title: Ironclad warship

text: The Union ironclads played an important role in the Mississippi and tributaries by providing tremendous fire upon Confederate forts, installations and vessels with relative impunity to enemy fire. They were not as heavily armored as the ocean-going monitors of the Union, but they were adequate for their intended use. More Western Flotilla Union ironclads were sunk by torpedoes (mines) than by enemy fire, and the most damaging fire for the Union ironclads was from shore installations, not Confederate vessels.


title: Ironclad warship

text: The first fleet battle, and the first ocean battle, involving ironclad warships was the Battle of Lissa in 1866. Waged between the Austrian and Italian navies, the battle pitted combined fleets of wooden frigates and corvettes and ironclad warships on both sides in the largest naval battle between the battles of Navarino and Tsushima.


title: Ironclad warship

text: The Italian fleet consisted of 12 ironclads and a similar number of wooden warships, escorting transports which carried troops intending to land on the Adriatic island of Lissa. Among the Italian ironclads were seven broadside ironclad frigates, four smaller ironclads, and the newly built  – a double-turreted ram. Opposing them, the Austrian navy had seven ironclad frigates.


title: Ironclad warship

text: The Austrians believed their ships to have less effective guns than their enemy, so decided to engage the Italians at close range and ram them. The Austrian fleet formed into an arrowhead formation with the ironclads in the first line, charging at the Italian ironclad squadron. In the melée which followed both sides were frustrated by the lack of damage inflicted by guns, and by the difficulty of ramming—nonetheless, the effective ramming attack being made by the Austrian flagship against the Italian attracted great attention in following years.


title: Ironclad warship

text: The superior Italian fleet lost its two ironclads, and , while the Austrian unarmored screw two-decker remarkably survived close actions with four Italian ironclads. The battle ensured the popularity of the ram as a weapon in European ironclads for many years, and the victory won by Austria established it as the predominant naval power in the Adriatic.


title: Ironclad warship

text: The battles of the American Civil War and at Lissa were very influential on the designs and tactics of the ironclad fleets that followed. In particular, it taught a generation of naval officers the (ultimately erroneous) lesson that ramming was the best way to sink enemy ironclads.


title: Ironclad warship

text: The adoption of iron armor meant that the traditional naval armament of dozens of light cannon became useless, since their shot would bounce off an armored hull. To penetrate armor, increasingly heavy guns were mounted on ships; nevertheless, the view that ramming was the only way to sink an ironclad became widespread. The increasing size and weight of guns also meant a movement away from the ships mounting many guns broadside, in the manner of a ship-of-the-line, towards a handful of guns in turrets for all-round fire.


title: Ironclad warship

text: From the 1860s to the 1880s many naval designers believed that the ram was again a vital weapon in naval warfare. With steam power freeing ships from the wind, iron construction increasing their structural strength, and armor making them invulnerable to shellfire, the ram seemed to offer the opportunity to strike a decisive blow.


title: Ironclad warship

text: The scant damage inflicted by the guns of "Monitor" and "Virginia" at Battle of Hampton Roads and the spectacular but lucky success of the Austrian flagship SMS "Erzherzog Ferdinand Max" sinking the Italian "Re d'Italia" at Lissa gave strength to the ramming craze. From the early 1870s to early 1880s most British naval officers thought that guns were about to be replaced as the main naval armament by the ram. Those who noted the tiny number of ships that had actually been sunk by ramming struggled to be heard.


title: Ironclad warship

text: The revival of ramming had a significant effect on naval tactics. Since the 17th century the predominant tactic of naval warfare had been the line of battle, where a fleet formed a long line to give it the best fire from its broadside guns. This tactic was totally unsuited to ramming, and the ram threw fleet tactics into disarray. The question of how an ironclad fleet should deploy in battle to make best use of the ram was never tested in battle, and if it had been, combat might have shown that rams could only be used against ships which were already stopped dead in the water.


title: Ironclad warship

text: The ram finally fell out of favour in the 1880s, as the same effect could be achieved with a torpedo, with less vulnerability to quick-firing guns.


title: Ironclad warship

text: The armament of ironclads tended to become concentrated in a small number of powerful guns capable of penetrating the armor of enemy ships at range; calibre and weight of guns increased markedly to achieve greater penetration. Throughout the ironclad era navies also grappled with the complexities of rifled versus smoothbore guns and breech-loading versus muzzle-loading.


title: Ironclad warship

text: Breech-loading guns seemed to offer important advantages. A breech-loader could be reloaded without moving the gun, a lengthy process particularly if the gun then needed to be re-aimed. "Warrior"s Armstrong guns also had the virtue of being lighter than an equivalent smoothbore and, because of their rifling, more accurate. Nonetheless, the design was rejected because of problems which plagued breech-loaders for decades.


title: Ironclad warship

text: The weakness of the breech-loader was the obvious problem of sealing the breech. All guns are powered by the explosive conversion of a solid propellant into gas. This explosion propels the shot or shell out of the front of the gun, but also imposes great stresses on the gun-barrel. If the breech—which experiences some of the greatest forces in the gun—is not entirely secure, then there is a risk that either gas will discharge through the breech or that the breech will break. This in turn reduces the muzzle velocity of the weapon and can also endanger the gun crew. "Warrior"s Armstrong guns suffered from both problems; the shells were unable to penetrate the armor of "Gloire", while sometimes the screw which closed the breech flew backwards out of the gun on firing. Similar problems were experienced with the breech-loading guns which became standard in the French and German navies.


title: Ironclad warship

text: These problems influenced the British to equip ships with muzzle-loading weapons of increasing power until the 1880s. After a brief introduction of the 100-pounder or smoothbore Somerset Gun, which weighed , the Admiralty introduced 7-inch (178 mm) rifled guns, weighing . These were followed by a series of increasingly mammoth weapons—guns weighing , , , and finally , with calibre increasing from 8 inches (203 mm) to 16 inches (406 mm).


title: Ironclad warship

text: The decision to retain muzzle-loaders until the 1880s has been criticised by historians. However, at least until the late 1870s, the British muzzle-loaders had superior performance in terms of both range and rate of fire than the French and Prussian breech-loaders, which suffered from the same problems as the first Armstrong guns.


title: Ironclad warship

text: From 1875 onwards, the balance between breech- and muzzle-loading changed. Captain de Bange invented a method of reliably sealing a breech, adopted by the French in 1873. Just as compellingly, the growing size of naval guns and consequently, their ammunition, made muzzle-loading much more complicated. With guns of such size there was no prospect of hauling in the gun for reloading, or even reloading by hand, and complicated hydraulic systems were required for reloading the gun outside the turret without exposing the crew to enemy fire. In 1882, the 81-ton, 16-inch guns of fired only once every 11 minutes while bombarding Alexandria during the Urabi Revolt. The , 450 mm (17.72 inch) guns of the s could each fire a round every 15 minutes.


title: Ironclad warship

text: In the Royal Navy, the switch to breech-loaders was finally made in 1879; as well as the significant advantages in terms of performance, opinion was swayed by an explosion on board caused by a gun being double-loaded, a problem which could only happen with a muzzle-loading gun.


title: Ironclad warship

text: The calibre and weight of guns could only increase so far. The larger the gun, the slower it would be to load, the greater the stresses on the ship's hull, and the less the stability of the ship. The size of the gun peaked in the 1880s, with some of the heaviest calibres of gun ever used at sea. carried two 16.25-inch (413 mm) breech-loading guns, each weighing . A few years afterwards, the Italians used 450 mm (17.72 inch) muzzle-loading guns on the "Duilio" class ships. One consideration which became more acute was that even from the original Armstrong models, following the Crimean War, range and hitting power far exceeded simple accuracy, especially at sea where the slightest roll or pitch of the vessel as 'floating weapons-platform' could negate the advantage of rifling. American ordnance experts accordingly preferred smoothbore monsters whose round shot could at least 'skip' along the surface of the water. Actual effective combat ranges, they had learned during the Civil War, were comparable to those in the Age of Sail—though a vessel could now be smashed to pieces in only a few rounds. Smoke and the general chaos of battle only added to the problem. As a result, many naval engagements in the 'Age of the Ironclad' were still fought at ranges within easy eyesight of their targets, and well below the maximum reach of their ships' guns.


title: Ironclad warship

text: Another method of increasing firepower was to vary the projectile fired or the nature of the propellant. Early ironclads used black powder, which expanded rapidly after combustion; this meant cannons had relatively short barrels, to prevent the barrel itself slowing the shell. The sharpness of the black powder explosion also meant that guns were subjected to extreme stress. One important step was to press the powder into pellets, allowing a slower, more controlled explosion and a longer barrel. A further step forward was the introduction of chemically different brown powder which combusted more slowly again. It also put less stress on the insides of the barrel, allowing guns to last longer and to be manufactured to tighter tolerances.


title: Ironclad warship

text: The development of smokeless powder, based on nitroglycerine or nitrocellulose, by the French inventor Paul Vielle in 1884 was a further step allowing smaller charges of propellant with longer barrels. The guns of the pre-Dreadnought battleships of the 1890s tended to be smaller in calibre compared to the ships of the 1880s, most often 12 in (305 mm), but progressively grew in length of barrel, making use of improved propellants to gain greater muzzle velocity.


title: Ironclad warship

text: The nature of the projectiles also changed during the ironclad period. Initially, the best armor-piercing projectile was a solid cast-iron shot. Later, shot of chilled iron, a harder iron alloy, gave better armor-piercing qualities. Eventually the armor-piercing shell was developed.


title: Ironclad warship

text: The first British, French and Russian ironclads, in a logical development of warship design from the long preceding era of wooden ships of the line, carried their weapons in a single line along their sides and so were called "broadside ironclads". Both and were examples of this type. Because their armor was so heavy, they could only carry a single row of guns along the main deck on each side rather than a row on each deck.


title: Ironclad warship

text: A significant number of broadside ironclads were built in the 1860s, principally in Britain and France, but in smaller numbers by other powers including Italy, Austria, Russia and the United States. The advantages of mounting guns on both broadsides was that the ship could engage more than one adversary at a time, and the rigging did not impede the field of fire.


