What is Litecoin? | A Beginner’s Guide

What is Litecoin?

Litecoin (LTC) is a decentralized peer-to-peer cryptocurrency that was released on October 7th, 2011 and went live on October 13th, 2011.

The silver to Bitcoins gold.

Bitcoins little brother that doesnt get out much.

These are just a few of the things you might hear being tossed around when talking about Litecoin. At a first glance, Litecoin doesnt garner much respect as a top 10 market cap cryptocurrency.

However, once you get into the weeds, Litecoin presents an extremely useful and interesting application of the original Bitcoin blockchain.

For all the flak Litecoin gets, its easy to overlook what it actually is, and what functions it serves.

Litecoin was founded by former Google employee Charlie Lee. It was one of the first forks of the Bitcoin core client. It was proposed as a solution to some of the bottlenecks and scalability issues with Bitcoin, most notably the number of transactions that could be processed within a given time.

The edge Litecoin has over Bitcoin is that the payment transaction costs are extremely low, and it is capable of facilitating payments around 4x as fast.

Litecoin originally started gathering attention during its explosive growth in November 2013, where it saw a near 15x spike in price. This jump in price, however, was short-lived and Litecoin hovered around the $4 per LTC range for about two years. It wasnt until May 2017 that it started to pick up steam again during a time where generally all cryptocurrencies experienced massive growth.

Litecoin has also been relatively innovative, adopting new technologies such as Segregated Witness and carrying out the first Lightning Network transaction that sent 0.00000001 LTC from Zurich, Switzerland to San Francisco, USA in under a single second.

Theres a reason Litecoin receives a lot of comparisons to Bitcoin. Except for a handful of minor distinctions, Litecoin serves the exact same purpose as Bitcoin. After all, it was one of the first Bitcoin forks.

Comparing Litecoin to Bitcoin not only makes sense from a convenience point of view, it also lets us zone in what makes it different at a technological level. Litecoin is meant to be used as peer-to-peer cryptocurrency and is actually able to accomplish the same job Bitcoin does at a faster and cheaper rate.

Transaction confirmation speed plays a huge role in how quickly a currency gets adopted. Bitcoin confirmations usually take around ten minutes and have been steadily increasing with periods hitting as high as 2,548 minutes. Litecoins network is able to confirm transactions at a much quicker rate.

Litecoins verification period lasts a fixed 2.5 minutes. For every individual Bitcoin block that gets confirmed, four Litecoin blocks of equal size get confirmed.

The cost of sending any denomination of Litecoin costs around $0.09, whereas Bitcoin currently hovers around $5.00. This is an immediate advantage Litecoin has over Bitcoin for small transactions, since splitting a $10 Uber with a friend doesnt make sense for most people if you have to pay $5.00 on top of that. Litecoin offers the option to pay for everyday goods without high fees that will start add up very quickly.

One of Litecoins goals is to distribute hash power more evenly than Bitcoins network. The problem that Litecoins founder Charlie Lee wanted to address was how Bitcoins hash power was largely distributed among mining pools, groups of miners, and generally a much smaller (and less decentralized) subset of miners. Litecoin aims to keep the hashing power decentralized.

Litecoins mining also keeps transaction fees relatively low due to the inherently higher total supply. There can only be 21 million Bitcoins existence, whereas there can be up to 84 million Litecoins. This matters because it makes mining less competitive, and the more competitive mining gets, the higher the transaction fees.

Whereas Bitcoin is near hitting some pretty serious scalability issues due to its high transaction fees, Litecoin is able to churn out block after block and retain its lower transaction costs. Granted, not as many people are using Litecoin as they are Bitcoin and Litecoin could theoretically end up dealing with the same scalability issues if it were to experience proportionate growth and usage, but that simply just isnt the case today.

Litecoin also uses the Scrypt hashing algorithm that utilizes much less processing power than the Bitcoin SHA256 hashing algorithm. Placing a higher emphasis on utilizing high-speed RAM, Litecoin makes it much less possible for a single player (or small collective group of big players) to dominate the mining world.

Fundamental Non-Technical Differences

Its important to also look at the differences in how both Bitcoin and Litecoin came about.

Bitcoins founders origins are relatively shrouded in mystery. Satoshi Nakamoto, the pseudonym of Bitcoins founder, is essentially relegated to legend and myth.

Litecoins founder, on the other hand, has been publicly available and active in the community. You can find Charlie Lee on Linkedin or on Twitter, as @SatoshiLite. After working at Google and founding Litecoin, he also worked on the engineering side at Coinbase, one of the largest cryptocurrency exchanges in the world.

Personally, I much rather prefer Lees accessible and open nature to the mysterious secretive Satoshi, and the fact that Lee is capable of making light (Lite) of the situation is very humanizing.

Additionally, youd be hard pressed to find any serious claims or illusions of grandeur within the Litecoin camp. Its meant to make cryptocurrency accessible and usable for everyone, and is perfectly fine with taking a back-seat role to Bitcoin.

Well, the fact that Litecoin can hold its own weight when it comes to having a legitimate use case says a lot, especially in a cryptocurrency world with over 700+ alt-coins with dubious purposes.

It does, after all, hold a market cap of upwards of $3 billion. That doesnt just happen by dumb luck.

When compared to Bitcoin, which has a market cap about 33x bigger, Litecoin does pose several advantages. As listed above, its capable of offering users lower transaction fees, faster transaction processing times, a more decentralized mining network, and its founder even throws out the occasional zinger on Twitter. These advantages technically make Litecoin a better coin for the vast majority of small transactions.

However, to be fair, Litecoin hasnt been pushed to its limits because there simply arent that many people using it. For the time being, Litecoin does exactly what it was created to do: offer low-cost, speedy transactions in a way that Bitcoin couldnt.

As is, Litecoin is simply another cryptocurrency that just so happened to prove its use case as a low-cost decentralized peer-to-peer payment method.

Litecoin was never made to go head to head with Bitcoin, but its technological advantages do pose somewhat of a threat. While it might be theoretically better than Bitcoin, Bitcoin has already run off with the network effect of having rapidly onboarded a much larger and active user base.

Bitcoin also has the benefit of being a near household name by now, whereas Litecoin is much more obscure (especially with hot new tokens on the block like Ethereum). The vast majority of people who jump into the cryptocurrency world will buy Bitcoin first, and if their hunger isnt satiated, maybe some Litecoin and Ethereum.

While Litecoin seems to function very well for what its meant for, its interesting to postulate ideas about situations where it could experience massive user adoption and growth. There isnt much meat on the bones of whatever Litecoin loyalists are chewing on, but its worth noting that it could only be a matter of time before more people start to add Litecoin into their portfolios.

If, and this is a big IF, Bitcoin isnt able to address its scalability issues, Litecoin will be there to at least offer the same utility without having to pay high (and if Bitcoin reaches the climax of its scalability problems extremely high) fees.

Until then, Litecoin will likely hang around the top 10 market-cap cryptocurrencies, doing the same thing it always has.

Related

Excerpt from:

What is Litecoin? | A Beginner’s Guide

Litecoin – Wikipedia

Litecoin

Official Litecoin logo

Litecoin (LTC or [4]) is a peer-to-peer cryptocurrency and open source software project released under the MIT/X11 license.[5] Creation and transfer of coins is based on an open source cryptographic protocol and is not managed by any central authority.[5][6] Litecoin was an early bitcoin spinoff or altcoin, starting in October 2011.[7] In technical details, litecoin is nearly identical to Bitcoin.

Litecoin was released via an open-source client on GitHub on October 7, 2011 by Charlie Lee, a Google employee and former Engineering Director at Coinbase.[8][9][10] The Litecoin network went live on October 13, 2011.[11] It was a fork of the Bitcoin Core client, differing primarily by having a decreased block generation time (2.5 minutes), increased maximum number of coins, different hashing algorithm (scrypt, instead of SHA-256), and a slightly modified GUI.[12]

During the month of November 2013, the aggregate value of Litecoin experienced massive growth which included a 100% leap within 24 hours.[13]

Litecoin reached a $1 billion market capitalization in November 2013.[14]

In May 2017, Litecoin became the first of the top 5 (by market cap) cryptocurrencies to adopt Segregated Witness.[15] Later in May of the same year, the first Lightning Network transaction was completed through Litecoin, transferring 0.00000001 LTC from Zrich to San Francisco in under one second.[16]

Litecoin is different in some ways from Bitcoin.

Due to Litecoin’s use of the scrypt algorithm, FPGA and ASIC devices made for mining Litecoin are more complicated to create and more expensive to produce than they are for Bitcoin, which uses SHA-256.[19]

Original post:

Litecoin – Wikipedia

Litecoin Definition | Investopedia

DEFINITION of ‘Litecoin’

Launched in the year 2011, Litecoin is an alternative cryptocurrency based on the model of Bitcoin. Litecoin was created by an MIT graduate and former Google engineer named Charlie Lee. Litecoin is based on an open source global payment network that is not controlled by any central authority. Litecoin differs from Bitcoins in aspects like faster block generation rate and use of scrypt as a proof of work scheme.

Litecoins were launched with the aim of being the “silver” to Bitcoin’s “gold,” and have gained much popularity since the time of inception. Litecoin is a peer-to-peer internet currency. It is a fully decentralized open source, global payment network. Litecoin was developed with the aim to improve on Bitcoin’s shortcomings, and has earned industry support along with high trade volume and liquidity over the years. The broader differences between the two cryptocurrencies are listed in the table below.

Bitcoin

Litecoin

Creation

2009

2011

Creator

Satoshi Nakamoto

Charles Lee

Coin Limit

21 Million

84 Million

Block Generation Time

10 Minutes

2.5 Minutes

Algorithm

SHA-256

Scrypt

Initial Reward

50 BTC

50 LTC

Current Block Reward (as of June 2014)

25 BTC

50 LTC

Rewards

Halved every 210,000 blocks

Halved every 840,000 blocks

Difficulty Retarget

2016 Block

2016 Block

Litecoin is designed to produce four times as many blocksas Bitcoin (1 new block every 2.5 minutes to Bitcoin’s 10), and it also allows for 4x the coin limit, making its main appeal over Bitcoin to do with speed and ease of acquisition. However, because Litecoin uses scrypt(as opposed to Bitcoin’sSHA-2)as a proof-of-work algorithm, the use of mining hardware such as ASIC miners or a GPU mining rig requires significantly more processing power.

Litecoin is consistently among the largest cryptocurrenciesinterms of market capitalization (though still remaining far below that of Bitcoin)and it currently has more than 50 million coins in circulation.

More:

Litecoin Definition | Investopedia

Litecoin (LTC) – Live trades, prices and market cap.

Litecoin (LTC) – Live trades, prices and market cap.

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Gene Therapy – Learn.Genetics

APA format:

Genetic Science Learning Center. (2012, December 1) Gene Therapy.Retrieved August 21, 2018, from https://learn.genetics.utah.edu/content/genetherapy/

CSE format:

Gene Therapy [Internet]. Salt Lake City (UT): Genetic Science Learning Center; 2012[cited 2018 Aug 21] Available from https://learn.genetics.utah.edu/content/genetherapy/

Chicago format:

Genetic Science Learning Center. “Gene Therapy.” Learn.Genetics.December 1, 2012. Accessed August 21, 2018. https://learn.genetics.utah.edu/content/genetherapy/.

See the article here:

Gene Therapy – Learn.Genetics

Gene therapy – Wikipedia

In the medicine field, gene therapy (also called human gene transfer) is the therapeutic delivery of nucleic acid into a patient’s cells as a drug to treat disease.[1][2] The first attempt at modifying human DNA was performed in 1980 by Martin Cline, but the first successful nuclear gene transfer in humans, approved by the National Institutes of Health, was performed in May 1989.[3] The first therapeutic use of gene transfer as well as the first direct insertion of human DNA into the nuclear genome was performed by French Anderson in a trial starting in September 1990.

Between 1989 and February 2016, over 2,300 clinical trials had been conducted, more than half of them in phase I.[4]

Not all medical procedures that introduce alterations to a patient’s genetic makeup can be considered gene therapy. Bone marrow transplantation and organ transplants in general have been found to introduce foreign DNA into patients.[5] Gene therapy is defined by the precision of the procedure and the intention of direct therapeutic effect.

Gene therapy was conceptualized in 1972, by authors who urged caution before commencing human gene therapy studies.

The first attempt, an unsuccessful one, at gene therapy (as well as the first case of medical transfer of foreign genes into humans not counting organ transplantation) was performed by Martin Cline on 10 July 1980.[6][7] Cline claimed that one of the genes in his patients was active six months later, though he never published this data or had it verified[8] and even if he is correct, it’s unlikely it produced any significant beneficial effects treating beta-thalassemia.

After extensive research on animals throughout the 1980s and a 1989 bacterial gene tagging trial on humans, the first gene therapy widely accepted as a success was demonstrated in a trial that started on 14 September 1990, when Ashi DeSilva was treated for ADA-SCID.[9]

The first somatic treatment that produced a permanent genetic change was performed in 1993.[citation needed]

Gene therapy is a way to fix a genetic problem at its source. The polymers are either translated into proteins, interfere with target gene expression, or possibly correct genetic mutations.

The most common form uses DNA that encodes a functional, therapeutic gene to replace a mutated gene. The polymer molecule is packaged within a “vector”, which carries the molecule inside cells.

