Atatürk, the founder and first President of Republic of Turkey. Naming Mond after Atatürk links up with their characteristics; he reigned during the time Brave New World was written and revolutionised the 'old' Ottoman state into a new nation.

Sources of names and references
The limited number of names that the World State assigned to its bottle-grown citizens can be traced to political and cultural figures who contributed to the bureaucratic, economic, and technological systems of Huxley's age, and presumably those systems in Brave New World.
 * Soma: Huxley took the name for the drug used by the state to control the population after the Vedic ritual drink Soma, inspired by his interest in Indian mysticism.
 * Malthusian belt: A contraceptive device worn by women. When Huxley was writing Brave New World, organizations such as the Malthusian League had spread throughout Europe, advocating contraception. Although the controversial economic theory of Malthusianism was derived from an essay by Thomas Malthus about the economic effects of population growth, Malthus himself was an advocate of abstinence rather than contraception.

Reception
Upon its publication, Rebecca West praised Brave New World as "The most accomplished novel Huxley has yet written", Joseph Needham lauded it as "Mr. Huxley's remarkable book", and Bertrand Russell also praised it, stating, "Mr. Aldous Huxley has shown his usual masterly skill in Brave New World." Brave New World also received negative responses from other contemporary critics, although his work was later embraced.

In an article in the 4 May 1935 issue of the Illustrated London News, G. K. Chesterton explained that Huxley was revolting against the "Age of Utopias". Much of the discourse on man's future before 1914 was based on the thesis that humanity would solve all economic and social issues. In the decade following the war the discourse shifted to an examination of the causes of the catastrophe. The works of H. G. Wells and George Bernard Shaw on the promises of socialism and a World State were then viewed as the ideas of naive optimists. Chesterton wrote:

Similarly, in 1944 economist Ludwig von Mises described Brave New World as a satire of utopian predictions of socialism: "Aldous Huxley was even courageous enough to make socialism's dreamed paradise the target of his sardonic irony."

Common misunderstandings
Various authors assume that the book was first and foremost a cautionary tale regarding human genetic enhancement,  indeed about – as an infamous report of Bush associate Leon Kass states –: "producing improved [,][...] perfect or post-human" people. In fact, the title itself has become a mere stand-in used to "evoke the general idea of a futuristic dystopia". And yet, all this appears to be one big misunderstanding of Huxley's much more nuanced motives, as geneticist Derek So notes. A more careful reading of the actual text, he argues, shows us that: "there does not seem to be any genetic testing in Brave New World, and most of the methods described involve hormones and chemicals rather than heritable interventions. Although Huxley wrote that ' eugenics and dysgenics were practiced systematically', this seems to refer only to selective breeding and not to any kind of direct manipulation on the genetic level. (The Bokanovsky process does represent a form of cloning, but this is not ethically equivalent to GGE, and references to Brave New World may lead some readers to confuse the two technologies.) [...] While it's true that the upper castes in Brave New World are smarter than the others, this is more because of the deliberate impairment of the lower castes than because the upper castes are 'perfect'. Rather than reducing the number of individuals born with genetic disorders or handicaps, Huxley's dystopia involves dramatically increasing their number. [...] Quite the opposite: Huxley thought that Brave New World might come about if we didn't start selecting better children." Overall, Derek So notes that "Huxley was much more worried about totalitarianism than about the new biotechnologies per se that he alluded to in Brave New World." Despite claims to the contrary then, Huxley remained a committed eugenicist all throughout his life, much like his comparably famous brother Julian, and one just as keen on stressing its humanistic underpinnings.

The World State and Fordism
The World State is built upon the principles of Henry Ford's assembly line: mass production, homogeneity, predictability, and consumption of disposable consumer goods. While the World State lacks any supernatural-based religions, Ford himself is revered as the creator of their society but not as a deity, and characters celebrate Ford Day and swear oaths by his name (e.g., "By Ford!"). In this sense, some fragments of traditional religion are present, such as Christian crosses, which had their tops cut off to be changed to a "T", representing the Ford Model T. In England, there is an Arch-Community-Songster of Canterbury, obviously continuing the Archbishop of Canterbury, and in America The Christian Science Monitor continues publication as The Fordian Science Monitor. The World State calendar numbers years in the "AF" era—"Anno Ford"—with the calendar beginning in AD 1908, the year in which Ford's first Model T rolled off his assembly line. The novel's Gregorian calendar year is AD 2540, but it is referred to in the book as AF 632.

From birth, members of every class are indoctrinated by recorded voices repeating slogans while they sleep (called "hypnopædia" in the book) to believe their own class is superior, but that the other classes perform needed functions. Any residual unhappiness is resolved by an antidepressant and hallucinogenic drug called soma.