title: Ironclad warship

text: Broadside armament also had disadvantages, which became more serious as ironclad technology developed. Heavier guns to penetrate ever-thicker armor meant that fewer guns could be carried. Furthermore, the adoption of ramming as an important tactic meant the need for ahead and all-round fire. These problems led to broadside designs being superseded by designs that gave greater all-round fire, which included central-battery, turret, and barbette designs.


title: Ironclad warship

text: There were two main design alternatives to the broadside. In one design, the guns were placed in an armored casemate amidships: this arrangement was called the 'box-battery' or 'centre-battery'. In the other, the guns could be placed on a rotating platform to give them a broad field of fire; when fully armored, this arrangement was called a turret and when partially armored or unarmored, a barbette.


title: Ironclad warship

text: The centre-battery was the simpler and, during the 1860s and 1870s, the more popular method. Concentrating guns amidships meant the ship could be shorter and handier than a broadside type. The first full-scale centre-battery ship was of 1865; the French laid down centre-battery ironclads in 1865 which were not completed until 1870. Centre-battery ships often, but not always, had a recessed freeboard enabling some of their guns to fire directly ahead.


title: Ironclad warship

text: The turret was first used in naval combat on in 1862, with a type of turret designed by the Swedish engineer John Ericsson. A competing turret design was proposed by the British inventor Cowper Coles with a prototype of this installed on in 1861 for testing and evaluation purposes. Ericsson's turret turned on a central spindle, and Coles's turned on a ring of bearings. Turrets offered the maximum arc of fire from the guns, but there were significant problems with their use in the 1860s. The fire arc of a turret would be considerably limited by masts and rigging, so they were unsuited to use on the earlier ocean-going ironclads. The second problem was that turrets were extremely heavy. Ericsson was able to offer the heaviest possible turret (guns and armor protection) by deliberately designing a ship with very low freeboard. The weight thus saved from having a high broadside above the waterline was diverted to actual guns and armor. Low freeboard, however, also meant a smaller hull and therefore a smaller capacity for coal storage—and therefore range of the vessel. In many respects, the turreted, low-freeboard "Monitor" and the broadside sailer HMS "Warrior" represented two opposite extremes in what an 'Ironclad' was all about. The most dramatic attempt to compromise these two extremes, or 'squaring this circle', was designed by Captain Cowper Phipps Coles: , a dangerously low freeboard turret ship which nevertheless carried a full rig of sail, and which subsequently capsized not long after her launch in 1870. Her half-sister was restricted to firing from her turrets only on the port and starboard beams. The third Royal Navy ship to combine turrets and masts was of 1876, which carried two turrets on either side of the centre-line, allowing both to fire fore, aft and broadside.


title: Ironclad warship

text: A lighter alternative to the turret, particularly popular with the French navy, was the barbette. These were fixed armored towers which held a gun on a turntable. The crew was sheltered from direct fire, but vulnerable to plunging fire, for instance from shore emplacements. The barbette was lighter than the turret, needing less machinery and no roof armor—though nevertheless some barbettes were stripped of their armor plate to reduce the top-weight of their ships. The barbette became widely adopted in the 1880s, and with the addition of an armored 'gun-house', transformed into the turrets of the pre-dreadnought battleships.


title: Ironclad warship

text: The ironclad age saw the development of explosive torpedoes as naval weapons, which helped complicate the design and tactics of ironclad fleets. The first torpedoes were static mines, used extensively in the American Civil War. That conflict also saw the development of the spar torpedo, an explosive charge pushed against the hull of a warship by a small boat. For the first time, a large warship faced a serious threat from a smaller one—and given the relative inefficiency of shellfire against ironclads, the threat from the spar torpedo was taken seriously. The U.S. Navy converted four of its monitors to become turretless armored spar-torpedo vessels while under construction in 1864–1865, but these vessels never saw action. Another proposal, the towed or 'Harvey' torpedo, involved an explosive on a line or outrigger; either to deter a ship from ramming or to make a torpedo attack by a boat less suicidal.


title: Ironclad warship

text: A more practical and influential weapon was the self-propelled or Whitehead torpedo. Invented in 1868 and deployed in the 1870s, it formed part of the armament of ironclads of the 1880s like HMS "Inflexible" and the Italian . The ironclad's vulnerability to the torpedo was a key part of the critique of armored warships made by the school of naval thought; it appeared that any ship armored enough to prevent destruction by gunfire would be slow enough to be easily caught by torpedo. In practice, however, the "Jeune Ecole" was only briefly influential and the torpedo formed part of the confusing mixture of weapons possessed by ironclads.


title: Ironclad warship

text: The first ironclads were built on wooden or iron hulls, and protected by wrought iron armor backed by thick wooden planking. Ironclads were still being built with wooden hulls into the 1870s.


title: Ironclad warship

text: Using wrought iron construction for warships offered advantages for the engineering of the hull. However, unarmored iron had many military disadvantages, and offered technical problems which kept wooden hulls in use for many years, particularly for long-range cruising warships.


title: Ironclad warship

text: Iron ships had first been proposed for military use in the 1820s. In the 1830s and 1840s, France, Britain and the United States had all experimented with iron-hulled but unarmored gunboats and frigates. However, the iron-hulled frigate was abandoned by the end of the 1840s, because iron hulls were more vulnerable to solid shot; iron was more brittle than wood, and iron frames more likely to fall out of shape than wood.


title: Ironclad warship

text: The unsuitability of unarmored iron for warship hulls meant that iron was only adopted as a building material for battleships when protected by armor. However, iron gave the naval architect many advantages. Iron allowed larger ships and more flexible design, for instance the use of watertight bulkheads on the lower decks. "Warrior", built of iron, was longer and faster than the wooden-hulled "Gloire". Iron could be produced to order and used immediately, in contrast to the need to give wood a long period of seasoning. And, given the large quantities of wood required to build a steam warship and the falling cost of iron, iron hulls were increasingly cost-effective. The main reason for the French use of wooden hulls for the ironclad fleet built in the 1860s was that the French iron industry could not supply enough, and the main reason why Britain built its handful of wooden-hulled ironclads was to make best use of hulls already started and wood already bought.


title: Ironclad warship

text: Wooden hulls continued to be used for long-range and smaller ironclads, because iron nevertheless had a significant disadvantage. Iron hulls suffered quick fouling by marine life, slowing the ships down—manageable for a European battlefleet close to dry docks, but a difficulty for long-range ships. The only solution was to sheath the iron hull first in wood and then in copper, a laborious and expensive process which made wooden construction remain attractive. Iron and wood were to some extent interchangeable: the Japanese and ordered in 1875 were sister-ships, but one was built of iron and the other of composite construction.


title: Ironclad warship

text: After 1872, steel started to be introduced as a material for construction. Compared to iron, steel allows for greater structural strength for a lower weight. The French Navy led the way with the use of steel in its fleet, starting with the , laid down in 1873 and launched in 1876. "Redoutable" nonetheless had wrought iron armor plate, and part of her exterior hull was iron rather than steel.


title: Ironclad warship

text: Even though Britain led the world in steel production, the Royal Navy was slow to adopt steel warships. The Bessemer process for steel manufacture produced too many imperfections for large-scale use on ships. French manufacturers used the Siemens-Martin process to produce adequate steel, but British technology lagged behind. The first all-steel warships built by the Royal Navy were the dispatch vessels "Iris" and "Mercury", laid down in 1875 and 1876.


title: Ironclad warship

text: Iron-built ships used wood as part of their protection scheme. HMS "Warrior" was protected by 4.5 in (114 mm) of wrought iron backed by 15 in (381 mm) of teak, the strongest shipbuilding wood. The wood played two roles, preventing spalling and also preventing the shock of a hit damaging the structure of the ship. Later, wood and iron were combined in 'sandwich' armor, for instance in HMS "Inflexible".


title: Ironclad warship

text: Steel was also an obvious material for armor. It was tested in the 1860s, but the steel of the time was too brittle and disintegrated when struck by shells. Steel became practical to use when a way was found to fuse steel onto wrought iron plates, giving a form of compound armor. This compound armor was used by the British in ships built from the late 1870s, first for turret armor (starting with HMS "Inflexible") and then for all armor (starting with of 1882). The French and German navies adopted the innovation almost immediately, with licenses being given for the use of the 'Wilson System' of producing fused armor.


title: Ironclad warship

text: The first ironclads to have all-steel armor were the two ships of the Duilio class. Though the ships were laid down in 1873 their armor was not purchased from France until 1877. The French navy decided in 1880 to adopt compound armor for its fleet, but found it limited in supply, so from 1884 the French navy was using steel armor. Britain stuck to compound armor until 1889.


title: Ironclad warship

text: The ultimate ironclad armor was case hardened nickel-steel. In 1890, the U.S. Navy tested steel armor hardened by the Harvey process and found it superior to compound armor. For several years 'Harvey steel' was the state of the art, produced in the U.S., France, Germany, Britain, Austria and Italy. In 1894, the German firm Krupp developed gas cementing, which further hardened steel armor. The German , laid down in 1895, was the first ship to benefit from the new 'Krupp armor' and the new armor was quickly adopted; the Royal Navy using it from , laid down in 1896. By 1901 almost all new battleships used Krupp armor, though the U.S. continued to use Harvey armor alongside until the end of the decade.


title: Ironclad warship

text: The equivalent strengths of the different armor plates was as follows: 15 in (381 mm) of wrought iron was equivalent to 12 in (305 mm) of either plain steel or compound iron and steel armor, and to 7.75 in (197 mm) of Harvey armor or 5.75 in (146 mm) of Krupp armor.


title: Ironclad warship

text: Ironclad construction also prefigured the later debate in battleship design between tapering and 'all-or-nothing' armor design. "Warrior" was only semi-armored, and could have been disabled by hits on the bow and stern. As the thickness of armor grew to protect ships from the increasingly heavy guns, the area of the ship which could be fully protected diminished. "Inflexible"s armor protection was largely limited to the central citadel amidships, protecting boilers and engines, turrets and magazines, and little else. An ingenious arrangement of cork-filled compartments and watertight bulkheads was intended to keep her stable and afloat in the event of damage to her un-armored sections.