Early clinical failures led to dismissals of gene therapy. Clinical successes since 2006 regained researchers’ attention, although as of 2014[update], it was still largely an experimental technique.[10] These include treatment of retinal diseases Leber’s congenital amaurosis[11][12][13][14] and choroideremia,[15] X-linked SCID,[16] ADA-SCID,[17][18] adrenoleukodystrophy,[19] chronic lymphocytic leukemia (CLL),[20] acute lymphocytic leukemia (ALL),[21] multiple myeloma,[22] haemophilia,[18] and Parkinson’s disease.[23] Between 2013 and April 2014, US companies invested over $600 million in the field.[24]

The first commercial gene therapy, Gendicine, was approved in China in 2003 for the treatment of certain cancers.[25] In 2011 Neovasculgen was registered in Russia as the first-in-class gene-therapy drug for treatment of peripheral artery disease, including critical limb ischemia.[26]In 2012 Glybera, a treatment for a rare inherited disorder, became the first treatment to be approved for clinical use in either Europe or the United States after its endorsement by the European Commission.[10][27]

Following early advances in genetic engineering of bacteria, cells, and small animals, scientists started considering how to apply it to medicine. Two main approaches were considered replacing or disrupting defective genes.[28] Scientists focused on diseases caused by single-gene defects, such as cystic fibrosis, haemophilia, muscular dystrophy, thalassemia, and sickle cell anemia. Glybera treats one such disease, caused by a defect in lipoprotein lipase.[27]

DNA must be administered, reach the damaged cells, enter the cell and either express or disrupt a protein.[29] Multiple delivery techniques have been explored. The initial approach incorporated DNA into an engineered virus to deliver the DNA into a chromosome.[30][31] Naked DNA approaches have also been explored, especially in the context of vaccine development.[32]

Generally, efforts focused on administering a gene that causes a needed protein to be expressed. More recently, increased understanding of nuclease function has led to more direct DNA editing, using techniques such as zinc finger nucleases and CRISPR. The vector incorporates genes into chromosomes. The expressed nucleases then knock out and replace genes in the chromosome. As of 2014[update] these approaches involve removing cells from patients, editing a chromosome and returning the transformed cells to patients.[33]

Gene editing is a potential approach to alter the human genome to treat genetic diseases,[34] viral diseases,[35] and cancer.[36] As of 2016[update] these approaches were still years from being medicine.[37][38]

Gene therapy may be classified into two types:

In somatic cell gene therapy (SCGT), the therapeutic genes are transferred into any cell other than a gamete, germ cell, gametocyte, or undifferentiated stem cell. Any such modifications affect the individual patient only, and are not inherited by offspring. Somatic gene therapy represents mainstream basic and clinical research, in which therapeutic DNA (either integrated in the genome or as an external episome or plasmid) is used to treat disease.

Over 600 clinical trials utilizing SCGT are underway[when?] in the US. Most focus on severe genetic disorders, including immunodeficiencies, haemophilia, thalassaemia, and cystic fibrosis. Such single gene disorders are good candidates for somatic cell therapy. The complete correction of a genetic disorder or the replacement of multiple genes is not yet possible. Only a few of the trials are in the advanced stages.[39]

In germline gene therapy (GGT), germ cells (sperm or egg cells) are modified by the introduction of functional genes into their genomes. Modifying a germ cell causes all the organism’s cells to contain the modified gene. The change is therefore heritable and passed on to later generations. Australia, Canada, Germany, Israel, Switzerland, and the Netherlands[40] prohibit GGT for application in human beings, for technical and ethical reasons, including insufficient knowledge about possible risks to future generations[40] and higher risks versus SCGT.[41] The US has no federal controls specifically addressing human genetic modification (beyond FDA regulations for therapies in general).[40][42][43][44]

The delivery of DNA into cells can be accomplished by multiple methods. The two major classes are recombinant viruses (sometimes called biological nanoparticles or viral vectors) and naked DNA or DNA complexes (non-viral methods).

In order to replicate, viruses introduce their genetic material into the host cell, tricking the host’s cellular machinery into using it as blueprints for viral proteins. Retroviruses go a stage further by having their genetic material copied into the genome of the host cell. Scientists exploit this by substituting a virus’s genetic material with therapeutic DNA. (The term ‘DNA’ may be an oversimplification, as some viruses contain RNA, and gene therapy could take this form as well.) A number of viruses have been used for human gene therapy, including retroviruses, adenoviruses, herpes simplex, vaccinia, and adeno-associated virus.[4] Like the genetic material (DNA or RNA) in viruses, therapeutic DNA can be designed to simply serve as a temporary blueprint that is degraded naturally or (at least theoretically) to enter the host’s genome, becoming a permanent part of the host’s DNA in infected cells.

Non-viral methods present certain advantages over viral methods, such as large scale production and low host immunogenicity. However, non-viral methods initially produced lower levels of transfection and gene expression, and thus lower therapeutic efficacy. Later technology remedied this deficiency.[citation needed]

Methods for non-viral gene therapy include the injection of naked DNA, electroporation, the gene gun, sonoporation, magnetofection, the use of oligonucleotides, lipoplexes, dendrimers, and inorganic nanoparticles.

Some of the unsolved problems include:

Three patients’ deaths have been reported in gene therapy trials, putting the field under close scrutiny. The first was that of Jesse Gelsinger, who died in 1999 because of immune rejection response.[51] One X-SCID patient died of leukemia in 2003.[9] In 2007, a rheumatoid arthritis patient died from an infection; the subsequent investigation concluded that the death was not related to gene therapy.[52]

In 1972 Friedmann and Roblin authored a paper in Science titled “Gene therapy for human genetic disease?”[53] Rogers (1970) was cited for proposing that exogenous good DNA be used to replace the defective DNA in those who suffer from genetic defects.[54]

In 1984 a retrovirus vector system was designed that could efficiently insert foreign genes into mammalian chromosomes.[55]

The first approved gene therapy clinical research in the US took place on 14 September 1990, at the National Institutes of Health (NIH), under the direction of William French Anderson.[56] Four-year-old Ashanti DeSilva received treatment for a genetic defect that left her with ADA-SCID, a severe immune system deficiency. The defective gene of the patient’s blood cells was replaced by the functional variant. Ashantis immune system was partially restored by the therapy. Production of the missing enzyme was temporarily stimulated, but the new cells with functional genes were not generated. She led a normal life only with the regular injections performed every two months. The effects were successful, but temporary.[57]

Cancer gene therapy was introduced in 1992/93 (Trojan et al. 1993).[58] The treatment of glioblastoma multiforme, the malignant brain tumor whose outcome is always fatal, was done using a vector expressing antisense IGF-I RNA (clinical trial approved by NIH protocolno.1602 November 24, 1993,[59] and by the FDA in 1994). This therapy also represents the beginning of cancer immunogene therapy, a treatment which proves to be effective due to the anti-tumor mechanism of IGF-I antisense, which is related to strong immune and apoptotic phenomena.

In 1992 Claudio Bordignon, working at the Vita-Salute San Raffaele University, performed the first gene therapy procedure using hematopoietic stem cells as vectors to deliver genes intended to correct hereditary diseases.[60] In 2002 this work led to the publication of the first successful gene therapy treatment for adenosine deaminase deficiency (ADA-SCID). The success of a multi-center trial for treating children with SCID (severe combined immune deficiency or “bubble boy” disease) from 2000 and 2002, was questioned when two of the ten children treated at the trial’s Paris center developed a leukemia-like condition. Clinical trials were halted temporarily in 2002, but resumed after regulatory review of the protocol in the US, the United Kingdom, France, Italy, and Germany.[61]

In 1993 Andrew Gobea was born with SCID following prenatal genetic screening. Blood was removed from his mother’s placenta and umbilical cord immediately after birth, to acquire stem cells. The allele that codes for adenosine deaminase (ADA) was obtained and inserted into a retrovirus. Retroviruses and stem cells were mixed, after which the viruses inserted the gene into the stem cell chromosomes. Stem cells containing the working ADA gene were injected into Andrew’s blood. Injections of the ADA enzyme were also given weekly. For four years T cells (white blood cells), produced by stem cells, made ADA enzymes using the ADA gene. After four years more treatment was needed.[62]

Jesse Gelsinger’s death in 1999 impeded gene therapy research in the US.[63][64] As a result, the FDA suspended several clinical trials pending the reevaluation of ethical and procedural practices.[65]

The modified cancer gene therapy strategy of antisense IGF-I RNA (NIH n 1602)[59] using antisense / triple helix anti-IGF-I approach was registered in 2002 by Wiley gene therapy clinical trial – n 635 and 636. The approach has shown promising results in the treatment of six different malignant tumors: glioblastoma, cancers of liver, colon, prostate, uterus, and ovary (Collaborative NATO Science Programme on Gene Therapy USA, France, Poland n LST 980517 conducted by J. Trojan) (Trojan et al., 2012). This anti-gene antisense/triple helix therapy has proven to be efficient, due to the mechanism stopping simultaneously IGF-I expression on translation and transcription levels, strengthening anti-tumor immune and apoptotic phenomena.

Sickle-cell disease can be treated in mice.[66] The mice which have essentially the same defect that causes human cases used a viral vector to induce production of fetal hemoglobin (HbF), which normally ceases to be produced shortly after birth. In humans, the use of hydroxyurea to stimulate the production of HbF temporarily alleviates sickle cell symptoms. The researchers demonstrated this treatment to be a more permanent means to increase therapeutic HbF production.[67]

A new gene therapy approach repaired errors in messenger RNA derived from defective genes. This technique has the potential to treat thalassaemia, cystic fibrosis and some cancers.[68]

Researchers created liposomes 25 nanometers across that can carry therapeutic DNA through pores in the nuclear membrane.[69]

In 2003 a research team inserted genes into the brain for the first time. They used liposomes coated in a polymer called polyethylene glycol, which unlike viral vectors, are small enough to cross the bloodbrain barrier.[70]

Short pieces of double-stranded RNA (short, interfering RNAs or siRNAs) are used by cells to degrade RNA of a particular sequence. If a siRNA is designed to match the RNA copied from a faulty gene, then the abnormal protein product of that gene will not be produced.[71]

Gendicine is a cancer gene therapy that delivers the tumor suppressor gene p53 using an engineered adenovirus. In 2003, it was approved in China for the treatment of head and neck squamous cell carcinoma.[25]

In March researchers announced the successful use of gene therapy to treat two adult patients for X-linked chronic granulomatous disease, a disease which affects myeloid cells and damages the immune system. The study is the first to show that gene therapy can treat the myeloid system.[72]

In May a team reported a way to prevent the immune system from rejecting a newly delivered gene.[73] Similar to organ transplantation, gene therapy has been plagued by this problem. The immune system normally recognizes the new gene as foreign and rejects the cells carrying it. The research utilized a newly uncovered network of genes regulated by molecules known as microRNAs. This natural function selectively obscured their therapeutic gene in immune system cells and protected it from discovery. Mice infected with the gene containing an immune-cell microRNA target sequence did not reject the gene.

In August scientists successfully treated metastatic melanoma in two patients using killer T cells genetically retargeted to attack the cancer cells.[74]

In November researchers reported on the use of VRX496, a gene-based immunotherapy for the treatment of HIV that uses a lentiviral vector to deliver an antisense gene against the HIV envelope. In a phase I clinical trial, five subjects with chronic HIV infection who had failed to respond to at least two antiretroviral regimens were treated. A single intravenous infusion of autologous CD4 T cells genetically modified with VRX496 was well tolerated. All patients had stable or decreased viral load; four of the five patients had stable or increased CD4 T cell counts. All five patients had stable or increased immune response to HIV antigens and other pathogens. This was the first evaluation of a lentiviral vector administered in a US human clinical trial.[75][76]

In May researchers announced the first gene therapy trial for inherited retinal disease. The first operation was carried out on a 23-year-old British male, Robert Johnson, in early 2007.[77]

Leber’s congenital amaurosis is an inherited blinding disease caused by mutations in the RPE65 gene. The results of a small clinical trial in children were published in April.[11] Delivery of recombinant adeno-associated virus (AAV) carrying RPE65 yielded positive results. In May two more groups reported positive results in independent clinical trials using gene therapy to treat the condition. In all three clinical trials, patients recovered functional vision without apparent side-effects.[11][12][13][14]

In September researchers were able to give trichromatic vision to squirrel monkeys.[78] In November 2009, researchers halted a fatal genetic disorder called adrenoleukodystrophy in two children using a lentivirus vector to deliver a functioning version of ABCD1, the gene that is mutated in the disorder.[79]

An April paper reported that gene therapy addressed achromatopsia (color blindness) in dogs by targeting cone photoreceptors. Cone function and day vision were restored for at least 33 months in two young specimens. The therapy was less efficient for older dogs.[80]

In September it was announced that an 18-year-old male patient in France with beta-thalassemia major had been successfully treated.[81] Beta-thalassemia major is an inherited blood disease in which beta haemoglobin is missing and patients are dependent on regular lifelong blood transfusions.[82] The technique used a lentiviral vector to transduce the human -globin gene into purified blood and marrow cells obtained from the patient in June 2007.[83] The patient’s haemoglobin levels were stable at 9 to 10 g/dL. About a third of the hemoglobin contained the form introduced by the viral vector and blood transfusions were not needed.[83][84] Further clinical trials were planned.[85] Bone marrow transplants are the only cure for thalassemia, but 75% of patients do not find a matching donor.[84]

Cancer immunogene therapy using modified antigene, antisense/triple helix approach was introduced in South America in 2010/11 in La Sabana University, Bogota (Ethical Committee 14 December 2010, no P-004-10). Considering the ethical aspect of gene diagnostic and gene therapy targeting IGF-I, the IGF-I expressing tumors i.e. lung and epidermis cancers were treated (Trojan et al. 2016).[86][87]

In 2007 and 2008, a man (Timothy Ray Brown) was cured of HIV by repeated hematopoietic stem cell transplantation (see also allogeneic stem cell transplantation, allogeneic bone marrow transplantation, allotransplantation) with double-delta-32 mutation which disables the CCR5 receptor. This cure was accepted by the medical community in 2011.[88] It required complete ablation of existing bone marrow, which is very debilitating.