The biological techniques used to control the populace in Brave New World do not include genetic engineering; Huxley wrote the book before the structure of DNA was known. However, Gregor Mendel's work with inheritance patterns in peas had been rediscovered in 1900 and the eugenics movement, based on artificial selection, was well established. Huxley's family included a number of prominent biologists including Thomas Huxley, half-brother and Nobel Laureate Andrew Huxley, and his brother Julian Huxley who was a biologist and involved in the eugenics movement. Nonetheless, Huxley emphasises conditioning over breeding (nurture versus nature); human embryos and fetuses are conditioned through a carefully designed regimen of chemical (such as exposure to hormones and toxins), thermal (exposure to intense heat or cold, as one's future career would dictate), and other environmental stimuli, although there is an element of selective breeding as well.

Comparisons with George Orwell's Nineteen Eighty-Four
In a letter to George Orwell about Nineteen Eighty-Four, Huxley wrote "Whether in actual fact the policy of the boot-on-the-face can go on indefinitely seems doubtful. My own belief is that the ruling oligarchy will find less arduous and wasteful ways of governing and of satisfying its lust for power, and these ways will resemble those which I described in Brave New World." He went on to write "Within the next generation I believe that the world's rulers will discover that infant conditioning and narco-hypnosis are more efficient, as instruments of government, than clubs and prisons, and that the lust for power can be just as completely satisfied by suggesting people into loving their servitude as by flogging and kicking them into obedience."

Social critic Neil Postman contrasted the worlds of Nineteen Eighty-Four and Brave New World in the foreword of his 1985 book Amusing Ourselves to Death. He writes: "What Orwell feared were those who would ban books. What Huxley feared was that there would be no reason to ban a book, for there would be no one who wanted to read one. Orwell feared those who would deprive us of information. Huxley feared those who would give us so much that we would be reduced to passivity and egoism. Orwell feared that the truth would be concealed from us. Huxley feared the truth would be drowned in a sea of irrelevance. Orwell feared we would become a captive culture. Huxley feared we would become a trivial culture, preoccupied with some equivalent of the feelies, the orgy porgy, and the centrifugal bumblepuppy. As Huxley remarked in Brave New World Revisited, the civil libertarians and rationalists who are ever on the alert to oppose tyranny 'failed to take into account man's almost infinite appetite for distractions.' In 1984, Huxley added, people are controlled by inflicting pain. In Brave New World, they are controlled by inflicting pleasure. In short, Orwell feared that what we hate will ruin us. Huxley feared that what we love will ruin us."

The writer Christopher Hitchens, who published several articles on Huxley and a book on Orwell, noted the difference between the two texts in the introduction to his 1999 article "Why Americans Are Not Taught History",

"We dwell in a present-tense culture that somehow, significantly, decided to employ the telling expression 'You're history' as a choice reprobation or insult, and thus elected to speak forgotten volumes about itself. By that standard, the forbidding dystopia of George Orwell's Nineteen Eighty-Four already belongs, both as a text and as a date, with Ur and Mycenae, while the hedonist nihilism of Huxley still beckons toward a painless, amusement-sodden, and stress-free consensus. Orwell's was a house of horrors. He seemed to strain credulity because he posited a regime that would go to any lengths to own and possess history, to rewrite and construct it, and to inculcate it by means of coercion. Whereas Huxley ... rightly foresaw that any such regime could break because it could not bend. In 1988, four years after 1984, the Soviet Union scrapped its official history curriculum and announced that a newly authorized version was somewhere in the works. This was the precise moment when the regime conceded its own extinction. For true blissed-out and vacant servitude, though, you need an otherwise sophisticated society where no serious history is taught."

Brave New World Revisited
In 1946, Huxley wrote in the foreword of the new edition of Brave New World:

"If I were now to rewrite the book, I would offer the Savage a third alternative. Between the Utopian and primitive horns of his dilemma would lie the possibility of sanity... In this community economics would be decentralist and Henry-Georgian, politics Kropotkinesque and co-operative. Science and technology would be used as though, like the Sabbath, they had been made for man, not (as at present and still more so in the Brave New World) as though man were to be adapted and enslaved to them. Religion would be the conscious and intelligent pursuit of man's Final End, the unitive knowledge of immanent Tao or Logos, the transcendent Godhead or Brahman. And the prevailing philosophy of life would be a kind of Higher Utilitarianism, in which the Greatest Happiness principle would be secondary to the Final End principle—the first question to be asked and answered in every contingency of life being: 'How will this thought or action contribute to, or interfere with, the achievement, by me and the greatest possible number of other individuals, of man's Final End?'"