title: Ironclad warship

text: The first ocean-going ironclads carried masts and sails like their wooden predecessors, and these features were only gradually abandoned. Early steam engines were inefficient; the wooden steam fleet of the Royal Navy could only carry "5 to 9 days coal", and the situation was similar with the early ironclads. "Warrior" also illustrates two design features which aided hybrid propulsion; she had retractable screws to reduce drag while under sail (though in practice the steam engine was run at a low throttle), and a telescopic funnel which could be folded down to the deck level.


title: Ironclad warship

text: Ships designed for coastal warfare, like the floating batteries of the Crimea, or and her sisters, dispensed with masts from the beginning. The British , started in 1869, was the first large, ocean-going ironclad to dispense with masts. Her principal role was for combat in the English Channel and other European waters; while her coal supplies gave her enough range to cross the Atlantic, she would have had little endurance on the other side of the ocean. The "Devastation" and the similar ships commissioned by the British and Russian navies in the 1870s were the exception rather than the rule. Most ironclads of the 1870s retained masts, and only the Italian navy, which during that decade was focused on short-range operations in the Adriatic, built consistently mastless ironclads.


title: Ironclad warship

text: During the 1860s, steam engines improved with the adoption of double-expansion steam engines, which used 30–40% less coal than earlier models. The Royal Navy decided to switch to the double-expansion engine in 1871, and by 1875 they were widespread. However, this development alone was not enough to herald the end of the mast. Whether this was due to a conservative desire to retain sails, or was a rational response to the operational and strategic situation, is a matter of debate. A steam-only fleet would require a network of coaling stations worldwide, which would need to be fortified at great expense to stop them falling into enemy hands. Just as significantly, because of unsolved problems with the technology of the boilers which provided steam for the engines, the performance of double-expansion engines was rarely as good in practice as it was in theory.


title: Ironclad warship

text: During the 1870s the distinction grew between 'first-class ironclads' or 'battleships' on the one hand, and 'cruising ironclads' designed for long-range work on the other. The demands on first-class ironclads for very heavy armor and armament meant increasing displacement, which reduced speed under sail; and the fashion for turrets and barbettes made a sailing rig increasingly inconvenient. , launched in 1876 but not commissioned until 1881, was the last British battleship to carry masts, and these were widely seen as a mistake. The start of the 1880s saw the end of sailing rig on ironclad battleships.


title: Ironclad warship

text: Sails persisted on 'cruising ironclads' for much longer. During the 1860s, the French navy had produced the and es as small, long-range ironclads as overseas cruisers and the British had responded with ships like of 1870. The Russian ship , laid down in 1870 and completed in 1875, was a model of a fast, long-range ironclad which was likely to be able to outrun and outfight ships like "Swiftsure". Even the later , often described as the first British armored cruiser, would have been too slow to outrun "General-Admiral". While "Shannon" was the last British ship with a retractable propeller, later armored cruisers of the 1870s retained sailing rig, sacrificing speed under steam in consequence. It took until 1881 for the Royal Navy to lay down a long-range armored warship capable of catching enemy commerce raiders, , which was completed in 1888. While sailing rigs were obsolescent for all purposes by the end of the 1880s, rigged ships were in service until the early years of the 20th century.


title: Ironclad warship

text: The final evolution of ironclad propulsion was the adoption of the triple-expansion steam engine, a further refinement which was first adopted in , laid down in 1885 and commissioned in 1891. Many ships also used a forced draught to get additional power from their engines, and this system was widely used until the introduction of the steam turbine in the middle of the first decade of the Twentieth Century.


title: Ironclad warship

text: While ironclads spread rapidly in navies worldwide, there were few pitched naval battles involving ironclads. Most European nations settled differences on land, and the Royal Navy struggled to maintain a deterrent parity with at least France, while providing suitable protection to Britain's commerce and colonial outposts worldwide. Ironclads remained, for the British Royal Navy, a matter of defending the British Isles first and projecting power abroad second. Those naval engagements of the latter half of the 19th century which involved ironclads normally involved colonial actions or clashes between second-rate naval powers. But these encounters were often enough to convince British policy-makers of the increasing hazards of strictly naval foreign intervention, from Hampton Roads in the American Civil War to the hardening combined defences of naval arsenals such as Kronstadt and Cherbourg.


title: Ironclad warship

text: The United Kingdom possessed the largest navy in the world for the whole of the ironclad period. The Royal Navy was the second to adopt ironclad warships, and it applied them worldwide in their whole range of roles. In the age of sail, the British strategy for war depended on the Royal Navy mounting a blockade of the ports of the enemy. Because of the limited endurance of steamships, this was no longer possible, so the British at times considered the risk-laden plan of engaging an enemy fleet in harbor as soon as war broke out. To this end, the Royal Navy developed a series of 'coast-defence battleships', starting with the "Devastation" class. These 'breastwork monitors' were markedly different from the other high-seas ironclads of the period and were an important precursor of the modern battleship. As long-range monitors they could reach Bermuda unescorted, for example. However, they were still armed with only four heavy guns and were as vulnerable to mines and obstructions (and enemy monitors) as the original monitors of the Union Navy proved to be during the Civil War.


title: Ironclad warship

text: The British prepared for an overwhelming mortar bombardment of Kronstadt by the close of the Crimean War, but never considered running the smoke-ridden, shallow-water gauntlet straight to St. Petersburg with ironclads. Likewise, monitors proved acutely unable to 'overwhelm' enemy fortifications single-handed during the American conflict, though their low-profile and heavy armor protection made them ideal for running artillery gauntlets. Mines and obstructions negated these advantages—a problem the British Admiralty frequently acknowledged but never countered throughout the period. The British never laid down enough "Devastation"-class 'battleships' to instantly overwhelm Cherbourg, Kronstadt or even New York City with gunfire. Although throughout the 1860s and 1870s the Royal Navy was still in many respects superior to its potential rivals, by the early 1880s widespread concern about the threat from France and Germany culminated in the Naval Defence Act, which promulgated the idea of a 'two-power standard', that Britain should possess as many ships as the next two navies combined. This standard provoked aggressive shipbuilding in the 1880s and 1890s.


title: Ironclad warship

text: British ships did not participate in any major wars in the ironclad period. The Royal Navy's ironclads only saw action as part of colonial battles or one-sided engagements like the bombardment of Alexandria in 1882. Defending British interests against Ahmed 'Urabi's Egyptian revolt, a British fleet opened fire on the fortifications around the port of Alexandria. A mixture of centre-battery and turret ships bombarded Egyptian positions for most of a day, forcing the Egyptians to retreat; return fire from Egyptian guns was heavy at first, but inflicted little damage, killing only five British sailors. Few Egyptian guns were actually dismounted, on the other hand, and the fortifications themselves were typically left intact. Had the Egyptians actually utilised the heavy mortars that were at their disposal, they might have quickly turned the tide, for the attacking British ironclads found it easy (for accuracy's sake) to simply anchor whilst firing—perfect targets for high-angle fire upon their thinly armored topdecks.


title: Ironclad warship

text: The French navy built the first ironclad to try to gain a strategic advantage over the British, but were consistently out-built by the British. Despite taking the lead with a number of innovations like breech-loading weapons and steel construction, the French navy could never match the size of the Royal Navy. In the 1870s, the construction of ironclads ceased for a while in France as the Jeune Ecole school of naval thought took prominence, suggesting that torpedo boats and unarmored cruisers would be the future of warships. Like the British, the French navy saw little action with its ironclads; the French blockade of Germany in the Franco-Prussian War was ineffective, as the war was settled entirely on land.


title: Ironclad warship

text: Russia built a number of ironclads, generally copies of British or French designs. Nonetheless, there were real innovations from Russia; the first true type of ironclad armored cruiser, "General-Admiral" of the 1870s, and a set of remarkably badly designed circular battleships referred to as 'popovkas' (for Admiral Popov, who conceived the design). The Russian Navy pioneered the wide-scale use of torpedo boats during the Russo-Turkish War of 1877–1878, mainly out of necessity because of the superior numbers and quality of ironclads used by the Turkish navy. Russia expanded her navy in the 1880s and 1890s with modern armored cruisers and battleships, but the ships were manned by inexperienced crews and politically appointed leadership, which enhanced their defeat in the Battle of Tsushima on 27 May 1905.


title: Ironclad warship

text: The US Navy ended the Civil War with about fifty monitor-type coastal ironclads; by the 1870s most of these were laid up in reserve, leaving the United States virtually without an ironclad fleet. Another five large monitors were ordered in the 1870s. The limitations of the monitor type effectively prevented the US from projecting power overseas, and until the 1890s the United States would have come off badly in a conflict with even Spain or the Latin American powers. The 1890s saw the beginning of what became the Great White Fleet, and it was the modern pre-Dreadnoughts and armored cruisers built in the 1890s which defeated the Spanish fleet in the Spanish–American War of 1898. This started a new era of naval warfare.


title: Ironclad warship

text: Ironclads were widely used in South America. Both sides used ironclads in the Chincha Islands War between Spain and the combined forces of Peru and Chile in the early 1860s. The powerful Spanish participated in the Battle of Callao but was unable to inflict significant damage upon the Callao defences. Besides, Peru was able to deploy two locally built ironclads based on American Civil War designs, "Loa" (a wooden ship converted into a casemate ironclad) and (a small monitor armed with a single 68-pdr gun), as well as two British-built ironclads: , a centre-battery ship, and the turret ship . "Numancia", a Spanish ship led by Casto Méndez Núñez, was the first ironclad to circumnavigate the world, arriving in Cádiz on 20 September 1867, and earning the motto: "Enloricata navis que primo terram circuivit" ["First ironclad ship to sail around the world"]). In the War of the Pacific in 1879, both Peru and Chile had ironclad warships, including some of those used a few years previously against Spain. While "Independencia" ran aground early on, the Peruvian ironclad made a great impact against Chilean shipping, delaying Chilean ground invasion by six months. She was eventually caught by two more modern Chilean centre-battery ironclads, and at the Battle of Angamos Point.