In August two of three subjects of a pilot study were confirmed to have been cured from chronic lymphocytic leukemia (CLL). The therapy used genetically modified T cells to attack cells that expressed the CD19 protein to fight the disease.[20] In 2013, the researchers announced that 26 of 59 patients had achieved complete remission and the original patient had remained tumor-free.[89]

Human HGF plasmid DNA therapy of cardiomyocytes is being examined as a potential treatment for coronary artery disease as well as treatment for the damage that occurs to the heart after myocardial infarction.[90][91]

In 2011 Neovasculgen was registered in Russia as the first-in-class gene-therapy drug for treatment of peripheral artery disease, including critical limb ischemia; it delivers the gene encoding for VEGF.[92][26] Neovasculogen is a plasmid encoding the CMV promoter and the 165 amino acid form of VEGF.[93][94]

The FDA approved Phase 1 clinical trials on thalassemia major patients in the US for 10 participants in July.[95] The study was expected to continue until 2015.[85]

In July 2012, the European Medicines Agency recommended approval of a gene therapy treatment for the first time in either Europe or the United States. The treatment used Alipogene tiparvovec (Glybera) to compensate for lipoprotein lipase deficiency, which can cause severe pancreatitis.[96] The recommendation was endorsed by the European Commission in November 2012[10][27][97][98] and commercial rollout began in late 2014.[99] Alipogene tiparvovec was expected to cost around $1.6 million per treatment in 2012,[100] revised to $1 million in 2015,[101] making it the most expensive medicine in the world at the time.[102] As of 2016[update], only one person had been treated with drug.[103]

In December 2012, it was reported that 10 of 13 patients with multiple myeloma were in remission “or very close to it” three months after being injected with a treatment involving genetically engineered T cells to target proteins NY-ESO-1 and LAGE-1, which exist only on cancerous myeloma cells.[22]

In March researchers reported that three of five adult subjects who had acute lymphocytic leukemia (ALL) had been in remission for five months to two years after being treated with genetically modified T cells which attacked cells with CD19 genes on their surface, i.e. all B-cells, cancerous or not. The researchers believed that the patients’ immune systems would make normal T-cells and B-cells after a couple of months. They were also given bone marrow. One patient relapsed and died and one died of a blood clot unrelated to the disease.[21]

Following encouraging Phase 1 trials, in April, researchers announced they were starting Phase 2 clinical trials (called CUPID2 and SERCA-LVAD) on 250 patients[104] at several hospitals to combat heart disease. The therapy was designed to increase the levels of SERCA2, a protein in heart muscles, improving muscle function.[105] The FDA granted this a Breakthrough Therapy Designation to accelerate the trial and approval process.[106] In 2016 it was reported that no improvement was found from the CUPID 2 trial.[107]

In July researchers reported promising results for six children with two severe hereditary diseases had been treated with a partially deactivated lentivirus to replace a faulty gene and after 732 months. Three of the children had metachromatic leukodystrophy, which causes children to lose cognitive and motor skills.[108] The other children had Wiskott-Aldrich syndrome, which leaves them to open to infection, autoimmune diseases, and cancer.[109] Follow up trials with gene therapy on another six children with Wiskott-Aldrich syndrome were also reported as promising.[110][111]

In October researchers reported that two children born with adenosine deaminase severe combined immunodeficiency disease (ADA-SCID) had been treated with genetically engineered stem cells 18 months previously and that their immune systems were showing signs of full recovery. Another three children were making progress.[18] In 2014 a further 18 children with ADA-SCID were cured by gene therapy.[112] ADA-SCID children have no functioning immune system and are sometimes known as “bubble children.”[18]

Also in October researchers reported that they had treated six hemophilia sufferers in early 2011 using an adeno-associated virus. Over two years later all six were producing clotting factor.[18][113]

In January researchers reported that six choroideremia patients had been treated with adeno-associated virus with a copy of REP1. Over a six-month to two-year period all had improved their sight.[114][115] By 2016, 32 patients had been treated with positive results and researchers were hopeful the treatment would be long-lasting.[15] Choroideremia is an inherited genetic eye disease with no approved treatment, leading to loss of sight.

In March researchers reported that 12 HIV patients had been treated since 2009 in a trial with a genetically engineered virus with a rare mutation (CCR5 deficiency) known to protect against HIV with promising results.[116][117]

Clinical trials of gene therapy for sickle cell disease were started in 2014.[118][119] There is a need for high quality randomised controlled trials assessing the risks and benefits involved with gene therapy for people with sickle cell disease.[120]

In February LentiGlobin BB305, a gene therapy treatment undergoing clinical trials for treatment of beta thalassemia gained FDA “breakthrough” status after several patients were able to forgo the frequent blood transfusions usually required to treat the disease.[121]

In March researchers delivered a recombinant gene encoding a broadly neutralizing antibody into monkeys infected with simian HIV; the monkeys’ cells produced the antibody, which cleared them of HIV. The technique is named immunoprophylaxis by gene transfer (IGT). Animal tests for antibodies to ebola, malaria, influenza, and hepatitis were underway.[122][123]

In March, scientists, including an inventor of CRISPR, Jennifer Doudna, urged a worldwide moratorium on germline gene therapy, writing “scientists should avoid even attempting, in lax jurisdictions, germline genome modification for clinical application in humans” until the full implications “are discussed among scientific and governmental organizations”.[124][125][126][127]

In October, researchers announced that they had treated a baby girl, Layla Richards, with an experimental treatment using donor T-cells genetically engineered using TALEN to attack cancer cells. One year after the treatment she was still free of her cancer (a highly aggressive form of acute lymphoblastic leukaemia [ALL]).[128] Children with highly aggressive ALL normally have a very poor prognosis and Layla’s disease had been regarded as terminal before the treatment.[129]

In December, scientists of major world academies called for a moratorium on inheritable human genome edits, including those related to CRISPR-Cas9 technologies[130] but that basic research including embryo gene editing should continue.[131]

In April the Committee for Medicinal Products for Human Use of the European Medicines Agency endorsed a gene therapy treatment called Strimvelis[132][133] and the European Commission approved it in June.[134] This treats children born with adenosine deaminase deficiency and who have no functioning immune system. This was the second gene therapy treatment to be approved in Europe.[135]

In October, Chinese scientists reported they had started a trial to genetically modify T-cells from 10 adult patients with lung cancer and reinject the modified T-cells back into their bodies to attack the cancer cells. The T-cells had the PD-1 protein (which stops or slows the immune response) removed using CRISPR-Cas9.[136][137]

A 2016 Cochrane systematic review looking at data from four trials on topical cystic fibrosis transmembrane conductance regulator (CFTR) gene therapy does not support its clinical use as a mist inhaled into the lungs to treat cystic fibrosis patients with lung infections. One of the four trials did find weak evidence that liposome-based CFTR gene transfer therapy may lead to a small respiratory improvement for people with CF. This weak evidence is not enough to make a clinical recommendation for routine CFTR gene therapy.[138]

In February Kite Pharma announced results from a clinical trial of CAR-T cells in around a hundred people with advanced Non-Hodgkin lymphoma.[139]

In March, French scientists reported on clinical research of gene therapy to treat sickle-cell disease.[140]

In August, the FDA approved tisagenlecleucel for acute lymphoblastic leukemia.[141] Tisagenlecleucel is an adoptive cell transfer therapy for B-cell acute lymphoblastic leukemia; T cells from a person with cancer are removed, genetically engineered to make a specific T-cell receptor (a chimeric T cell receptor, or “CAR-T”) that reacts to the cancer, and are administered back to the person. The T cells are engineered to target a protein called CD19 that is common on B cells. This is the first form of gene therapy to be approved in the United States. In October, a similar therapy called axicabtagene ciloleucel was approved for non-Hodgkin lymphoma.[142]

In December the results of using an adeno-associated virus with blood clotting factor VIII to treat nine haemophilia A patients were published. Six of the seven patients on the high dose regime increased the level of the blood clotting VIII to normal levels. The low and medium dose regimes had no effect on the patient’s blood clotting levels.[143][144]

In December, the FDA approved Luxturna, the first in vivo gene therapy, for the treatment of blindness due to Leber’s congenital amaurosis.[145] The price of this treatment was 850,000 US dollars for both eyes.[146][147]

Speculated uses for gene therapy include:

Gene therapy techniques have the potential to provide alternative treatments for those with infertility. Recently, successful experimentation on mice has proven that fertility can be restored by using the gene therapy method, CRISPR.[148] Spermatogenical stem cells from another organism were transplanted into the testes of an infertile male mouse. The stem cells re-established spermatogenesis and fertility.[149]

Athletes might adopt gene therapy technologies to improve their performance.[150] Gene doping is not known to occur, but multiple gene therapies may have such effects. Kayser et al. argue that gene doping could level the playing field if all athletes receive equal access. Critics claim that any therapeutic intervention for non-therapeutic/enhancement purposes compromises the ethical foundations of medicine and sports.[151]

Genetic engineering could be used to cure diseases, but also to change physical appearance, metabolism, and even improve physical capabilities and mental faculties such as memory and intelligence. Ethical claims about germline engineering include beliefs that every fetus has a right to remain genetically unmodified, that parents hold the right to genetically modify their offspring, and that every child has the right to be born free of preventable diseases.[152][153][154] For parents, genetic engineering could be seen as another child enhancement technique to add to diet, exercise, education, training, cosmetics, and plastic surgery.[155][156] Another theorist claims that moral concerns limit but do not prohibit germline engineering.[157]

Possible regulatory schemes include a complete ban, provision to everyone, or professional self-regulation. The American Medical Associations Council on Ethical and Judicial Affairs stated that “genetic interventions to enhance traits should be considered permissible only in severely restricted situations: (1) clear and meaningful benefits to the fetus or child; (2) no trade-off with other characteristics or traits; and (3) equal access to the genetic technology, irrespective of income or other socioeconomic characteristics.”[158]

As early in the history of biotechnology as 1990, there have been scientists opposed to attempts to modify the human germline using these new tools,[159] and such concerns have continued as technology progressed.[160][161] With the advent of new techniques like CRISPR, in March 2015 a group of scientists urged a worldwide moratorium on clinical use of gene editing technologies to edit the human genome in a way that can be inherited.[124][125][126][127] In April 2015, researchers sparked controversy when they reported results of basic research to edit the DNA of non-viable human embryos using CRISPR.[148][162] A committee of the American National Academy of Sciences and National Academy of Medicine gave qualified support to human genome editing in 2017[163][164] once answers have been found to safety and efficiency problems “but only for serious conditions under stringent oversight.”[165]

Regulations covering genetic modification are part of general guidelines about human-involved biomedical research. There are no international treaties which are legally binding in this area, but there are recommendations for national laws from various bodies.

The Helsinki Declaration (Ethical Principles for Medical Research Involving Human Subjects) was amended by the World Medical Association’s General Assembly in 2008. This document provides principles physicians and researchers must consider when involving humans as research subjects. The Statement on Gene Therapy Research initiated by the Human Genome Organization (HUGO) in 2001 provides a legal baseline for all countries. HUGOs document emphasizes human freedom and adherence to human rights, and offers recommendations for somatic gene therapy, including the importance of recognizing public concerns about such research.[166]

No federal legislation lays out protocols or restrictions about human genetic engineering. This subject is governed by overlapping regulations from local and federal agencies, including the Department of Health and Human Services, the FDA and NIH’s Recombinant DNA Advisory Committee. Researchers seeking federal funds for an investigational new drug application, (commonly the case for somatic human genetic engineering,) must obey international and federal guidelines for the protection of human subjects.[167]

NIH serves as the main gene therapy regulator for federally funded research. Privately funded research is advised to follow these regulations. NIH provides funding for research that develops or enhances genetic engineering techniques and to evaluate the ethics and quality in current research. The NIH maintains a mandatory registry of human genetic engineering research protocols that includes all federally funded projects.

An NIH advisory committee published a set of guidelines on gene manipulation.[168] The guidelines discuss lab safety as well as human test subjects and various experimental types that involve genetic changes. Several sections specifically pertain to human genetic engineering, including Section III-C-1. This section describes required review processes and other aspects when seeking approval to begin clinical research involving genetic transfer into a human patient.[169] The protocol for a gene therapy clinical trial must be approved by the NIH’s Recombinant DNA Advisory Committee prior to any clinical trial beginning; this is different from any other kind of clinical trial.[168]

As with other kinds of drugs, the FDA regulates the quality and safety of gene therapy products and supervises how these products are used clinically. Therapeutic alteration of the human genome falls under the same regulatory requirements as any other medical treatment. Research involving human subjects, such as clinical trials, must be reviewed and approved by the FDA and an Institutional Review Board.[170][171]

Gene therapy is the basis for the plotline of the film I Am Legend[172] and the TV show Will Gene Therapy Change the Human Race?.[173] In 1994, gene therapy was a plot element in The Erlenmeyer Flask, The X-Files’ first-season finale. It is also used in Stargate as a means of allowing humans to use Ancient technology.[174]

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Gene therapy – Wikipedia

gene therapy | Encyclopedia.com

Definition

Gene therapy is a rapidly growing field of medicine in which genes are introduced into the body to treat diseases. Genomics is the DNA which is found in an organism’s total set of genes and is passed on to the offspring as information necessary for survival. Genetics is the study of the patterns of inheritance of specific traits. Genes control heredity and provide the basic biological code for determining a cell’s specific functions. Gene therapy seeks to provide genes that correct or supplant the disease-controlling functions of cells that are not performing in a normal manner.

Somatic gene therapy introduces therapeutic genes at the tissue or cellular level to treat a specific individual. Germ-line gene therapy inserts genes into reproductive cells or possibly into embryos to correct genetic abnormalities that could be passed on to future generations. Initially conceived as an approach for treating inherited diseases such as cystic fibrosis and Huntington’s disease, the scope of potential gene therapies has grown to include treatments for cancer, arthritis, and infectious diseases.

In the early 1970s, scientists proposed “gene surgery” for treating inherited diseases caused by abnormally functioning genes. The idea was to take out the disease-causing gene and surgically implant a gene that functioned correctly. Although sound in theory, and after some advances in science, this technique has not yet been successful.

However, in 1983, a group of scientists from Baylor College of Medicine in Houston, Texas, proposed that gene therapy could one day be a viable approach for treating Lesch-Nyhan disease, a rare neurological disorder. The scientists conducted experiments in which an enzyme-producing gene (a specific type of protein) for correcting the disease was injected into a group of cells for replication. The scientists theorized the cells could then be injected into people with Lesch-Nyhan disease, thus correcting the genetic abnormality that caused the disease.