Brave New World Revisited (Harper & Brothers, US, 1958; Chatto & Windus, UK, 1959), written by Huxley almost thirty years after Brave New World, is a non-fiction work in which Huxley considered whether the world had moved toward or away from his vision of the future from the 1930s. He believed when he wrote the original novel that it was a reasonable guess as to where the world might go in the future. In Brave New World Revisited, he concluded that the world was becoming like Brave New World much faster than he originally thought.

Huxley analysed the causes of this, such as overpopulation, as well as all the means by which populations can be controlled. He was particularly interested in the effects of drugs and subliminal suggestion. Brave New World Revisited is different in tone because of Huxley's evolving thought, as well as his conversion to Hindu Vedanta in the interim between the two books.

The last chapter of the book aims to propose action which could be taken to prevent a democracy from turning into the totalitarian world described in Brave New World. In Huxley's last novel, Island, he again expounds similar ideas to describe a utopian nation, which is generally viewed as a counterpart to Brave New World.

Censorship
According to American Library Association, Brave New World has frequently been banned and challenged in the United States due to insensitivity, offensive language, nudity, racism, conflict with a religious viewpoint, and being sexually explicit. It landed on the list of the top ten most challenged books in 2010 (3) and 2011 (7). The book also secured a spot on the association's list of the top one hundred challenged books for 1990–1999 (54), 2000–2009 (36), and 2010–2019 (26).

The following include specific instances of when the book has been censored, banned, or challenged:
 * In 1932, the book was banned in Ireland for its language, and for supposedly being anti-family and anti-religion.
 * In 1965, a Maryland English teacher alleged that he was fired for assigning Brave New World to students. The teacher sued for violation of First Amendment rights but lost both his case and the appeal, with the appeals court ruling that the assignment of the book was not the reason for his firing.
 * The book was banned in India in 1967, with Huxley accused of being a "pornographer".
 * In 1980, it was removed from classrooms in Miller, Missouri among other challenges.
 * The version of Brave New World Revisited published in China lacks explicit mentions of China itself.

Influences and allegations of plagiarism
The English writer Rose Macaulay published What Not: A Prophetic Comedy in 1918. What Not depicts a dystopian future where people are ranked by intelligence, the government mandates mind training for all citizens, and procreation is regulated by the state. Macaulay and Huxley shared the same literary circles and he attended her weekly literary salons.

Bertrand Russell felt Brave New World borrowed from his 1931 book "The Scientific Outlook", and wrote in a letter to his publisher that Huxley's novel was "merely an expansion of the two penultimate chapters of 'The Scientific Outlook.'"

H. G. Wells' novel The First Men in the Moon (1901) used concepts that Huxley added to his story. Both novels introduce a society consisting of a specialized caste system, new generations are produced in jars and bottles where their designated caste is decided before birth by tempering with the fetus' development, and individuals are drugged down when they are not needed.

George Orwell believed that Brave New World must have been partly derived from the 1921 novel We by Russian author Yevgeny Zamyatin. However, in a 1962 letter to Christopher Collins, Huxley says that he wrote Brave New World long before he had heard of We. According to We translator Natasha Randall, Orwell believed that Huxley was lying. Kurt Vonnegut said that in writing Player Piano (1952), he "cheerfully ripped off the plot of Brave New World, whose plot had been cheerfully ripped off from Yevgeny Zamyatin's We".

In 1982, Polish author Antoni Smuszkiewicz, in his analysis of Polish science-fiction Zaczarowana gra ("The Magic Game"), presented accusations of plagiarism against Huxley. Smuszkiewicz showed similarities between Brave New World and two science fiction novels written earlier by Polish author Mieczysław Smolarski, namely Miasto światłości ("The City of Light", 1924) and Podróż poślubna pana Hamiltona ("Mr Hamilton's Honeymoon Trip", 1928). Smuszkiewicz wrote in his open letter to Huxley: "This work of a great author, both in the general depiction of the world as well as countless details, is so similar to two of my novels that in my opinion there is no possibility of accidental analogy."

Kate Lohnes, writing for Encyclopædia Britannica, notes similarities between Brave New World and other novels of the era could be seen as expressing "common fears surrounding the rapid advancement of technology and of the shared feelings of many tech-skeptics during the early 20th century". Other dystopian novels followed Huxley's work, including C.S. Lewis's That Hideous Strength (1945) and Orwell's Nineteen Eighty-Four (1949).

Legacy
In 1999, the Modern Library ranked Brave New World fifth on its list of the 100 best English-language novels of the 20th century. In 2003, Robert McCrum writing for The Observer included Brave New World chronologically at number 53 in "the top 100 greatest novels of all time", and the novel was listed at number 87 on the BBC's survey The Big Read.