title: Ironclad warship

text: Ironclads were also used from the inception of the Imperial Japanese Navy (IJN). (Japanese: 甲鉄, literally "Ironclad", later renamed Azuma 東, "East") had a decisive role in the Naval Battle of Hakodate Bay in May 1869, which marked the end of the Boshin War, and the complete establishment of the Meiji Restoration. The IJN continued to develop its strength and commissioned a number of warships from British and European shipyards, first ironclads and later armored cruisers. These ships engaged the Chinese Beiyang fleet which was superior on paper at least at the Battle of the Yalu River. Thanks to superior short-range firepower, the Japanese fleet came off better, sinking or severely damaging eight ships and receiving serious damage to only four. The naval war was concluded the next year at the Battle of Weihaiwei, where the strongest remaining Chinese ships were surrendered to the Japanese.


title: Ironclad warship

text: There is no clearly defined end to the ironclad, besides the transition from wood hulls to all-metal. Ironclads continued to be used in World War I. Towards the end of the 19th century, the descriptions 'battleship' and 'armored cruiser' came to replace the term 'ironclad'.


title: Ironclad warship

text: The proliferation of ironclad battleship designs came to an end in the 1890s as navies reached a consensus on the design of battleships, producing the type known as the pre-dreadnought. These ships are sometimes covered in treatments of the ironclad warship. The next evolution of battleship design, the dreadnought, is never referred to as an 'ironclad'.


title: Ironclad warship

text: H. G. Wells coined the term "The Land Ironclads" in a short story published in 1903, to describe fictional large armored fighting vehicles moving on pedrail wheels.


title: Time travel claims and urban legends

text: There have been various accounts of persons who allegedly travelled through time reported by the press or circulated on the Internet. These reports have turned out either to be hoaxes or to be based on incorrect assumptions, incomplete information, or interpretation of fiction as fact, many being now recognized as urban legends.


title: Time travel claims and urban legends

text: The Moberly–Jourdain incident, or the Ghosts refers to claims of time travel and hauntings made by Charlotte Anne Moberly (1846–1937) and Eleanor Jourdain (1863–1924). In 1911, Moberly and Jourdain published a book entitled "An Adventure", under the names of "Elizabeth Morison" and "Frances Lamont". Their book describes a visit they made to the "Petit Trianon", a small "château" in the grounds of the Palace of Versailles where they claimed they saw ghosts including Marie Antoinette and others. Their story caused a sensation, and was subject to much ridicule.


title: Time travel claims and urban legends

text: In October 2010, Northern Irish filmmaker George Clarke uploaded a video clip entitled "Chaplin's Time Traveller" to YouTube. The clip analyzes bonus material in a DVD of the Charlie Chaplin film "The Circus". Included in the DVD is footage from the film's Los Angeles premiere at Grauman's Chinese Theatre in 1928. At one point, a woman is seen walking by, holding up an object to her ear. Clarke said that, on closer examination, she was talking into a thin, black device that had appeared to be a "phone". Clarke concluded that the woman was possibly a time traveller. The clip received millions of hits and was the subject of televised news stories.


title: Time travel claims and urban legends

text: Nicholas Jackson, associate editor for "The Atlantic", says the most likely answer is that she was using a portable hearing aid, a technology that was just being developed at the time. Philip Skroska, an archivist at the Bernard Becker Medical Library of Washington University in St. Louis, thought that the woman might have been holding a rectangular ear trumpet. "New York Daily News" writer Michael Sheridan said the device was probably an early hearing aid, perhaps an Acousticon manufactured by Miller Reese Hutchison.


title: Time travel claims and urban legends

text: A photograph from 1941 of genuine authenticity of the re-opening of the South Fork Bridge in Gold Bridge, British Columbia was alleged to show a time traveler. It was claimed that his clothing and sunglasses were of the present day and not of the styles worn in the '40s.


title: Time travel claims and urban legends

text: Further research suggested that the present-day appearance of the man may not have been so new. The style of sunglasses first appeared in the 1920s. On first glance the man is taken by many to be wearing a printed T-shirt, but on closer inspection it seems to be a sweater with a sewn-on emblem, the kind of clothing often worn by sports teams of the period. The shirt is very similar to the one that was used by the Montreal Maroons, an ice hockey team from that era. The remainder of his clothing would appear to have been available at the time, though his clothes are far more casual than those worn by the other individuals in the photograph.


title: Time travel claims and urban legends

text: The "Time Traveling Hipster" became a case study in viral Internet phenomena in museums which was presented at the Museums and the Web 2011 conference in Philadelphia, Pennsylvania.


title: Time travel claims and urban legends

text: A photograph from 1943 of genuine authenticity, showing a scene of holidaymakers on Towan Beach in Newquay, Cornwall, was uploaded to Twitter in November 2018 by multimedia artist Stuart Humphryes, which was alleged by some viewers to show a time traveller operating an anachronistic mobile device, such as a phone. This tweet was picked up by news outlets including Fox News in the US, and various tabloid newspapers in the UK, such as "The Daily Mirror". Fuelled by media websites such as LADbible it gained global coverage via news outlets in Russia, Iran, Taiwan, Hungary, China and Vietnam. amongst others. Humphryes, the original uploader, was quoted in these stories as dismissing the time travel theories, stating that the man in question was probably just rolling a cigarette.


title: Time travel claims and urban legends

text: The story of Rudolph Fentz is an urban legend from the early 1950s and has been repeated since as a reproduction of facts and presented as evidence for the existence of time travel. The essence of the legend is that in New York City in 1951 a man wearing 19th-century clothes was hit by a car. The subsequent investigation revealed that the man had disappeared without a trace in 1876. The items in his possession suggested that the man had traveled through time from 1876 to 1951 directly.


title: Time travel claims and urban legends

text: The folklorist Chris Aubeck investigated the story and found it originated in a science fiction book of the 1950s, "A Voice from the Gallery" by Ralph M. Holland, which had copied the tale from "I'm Scared", a short story by Jack Finney (1911–1995).


title: Time travel claims and urban legends

text: Between 2000 and 2001, an online bulletin board user self-identified as John Titor became popular as he claimed to be a time traveler from 2036 on a military mission. Holding the many-worlds interpretation as correct and consequently every time travel paradox as impossible, he stated that many events which occurred up to his time would indeed occur in this timeline. These included a devastating civil war in the US in 2008 followed by a short nuclear World War III in 2015, which will "kill three billion people".


title: Time travel claims and urban legends

text: In the years following his last posts and disappearance in 2001, the non-fulfilment of his specific predictions made his popularity decrease. Criticism has pointed out flaws in Titor's stories and investigations suggested his character may be a hoax and a creation of two siblings from Florida.


title: Time travel claims and urban legends

text: The story has been retold on numerous web sites, in a book, in the Japanese visual novel/anime "Steins;Gate", and in a play. He may also have been discussed occasionally on the radio show "Coast to Coast AM". In this respect, the Titor story may be unique in terms of broad appeal from an originally limited medium, an Internet discussion board.


title: Time travel claims and urban legends

text: Similar to John Titor, Bob White or Tim Jones sent an unknown number of spam emails onto the internet between 2001 and 2003. The subject of the emails was always the same: that an individual was seeking to find someone who could supply a "Dimensional Warp Generator." In some instances, he claimed to be a time traveler stuck in 2003, and in others he claimed to be seeking the parts only from other time travelers. Several recipients began to respond in kind, claiming to have equipment such as the requested dimensional warp generator. One recipient, Dave Hill, set up an online shop from which the time traveler purchased the warp generator (formerly a Hard Drive Motor), while another Dave charged thousands of dollars for time-travel "courses" before he would sell the requested hardware.


title: Time travel claims and urban legends

text: The name "Bob White" was taken from an alias that the second Dave used when responding (a reference to the "Bobwhites" of Trixie Belden-fame).


title: Time travel claims and urban legends

text: Soon afterward, the time traveler was identified as professional spammer Robert J. Todino (known as "Robby"). Todino's attempts to travel in time were a serious belief, and while he believed he was "perfectly mentally stable," his father was concerned that those replying to his emails had been preying on Todino's psychological problems.


title: Time travel claims and urban legends

text: In his book "Spam Kings", journalist Brian S. McWilliams, who had originally uncovered Todino's identity for "Wired" magazine, revealed that Todino had been previously diagnosed with dissociative disorder and schizophrenia, explaining the psychological problems of which his father had spoken. Todino's time traveller was referenced in the song "Rewind" by jazz trio Groovelily on their 2003 album "Are we there yet?" The song used phrases taken from Todino's emails within its lyrics.


title: Time travel claims and urban legends

text: Andrew Carlssin was supposedly arrested in March 2003 for SEC violations for making 126 high-risk stock trades and being successful on every one. As reported, Carlssin started with an initial investment of $800 and ended with over $350,000,000 which drew the attention of the SEC. Later reports suggest that after his arrest, he submitted a four-hour confession wherein he claimed to be a time traveler from 200 years in the future. He offered to tell investigators such things as the whereabouts of Osama bin Laden and the cure for AIDS in return for a lesser punishment and to be allowed to return to his time craft, although he refused to tell investigators the location or workings of his craft. A mysterious man posted his bail and Carlssin was scheduled for court hearing but was never seen again; records show that he never existed.


title: Time travel claims and urban legends

text: The Carlssin story likely originated as a fictional piece in "Weekly World News", a satirical newspaper, and was later repeated by Yahoo! News, where its fictitious nature became less apparent. It was soon reported by other newspapers and magazines as fact. This in turn drove word-of-mouth spread through email inboxes and internet forums, leading to far more detailed descriptions of events.


title: Time travel claims and urban legends

text: A video uploaded in 2006 shows a Swedish man named Håkan Nordkvist claiming that he had been accidentally transported to 2046 when attempting to fix the sink in his kitchen. There in the future, he immediately met someone who revealed and proved to be himself about 70 years old, and with whom he "had a great time". He filmed a short footage of the two smiling and hugging each other and showing the tattoo they had on their right arms. The story was a marketing campaign promoting the pension plans of the insurance company AMF.


title: Time travel claims and urban legends

text: Some online viewers claimed that an 1860 painting by Austrian artist Ferdinand Georg Waldmüller titled "The Expected One" allegedly depicted a woman holding and staring down at an iPhone while strolling along a path in the countryside. However, art experts debunked these claims and stated that the alleged iPhone the woman was holding in the painting was actually a prayer book.