As the science of genetics advanced throughout the 1980s, gene therapy grew in the estimation of medical scientists as a promising approach to treatments for specific diseases. One of the major reasons for the growth of gene therapy was the increasing body of knowledge available to assist in identifying the specific genetic malfunctions that caused inherited diseases. Interest grew as further studies of DNA and chromosomes (where genes reside) showed that specific genetic abnormalities in one or more genes occurred in successive generations of certain family members who experienced diseases like intestinal cancer, manic-depression (bipolar disorder), Alzheimer’s disease, heart disease, diabetes, and many more. Although genes may not be the only cause of the disease in all cases, they may make certain individuals more susceptible to developing a particular condition due to environmental influences such as smoking, pollution, and stress. In fact, some scientists theorize that all diseases may have a genetic component.

Gene therapy has grown out of the science of genetics or how heredity functions. Scientists know that life begins in a cell, the basic building block of all multicellular organisms. Humans, for instance, are made up of trillions of cells, each performing a specific function. Within each cell’s nucleus (the center part of a cell that regulates its chemical functions) are pairs of chromosomes. These threadlike structures are made up of deoxyribonucleic acid (DNA), which carries the blueprint of life in the form of codes, or genes, that determine dominant or recessive inherited characteristics.

A DNA molecule looks like two ladders with one of the sides taken off both and then twisted around each othera formation known as the double helix. The rungs of these ladders meet (resulting in a spiral staircase-like structure) and are called base pairs. Base pairs are made up of nitrogen-containing molecules and arranged in specific sequences. Millions of these base pairs, or sequences, constitute a single gene, specifically defined as a segment of the chromosome and DNA that contains certain hereditary information. The gene, or combination of genes formed by these base pairs, ultimately directs an organism’s growth and characteristics through the production of certain chemicalsprimarily proteins that carry out most of the body’s chemical functions and biological reactions.

Scientists have long known that alterations in the genes present within cells may cause inherited diseases such as cystic fibrosis, sickle cell disease, and hemophilia. Similarly, errors in entire chromosomes may cause conditions such as Down syndrome or Turner syndrome. As the study of genetics advanced, however, scientists learned that altered genetic sequences may also make people more susceptible to diseases such as atherosclerosis, cancer, and schizophrenia. These diseases have a genetic component, but are also influenced by environmental factors such as diet and lifestyle. The objective of gene therapy is to treat diseases by introducing functional genes into the body to alter the cells involved in the disease process, either by replacing missing genes or by providing copies of functioning genes to replace nonfunctioning ones. The inserted genes may be naturally occurring genes that produce the desired effect or may be engineered (or altered) genes.

Scientists have known how to manipulate a gene’s structure in the laboratory since the early 1970s through a process called gene splicing. The process involves removing a fragment of DNA containing a specific desired genetic sequence and then inserting it into the DNA of another gene. The resultant product is called recombinant DNA, and the process is called genetic engineering. This technique is used in preparing some new therapies (monoclonal antibodies, blood component replacements for hemophilia, anti-inflammatory therapy for collagen diseases).

There are two types of gene therapy. Germ-line gene therapy introduces genes into reproductive cells (sperm and eggs) to participate in germination. Some scientists hope that it may eventually be possible to insert genes into embryos in hopes of correcting genetic abnormalities that can then be passed on to future generations. Most of the current work in applied gene therapy, however, has been in the realm of somatic therapy. In this type of gene therapy, therapeutic genes are inserted into tissue or cells to produce a naturally occurring protein or substance that is lacking or not functioning correctly in an individual.

In both types of therapy, scientists need a mechanism to transport either an entire gene or a recombinant DNA to a cell’s nucleus, where the chromosomes and DNA reside. In essence, vectors are molecular delivery trucks. One of the first and most widely used vectors to be developed were viruses, because they invade cells as part of their natural infection process. Viruses have the potential to be excellent vectors because they have a specific relationship with a host in that they colonize certain cell types and tissues in specific organs. As a result, vectors are chosen according to their attraction to certain cells and areas of the body.

One of the first classes of vectors used were retroviruses. Because these viruses are easily cloned (artificially reproduced) in the laboratory, scientists have studied them extensively and learned a great deal about their biologic action. They have also learned how to remove the genetic information that governs viral replication, thus reducing the chances of infection from the host vector.

Retroviruses work best in actively dividing cells, but most cells in a human body are relatively stable and do not often divide. As a result, these cells are used primarily for ex vivo (outside the body) manipulation. First, the cells are removed from a person’s body, and the vector, or virus carrying the gene, is inserted into them. Next, the cells are placed into a nutrient culture where they grow and replicate. Once enough cells are gathered, they are returned to the body, usually by injection into the blood stream. Theoretically, as long as these cells survive, they will provide the desired therapy.

Another class of viruses, called adenoviruses, may also prove to be good gene vectors. These viruses effectively infect non-dividing cells in the body, where the desired gene product is then expressed naturally. In addition to being a more efficient approach to the problem of gene transportation, these viruses, which are known to cause respiratory infections, are more easily purified and stabilized than are retroviruses. The result is less liklihood of unintended viral infection. However, these viruses live for several days in the body, and there is some concern about the possibility of infecting other people with the viruses through sneezing or coughing. Other viral vectors include influenza viruses, Sindbis virus, and a herpes virus that infects nerve cells.

Scientists have also studied nonviral vectors. These vectors rely on the natural biologic process in which cells take up (or gather) macromolecules. One approach is to use liposomes, globules of fat produced by the body and taken up by cells. Scientists are also investigating the introduction of raw recombinant DNA by injecting it into the bloodstream or placing it on microscopic beads of gold injected into the skin using air pressure. Another possible vector under development is based on dendrimer molecules. A class of polymers (naturally occurring or artificial substances that have a high molecular weight and are formed by smaller molecules of the same or similar substances) is constructed in a laboratory by combining these smaller molecules. They have been used in manufacturing styrofoam, polyethylene cartons, and Plexiglas. In the laboratory, dendrimers have shown the ability to transport genetic material into human cells. They can also be designed to form an affinity for particular cell membranes by attaching to certain sugars and protein groups. Much additional research must be conducted before dendrimers can be used on a routine basis.

On September 14, 1990, a four-year old girl who had a genetic disorder that prevented her body from producing a crucial enzyme became the first person to undergo gene therapy in the United States. Because her body could not produce adenosine deaminase (ADA), she had a weakened immune system, making her extremely susceptible to severe, life-threatening infections. W. French Anderson and colleagues at the National Institutes of Health’s Clinical Center in Bethesda, Maryland, took white blood cells (which are crucial to proper immune system functioning) from the girl, inserted ADA-producing genes into them, and then transfused the cells back into the girl. Although the young girl continued to show an increased ability to produce ADA, debate arose as to whether the improvement resulted from the gene therapy or from an additional drug treatment she received.

Although gene therapy testing in humans has advanced rapidly, many questions surround its use. For example, some scientists are concerned that the therapeutic genes themselves may cause disease. Others fear that germ-line gene therapy may be used to control human development in ways not connected with disease, such as intelligence or physical appearance.

Nevertheless, a new era of gene therapy began as more and more scientists sought to conduct clinical trial (testing in humans) research in this area. In that same year, gene therapy was tested on persons with melanoma (skin cancer). The goal was to help them produce antibodies (disease fighting substances in the immune system) to battle the cancer.

The relative success of these experiments prompted a growing number of attempts at gene therapies designed to perform a variety of functions in the body. For example, a gene therapy for cystic fibrosis aims to supply a gene that alters cells, enabling people with cystic fibrosis to produce a specific protein to battle the disease. Another approach was used for people with brain cancer, in which the inserted gene was designed to make the cancer cells more likely to respond to drug treatment. A third gene therapeutic approach for people experiencing artery blockage, which can lead to strokes, induces the growth of new blood vessels (collateral circulation) near clogged arteries, thus ensuring relatively normal blood circulation.

In the United States, both nucleic acid-based (in vivo) treatments and cell-based (ex vivo) treatments are being investigated. Nucleic acid-based gene therapy uses vectors (such as viruses) to deliver modified genes to target cells. Cell-based gene therapy requires removal of cells from a person, genetically altering the cells and then reintroducing them into the body of the person being treated. Presently, gene therapies for the following diseases are being studied: cystic fibrosis (using adenoviral vector), HIV infection (cell-based), malignant melanoma (cell-based), Duchenne muscular dystrophy (cell-based), hemophilia B (cell-based), kidney cancer (cell-based), Gaucher disease (retroviral vector), breast cancer (retroviral vector), and lung cancer (retroviral vector). When a cell or individual is treated using gene therapy and successful incorporation of engineered genes has occurred, the cell or individual is said to be transgenic.

The medical establishment’s contribution to transgenic research has been supported by increased government funding. In 1991, the U.S. government provided $58 million for gene therapy research, with increases in funding of $15-40 million dollars a year over the following four years. With fierce competition over the promise of societal benefits in addition to huge profits, large pharmaceutic corporations have moved to the forefront of transgenic research. In an effort to be first in developing new therapies, and armed with billions of dollars of research funds, such corporations are making impressive progress toward making gene therapy a viable reality in the treatment of once elusive diseases.

Although great strides have been made in gene therapy in a relatively short time, its potential usefulness has been limited by lack of scientific data concerning the multitude of functions that genes control in the human body. For instance, it is now known that much genetic material is contained in non-coding regions. That is, they merely store information that may be used at different times in a cell’s life cycle. Some of these large portions of the genome are involved in control and regulation of gene expression. Each individual cell in the body carries thousands of genes that have coding for proteins. Some experts estimate this number to be 150,000 genes. For gene therapy to advance to its full potential, scientists must discover the biologic role for each of these individual genes and identify the location on the DNA helix for each of the base pairs that comprise them.

To address this issue, the National Institutes of Health initiated the Human Genome Project in 1990. Led by Dr. James Watson (one of the co-discoverers of the chemical makeup of DNA) the project’s 15-year goal is to map the entire human genome (a combination of the words gene and chromosome). A genome map would clearly identify the location of all genes as well as the more than three billion base pairs that comprise them. With a precise knowledge of gene locations and functions, scientists may one day be able to conquer or control diseases that have plagued humanity for centuries.

Scientists participating in the Human Genome Project have identified an average of one new gene a day, but many expect this rate of discovery to increase. In February of 2001, scientists published a rough draft of the complete human genome; the final complete sequence was published in 2003.

Some of the genes identified through this project include a gene that predisposes people to obesity; one associated with programmed cell death (apoptosis); a gene that guides HIV viral reproduction; and the genes of inherited disorders like Huntington’s disease, amyotrophic lateral aclerosis (Lou Gehrig’s disease), and some colon and breast cancers.

The potential scope of gene therapy is enormous. More than 4,200 diseases have been identified as resulting directly from non-functioning or abnormal genes, and countless others that may be partially influenced by a person’s genetic makeup. Initial research has concentrated on developing gene therapies for diseases whose genetic origins have been established and for other diseases that can be cured or ameliorated by substances genes produce.

The following are examples of potential gene therapies. People with cystic fibrosis lack a gene needed to produce a salt-regulating protein. This protein regulates the flow of chloride into epithelial cells (the cells that line the inner and outer skin layers), that cover the air passages of the nose and lungs. Without this regulation, people with cystic fibrosis have a buildup of thick mucus in their lungs. In turn, this mucus makes these patients prone to lung infections and respiratory problems, and usually leads to death within the first 29 years of life. A gene therapy technique to correct this abnormality might employ an adenovirus to transfer a normal copy of what scientists call the cystic fibrosis transmembrane conductance regulator (CTRF) gene. The gene is introduced into a person by spraying it into the nose or lungs.

Familial hypercholesterolemia (FH) is also an inherited disease, resulting in the inability to process cholesterol properly, which leads to high levels of artery-clogging fat in the bloodstream of even the youngest family members. Persons with FH often suffer heart attacks and strokes because of blocked arteries. A gene therapy approach used to address FH is much more intricate than most gene therapies because it involves partial surgical removal of persons’ livers (ex vivo transgene therapy). Corrected copies of a gene that acts to reduce cholesterol buildup are inserted into the liver sections, which are then transplanted back into the people.

Gene therapy has also been tested on persons with acquired immune difficiency syndrome (AIDS ). AIDS is caused by the human immunodeficiency virus (HIV), which weakens the body’s immune system to the point that people with the condition are unable to fight off diseases such as pneumonia and cancer. In one approach, genes that produce specific HIV proteins have been altered to stimulate immune system functioning without causing the negative effects that a complete HIV molecule has on the immune system. These genes are then injected in a person’s blood stream. Another approach to treating AIDS is to insert, via white blood cells, genes that have been genetically engineered to produce a receptor that would attract HIV and reduce its chances of replicating. These approaches are still primarily experimental.

Several cancers also have the potential to be treated with gene therapy. A therapy tested for melanoma, a progressive, agressive skin cancer, would introduce a gene with an anticancer protein called tumor necrosis factor (TNF) into test tube samples of a person’s own cancer cells, which are then reintroduced into the person’s body. In brain cancer, the approach is to insert a specific gene that increases the cancer cells’ susceptibility to a common drug used in fighting the disease.

Gaucher disease is an inherited disease caused by a mutant gene that inhibits the production of an enzyme called glucocerebrosidase. Persons with Gaucher disease have enlarged livers (hepatomegaly) and spleens (splenomegaly). Clinical gene therapy trials will focus on inserting the gene for producing the missing enzyme.

Gene therapy is also being considered as an approach to solving a problem associated with a surgical procedure known as balloon angioplasty. In this procedure, a stent (a piece of tubular material resembling a straw) is used to open the clogged artery. However, in a “fail-safe” response to the trauma of the stent insertion, the body initiates a natural healing process that produces too many cells in the artery and results in restenosis or reclosing of the artery. The gene therapy approach to preventing this unwanted side effect is to cover the outside surfaces of an inserted stent with a soluble gel containing vectors for genes that may reduce an overactive healing response.

Gene therapy seems elegantly simple in its concept: supply the human body with a gene that can correct a biologic malfunction causing a disease. However, there are many obstacles and some distinct questions concerning the viability of gene therapy. For example, viral vectors must be carefully controlled lest they infect a person with a viral disease. Some vectors, like retroviruses, can also enter normally functioning cells and interfere with natural biologic processes, possibly leading to other diseases. Other viral vectors, such as adenoviruses, are often recognized and destroyed by the immune system so their therapeutic effects are short-lived. Maintaining gene expression so that it performs its role properly after vector delivery is difficult. As a result, some therapies need to be repeated often to provide long-lasting benefits.