On 5 November 2019, BBC News listed Brave New World on its list of the 100 most influential novels. In 2021, Brave New World was one of six classic science fiction novels by British authors selected by Royal Mail to feature on a series of UK postage stamps.

Theatre

 * Brave New World (opened 4 September 2015) in co-production by Royal & Derngate, Northampton and Touring Consortium Theatre Company which toured the UK. The adaptation was by Dawn King, composed by These New Puritans and directed by James Dacre.

Radio

 * Brave New World (radio broadcast) CBS Radio Workshop (27 January and 3 February 1956): music composed and conducted by Bernard Herrmann. Adapted for radio by William Froug. Introduced by William Conrad and narrated by Aldous Huxley. Featuring the voices of Joseph Kearns, Bill Idelson, Gloria Henry, Charlotte Lawrence, Byron Kane, Sam Edwards, Jack Kruschen, Vic Perrin, Lurene Tuttle, Herb Butterfield, Doris Singleton.
 * Brave New World (radio broadcast) BBC Radio 4 (May 2013)
 * Brave New World (radio broadcast) BBC Radio 4 (22, 29 May 2016)

Film

 * Brave New World (1980), a television film directed by Burt Brinckerhoff
 * Brave New World (1998), a television film directed by Leslie Libman and Larry Williams
 * In 2009, a theatrical film was announced to be in development, with collaboration between Ridley Scott and Leonardo DiCaprio. By May 2013 the project was placed on hold.
 * Brave New World (2014), fan film directed by Nathan Hyde

Television

 * Brave New World (2010), miniseries directed by Leonard Menchiari
 * Brave New World (2020), series created by David Wiener
 * In May 2015, The Hollywood Reporter reported that Steven Spielberg's Amblin Television would bring Brave New World to Syfy network as a scripted series, adapted by Les Bohem. The adaptation was eventually written by David Wiener with Grant Morrison and Brian Taylor, with the series ordered to air on USA Network in February 2019. The series eventually moved to the Peacock streaming service and premiered on 15 July 2020. In October 2020, the series was cancelled after one season.

license: Creative Commons - Attribution Share-Alike - https://creativecommons.org/licenses/by-sa/4.0/

title: Brave New World


text:
Linear predictive coding

Linear predictive coding (LPC) is a method used mostly in audio signal processing and speech processing for representing the spectral envelope of a digital signal of speech in compressed form, using the information of a linear predictive model.

LPC is the most widely used method in speech coding and speech synthesis. It is a powerful speech analysis technique, and a useful method for encoding good quality speech at a low bit rate.

Overview
LPC starts with the assumption that a speech signal is produced by a buzzer at the end of a tube (for voiced sounds), with occasional added hissing and popping sounds (for voiceless sounds such as sibilants and plosives). Although apparently crude, this Source–filter model is actually a close approximation of the reality of speech production. The glottis (the space between the vocal folds) produces the buzz, which is characterized by its intensity (loudness) and frequency (pitch). The vocal tract (the throat and mouth) forms the tube, which is characterized by its resonances; these resonances give rise to formants, or enhanced frequency bands in the sound produced. Hisses and pops are generated by the action of the tongue, lips and throat during sibilants and plosives.

LPC analyzes the speech signal by estimating the formants, removing their effects from the speech signal, and estimating the intensity and frequency of the remaining buzz. The process of removing the formants is called inverse filtering, and the remaining signal after the subtraction of the filtered modeled signal is called the residue.

The numbers which describe the intensity and frequency of the buzz, the formants, and the residue signal, can be stored or transmitted somewhere else. LPC synthesizes the speech signal by reversing the process: use the buzz parameters and the residue to create a source signal, use the formants to create a filter (which represents the tube), and run the source through the filter, resulting in speech.

Because speech signals vary with time, this process is done on short chunks of the speech signal, which are called frames; generally, 30 to 50 frames per second give an intelligible speech with good compression.

Early history
Linear prediction (signal estimation) goes back to at least the 1940s when Norbert Wiener developed a mathematical theory for calculating the best filters and predictors for detecting signals hidden in noise. Soon after Claude Shannon established a general theory of coding, work on predictive coding was done by C. Chapin Cutler, Bernard M. Oliver and Henry C. Harrison. Peter Elias in 1955 published two papers on predictive coding of signals.