title: Time travel claims and urban legends

text: In 1995, a man named as Mike “Madman” Marcum reportedly claimed to have built a time-machine in his home. In 1996, he reportedly disappeared (after few days of limelight) and was never heard of again. His tale is also mentioned in audible and SoundCloud.


title: Time travel claims and urban legends

text: "Die Glocke" ("The Bell") is a purported Nazi time machine that was supposedly part of a flying saucer.


title: Time travel claims and urban legends

text: Italian Benedictine monk claimed to have used a time viewer which could film the past without sound called a chronovisor to obtain a photograph of the Crucifixion of Jesus and view scenes from ancient Rome, including a performance of the lost play Thyestes. According to author Paul J. Nahin, a short story by Horace Gold called "The Biography Project" published in "Galaxy Science Fiction" magazine may have influenced Ernetti's claim. According to "Guardian" writer Mark Pilkington, "Ernetti's glory was shortlived. Another magazine revealed that Christ was a reversed image of a postcard from the Santuario dell'Amore Misericordioso, in the town of Collevalenza. More recently, doubt has been cast on his "transcription" of Thyestes, and an apparent deathbed confession has also surfaced."


title: Time travel claims and urban legends

text: In April 2013, the Iranian news agency Fars carried a story claiming a 27-year-old Iranian scientist had invented a time machine that allowed people to see into the future. A few days later, the story was removed, and replaced with a story quoting an Iranian government official that no such device had been registered.


title: Time travel claims and urban legends

text: The Philadelphia Experiment is the name given to a naval military experiment which was supposedly carried out at the Philadelphia Naval Shipyard in Philadelphia, Pennsylvania, USA, sometime around October 28, 1943. It is alleged that the U.S. Navy destroyer escort USS "Eldridge" was to be rendered invisible (or "cloaked") to enemy devices. The experiment is also referred to as Project Rainbow. Some reports allege that the warship travelled back in time for about 10 seconds; however, popular culture has represented far bigger time jumps.


title: Time travel claims and urban legends

text: The story is widely regarded as a hoax. The U.S. Navy maintains that no such experiment occurred, and details of the story contradict well-established facts about the "Eldridge" as well as the known laws of physics.


title: Time travel claims and urban legends

text: The Montauk Project was alleged to be a series of secret United States government projects conducted at Camp Hero or Montauk Air Force Station on Montauk, Long Island, for the purpose of exotic research, including time travel. Jacques Vallée describes allegations of the Montauk Project as an outgrowth of stories about the Philadelphia Experiment.


title: Todd Fisher

text: Todd Emmanuel Fisher (born February 24, 1958) is an American director, cinematographer, producer and actor of television films and documentaries. Fisher is the son of singer Eddie Fisher and actress Debbie Reynolds and brother of actress Carrie Fisher.


title: Todd Fisher

text: He has a professional background in architectural design and sound engineering, with experience designing and building sound stages, recording studios, and television facilities. Fisher is also a business executive; the former CEO, president, CFO, and treasurer of the Debbie Reynolds Hotel & Casino (DRHC), Debbie Reynolds Management Company, Inc., and Debbie Reynolds Resorts, Inc. , he is the CEO and curator of the Hollywood Motion Picture Museum, which is housed at Debbie Reynolds Studios (DR Studios) in North Hollywood and at his ranch.


title: Todd Fisher

text: Fisher was born on February 24, 1958, in Burbank, California, to actors Eddie Fisher and Debbie Reynolds. Fisher's paternal grandparents were Russian-Jewish immigrants, while his mother's ancestry was Protestant, Scots-Irish, and English. Fisher, who was named after his father's best friend, Mike Todd, is the second of two children born to his parents. He is the younger brother of Carrie Fisher (1956-2016).


title: Todd Fisher

text: His parents divorced in 1959. A later marriage between his father and actress Connie Stevens resulted in the births of Fisher's two half-sisters, Joely Fisher and Tricia Leigh Fisher. In 1960, his mother married Harry Karl, a shoe store chain owner. His mother and stepfather divorced in 1973, when Fisher was 15 years old.


title: Todd Fisher

text: Fisher attended Beverly Hills High School, graduating in 1976. Following high school graduation, he attended the Southern California Institute of Architecture in Los Angeles.


title: Todd Fisher

text: In 1980, Fisher became a born-again Christian and was subsequently ordained as a minister in 1982. Following his ordination, he founded Hiding Place Church, along with musician Henry Cutrona of Christian country rock band Gentle Faith. A non-denominational, charismatic congregation, the church first met in North Hollywood at his mother's DR Studios. After outgrowing that location, the church was moved to Beverly Theater in Beverly Hills. By 1986, the church had relocated from that location to Emerson Middle School in Westwood, Los Angeles, California with an average Sunday attendance of 1,000.


title: Todd Fisher

text: On February 15, 1981, Fisher married his high school sweetheart, Donna Freberg, daughter of Stan Freberg. After the couple's divorce, Fisher married Christi Zabel. With their marriage, Fisher became stepfather to Vanessa, James, and Brandon, Rivers' children from her marriage to singer Johnny Rivers. Zabel died from cancer in 2008. Fisher then married actress-businessperson Catherine Hickland on December 22, 2012. The couple have a home in Las Vegas and a ranch in California.


title: Todd Fisher

text: Fisher's involvement in the entertainment industry began when he was an infant with his appearance in documentaries and short films about his mother. During his youth, Fisher began showing an interest in the technical aspects of filmmaking and focused his efforts on shooting commercials, short films, and documentaries. He was one of the youngest members of the International Alliance of Theatrical Stage Employees (IATSE) labor union. As an adult, his technical and creative experience in professional technical and creative experience began in the 1980s. Fisher is a member of the American Society of Cinematographers.


title: Todd Fisher

text: In the early 1980s, Fisher worked with Trinity Broadcasting Network, where he wrote, produced and directed the comedy television program "Nightlight", starring as satirical television evangelist, Reverend Hype. The show was modeled on the NBC program "Saturday Night Live" and featured actors and comedians such as Dan Aykroyd, Jerry Houser, Miguel Ferrer, Rene Russo, and Bernie Leadon.


title: Todd Fisher

text: In 1970, Fisher's mother began curating a large collection of Hollywood memorabilia starting with purchasing items from the Metro-Goldwyn-Mayer auction that same year. She spent $180,000, which accounted for the purchase of thousands of items, serving as the beginning of her ownership of movie memorabilia. In 1972, she established the Hollywood Motion Picture Museum (HMPM) as a federally tax-exempt corporation. The museum has been recognized as the largest individual collection of Hollywood memorabilia in the world.


title: Todd Fisher

text: In 1992, Reynolds and her husband Richard Hamlett bought the Paddlewheel Hotel & Casino on the Las Vegas Strip for $2.2 million at auction. The purchase was made in anticipation of spending $15 million on renovations, which included plans for establishing a home for the Hollywood Motion Picture Museum. The Paddlewheel Hotel & Casino reopened in 1993, renamed The Debbie Reynolds Hotel & Casino. In 1994, Fisher designed the hotel and casino's 500-seat showroom, where Reynolds performed her nightclub act, songs from her career of over 50 years in the entertainment industry. The showroom also serves as a complete television production studio. In addition to the showroom, Fisher also conceived and designed the Hollywood Motion Picture Museum. When Reynolds struggled with the financing to complete the project, she decided to take the company public in order to raise funds. When the museum celebrated its opening the following year, it was one of the first sites in the United States to exhibit high-definition video projection.


title: Todd Fisher

text: In March 1994, Fisher was appointed the chief financial officer and treasurer of the Debbie Reynolds Hotel & Casino, joining his mother, who served as chairman and secretary with both holding seats on the board of directors. When he assumed the role of CFO, it became evident that the hotel and casino was losing money each month, due to the company's poor capital structure and unsuccessful lease with the casino operator. Debbie eventually won a $10 million judgment in court against her former husband Richard Hamlett, in part for spurious financial dealing with the hotel and her personally. Additional board members of the Hollywood Museum have included Carrie Fisher, director George Lucas, Shirley MacLaine, and Elizabeth Taylor.


title: Todd Fisher

text: Upon assuming the role of CEO, Fisher began restructuring the company, in order to address financial mismanagement, diminished employee morale, and poor customer service and quality throughout the hotel, casino, and restaurant. Prior to March 31, 1996, Jackpot Enterprises contracted with the company to lease space to operate the casino in the hotel. The company gave notice of intent to terminate the lease agreement with Jackpot in February 1996, in accordance with the terms, owing to monthly loss of revenue on a consistent basis. Gambling operations discontinued as of March 31, 1996. By December 31, 1996, the company was in default, unable to make principal and interest payments on their mortgage. Payroll taxes of approximately $1,063,000, along with other accounts payable and accrued liabilities of approximately $3,643,000, were also in default.


title: Todd Fisher

text: In 1997, Fisher began pursuing avenues to sell the property to timeshare developer ILX (now known as Diamond Resorts International) for $16.8 million. After the deal fell through, Debbie Reynolds Hotel & Casino filed Chapter 11 bankruptcy as part of a reorganization plan. The company entered into a $22.5 million merger agreement with CFI (Central Florida Investments), also known as Westgate Resorts, which would have saved the hotel and the public company. The unsecured creditors rejected the deal and opted to auction the property hoping for a better deal. Over the objection of Management, the property was put up for auction the following year, with the winning bid at $10.65 million, going to the World Wrestling Federation.


title: Todd Fisher

text: By 1999, Reynolds and Fisher began preparing to move the Hollywood Motion Picture Museum to a new location near the Kodak Theatre in Los Angeles, which was scheduled to open in 2004. When the Los Angeles museum's lender could no longer fund the project, the museum was unable to complete construction on the property. In turn, they could not repay a $1.6 million bridge loan, which later became the center of a lawsuit filed against the museum by Gregory Orman.