One of the most pressing issues, however, is gene regulation. Genes work in concert to regulate their functioning. In other words, several genes may play a part in turning other genes on and off. For example, certain genes work together to stimulate cell division and growth; but if these are not regulated, the inserted genes could cause tumor formation and cancer. Another difficulty is learning how to make the gene go into action only when needed. For the best and safest therapeutic effort, a specific gene should turn on, for example, when certain levels of a protein or enzyme are low and must be replaced. But the gene should also remain dormant when not needed to ensure that it does not oversupply a substance and disturb the body’s delicate chemical balance.

One approach to gene regulation is to attach other genes that detect certain biologic activities and then react as a type of automatic off-and-on switch, regulating the activity of other genes according to biologic cues. Although still in the rudimentary stages, researchers are making progress in inhibiting some gene functioning by using a synthetic DNA to block gene transcriptions (the copying of genetic information). This approach may have applications for gene therapy.

While gene therapy holds promise as a revolutionary approach for treating disease, ethical concerns over its use and ramifications have been expressed by scientists and lay people alike. For example, since much needs to be learned about how these genes actually work and their long-term effects, is it ethical to test these therapies on humans, in whom they could have a disastrous result? As with most clinical trials concerning new therapies, including many drugs, the people participating in these studies have usually not responded to more established therapies and are often so ill that the novel therapy is their only hope for long-term survival.

Another questionable outgrowth of gene therapy is that scientists could potentially manipulate genes to control traits in human offspring that are not related to health. For example, perhaps a gene could be inserted to ensure that a child would not be bald, a seemingly harmless goal. However, what if genetic manipulation was used to alter skin color, prevent homosexuality, or ensure good looks? If a gene is found that can enhance intelligence of children who are not yet born, will all members of society have access to the technology, or will it be so expensive that only the elite can afford it?

The Human Genome Project, which plays such an integral role for the future of gene therapy, also has social repercussions. If individual genetic codes can be determined, will such information be used against people? For example, will someone more susceptible to a disease have to pay higher insurance premiums or be denied health insurance altogether? Will employers discriminate between two potential employees, one with a healthy genome and the other with genetic abnormalities?

Cells The smallest living units of the body that carry a full complement of the DNA, and which group together to form tissues and help the body perform specific functions.

Chromosome Threadlike structures in a cell that carry most of the genetic material in the form of DNA and genes.

Clinical trial The testing of a drug or some other type of therapy in a specific human population.

Clone A cell or organism derived through asexual (without sex) reproduction, and which contains the identical genetic information of the parent cell or organism.

DNA (deoxyribonucleic acid) The specific molecules that comprise chromosomes and genes.

Embryo The earliest stage of development of the zygote before the human or animal is considered a fetus (which is usually the point at which the embryo takes on the basic physical form of its species). Embryos are formed in vivo (in utero) or in vitro (in a laboratory) in preparation for implantation.

Enzyme Atypeofmoleculemadebycells that,when released, facilitates chemical reactions in the body.

Eugenics A social movement in which the population of a society, country, or the world is to be improved by selective mating, controlling the passage of hereditary information.

Gene A specific biologic component found in the cell nucleus that carries the instructions for the formation of an organism and its specific traits, such as eye or hair color.

Gene transcription The process by which genetic information is copied from DNA to RNA, resulting in a specific protein formation.

Genetic engineering The manipulation of genetic material to produce specific results in an organism.

Genetics The study of hereditary traits passed on through genes.

Genome The total set of genes carried by an individual or cell.

Genomics The DNA which is found in the organism’s total set of genes carried by an individual or cell and is passed on to offspring as information necessary for survival.

Germ-line gene therapy The introduction of genes (natural or engineered) into reproductive cells or embryos to correct inherited genetic abnormalities that can cause disease by replication.

Liposome Fat organelle made up of layers of lipids.

Macromolecule A large molecule composed of thousands of atoms.

Nitrogen An element that is a component of the base pairs in DNA.

Nucleus The central part of a cell that contains most of its genetic material, including chromosomes and DNA.

Protein Macromolecule made up of long sequences of amino acids. Proteins comprise the dry weight of most cells and are involved in structures, hormones, and enzymes in muscle contraction, immunological response, and many other functions essential to life.

Somatic gene therapy The introduction of genes into tissue or cells to treat a genetic disease in an individual.

Vector Something used to transport genetic information to a cell.

Some of these concerns can be traced back to the eugenics movement that was popular in the first half of the twentieth century. This genetic philosophy was a societal movement that encouraged people with so-called positive traits to reproduce while those with less desirable traits were sanctioned from having children. Eugenics was used to pass strict immigration laws in the United States, barring less suitable people from entering the country lest they reduce the quality of the country’s collective gene pool. Probably the most notorious example of eugenics in action was the rise of Nazism in Germany, which fostered the Eugenic Sterilization Law of 1933. The law required sterilization for those with certain disabilities and even for some persons who were simply deemed to be unattractive. To ensure that this novel science is not abused, many governments have established organizations specifically for overseeing the development of gene therapy. In the United States, the Food and Drug Administration and the National Institutes of Health require scientists to take a precise series of steps and meet stringent requirements before approving clinical trials.

In fact, gene therapy has been immersed in more controversy and is surrounded by more scrutiny from both the health care and ethics communities than most other technologies (except, perhaps, for cloning) that have the potential to substantially change society. Despite the health and ethical questions surrounding gene therapy, the field will continue to grow and is likely to change medicine more quickly than any previous medical advancement.

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McKay, D. “Restoring sight by gene therapy.” Trends in Biotechnology, 19 no.7 (2001): 243-246.

Newman, C.M., Lawrie, A., Brisken, A.F., Cumberland, D.C. “Ultrasound gene therapy: on the road from concept to reality.” Echocardiography 18 no.4 (2001): 339-347.

Savulescu, J. “Harm, ethics committees and the gene therapy death.” Journal of Medical Ethics 27 no.3 (2001): 148-150.

Verma, I.M. “Ombudsman or Hotline for Gene Therapy Clinical Trials?” Molecular Therapeutics 3 no.6 (2001): 817-818.

American Academy of Family Physicians. 11400 Tomahawk Creek Parkway, Leawood, KS 66211-2672, (913) 906-6000, http://www.aafp.org.

American Society of Gene Therapy. 611 East Wells Street, Milwaukee, WI 53202, (414) 278-1341, (414) 276-3349. http://www.asgt.org.

World Health Organization. 20 Avenue Appia, 1211 Geneva 27, Switzerland, +41 (22) 791 4140, +41 (22) 791 4268. http://www.who.int/gtb.

American Civil Liberties Union. http://www.aclu.org/issues/aids/docket98.html.

Association of American Medical Colleges. http://www.aamc.org/newsroom/reporter/june2000/view.htm.

Human Genome Project Information. http://www.ornl.gov/hgmis/medicine/genetherapy.html.

National Cancer Institute. http://cancernet.nci.nih.gov/clinpdq/therapy/Questions_and_Answers_About_Gene_Therapy.html.

Public Broadcasting System (animation). http://www.pbs.org/wnet/innovation/show1/html/animation2.html.

University of Pennsylvania. http://www.med.upenn.edu/ihgt/info/whatisgt.html.

U.S. Food and Drug Administration. http://www.fda.gov/fdac/features/2000/gene.html.

Vanderbilt University. http://www.mc.vanderbilt.edu/gcrc/gene.

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gene therapy | Encyclopedia.com

Center for Gene Therapy – nationwidechildrens.org

The mission of the Center for Gene Therapy is to investigate and employ the use of gene and cell based therapeutics for prevention and treatment of human diseases including: neuromuscular and neurodegenerative diseases, lysosomal storage disorders, ischemia and re-perfusion injury, neonatal hypertension, cancer and infectious diseases.

Link:

Center for Gene Therapy – nationwidechildrens.org

Gene Therapy :: Sangamo Therapeutics, Inc. (SGMO)

Sangamo is developing state of the art AAV-based gene therapies for the treatment of monogenic diseases, such as hemophilia A and certain inherited metabolic disorders.

A gene is a unit of genetic information contained in an organisms genome or DNA, which encodes the instructions for making a protein. Collectively, genes provide the information for the organisms development and characteristics. Humans have about 20,000 genes on their 23 pairs of chromosomes.

In monogenic diseases an essential protein isnt made properly, or in sufficient quantities, as a result of a mutation in a single gene. One therapeutic solution is to deliver a new copy of the defective gene to cells so that they can now make the protein and alleviate symptoms of the disease. This is known as gene therapy.

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Gene Therapy :: Sangamo Therapeutics, Inc. (SGMO)

Gene Therapy The Future of Medicine? | Science Care

Gene therapy is an experimental method of fighting disease that involves correcting or replacing a persons mutated or malfunctioning genes. This promising research is now being used in clinical trials and may lead to improved health outcomes for patients with inherited bleeding and immune disorders as well as some forms of blood cancer and other diseases.

What Is Gene Therapy?

Genes carry the DNA information needed to make proteins that are the building blocks of the human body. Some of these genes can become damaged through mutation, which can lead to disease conditions. Gene therapy is a scientific technique that uses genes to prevent or treat disease in a number of different ways:

Finding the Keys to Alter Body Chemistry

Currently, gene therapy can be used for conditions in which a change in the genetic coding of somatic cells can alter the course of a disease. For example, to correct a disease in which a specific enzyme is missing, the addition of a necessary gene component for production of the enzyme would fix the underlying problem of the disease. In many cases, harmless viruses are employed to serve as packets to carry the new gene to where it is needed. When used this way, the viruses are called vectors, and their own genes may be removed and replaced with the working human gene. Once the gene is correctly placed, it can be switched on to provide the working instructions for correct function.

Conditions Being Treated with Gene Therapy

Although much of this may still sound like the realm of mad scientists tinkering with the human body, gene therapy is an accepted experimental technique that is currently being used to help patients with certain types of cancer to target specific antibodies that can be used to fight the disease. Gene therapy is also being used to correct deficiencies in the production of dopamine, such as in Parkinsons disease, correct some immune system problems, and restore components needed for normal blood cell function in those with certain blood diseases, such hemophilia and beta-Thalassemia. Gene therapy holds promise for treating a wide range of diseases, including cancer, cystic fibrosis, heart disease, diabetes, hemophilia and AIDS.

Potential Risks

Gene therapy does come with some potential risks, all of which, researchers are hoping to overcome. Because the genes have to be delivered using a carrier or vector, the bodys immune system may see the newly introduced viruses as intruders and attack them. Its also possible that the altered viruses may infect additional cells, not just the targeted cells containing mutated genes. There may also be some concern that the viruses may recover their original ability to cause disease, or that the new genes get inserted in the wrong spot in a patients DNA, leading to tumor formation.

Hope for the Future

Gene therapy holds promise as an effective treatment option for a variety of diseases at some point in the near future. An estimated 4,000 medical conditions are a result of gene disorders. If some of these genetic problems can be corrected through gene replacement or manipulation, individuals suffering from these diseases may enjoy longer, healthier lives, free of symptoms and the associated medical expenses.

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Gene Therapy The Future of Medicine? | Science Care

Gene Therapy in Muscular Dystrophy

Gene therapy, the use of genetic material to treat a disease or disorder, is making strides in muscular dystrophy. Although the approach is still considered experimental, studies in animal models have shown promising results and clinical trials in humans are underway.

Gene therapy has the potential to help people with inherited disorders, in which a gene mutation causes cells to produce a defective protein or no protein at all, leading to disease symptoms.

To deliver the genetic material to the cells, scientists use a tool called a vector. This is typically a virus that has been modified so that it doesnt cause disease. It is hoped that the vector will carry the therapeutic gene into the cells nucleus, where it will provide the instructions necessary to make the desired protein.

The most common form of muscular dystrophy, Duchenne muscular dystrophy, is caused by a mutation in the DMD gene, which codes for a protein called dystrophin. Dystrophin is part of a protein complex that strengthens and protects muscle fibers. When the cells dont have functional dystrophin due to the gene mutation, muscles progressively weaken. Scientists think that supplying a gene that codes for a functional form of dystrophin might be an effective treatment for Duchenne muscular dystrophy.

Using gene therapy to deliver a correct form of the dystrophin gene has been challenging because of the size of the DMD gene, which is the largest gene in the human genome so it does not fit into commonly used vectors.

Scientists are having more success with a shortened version of the DMD gene that produces a protein called micro-dystrophin. Even though its a smaller version of dystrophin, micro-dystrophin includes key elements of the protein and is functional.

Administering a gene for micro-dystrophin to golden retriever dogs that naturally develop muscular dystrophy showed promising results in a study published in July 2017. Muscular dystrophy symptoms were reduced for more than two years following the treatment and the dogs muscle strength improved. The gene was delivered using a recombinant adeno-associated virus, or rAAV, as the vector.

A similar therapy is now being tested in people in a Phase 1/2 clinical trial (NCT03375164)at Nationwide Childrens Hospital in Columbus, Ohio. A single dose of the gene therapytreatment containing the gene encoding for micro-dystrophinwill be infused into the blood system of 12 patients in two age groups: 3 months to 3 years, and 4 to 7 years. The first patient in the trial, which is recruiting participants, already has received the treatment, according to a January 2018 press release.

The biopharmaceutical company Sarepta Therapeutics is contributing funding and other support to the project.

Sarepta is developing another potential gene therapy for Duchenne muscular dystrophy where rather than targeting the DMD gene that codes for dystrophin, the therapy will be used to try to increase the expression of a gene called GALGT2. The overproduction of this gene is thought to produce changes in muscle cell proteins that strengthen them and protect them from damage, even in the absence of functional dystrophin.

A Phase 1/2a clinical trial (NCT03333590) was launched in November 2017 at Nationwide Childrens Hospital for the therapy, called rAAVrh74.MCK.GALGT2.

***

Muscular Dystrophy Newsis strictly a news and information website about the disease. It does not provide medical advice, diagnosis, or treatment. This content is not intended to be a substitute for professional medical advice, diagnosis, or treatment. Always seek the advice of your physician or other qualified health provider with any questions you may have regarding a medical condition. Never disregard professional medical advice or delay in seeking it because of something you have read on this website.