Linear predictors were applied to speech analysis independently by Fumitada Itakura of Nagoya University and Shuzo Saito of Nippon Telegraph and Telephone in 1966 and in 1967 by Bishnu S. Atal, Manfred R. Schroeder and John Burg. Itakura and Saito described a statistical approach based on maximum likelihood estimation; Atal and Schroeder described an adaptive linear predictor approach; Burg outlined an approach based on principle of maximum entropy.

In 1969, Itakura and Saito introduced method based on partial correlation (PARCOR), Glen Culler proposed real-time speech encoding, and Bishnu S. Atal presented an LPC speech coder at the Annual Meeting of the Acoustical Society of America. In 1971, realtime LPC using 16-bit LPC hardware was demonstrated by Philco-Ford; four units were sold. LPC technology was advanced by Bishnu Atal and Manfred Schroeder during the 1970s–1980s. In 1978, Atal and Vishwanath et al. of BBN developed the first variable-rate LPC algorithm. The same year, Atal and Manfred R. Schroeder at Bell Labs proposed an LPC speech codec called adaptive predictive coding, which used a psychoacoustic coding algorithm exploiting the masking properties of the human ear. This later became the basis for the perceptual coding technique used by the MP3 audio compression format, introduced in 1993. Code-excited linear prediction (CELP) was developed by Schroeder and Atal in 1985.

LPC is the basis for voice-over-IP (VoIP) technology. In 1972, Bob Kahn of ARPA with Jim Forgie of Lincoln Laboratory (LL) and Dave Walden of BBN Technologies started the first developments in packetized speech, which would eventually lead to voice-over-IP technology. In 1973, according to Lincoln Laboratory informal history, the first real-time 2400 bit/s LPC was implemented by Ed Hofstetter. In 1974, the first real-time two-way LPC packet speech communication was accomplished over the ARPANET at 3500 bit/s between Culler-Harrison and Lincoln Laboratory. In 1976, the first LPC conference took place over the ARPANET using the Network Voice Protocol, between Culler-Harrison, ISI, SRI, and LL at 3500 bit/s.

LPC coefficient representations
LPC is frequently used for transmitting spectral envelope information, and as such it has to be tolerant of transmission errors. Transmission of the filter coefficients directly (see linear prediction for a definition of coefficients) is undesirable, since they are very sensitive to errors. In other words, a very small error can distort the whole spectrum, or worse, a small error might make the prediction filter unstable.

There are more advanced representations such as log area ratios (LAR), line spectral pairs (LSP) decomposition and reflection coefficients. Of these, especially LSP decomposition has gained popularity since it ensures the stability of the predictor, and spectral errors are local for small coefficient deviations.

Applications
LPC is the most widely used method in speech coding and speech synthesis. It is generally used for speech analysis and resynthesis. It is used as a form of voice compression by phone companies, such as in the GSM standard, for example. It is also used for secure wireless, where voice must be digitized, encrypted and sent over a narrow voice channel; an early example of this is the US government's Navajo I.

LPC synthesis can be used to construct vocoders where musical instruments are used as an excitation signal to the time-varying filter estimated from a singer's speech. This is somewhat popular in electronic music. Paul Lansky made the well-known computer music piece notjustmoreidlechatter using linear predictive coding. A 10th-order LPC was used in the popular 1980s Speak & Spell educational toy.

LPC predictors are used in Shorten, MPEG-4 ALS, FLAC, SILK audio codec, and other lossless audio codecs.

LPC has received some attention as a tool for use in the tonal analysis of violins and other stringed musical instruments.

title: Linear predictive coding


text:
User:Clasqm

I suppose I really should introduce myself. I lecture in Religious Studies at the University of South Africa. I'll probably concentrate on Eastern religions and philosophies, but I may pop up elsewhere ... and usually do.

Depending on which browser I'm using, I may show up on Recent Changes as 196.2.20.xxx

Dr Michel Clasquin clasqm@unisa.ac.za / clasqm@mweb.co.za

Here are some of the pages I've done a fair bit of work on

 * Religion and mythology
 * Hinduism
 * Sikhism
 * Jainism
 * Confucianism
 * Shinto
 * Definition of religion
 * Norse Mythology
 * Celts
 * Celtic Mythology

 * Zoology
 * Canidae
 * Hyaenidae
 * Ursidae

 * Other
 * South Africa - wikified the CIA factbook material and added national symbols
 * South African English
 * Rulers of Japan
 * Aquarium
 * Jonathan Livingston Seagull

plus a lot of subsidiary links off these

I've also annoyed lots of people by setting myself up as the Year in Review police, making sure that dates mentioned in biographical articles get cross-referenced to the correct year and, where possible to the correct Historical anniversaries too. I started this by filling in my own birthday, so now you know why history in the Wikipedia seems to revolve around February 11!

title: User:Clasqm