title: Todd Fisher

text: While the lawsuit between the museum and Orman dragged on in the courts, the museum signed a deal to anchor the proposed Belle Island Village tourist attraction, which was scheduled to debut in fall 2008, in Pigeon Forge, Tennessee. When the developer of the Belle Island Village resort met with financial struggles of their own, the construction lender Regions Bank foreclosed on the unfinished property. In response, the museum itself sought Chapter 11 protection in June 2009. The bank initially agreed to sell the resort property to Tennessee Investment Partners, which is partially owned by the real estate investment firm of Matisse Capital, the original developer of the proposed Belle Island Village. The purchase was scheduled to close by the end of March 2010, with assurances that the buyer intended to reinstate the Hollywood Motion Picture Museum as the centerpiece attraction of the new resort. The deal additionally called for agreements for the new investor to cover the lawsuit and financial claim made by Orman. When the sale of the property to Tennessee Investment Partners and subsequent plans to relocate the museum to Tennessee fell through, Reynolds and Fisher began making plans to liquidate the memorabilia collection.


title: Todd Fisher

text: In 2011, Reynolds and Fisher contracted with Profiles in History to begin auctioning the collection of Hollywood memorabilia, until enough proceeds were generated to pay off their creditors. In statements made to the press, Fisher announced that his mother was "heartbroken" to have to auction off her collection, which was valued at $10.79 million in the bankruptcy filing. The collection was sold in a series of auctions from June to December 2011.


title: Todd Fisher

text: On June 18, 2011, Marilyn Monroe's "subway dress", whose skirt is raised by the updraft of a passing subway train in "The Seven Year Itch", sold for $4.6 million, far in excess of pre-auction estimates of $1–2 million. Another Monroe dress, worn in "Gentlemen Prefer Blondes", fetched $1.2 million; it had been expected to go for $200,000 to $300,000. Estimated at $60,000 to $80,000, a blue cotton dress Judy Garland used in test shots for "The Wizard of Oz" went for $910,000. In total, the auction grossed $22.8 million.


title: Todd Fisher

text: In the second auction, held on December 3, 2011, a still-functioning Panavision PSR 35 mm camera used to film "Star Wars" went for $520,000, breaking records for "Star Wars" memorabilia and vintage cameras.


title: President of Brazil

text: The president of Brazil (), officially the president of the Federative Republic of Brazil () or simply the "President of the Republic", is the head of state and head of government of Brazil. The president leads the executive branch of the federal government and is the commander-in-chief of the Brazilian Armed Forces.


title: President of Brazil

text: The presidential system was established in 1889, upon the proclamation of the republic in a military coup d'état against Emperor Pedro II. Since then, Brazil has had six constitutions, three dictatorships, and three democratic periods. During the democratic periods, voting has always been compulsory. The Constitution of Brazil, along with several constitutional amendments, establishes the requirements, powers, and responsibilities of the president, their term of office and the method of election.


title: President of Brazil

text: Jair Bolsonaro is the 38th and current president. He was sworn in on 1 January 2019 following the 2018 presidential election. Luiz Inácio Lula da Silva, who previously occupied the presidency from 2003 to 2010, was elected president following the 2022 Brazilian general election and is expected to take up office on 1 January 2023.


title: President of Brazil

text: As a republic with a presidential executive, Brazil grants significant powers to the president, who effectively controls the executive branch, represents the country abroad, and appoints the cabinet and, with the approval of the Senate, the judges for the Supreme Federal Court. The president is also the commander-in-chief of the armed forces.


title: President of Brazil

text: Presidents in Brazil have significant lawmaking powers, exercised either by proposing laws to the National Congress or by using (provisional measures), an instrument with the force of law that the president can enact in cases of urgency and necessity except to make changes to some areas of law (provisional measures cannot be used to change criminal law or electoral law). A provisional measure comes into effect immediately, before Congress votes on it, and remains in force for up to 60 days unless Congress votes to rescind it. The 60-day period can be extended once, up to 120 days. If Congress, on the other hand, votes to approve the provisional measure, it becomes an actual law, with changes decided by the legislative branch. The provisional measure expires at the end of the 60-day period (or the 120-day, in the case of extension), or sooner, if rejected by one of the Houses of Congress.


title: President of Brazil

text: The Constitution of Brazil requires that a president be a native-born citizen of Brazil, at least 35 years of age, a resident of Brazil, in full exercise of their electoral rights, a registered voter, and a member of a political party (write-in or independent candidates are prohibited).


title: President of Brazil

text: The president of Brazil serves for a term of four years, and may be re-elected for a single consecutive term. This two-term limit, however, is not for life—a former president who has served for two consecutive terms may run for the presidency again after at least one term has elapsed.


title: President of Brazil

text: A vice president or other officer who succeeds to the presidency or who serves, albeit briefly, as acting president during a certain presidential term may subsequently be elected or reelected to the presidency only once, as the consecutive term limit already applies. In practice, Brazilian vice-presidents almost always serve as acting president at some point during a presidential term, given that, according to the Constitution, the vice-president becomes acting president during the president's travels abroad.


title: President of Brazil

text: A sitting president (or governor or mayor) who wishes to run for a different office, regardless of the intended jurisdiction or branch of government, must resign from office at least six months before election day.


title: President of Brazil

text: The possibility of reelection was established by the 16th Amendment to the Constitution, in 1997. Before that, presidents had been barred from immediate reelection for all of Brazil's republican history, with the single exception of the latter half of the Vargas Era, from 1937 to 1945. The office was limited to men until the 1937 Constitution.


title: President of Brazil

text: As of 2015, the president receives a monthly salary of R$30,934.70, along with an undisclosed expense account to cover travel, goods and services while in office. Given that in Brazil all private and public sector employees and civil servants receive an additional compensation equivalent to one monthly salary after a year of work (this compensation is known as the "thirteenth salary"), the president receives 13 payments per year, resulting in an annual salary of R$402,151.10.


title: President of Brazil

text: The "Palácio do Planalto" in Brasília is the official workplace of the president and the "Palácio da Alvorada" their official residence. The president is entitled to use its staff and facilities. The "Residência Oficial do Torto", popularly known as "Granja do Torto", is a ranch located on the outskirts of the capital and is used as a country retreat by the president. The "Palácio Rio Negro" in Petrópolis, Rio de Janeiro, is a summer retreat of the president, although used rarely.


title: President of Brazil

text: In addition, the presidency of the republic also maintains the Jaburu Palace in Brasília for use by the vice president of the Republic as his or her official residence.


title: President of Brazil

text: In the 2000s, the federal government decided to establish "Regional Offices of the Presidency of the Republic" in certain key Brazilian cities. Those regional offices are not presidential residences, but they are fully staffed offices ready to receive the president and his ministers at any time, and they function as a presidential workplace when the president is in those cities. The first regional office of the presidency was established in the city of São Paulo, and is located at the Banco do Brasil building at the Paulista Avenue; the building also houses Banco do Brasil's regional headquarters in São Paulo. The presidency of the republic also maintains regional offices in Porto Alegre and in Belo Horizonte.


title: President of Brazil

text: For ground travel, the president uses the presidential state car, which is an armored version of the 2019 Ford Fusion Hybrid built on a Ford CD3 platform. A 1952 Rolls-Royce Silver Wraith is used by the president on ceremonial occasions, such as Independence Day commemorations, state visits and the inauguration of the president-elect. A modified version of the Airbus A319, air force designation VC-1A, is used to transport the president on all medium international flights, for intercontinental flights the president uses a military version of a Airbus A330-200, called KC-30. Two modified Embraer 190 jets, air force designation VC-2, are used for short and medium range presidential travel. When the president is on board, the aircraft receive the call sign "Brazilian Air Force One". Two modified military versions of the Eurocopter Super Puma, air force designation VH-34, are currently used as the main presidential helicopters.


title: President of Brazil

text: The president may be removed from office using one of two procedures. In either case, two-thirds of the Chamber of Deputies must accept charges against the officeholder (impeachment); and if the Senate accepts the investigation, the president is suspended from exercising the functions of office for up to 180 days. In the case of "common criminal offenses", a trial then takes place at the Supreme Federal Court. In the case of "crimes of malversation", which must fall into one of seven broad areas and which is defined in more detail in law, a trial takes place at the Federal Senate. During the trial, the vice president exercises executive power. If the trial does not result in a conviction within 180 days, the president resumes office; a conviction results in removal from office and succession by the vice president. The seven areas are:


title: President of Brazil

text: All presidents of Brazil have borne the title "President of the Republic". That title has been used by all the constitutions of Brazil since the proclamation of the Republic to refer to the head of the Executive Branch. However, from the proclamation of the Republic in 1889 until 1937 the country was officially styled "Republic of the United States of Brazil", and from 1937 to 1967 the country was styled simply "The United States of Brazil", and thus the full title of the presidents of the Republic from 1891 until 1967—that is, from Deodoro da Fonseca's inauguration as President (between 1889 and 1891 he served as Head of the Provisional Government) until the end of Humberto Castello Branco's term in 1967—was "President of the Republic of the United States of Brazil". On 15 March 1967, the country's official name was changed to "Federative Republic of Brazil". On that same date, Arthur da Costa e Silva was sworn in as President succeeding Castello Branco. Since Costa e Silva, therefore, all presidents of Brazil have borne the full title of "President of the Federative Republic of Brazil".


title: CRISPR gene editing

text: CRISPR gene editing (pronounced "crisper") is a genetic engineering technique in molecular biology by which the genomes of living organisms may be modified. It is based on a simplified version of the bacterial CRISPR-Cas9 antiviral defense system. By delivering the Cas9 nuclease complexed with a synthetic guide RNA (gRNA) into a cell, the cell's genome can be cut at a desired location, allowing existing genes to be removed and/or new ones added "in vivo".


title: CRISPR gene editing

text: The technique is considered highly significant in biotechnology and medicine as it enables editing genomes "in vivo" very precisely, cheaply, and easily. It can be used in the creation of new medicines, agricultural products, and genetically modified organisms, or as a means of controlling pathogens and pests. It also has possibilities in the treatment of inherited genetic diseases as well as diseases arising from somatic mutations such as cancer. However, its use in human germline genetic modification is highly controversial. The development of the technique earned Jennifer Doudna and Emmanuelle Charpentier the Nobel Prize in Chemistry in 2020. The third researcher group that shared the Kavli Prize for the same discovery, led by Virginijus Šikšnys, was not awarded the Nobel prize.