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Gene Therapy in Muscular Dystrophy

Gene & Cell Therapy Defined | ASGCT – American Society of …

Gene therapy is a field of biomedical research with the goal of influencing the course of various genetic and acquired (so-called multi factorial) diseases at the DNA/RNA level. Cell therapy aims at targeting various diseases at the cellular level, i.e. by restoring a certain cell population or using cells as carriers of therapeutic cargo. For many diseases, gene and cell therapy are applied in combination. In addition, these two fields have helped provide reagents, concepts, and techniques that are illuminating the finer points of gene regulation, stem cell lineage, cell-cell interactions, feedback loops, amplification loops, regenerative capacity, and remodeling.

Gene therapy is defined as a set of strategies that modify the expression of an individuals genes or repair abnormal genes. Each strategy involves the administration of a specific nucleic acid (DNA or RNA). Nucleic acids are normally not taken up by cells, thus special carriers, so-called ‘vectors’ are required. Vectors can be of either viral or non-viral nature.

Cell therapy is defined as the administration of living whole cells for the patient for the treatment of a disease. The origin of the cells can be from the same individual (autologous source) or from another individual (allogeneic source). Cells can be derived from stem cells, such as bone marrow or induced pluripotent stem cells (iPSCs), reprogrammed from skin fibroblasts or adipocytes. Stem cells are applied in the context of bone marrow transplantation directly. Other strategies involve the application of more or less mature cells, differentiated in vitro (in a dish) from stem cells.

Historically, the discovery of recombinant DNA technology in the 1970s provided the tools to efficiently develop gene therapy. Scientists used these techniques to readily manipulate bacterial and viral genomes, isolate genes, identify mutations involved in human diseases, characterize and regulate gene expression and produce human proteins from genes (e.g. production of insulin in bacteria revolutionized medicine). Later, various viral and non-viral vectors were developed along with the development of regulatory elements (e.g. promoters that regulate gene expression), which are necessary to induce and control gene expression. Gene transfer in animal models of disease have been attempted and led to early success. Various routes of administrations have been explored (injection into the bloodstream, into the ventricles of the brain, into muscle etc).

The development of suitable gene therapy treatments for many genetic diseases and some acquired diseases has encountered many challenges, such as immune response against the vector or the inserted gene. Current vectors are considered very safe and recent gene therapy trials documented excellent safety profile of modern gene therapy products. Further development involves uncovering basic scientific knowledge of the affected tissues, cells, and genes, as well as redesigning vectors, formulations, and regulatory cassettes for the genes. While effective long-term treatments for many genetic and inherited diseases are elusive today, some success is being observed in the treatment of several types of immunodeficiency diseases, cancers, and eye disorders.

Historically, blood transfusions were the first type of cell therapy and are now considered routine. Bone marrow transplantation has also become a well-established medical treatment for many diseases, including cancer, immune deficiency and others. Cell therapy is expanding its repertoire of cell types for administration. Cell therapy treatment strategies include: isolation and transfer of specific stem cell populations, induction of mature cells to become pluripotent cells, administration of effector cells and reprogramming of mature cells into iPSCs. Administration of large numbers of effector cells has benefited cancer patients, transplant patients with unresolved infections, and patients with vision problems.

Several diseases benefit most from treatments that combine the technologies of gene and cell therapy. For example, some patients have a severe combined immunodeficiency disease (SCID) but unfortunately, do not have a suitable donor of bone marrow. Scientists have identified that patients with SCID are deficient in adenosine deaminase gene (ADA-SCID), or the common gamma chain located on the X chromosome (X-linked SCID). Several dozen patients have been treated with a combined gene and cell therapy approach. Each individuals hematopoietic stem cells were treated with a viral vector that expressed a copy of the relevant normal gene. After selection and expansion, these corrected stem cells were returned to the patients. Many patients improved and required less exogenous enzymes. However, some serious adverse events did occur and their incidence is prompting development of theoretically safer vectors and protocols. The combined approach also is pursued in several cancer therapies.

Genome editing (gene editing) has recently gained significant attention, due to the discovery and application of the clustered regularly interspaced short palindromic repeats (CRISPR) system. Actually, genome editing dates back several years and earlier generation genome editing systems are currently tested in clinical trials (such as zinc-finger nucleases). The aim of genome editing is to disrupt a disease-causing mutation or correct faulty genes at the chromosomal DNA. Genome editing can be performed in the patients own cells in vitro and edited cells can be administered to the patient (thus genome editing can be combined with cell therapy). However, it is also possible to perform genome editing in vivo by administering the genome editing agent packaged in viral and non-viral vectors.

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Gene & Cell Therapy Defined | ASGCT – American Society of …

Gene therapy | medicine | Britannica.com

Gene therapy, also called gene transfer therapy, introduction of a normal gene into an individuals genome in order to repair a mutation that causes a genetic disease. When a normal gene is inserted into the nucleus of a mutant cell, the gene most likely will integrate into a chromosomal site different from the defective allele; although that may repair the mutation, a new mutation may result if the normal gene integrates into another functional gene. If the normal gene replaces the mutant allele, there is a chance that the transformed cells will proliferate and produce enough normal gene product for the entire body to be restored to the undiseased phenotype.

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cancer: Gene therapy

Knowledge about the genetic defects that lead to cancer suggests that cancer can be treated by fixing those altered genes. One strategy is to replace a defective gene with its normal counterpart, using methods of recombinant DNA technology. Methods to insert genes into

Human gene therapy has been attempted on somatic (body) cells for diseases such as cystic fibrosis, adenosine deaminase deficiency, familial hypercholesterolemia, cancer, and severe combined immunodeficiency (SCID) syndrome. Somatic cells cured by gene therapy may reverse the symptoms of disease in the treated individual, but the modification is not passed on to the next generation. Germline gene therapy aims to place corrected cells inside the germ line (e.g., cells of the ovary or testis). If that is achieved, those cells will undergo meiosis and provide a normal gametic contribution to the next generation. Germline gene therapy has been achieved experimentally in animals but not in humans.

Scientists have also explored the possibility of combining gene therapy with stem cell therapy. In a preliminary test of that approach, scientists collected skin cells from a patient with alpha-1 antitrypsin deficiency (an inherited disorder associated with certain types of lung and liver disease), reprogrammed the cells into stem cells, corrected the causative gene mutation, and then stimulated the cells to mature into liver cells. The reprogrammed, genetically corrected cells functioned normally.

Prerequisites for gene therapy include finding the best delivery system (often a virus, typically referred to as a viral vector) for the gene, demonstrating that the transferred gene can express itself in the host cell, and establishing that the procedure is safe. Few clinical trials of gene therapy in humans have satisfied all those conditions, often because the delivery system fails to reach cells or the genes are not expressed by cells. Improved gene therapy systems are being developed by using nanotechnology. A promising application of that research involves packaging genes into nanoparticles that are targeted to cancer cells, thereby killing cancer cells specifically and leaving healthy cells unharmed.

Some aspects of gene therapy, including genetic manipulation and selection, research on embryonic tissue, and experimentation on human subjects, have aroused ethical controversy and safety concerns. Some objections to gene therapy are based on the view that humans should not play God and interfere in the natural order. On the other hand, others have argued that genetic engineering may be justified where it is consistent with the purposes of God as creator. Some critics are particularly concerned about the safety of germline gene therapy, because any harm caused by such treatment could be passed to successive generations. Benefits, however, would also be passed on indefinitely. There also has been concern that the use of somatic gene therapy may affect germ cells.

Although the successful use of somatic gene therapy has been reported, clinical trials have revealed risks. In 1999 American teenager Jesse Gelsinger died after having taken part in a gene therapy trial. In 2000 researchers in France announced that they had successfully used gene therapy to treat infants who suffered from X-linked SCID (XSCID; an inherited disorder that affects males). The researchers treated 11 patients, two of whom later developed a leukemia-like illness. Those outcomes highlight the difficulties foreseen in the use of viral vectors in somatic gene therapy. Although the viruses that are used as vectors are disabled so that they cannot replicate, patients may suffer an immune response.

Another concern associated with gene therapy is that it represents a form of eugenics, which aims to improve future generations through the selection of desired traits. Some have argued that gene therapy is eugenic but that it is a treatment that can be adopted to avoid disability. To others, such a view of gene therapy legitimates the so-called medical model of disability (in which disability is seen as an individual problem to be fixed with medicine) and raises peoples hopes for new treatments that may never materialize.

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Gene therapy | medicine | Britannica.com

Gene Therapy | Microbiology

Learning Objectives

Many types of genetic engineering have yielded clear benefits with few apparent risks. Few would question, for example, the value of our now abundant supply of human insulin produced by genetically engineered bacteria. However, many emerging applications of genetic engineering are much more controversial, often because their potential benefits are pitted against significant risks, real or perceived. This is certainly the case for gene therapy, a clinical application of genetic engineering that may one day provide a cure for many diseases but is still largely an experimental approach to treatment.

Human diseases that result from genetic mutations are often difficult to treat with drugs or other traditional forms of therapy because the signs and symptoms of disease result from abnormalities in a patients genome. For example, a patient may have a genetic mutation that prevents the expression of a specific protein required for the normal function of a particular cell type. This is the case in patients with Severe Combined Immunodeficiency (SCID), a genetic disease that impairs the function of certain white blood cells essential to the immune system.

Gene therapy attempts to correct genetic abnormalities by introducing a nonmutated, functional gene into the patients genome. The nonmutated gene encodes a functional protein that the patient would otherwise be unable to produce. Viral vectors such as adenovirus are sometimes used to introduce the functional gene; part of the viral genome is removed and replaced with the desired gene (Figure1). More advanced forms of gene therapy attempt to correct the mutation at the original site in the genome, such as is the case with treatment of SCID.

Figure1. Gene therapy using an adenovirus vector can be used to treat or cure certain genetic diseases in which a patient has a defective gene. (credit: modification of work by National Institutes of Health)

So far, gene therapies have proven relatively ineffective, with the possible exceptions of treatments for cystic fibrosis and adenosine deaminase deficiency, a type of SCID. Other trials have shown the clear hazards of attempting genetic manipulation in complex multicellular organisms like humans. In some patients, the use of an adenovirus vector can trigger an unanticipated inflammatory response from the immune system, which may lead to organ failure. Moreover, because viruses can often target multiple cell types, the virus vector may infect cells not targeted for the therapy, damaging these other cells and possibly leading to illnesses such as cancer. Another potential risk is that the modified virus could revert to being infectious and cause disease in the patient. Lastly, there is a risk that the inserted gene could unintentionally inactivate another important gene in the patients genome, disrupting normal cell cycling and possibly leading to tumor formation and cancer. Because gene therapy involves so many risks, candidates for gene therapy need to be fully informed of these risks before providing informed consent to undergo the therapy.

The risks of gene therapy were realized in the 1999 case of Jesse Gelsinger, an 18-year-old patient who received gene therapy as part of a clinical trial at the University of Pennsylvania. Jesse received gene therapy for a condition called ornithine transcarbamylase (OTC) deficiency, which leads to ammonia accumulation in the blood due to deficient ammonia processing. Four days after the treatment, Jesse died after a massive immune response to the adenovirus vector.

Until that point, researchers had not really considered an immune response to the vector to be a legitimate risk, but on investigation, it appears that the researchers had some evidence suggesting that this was a possible outcome. Prior to Jesses treatment, several other human patients had suffered side effects of the treatment, and three monkeys used in a trial had died as a result of inflammation and clotting disorders. Despite this information, it appears that neither Jesse nor his family were made aware of these outcomes when they consented to the therapy. Jesses death was the first patient death due to a gene therapy treatment and resulted in the immediate halting of the clinical trial in which he was involved, the subsequent halting of all other gene therapy trials at the University of Pennsylvania, and the investigation of all other gene therapy trials in the United States. As a result, the regulation and oversight of gene therapy overall was reexamined, resulting in new regulatory protocols that are still in place today.

Presently, there is significant oversight of gene therapy clinical trials. At the federal level, three agencies regulate gene therapy in parallel: the Food and Drug Administration (FDA), the Office of Human Research Protection (OHRP), and the Recombinant DNA Advisory Committee (RAC) at the National Institutes of Health (NIH). Along with several local agencies, these federal agencies interact with the institutional review board to ensure that protocols are in place to protect patient safety during clinical trials. Compliance with these protocols is enforced mostly on the local level in cooperation with the federal agencies. Gene therapies are currently under the most extensive federal and local review compared to other types of therapies, which are more typically only under the review of the FDA. Some researchers believe that these extensive regulations actually inhibit progress in gene therapy research. In 2013, the Institute of Medicine (now the National Academy of Medicine) called upon the NIH to relax its review of gene therapy trials in most cases. However, ensuring patient safety continues to be of utmost concern.

Beyond the health risks of gene therapy, the ability to genetically modify humans poses a number of ethical issues related to the limits of such therapy. While current research is focused on gene therapy for genetic diseases, scientists might one day apply these methods to manipulate other genetic traits not perceived as desirable. This raises questions such as:

The ability to alter reproductive cells using gene therapy could also generate new ethical dilemmas. To date, the various types of gene therapies have been targeted to somatic cells, the non-reproductive cells within the body. Because somatic cell traits are not inherited, any genetic changes accomplished by somatic-cell gene therapy would not be passed on to offspring. However, should scientists successfully introduce new genes to germ cells (eggs or sperm), the resulting traits could be passed on to offspring. This approach, called germ-line gene therapy, could potentially be used to combat heritable diseases, but it could also lead to unintended consequences for future generations. Moreover, there is the question of informed consent, because those impacted by germ-line gene therapy are unborn and therefore unable to choose whether they receive the therapy. For these reasons, the U.S. government does not currently fund research projects investigating germ-line gene therapies in humans.

While there are currently no gene therapies on the market in the United States, many are in the pipeline and it is likely that some will eventually be approved. With recent advances in gene therapies targeting p53, a gene whose somatic cell mutations have been implicated in over 50% of human cancers, cancer treatments through gene therapies could become much more widespread once they reach the commercial market.

Bringing any new therapy to market poses ethical questions that pit the expected benefits against the risks. How quickly should new therapies be brought to the market? How can we ensure that new therapies have been sufficiently tested for safety and effectiveness before they are marketed to the public? The process by which new therapies are developed and approved complicates such questions, as those involved in the approval process are often under significant pressure to get a new therapy approved even in the face of significant risks.

To receive FDA approval for a new therapy, researchers must collect significant laboratory data from animal trials and submit an Investigational New Drug (IND) application to the FDAs Center for Drug Evaluation and Research (CDER). Following a 30-day waiting period during which the FDA reviews the IND, clinical trials involving human subjects may begin. If the FDA perceives a problem prior to or during the clinical trial, the FDA can order a clinical hold until any problems are addressed. During clinical trials, researchers collect and analyze data on the therapys effectiveness and safety, including any side effects observed. Once the therapy meets FDA standards for effectiveness and safety, the developers can submit a New Drug Application (NDA) that details how the therapy will be manufactured, packaged, monitored, and administered.

Because new gene therapies are frequently the result of many years (even decades) of laboratory and clinical research, they require a significant financial investment. By the time a therapy has reached the clinical trials stage, the financial stakes are high for pharmaceutical companies and their shareholders. This creates potential conflicts of interest that can sometimes affect the objective judgment of researchers, their funders, and even trial participants. The Jesse Gelsinger case (see Gene Therapy Gone Wrong above) is a classic example. Faced with a life-threatening disease and no reasonable treatments available, it is easy to see why a patient might be eager to participate in a clinical trial no matter the risks. It is also easy to see how a researcher might view the short-term risks for a small group of study participants as a small price to pay for the potential benefits of a game-changing new treatment.

Gelsingers death led to increased scrutiny of gene therapy, and subsequent negative outcomes of gene therapy have resulted in the temporary halting of clinical trials pending further investigation. For example, when children in France treated with gene therapy for SCID began to develop leukemia several years after treatment, the FDA temporarily stopped clinical trials of similar types of gene therapy occurring in the United States. Cases like these highlight the need for researchers and health professionals not only to value human well-being and patients rights over profitability, but also to maintain scientific objectivity when evaluating the risks and benefits of new therapies.

At what point can the FDA halt the development or use of gene therapy?

Answer d. The FDA halt the development or use of gene therapy at any of the points listed above.

_____________ is a common viral vector used in gene therapy for introducing a new gene into a specifically targeted cell type.

Adenovirus is a common viral vector used in gene therapy for introducing a new gene into a specifically targeted cell type.

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Gene Therapy | Microbiology

Jordan – Wikipedia

Hashemite Kingdom of Jordan (Arabic)Motto:”God, Country, King”[1]” “al-Lh, al-Waan, al-MalkCapitaland largest cityAmman3157N 3556E / 31.950N 35.933E / 31.950; 35.933OfficiallanguagesArabicEthnicgroups Religion DemonymJordanianGovernmentUnitary parliamentaryconstitutional monarchyAbdullah IIOmar RazzazLegislatureParliamentSenateHouse of RepresentativesIndependencefrom the United Kingdom11 April 192125 May 194611 January 1952Area

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Jordan (Arabic: Al-Urdunn [al.ur.dunn]), officially the Hashemite Kingdom of Jordan (Arabic: Al-Mamlakah Al-Urdunnyah Al-Hshimyah), is a sovereign Arab state in Western Asia, on the East Bank of the Jordan River. Jordan is bordered by Saudi Arabia to the south, Iraq to the north-east, Syria to the north, Israel and Palestine to the west. The Dead Sea lies along its western borders and the country has a small shoreline on the Red Sea in its extreme south-west, but is otherwise landlocked.[7] Jordan is strategically located at the crossroads of Asia, Africa and Europe.[8] The capital, Amman, is Jordan’s most populous city as well as the country’s economic, political and cultural centre.[9]

What is now Jordan has been inhabited by humans since the Paleolithic period. Three stable kingdoms emerged there at the end of the Bronze Age: Ammon, Moab and Edom. Later rulers include the Nabataean Kingdom, the Roman Empire, and the Ottoman Empire. After the Great Arab Revolt against the Ottomans in 1916 during World War I, the Ottoman Empire was partitioned by Britain and France. The Emirate of Transjordan was established in 1921 by the Hashemite, then Emir, Abdullah I, and the emirate became a British protectorate. In 1946, Jordan became an independent state officially known as the Hashemite Kingdom of Transjordan, but was renamed in 1949 to the Hashemite Kingdom of Jordan after the country captured the West Bank during the 1948 ArabIsraeli War and annexed it until it was lost to Israel in 1967. Jordan renounced its claim to the territory in 1988, and became one of two Arab states to have signed a peace treaty with Israel in 1994.[10] Jordan is a founding member of the Arab League and the Organisation of Islamic Co-operation. The country is a constitutional monarchy, but the king holds wide executive and legislative powers.

Jordan is a relatively-small, semi-arid, almost-landlocked country with an area of 89,342km2 (34,495sqmi) and a population numbering 10 million, making it the 11th-most populous Arab country. Sunni Islam, practiced by around 95% of the population, is the dominant religion in Jordan that coexists with an indigenous Christian minority. Jordan has been repeatedly referred to as an “oasis of stability” in a turbulent region. It has been mostly unscathed from the violence that swept the region following the Arab Spring in 2010.[11] From as early as 1948, Jordan has accepted refugees from multiple neighbouring countries in conflict. An estimated 2.1 million Palestinian and 1.4 million Syrian refugees are present in Jordan as of a 2015 census.[3] The kingdom is also a refuge to thousands of Iraqi Christians fleeing persecution by ISIL.[12] While Jordan continues to accept refugees, the recent large influx from Syria placed substantial strain on national resources and infrastructure.[13]

Jordan is classified as a country of “high human development” with an “upper middle income” economy. The Jordanian economy, one of the smallest economies in the region, is attractive to foreign investors based upon a skilled workforce.[14] The country is a major tourist destination, also attracting medical tourism due to its well developed health sector.[15] Nonetheless, a lack of natural resources, large flow of refugees and regional turmoil have hampered economic growth.[16]

Jordan takes its name from the Jordan River which forms much of the country’s northwestern border.[17] Much of the area that makes up modern Jordan was historically[when?] called Transjordan, meaning “across the Jordan”, used to denote the lands east of the river. The Hebrew Bible refers to the area as “the other side of the Jordan”.[18] Jund Al-Urdunn was a military district around the river in the early Islamic era.[19] Later, during the Crusades in the beginning of the second millennium, a lordship was established in the area under the name of Oultrejordain.[20]The modern country was established in 1921 as the Emirate of Transjordan, a British protectorate, before becoming the Hashemite Kingdom of Transjordan in 1946 and finally adopting its current name, the Hashemite Kingdom of Jordan, in 1949.

The oldest evidence of hominid habitation in Jordan dates back at least 200,000 years.[21] Jordan is rich in Paleolithic (up to 20,000 years ago) remains due to its location within the Levant where expansions of hominids out of Africa converged.[22] Past lakeshore environments attracted different hominids, and several remains of tools have been found from this period.[22] The world’s oldest evidence of bread-making was found in a 14,500 years old Natufian site in Jordan’s northeastern desert.[23] The transition from hunter-gatherer to establishing populous agricultural villages occurred during the Neolithic period (10,0004,500 BC).[24] ‘Ain Ghazal, one such village located in today’s eastern Amman, is one of the largest known prehistoric settlements in the Near East.[25] Dozens of plaster statues of the human form dating to 7250 BC were uncovered there and they are among the oldest ever found.[26] Other than the usual Chalcolithic (45003600 BC) villages such as Tulaylet Ghassul in the Jordan Valley,[27] a series of circular stone enclosures in the eastern basalt desertwhose purpose remains uncertainhave baffled archaeologists.[28]

Fortified towns and urban centers first emerged in the southern Levant early on in the Bronze Age (36001200 BC).[29] Wadi Feynan became a regional center for copper extraction, which was exploited on a large-scale to produce bronze.[30] Trade and movement of people in the Middle East peaked, spreading and refining civilizations.[31] Villages in Transjordan expanded rapidly in areas with reliable water resources and agricultural land.[31] Ancient Egyptians expanded towards the Levant and controlled both banks of the Jordan River.[32] During the Iron Age (1200332 BC) after the withdrawal of the Egyptians, Transjordan was home to Ammon, Edom and Moab.[33] They spoke Semitic languages of the Canaanite group, and are considered to be tribal kingdoms rather than states.[33] Ammon was located in the Amman plateau; Moab in the highlands east of the Dead Sea; and Edom in the area around Wadi Araba down south.[33]

These Transjordanian kingdoms were in continuous conflict with the neighbouring Hebrew kingdoms of Israel and Judah, centered west of the Jordan Riverthough the former was known to have at times controlled small parts east of the river.[34] One record of this is the Mesha Stele erected by the Moabite king Mesha in 840 BC on which he lauds himself for the building projects that he initiated in Moab and commemorates his glory and victory against the Israelites.[35] The stele constitutes one of the most important direct accounts of Biblical history.[36] Around 700 BC, the kingdoms benefited from trade between Syria and Arabia when the Assyrian Empire controlled the Levant.[37] Babylonians took over the empire after its disintegration in 627 BC.[37] Although the kingdoms supported the Babylonians against Judah in the 597 BC sack of Jerusalem, they rebelled against them a decade later.[37] The kingdoms were reduced to vassals, and they remained to be so under the Persian and Hellenic Empires.[37] However, by the time of Roman rule around 63 BC, Ammon, Edom and Moab had lost their distinct identities, and were assimilated into Roman culture.[33]

Alexander the Great’s conquest of the Persian Empire in 332 BC introduced Hellenistic culture to the Middle East. After Alexander’s death in 323 BC, the empire split among his generals, and in the end much of Transjordan was disputed between the Ptolemies based in Egypt and the Seleucids based in Syria. The Nabataeans, nomadic Arabs based south of Edom, managed to establish an independent kingdom in 169 BC by exploiting the struggle between the two Greek powers. The Nabataean Kingdom controlled much of the trade routes of the region, and it stretched south along the Red Sea coast into the Hejaz desert, up to as far north as Damascus, which it controlled for a short period (8571) BC. The Nabataeans massed a fortune from their control of the trade routes, often drawing the envy of their neighbors. Petra, Nabataea’s barren capital, flourished in the 1st century AD, driven by its extensive water irrigation systems and agriculture. The Nabataeans were also talented stone carvers, building their most elaborate structure, Al-Khazneh, in the first century AD.[42] It is believed to be the mausoleum of the Arab Nabataean King Aretas IV.[42]

Roman legions under Pompey conquered much of the Levant in 63 BC, inaugurating a period of Roman rule that lasted four centuries.[43] In 106 AD, Emperor Trajan annexed Nabataea unopposed, and rebuilt the King’s Highway which became known as the Via Traiana Nova road.[43] The Romans gave the Greek cities of TransjordanPhiladelphia (Amman), Gerasa (Jerash), Gedara (Umm Qays), Pella (Tabaqat Fahl) and Arbila (Irbid)and other Hellenistic cities in Palestine and southern Syria, a level of autonomy by forming the Decapolis, a ten-city league.[44] Jerash is one of the best preserved Roman cities in the East; it was even visited by Emperor Hadrian during his journey to Palestine.[45]

In 324 AD, the Roman Empire split, and the Eastern Roman Empirelater known as the Byzantine Empirecontinued to control or influence the region until 636 AD.[46] Christianity had become legal within the empire in 313 AD and the official state religion in 390 AD, after Emperor Constantine converted to Christianity.[46] Transjordan prospered during the Byzantine era, and Christian churches were built everywhere. The Aqaba Church in Ayla was built during this era, it is considered to be the world’s first purpose built Christian church.[48] Umm ar-Rasas in southern Amman contains at least 16 Byzantine churches.[49] Meanwhile, Petra’s importance declined as sea trade routes emerged, and after a 363 earthquake destroyed many structures, until it became an abandoned place.[42] The Sassanian Empire in the east became the Byzantines’ rivals, and frequent confrontations sometimes led to the Sassanids controlling some parts of the region, including Transjordan.[50]

In 629 AD, during the Battle of Mu’tah in what is today Al-Karak, the Byzantines and their Arab Christian clients, the Ghassanids, staved off an attack by a Muslim Rashidun force that marched northwards towards the Levant from the Hejaz (in modern-day Saudi Arabia).[51] The Byzantines however were defeated by the Muslims in 636 AD at the decisive Battle of Yarmouk just north of Transjordan.[51] Transjordan was an essential territory for the conquest of Damascus.[52] The first, or Rashidun, caliphate was followed by that of the Ummayads (661750).[52] Under the Umayyad Caliphate, several desert castles were constructed in Transjordan, including: Qasr Al-Mshatta and Qasr Al-Hallabat.[52] The Abbasid Caliphate’s campaign to take over the Umayyad’s began in Transjordan.[53] A powerful 747 AD earthquake is thought to have contributed to the Umayyads defeat to the Abbasids, who moved the caliphate’s capital from Damascus to Baghdad.[53] During Abbasid rule (750969), several Arab tribes moved northwards and settled in the Levant.[52] Concurrently, growth of maritime trade diminished Transjordan’s central position, and the area became increasingly impoverished. After the decline of the Abbasids, Transjordan was ruled by the Fatimid Caliphate (9691070), then by the Crusader Kingdom of Jerusalem (11151187).