title: CRISPR gene editing

text: Working like genetic scissors, the Cas9 nuclease opens both strands of the targeted sequence of DNA to introduce the modification by one of two methods. Knock-in mutations, facilitated via homology directed repair (HDR), is the traditional pathway of targeted genomic editing approaches. This allows for the introduction of targeted DNA damage and repair. HDR employs the use of similar DNA sequences to drive the repair of the break via the incorporation of exogenous DNA to function as the repair template. This method relies on the periodic and isolated occurrence of DNA damage at the target site in order for the repair to commence. Knock-out mutations caused by CRISPR-Cas9 result in the repair of the double-stranded break by means of non-homologous end joining (NHEJ). NHEJ can often result in random deletions or insertions at the repair site, which may disrupt or alter gene functionality. Therefore, genomic engineering by CRISPR-Cas9 gives researchers the ability to generate targeted random gene disruption. Because of this, the precision of genome editing is a great concern. Genomic editing leads to irreversible changes to the genome.


title: CRISPR gene editing

text: While genome editing in eukaryotic cells has been possible using various methods since the 1980s, the methods employed had proved to be inefficient and impractical to implement on a large scale. With the discovery of CRISPR and specifically the Cas9 nuclease molecule, efficient and highly selective editing is now a reality. Cas9 derived from the bacterial species "Streptococcus pyogenes" has facilitated targeted genomic modification in eukaryotic cells by allowing for a reliable method of creating a targeted break at a specific location as designated by the crRNA and tracrRNA guide strands. The ease with which researchers can insert Cas9 and template RNA in order to silence or cause point mutations at specific loci has proved invaluable to the quick and efficient mapping of genomic models and biological processes associated with various genes in a variety of eukaryotes. Newly engineered variants of the Cas9 nuclease have been developed that significantly reduce off-target activity.


title: CRISPR gene editing

text: CRISPR-Cas9 genome editing techniques have many potential applications, including in medicine and agriculture. The use of the CRISPR-Cas9-gRNA complex for genome editing was the AAAS's choice for Breakthrough of the Year in 2015. Many bioethical concerns have been raised about the prospect of using CRISPR for germline editing, especially in human embryos.


title: CRISPR gene editing

text: In the early 2000s, German researchers began developing zinc finger nucleases (ZFNs), synthetic proteins whose DNA-binding domains enable them to create double-stranded breaks in DNA at specific points. ZFNs has a higher precision and the advantage of being smaller than Cas9, but ZFNs are not as commonly used as CRISPR-based methods. In 2010, synthetic nucleases called transcription activator-like effector nucleases (TALENs) provided an easier way to target a double-stranded break to a specific location on the DNA strand. Both zinc finger nucleases and TALENs require the design and creation of a custom protein for each targeted DNA sequence, which is a much more difficult and time-consuming process than that of designing guide RNAs. CRISPRs are much easier to design because the process requires synthesizing only a short RNA sequence, a procedure that is already widely used for many other molecular biology techniques (e.g. creating oligonucleotide primers).


title: CRISPR gene editing

text: Whereas methods such as RNA interference (RNAi) do not fully suppress gene function, CRISPR, ZFNs, and TALENs provide full irreversible gene knockout. CRISPR can also target several DNA sites simultaneously simply by introducing different gRNAs. In addition, the costs of employing CRISPR are relatively low.


title: CRISPR gene editing

text: In 2012 Jennifer Doudna and Emmanuelle Charpentier published their finding that CRISPR-Cas9 could be programmed with RNA to edit genomic DNA, now considered one of the most significant discoveries in the history of biology.


title: CRISPR gene editing

text: , SAGE Labs (part of Horizon Discovery group) had exclusive rights from one of those companies to produce and sell genetically engineered rats and non-exclusive rights for mouse and rabbit models. , Thermo Fisher Scientific had licensed intellectual property from ToolGen to develop CRISPR reagent kits.


title: CRISPR gene editing

text: , patent rights to CRISPR were contested. Several companies formed to develop related drugs and research tools. As companies ramped up financing, doubts as to whether CRISPR could be quickly monetized were raised. In 2014, Feng Zhang of the Broad Institute of MIT and Harvard and nine others were awarded patent number 8697359 over the use of CRISPR–Cas9 gene editing in eukaryotes. Although Charpentier and Doudna (referred to as CVC) were credited for the conception of CRISPR, the Broad Institute was the first to achieve a "reduction to practice" according to patent judges Sally Gardner Lane, James T. Moore and Deborah Katz.


title: CRISPR gene editing

text: The first set of patents was awarded to the Broad team in 2015, prompting attorneys for the CVC group to request the first interference proceeding. In February 2017 the US Patent Office ruled on a patent interference case brought by University of California with respect to patents issued to the Broad Institute, and found that the Broad patents, with claims covering the application of CRISPR-Cas9 in eukaryotic cells, were distinct from the inventions claimed by University of California.


title: CRISPR gene editing

text: Shortly after, University of California filed an appeal of this ruling. In 2019 the second interference dispute was opened. This was in response to patent applications made by CVC that required the appeals board to determine the original inventor of the technology. The USPTO ruled in March 2022 against UC, stating that the Broad Institute were first to file. The decision affected many of the licensing agreements for the CRISPR editing technology that was licensed from UC Berkeley. UC stated its intent to appeal the USPTO's ruling.


title: CRISPR gene editing

text: In March 2017, the European Patent Office (EPO) announced its intention to allow claims for editing all types of cells to Max-Planck Institute in Berlin, University of California, and University of Vienna, and in August 2017, the EPO announced its intention to allow CRISPR claims in a patent application that MilliporeSigma had filed. the patent situation in Europe was complex, with MilliporeSigma, ToolGen, Vilnius University, and Harvard contending for claims, along with University of California and Broad.


title: CRISPR gene editing

text: In July 2018, the ECJ ruled that gene editing for plants was a sub-category of GMO foods and therefore that the CRISPR technique would henceforth be regulated in the European Union by their rules and regulations for GMOs.


title: CRISPR gene editing

text: In October 2020, researchers Emmanuelle Charpentier and Jennifer Doudna were awarded the Nobel Prize in Chemistry for their work in this field. They made history as the first two women to share this award without a male contributor.


title: CRISPR gene editing

text: In June 2021, the first, small clinical trial of intravenous CRISPR gene editing in humans concludes with promising results.


title: CRISPR gene editing

text: In September 2021, the first CRISPR-edited food has gone on public sale in Japan. Tomatoes were genetically modified for around five times the normal amount of possibly calming GABA. CRISPR was first applied in tomatoes in 2014.


title: CRISPR gene editing

text: In December 2021, it was reported that the first CRISPR-gene-edited marine animal/seafood and second set of CRISPR-edited food has gone on public sale in Japan: two fish of which one species grows to twice the size of natural specimens due to disruption of leptin, which controls appetite, and the other grows to 1.2 the natural average size with the same amount of food due to disabled myostatin, which inhibits muscle growth.


title: CRISPR gene editing

text: A 2022 study has found that knowing more about CRISPR tomatoes had a strong effect on the participants' preference. "Almost half of the 32 participants from Germany who are scientists demonstrated constant choices, while the majority showed increased willingness to buy CRISPR tomatoes, mostly non-scientists."


title: CRISPR gene editing

text: CRISPR-Cas9 genome editing is carried out with a Type II CRISPR system. When utilized for genome editing, this system includes Cas9, crRNA, and tracrRNA along with an optional section of DNA repair template that is utilized in either non-homologous end joining (NHEJ) or homology directed repair (HDR).


title: CRISPR gene editing

text: CRISPR-Cas9 often employs a plasmid to transfect the target cells. The main components of this plasmid are displayed in the image and listed in the table. The crRNA is uniquely designed for each application, as this is the sequence that Cas9 uses to identify and directly bind to specific sequences within the host cell's DNA. The crRNA must bind only where editing is desired. The repair template is also uniquely designed for each application, as it must complement to some degree the DNA sequences on either side of the cut and also contain whatever sequence is desired for insertion into the host genome.


title: CRISPR gene editing

text: Multiple crRNAs and the tracrRNA can be packaged together to form a single-guide RNA (sgRNA). This sgRNA can be included alongside the gene that codes for the Cas9 protein and made into a plasmid in order to be transfected into cells. Many online tools are available to aid in designing effective sgRNA sequences.


title: CRISPR gene editing

text: CRISPR-Cas9 offers a high degree of fidelity and relatively simple construction. It depends on two factors for its specificity: the target sequence and the protospacer adjacent motif (PAM) sequence. The target sequence is 20 bases long as part of each CRISPR locus in the crRNA array. A typical crRNA array has multiple unique target sequences. Cas9 proteins select the correct location on the host's genome by utilizing the sequence to bond with base pairs on the host DNA. The sequence is not part of the Cas9 protein and as a result is customizable and can be independently synthesized.


title: CRISPR gene editing

text: The PAM sequence on the host genome is recognized by Cas9. Cas9 cannot be easily modified to recognize a different PAM sequence. However, this is ultimately not too limiting, as it is typically a very short and nonspecific sequence that occurs frequently at many places throughout the genome (e.g. the SpCas9 PAM sequence is 5'-NGG-3' and in the human genome occurs roughly every 8 to 12 base pairs).


title: CRISPR gene editing

text: Once these sequences have been assembled into a plasmid and transfected into cells, the Cas9 protein with the help of the crRNA finds the correct sequence in the host cell's DNA and – depending on the Cas9 variant – creates a single- or double-stranded break at the appropriate location in the DNA.


title: CRISPR gene editing

text: Properly spaced single-stranded breaks in the host DNA can trigger homology directed repair, which is less error-prone than the non-homologous end joining that typically follows a double-stranded break. Providing a DNA repair template allows for the insertion of a specific DNA sequence at an exact location within the genome. The repair template should extend 40 to 90 base pairs beyond the Cas9-induced DNA break. The goal is for the cell's native HDR process to utilize the provided repair template and thereby incorporate the new sequence into the genome. Once incorporated, this new sequence is now part of the cell's genetic material and passes into its daughter cells.


title: CRISPR gene editing

text: Delivery of Cas9, sgRNA, and associated complexes into cells can occur via viral and non-viral systems. Electroporation of DNA, RNA, or ribonucleocomplexes is a common technique, though it can result in harmful effects on the target cells. Chemical transfection techniques utilizing lipids and peptides have also been used to introduce sgRNAs in complex with Cas9 into cells. Nanoparticle-based delivery has also been used for transfection. Types of cells that are more difficult to transfect (e.g., stem cells, neurons, and hematopoietic cells) require more efficient delivery systems, such as those based on lentivirus (LVs), adenovirus (AdV), and adeno-associated virus (AAV).


title: CRISPR gene editing

text: Efficiency of CRISPR-Cas9 has been found to greatly increase when various components of the system including the entire CRISPR/Cas9 structure to Cas9-gRNA complexes delivered in assembled form rather than using transgenics. This has found particular value in genetically modified crops for mass commercialization. Since the host's replication machinery is not needed to produce these proteins, the chance of the recognizing sequence of the sgRNA is almost none, decreasing the chance of off-target effects.


title: CRISPR gene editing

text: Further improvements and variants of the CRISPR-Cas9 system have focused on introducing more control into its use. Specifically, the research aimed at improving this system includes improving its specificity, its efficiency, and the granularity of its editing power. Techniques can further be divided and classified by the component of the system they modify. These include using a different variants or novel creations of the Cas protein, using an altogether different effector protein, modifying the sgRNA, or using an algorithmic approach to identify existing optimal solutions.


title: CRISPR gene editing

text: Specificity is an important aspect to improve the CRISPR-Cas9 system because the off-target effects it generates have serious consequences for the genome of the cell and invokes caution for its use. Minimizing off-target effects is thus maximizing the safety of the system. Novel variations of Cas9 proteins that increase specificity include effector proteins with comparable efficiency and specificity to the original SpCas9 that are able to target the previously untargetable sequences and a variant that has virtually no off-target mutations. Research has also been conducted in engineering new Cas9 proteins, including some that partially replace RNA nucleotides in crRNA with DNA and a structure-guided Cas9 mutant generating procedure that all had reduced off-target effects. Iteratively truncated sgRNAs and highly stabilized gRNAs have been shown to also decrease off-target effects. Computational methods including machine learning have been used to predict the affinity of and create unique sequences for the system to maximize specificity for given targets.


title: CRISPR gene editing

text: Several variants of CRISPR-Cas9 allow gene activation or genome editing with an external trigger such as light or small molecules. These include photoactivatable CRISPR systems developed by fusing light-responsive protein partners with an activator domain and a dCas9 for gene activation, or by fusing similar light-responsive domains with two constructs of split-Cas9, or by incorporating caged unnatural amino acids into Cas9, or by modifying the guide RNAs with photocleavable complements for genome editing.


title: CRISPR gene editing

text: Methods to control genome editing with small molecules include an allosteric Cas9, with no detectable background editing, that will activate binding and cleavage upon the addition of 4-hydroxytamoxifen (4-HT), 4-HT responsive intein-linked Cas9, or a Cas9 that is 4-HT responsive when fused to four ERT2 domains. Intein-inducible split-Cas9 allows dimerization of Cas9 fragments and rapamycin-inducible split-Cas9 system developed by fusing two constructs of split-Cas9 with FRB and FKBP fragments. Other studies have been able to induce transcription of Cas9 with a small molecule, doxycycline. Small molecules can also be used to improve homology directed repair, often by inhibiting the non-homologous end joining pathway. A system with the Cpf1 effector protein was created that is induced by small molecules VE-822 and AZD-7762. These systems allow conditional control of CRISPR activity for improved precision, efficiency, and spatiotemporal control. Spatiotemporal control is a form of removing off-target effects—only certain cells or parts of the organism may need to be modified, and thus light or small molecules can be used as a way to conduct this. Efficiency of the CRISPR-Cas9 system is also greatly increased by proper delivery of the DNA instructions for creating the proteins and necessary reagents.


title: CRISPR gene editing

text: CRISPR also utilizes single base-pair editing proteins to create specific edits at one or two bases in the target sequence. CRISPR/Cas9 was fused with specific enzymes that initially could only change C to T and G to A mutations and their reverse. This was accomplished eventually without requiring any DNA cleavage. With the fusion of another enzyme, the base editing CRISPR-Cas9 system can also edit C to G and its reverse.


title: CRISPR gene editing

text: The clustered regularly interspaced short palindrome repeats (CRISPR)/Cas9 system is a gene-editing technology that can induce double-strand breaks (DSBs) anywhere guide ribonucleic acids (gRNA) can bind with the protospacer adjacent motif (PAM) sequence. Single-strand nicks can also be induced by Cas9 active-site mutants, also known as Cas9 nickases. By simply changing the sequence of gRNA, the Cas9-endonuclease can be delivered to a gene of interest and induce DSBs. The efficiency of Cas9-endonuclease and the ease by which genes can be targeted led to the development of CRISPR-knockout (KO) libraries both for mouse and human cells, which can cover either specific gene sets of interest or the whole-genome. CRISPR screening helps scientist to create a systematic and high-throughput genetic perturbation within live model organisms. This genetic perturbation is necessary for fully understanding gene function and epigenetic regulation. The advantage of pooled CRISPR libraries is that more genes can be targeted at once.


title: CRISPR gene editing

text: Knock-out libraries are created in a way to achieve equal representation and performance across all expressed gRNAs and carry an antibiotic or fluorescent selection marker that can be used to recover transduced cells. There are two plasmid systems in CRISPR/Cas9 libraries. First, is all in one plasmid, where sgRNA and Cas9 are produced simultaneously in a transfected cell. Second, is a two-vector system: sgRNA and Cas9 plasmids are delivered separately. It's important to deliver thousands of unique sgRNAs-containing vectors to a single vessel of cells by viral transduction at low multiplicity of infection (MOI, typically at 0.1-0.6), it prevents the probability that an individual cell clone will get more than one type of sgRNA otherwise it can lead to incorrect assignment of genotype to phenotype.


title: CRISPR gene editing

text: Once pooled library is prepared it is necessary to carry out a deep sequencing (NGS, next generation sequencing) of PCR-amplifed plasmid DNA in order to reveal abundance of sgRNAs. Cells of interest can be consequentially infected by the library and then selected according to the phenotype. There are 2 types of selection: negative and positive. By negative selection dead or slow growing cells are efficiently detected. It can identify survival-essential genes, which can be further serve as candidates for molecularly targeted drugs. On the other hand, positive selection gives a collection of growth-advantage acquired populations by random mutagenesis. After selection genomic DNA is collected and sequenced by NGS. Depletion or enrichment of sgRNAs is detected and compared to the original sgRNA library, annotated with the target gene that sgRNA corresponds to. Statistical analysis then identify genes that are significantly likely to be relevant to the phenotype of interest.


title: CRISPR gene editing

text: Apart from knock-out there are also knock-down (CRISPRi) and activation (CRISPRa) libraries, which using the ability of proteolytically deactivated Cas9-fusion proteins (dCas9) to bind target DNA, which means that gene of interest is not cut but is over-expressed or repressed. It made CRISPR/Cas9 system even more interesting in gene editing. Inactive dCas9 protein modulate gene expression by targeting dCas9-repressors or activators toward promoter or transcriptional start sites of target genes. For repressing genes Cas9 can be fused to KRAB effector domain that makes complex with gRNA, whereas CRISPRa utilizes dCas9 fused to different transcriptional activation domains, which are further directed by gRNA to promoter regions to upregulate expression.


title: CRISPR gene editing

text: Cas9 genomic modification has allowed for the quick and efficient generation of transgenic models within the field of genetics. Cas9 can be easily introduced into the target cells along with sgRNA via plasmid transfection in order to model the spread of diseases and the cell's response to and defense against infection. The ability of Cas9 to be introduced "in vivo" allows for the creation of more accurate models of gene function and mutation effects, all while avoiding the off-target mutations typically observed with older methods of genetic engineering.


title: CRISPR gene editing

text: The CRISPR and Cas9 revolution in genomic modeling does not extend only to mammals. Traditional genomic models such as "Drosophila melanogaster", one of the first model organisms, have seen further refinement in their resolution with the use of Cas9. Cas9 uses cell-specific promoters allowing a controlled use of the Cas9. Cas9 is an accurate method of treating diseases due to the targeting of the Cas9 enzyme only affecting certain cell types. The cells undergoing the Cas9 therapy can also be removed and reintroduced to provide amplified effects of the therapy.


title: CRISPR gene editing

text: CRISPR-Cas9 can be used to edit the DNA of organisms "in vivo" and to eliminate individual genes or even entire chromosomes from an organism at any point in its development. Chromosomes that have been successfully deleted "in vivo" using CRISPR techniques include the Y chromosome and X chromosome of adult lab mice and human chromosomes 14 and 21, in embryonic stem cell lines and aneuploid mice respectively. This method might be useful for treating genetic disorders caused by abnormal numbers of chromosomes, such as Down syndrome and intersex disorders.


title: CRISPR gene editing

text: Successful "in vivo" genome editing using CRISPR-Cas9 has been shown in numerous model organisms, including "Escherichia coli", "Saccharomyces cerevisiae", "Candida albicans, Methanosarcina acetivorans", "Caenorhabditis elegans", "Arabidopsis" spp., "Danio rerio", and "Mus musculus". Successes have been achieved in the study of basic biology, in the creation of disease models, and in the experimental treatment of disease models.


title: CRISPR gene editing

text: Concerns have been raised that off-target effects (editing of genes besides the ones intended) may confound the results of a CRISPR gene editing experiment (i.e. the observed phenotypic change may not be due to modifying the target gene, but some other gene). Modifications to CRISPR have been made to minimize the possibility of off-target effects. Orthogonal CRISPR experiments are often recommended to confirm the results of a gene editing experiment.


title: CRISPR gene editing

text: CRISPR simplifies the creation of genetically modified organisms for research which mimic disease or show what happens when a gene is knocked down or mutated. CRISPR may be used at the germline level to create organisms in which the targeted gene is changed everywhere (i.e. in all cells/tissues/organs of a multicellular organism), or it may be used in non-germline cells to create local changes that only affect certain cell populations within the organism.