The Crusaders constructed several Crusader castles as part of the Lordship of Oultrejordain, including those of Montreal and Al-Karak.[56] The Ayyubids built the Ajloun Castle and rebuilt older castles, to be used as military outposts against the Crusaders. During the Battle of Hattin (1187) near Lake Tiberias just north of Transjordan, the Crusaders lost to Saladin, the founder of the Ayyubid dynasty (11871260). Villages in Transjordan under the Ayyubids became important stops for Muslim pilgrims going to Mecca who travelled along the route that connected Syria to the Hejaz.[58] Several of the Ayyubid castles were used and expanded by the Mamluks (12601516), who divided Transjordan between the provinces of Karak and Damascus. During the next century Transjordan experienced Mongol attacks, but the Mongols were ultimately repelled by the Mamluks after the Battle of Ain Jalut (1260).[60]

In 1516, the Ottoman Caliphate’s forces conquered Mamluk territory. Agricultural villages in Transjordan witnessed a period of relative prosperity in the 16th century, but were later abandoned.[62] Transjordan was of marginal importance to the Ottoman authorities.[63] As a result, Ottoman presence was virtually absent and reduced to annual tax collection visits.[62] More Arab bedouin tribes moved into Transjordan from Syria and the Hejaz during the first three centuries of Ottoman rule, including the Adwan, the Bani Sakhr and the Howeitat. These tribes laid claims to different parts of the region, and with the absence of a meaningful Ottoman authority, Transjordan slid into a state of anarchy that continued till the 19th century. This led to a short-lived occupation by the Wahhabi forces (18031812), an ultra-orthodox Islamic movement that emerged in Najd (in modern-day Saudi Arabia). Ibrahim Pasha, son of the governor of the Egypt Eyalet under the request of the Ottoman sultan, rooted out the Wahhabis by 1818. In 1833 Ibrahim Pasha turned on the Ottomans and established his rule over the Levant.[68] His oppressive policies led to the unsuccessful peasants’ revolt in Palestine in 1834.[68] Transjordanian cities of Al-Salt and Al-Karak were destroyed by Ibrahim Pasha’s forces for harbouring a peasants’ revolt leader.[68] Egyptian rule was forcibly ended in 1841, with Ottoman rule restored.[68]

Only after Ibrahim Pasha’s campaign did the Ottoman Empire try to solidify its presence in the Syria Vilayet, which Transjordan was part of. A series of tax and land reforms (Tanzimat) in 1864 brought some prosperity back to agriculture and to abandoned villages, while it provoked a backlash in other areas of Transjordan. Muslim Circassians and Chechens, fleeing Russian persecution, sought refuge in the Levant.[70] In Transjordan and with Ottoman support, Circassians first settled in the long-abandoned vicinity of Amman in 1867, and later in the surrounding villages.[70] After having established its administration, conscription and heavy taxation policies by the Ottoman authorities, led to revolts in the areas it controlled. Transjordan’s tribes in particular revolted during the Shoubak (1905) and the Karak Revolts (1910), which were brutally suppressed.[70] The construction of the Hejaz Railway in 1908stretching across the length of Transjordan and linking Mecca with Istanbulhelped the population economically as Transjordan became a stopover for pilgrims.[70] However, increasing policies of Turkification and centralization adopted by the Ottoman Empire disenchanted the Arabs of the Levant.

Four centuries of stagnation during Ottoman rule came to an end during World War I by the 1916 Arab Revolt; driven by long-term resentment towards the Ottoman authorities, and growing Arab nationalism.[70] The revolt was led by Sharif Hussein of Mecca, and his sons Abdullah, Faisal and Ali, members of the Hashemite dynasty of the Hejaz, descendants of the Prophet Muhammad.[70] Locally, the revolt garnered the support of the Transjordanian tribes, including Bedouins, Circassians and Christians. The Allies of World WarI, including Britain and France, whose imperial interests converged with the Arabist cause, offered support. The revolt started on 5 June 1916 from Medina and pushed northwards until the fighting reached Transjordan in the Battle of Aqaba on 6 July 1917.[75] The revolt reached its climax when Faisal entered Damascus in October 1918, and established the Arab Kingdom of Syria, which Transjordan was part of.

The nascent Hashemite Kingdom was forced to surrender to French troops on 24 July 1920 during the Battle of Maysalun.[76] Arab aspirations failed to gain international recognition, due mainly to the secret 1916 SykesPicot Agreement, which divided the region into French and British spheres of influence, and the 1917 Balfour Declaration. This was seen by the Hashemites and the Arabs as a betrayal of their previous agreements with the British, including the 1915 McMahonHussein Correspondence, in which the British stated their willingness to recognize the independence of a unified Arab state stretching from Aleppo to Aden under the rule of the Hashemites.[79]:55 Abdullah, the second son of Sharif Hussein, arrived from Hejaz by train in Ma’an in southern Transjordan on 21 November 1920 to redeem the Kingdom his brother had lost. Transjordan then was in disarray; widely considered to be ungovernable with its dysfunctional local governments. Abdullah then moved to Amman and established the Emirate of Transjordan on 11 April 1921.

The British reluctantly accepted Abdullah as ruler of Transjordan. Abdullah gained the trust of Tansjordan’s tribal leaders before scrambling to convince them of the benefits of an organized government. Abdullah’s successes drew the envy of the British, even when it was in their interest. In September 1922, the Council of the League of Nations recognised Transjordan as a state under the British Mandate for Palestine and the Transjordan memorandum, and excluded the territories east of the Jordan River from the provisions of the mandate dealing with Jewish settlement.[86][87] Transjordan remained a British mandate until 1946, but it had been granted a greater level of autonomy than the region west of the Jordan River.[88]

The first organised army in Jordan was established on 22 October 1920, and was named the “Arab Legion”.[89] The Legion grew from 150 men in 1920 to 8,000 in 1946.[90] Multiple difficulties emerged upon the assumption of power in the region by the Hashemite leadership.[89] In Transjordan, small local rebellions at Kura in 1921 and 1923 were suppressed by Emir Abdullah with the help of British forces.[89] Wahhabis from Najd regained strength and repeatedly raided the southern parts of his territory in (19221924), seriously threatening the Emir’s position.[89] The Emir was unable to repel those raids without the aid of the local Bedouin tribes and the British, who maintained a military base with a small RAF detachment close to Amman.[89]

The Treaty of London, signed by the British Government and the Emir of Transjordan on 22 March 1946, recognised the independence of Transjordan upon ratification by both countries’ parliaments.[91] On 25 May 1946, the Emirate of Transjordan became the Hashemite Kingdom of Transjordan, as the ruling Emir was re-designated as King by the parliament of Transjordan on the day it ratified the Treaty of London.[92] The name was changed to the Hashemite Kingdom of Jordan in 1949.[10] Jordan became a member of the United Nations on 14 December 1955.[10]

On 15 May 1948, as part of the 1948 ArabIsraeli War, Jordan invaded Palestine together with other Arab states.[93] Following the war, Jordan controlled the West Bank and on 24 April 1950 Jordan formally annexed these territories.[94][95] In response, some Arab countries demanded Jordan’s expulsion from the Arab League.[94] On 12 June 1950, the Arab League declared that the annexation was a temporary, practical measure and that Jordan was holding the territory as a “trustee” pending a future settlement.[96] King Abdullah was assassinated at the Al-Aqsa Mosque in 1951 by a Palestinian militant, amid rumours he intended to sign a peace treaty with Israel.[97]

Abdullah was succeeded by his son Talal, who would soon abdicate due to illness in favour of his eldest son Hussein.[98] Talal established the country’s modern constitution in 1952.[98] Hussein ascended to the throne in 1953 at the age of 17.[97] Jordan witnessed great political uncertainty in the following period.[99] The 1950s were a period of political upheaval, as Nasserism and Pan-Arabism swept the Arab World.[99] On 1 March 1956, King Hussein Arabized the command of the Army by dismissing a number of senior British officers, an act made to remove remaining foreign influence in the country.[100] In 1958, Jordan and neighbouring Hashemite Iraq formed the Arab Federation as a response to the formation of the rival United Arab Republic between Nasser’s Egypt and Syria.[101] The union lasted only six months, being dissolved after Iraqi King Faisal II (Hussein’s cousin) was deposed by a bloody military coup on 14 July 1958.[101]

Jordan signed a military pact with Egypt just before Israel launched a preemptive strike on Egypt to begin the Six-Day War in June 1967, where Jordan and Syria joined the war.[102] The Arab states were defeated and Jordan lost control of the West Bank to Israel.[102] The War of Attrition with Israel followed, which included the 1968 Battle of Karameh where the combined forces of the Jordanian Armed Forces and the Palestine Liberation Organization (PLO) repelled an Israeli attack on the Karameh camp on the Jordanian border with the West Bank.[102] Despite the fact that the Palestinians had limited involvement against the Israeli forces, the events at Karameh gained wide recognition and acclaim in the Arab world.[103] As a result, the time period following the battle witnessed an upsurge of support for Palestinian paramilitary elements (the fedayeen) within Jordan from other Arab countries.[103] The fedayeen activities soon became a threat to Jordan’s rule of law.[103] In September 1970, the Jordanian army targeted the fedayeen and the resultant fighting led to the expulsion of Palestinian fighters from various PLO groups into Lebanon, in a civil war that became known as Black September.[103]

In 1973, Egypt and Syria waged the Yom Kippur War on Israel, and fighting occurred along the 1967 Jordan River cease-fire line.[103] Jordan sent a brigade to Syria to attack Israeli units on Syrian territory but did not engage Israeli forces from Jordanian territory.[103] At the Rabat summit conference in 1974, Jordan agreed, along with the rest of the Arab League, that the PLO was the “sole legitimate representative of the Palestinian people”.[103] Subsequently, Jordan renounced its claims to the West Bank in 1988.[103]

At the 1991 Madrid Conference, Jordan agreed to negotiate a peace treaty sponsored by the US and the Soviet Union.[103] The Israel-Jordan Treaty of Peace was signed on 26 October 1994.[103] In 1997, Israeli agents entered Jordan using Canadian passports and poisoned Khaled Meshal, a senior Hamas leader.[103] Israel provided an antidote to the poison and released dozens of political prisoners, including Sheikh Ahmed Yassin after King Hussein threatened to annul the peace treaty.[103]

On 7 February 1999, Abdullah II ascended the throne upon the death of his father Hussein.[104] Abdullah embarked on aggressive economic liberalisation when he assumed the throne, and his reforms led to an economic boom which continued until 2008.[105] Abdullah II has been credited with increasing foreign investment, improving public-private partnerships and providing the foundation for Aqaba’s free-trade zone and Jordan’s flourishing information and communication technology (ICT) sector.[105] He also set up five other special economic zones.[105] However, during the following years Jordan’s economy experienced hardship as it dealt with the effects of the Great Recession and spillover from the Arab Spring.[106]

Al-Qaeda under Abu Musab al-Zarqawi’s leadership launched coordinated explosions in three hotel lobbies in Amman on 9 November 2005, resulting in 60 deaths and 115 injured.[107] The bombings, which targeted civilians, caused widespread outrage among Jordanians.[107] The attack is considered to be a rare event in the country, and Jordan’s internal security was dramatically improved afterwards.[107] No major terrorist attacks have occurred since then.[108] Abdullah and Jordan are viewed with contempt by Islamic extremists for the country’s peace treaty with Israel and its relationship with the West.[109]

The Arab Spring were large-scale protests that erupted in the Arab World in 2011, demanding economic and political reforms.[110] Many of these protests tore down regimes in some Arab nations, leading to instability that ended with violent civil wars.[110] In Jordan, in response to domestic unrest, Abdullah replaced his prime minister and introduced a number of reforms including: reforming the Constitution, and laws governing public freedoms and elections.[110] Proportional representation was re-introduced to the Jordanian parliament in the 2016 general election, a move which he said would eventually lead to establishing parliamentary governments.[111] Jordan was left largely unscathed from the violence that swept the region despite an influx of 1.4 million Syrian refugees into the natural resources-lacking country and the emergence of the Islamic State of Iraq and the Levant (ISIL).[111]

Jordan sits strategically at the crossroads of the continents of Asia, Africa and Europe,[8] in the Levant area of the Fertile Crescent, a cradle of civilization.[112] It is 89,341 square kilometres (34,495sqmi) large, and 400 kilometres (250mi) long between its northernmost and southernmost points; Umm Qais and Aqaba respectively.[17] The kingdom lies between 29 and 34 N, and 34 and 40 E. The east is an arid plateau irrigated by oases and seasonal water streams.[17] Major cities are overwhelmingly located on the north-western part of the kingdom due to its fertile soils and relatively abundant rainfall.[113] These include Irbid, Jerash and Zarqa in the northwest, the capital Amman and Al-Salt in the central west, and Madaba, Al-Karak and Aqaba in the southwest.[113] Major towns in the eastern part of the country are the oasis towns of Azraq and Ruwaished.[112]

In the west, a highland area of arable land and Mediterranean evergreen forestry drops suddenly into the Jordan Rift Valley.[112] The rift valley contains the Jordan River and the Dead Sea, which separates Jordan from Israel and the Palestinian Territories.[112] Jordan has a 26 kilometres (16mi) shoreline on the Gulf of Aqaba in the Red Sea, but is otherwise landlocked.[7] The Yarmouk River, an eastern tributary of the Jordan, forms part of the boundary between Jordan and Syria (including the occupied Golan Heights) to the north.[7] The other boundaries are formed by several international and local agreements and do not follow well-defined natural features.[112] The highest point is Jabal Umm al Dami, at 1,854m (6,083ft) above sea level, while the lowest is the Dead Sea 420m (1,378ft), the lowest land point on earth.[112]

Jordan has a diverse range of habitats, ecosystems and biota due to its varied landscapes and environments.[114] The Royal Society for the Conservation of Nature was set up in 1966 to protect and manage Jordan’s natural resources.[115] Nature reserves in Jordan include the Dana Biosphere Reserve, the Azraq Wetland Reserve, the Shaumari Wildlife Reserve and the Mujib Nature Reserve.[115]

The climate in Jordan varies greatly. Generally, the further inland from the Mediterranean, greater contrasts in temperature occur and the less rainfall there is.[17] The country’s average elevation is 812m (2,664ft) (SL).[17] The highlands above the Jordan Valley, mountains of the Dead Sea and Wadi Araba and as far south as Ras Al-Naqab are dominated by a Mediterranean climate, while the eastern and northeastern areas of the country are arid desert.[116] Although the desert parts of the kingdom reach high temperatures, the heat is usually moderated by low humidity and a daytime breeze, while the nights are cool.[117]

Summers, lasting from May to September, are hot and dry, with temperatures averaging around 32C (90F) and sometimes exceeding 40C (104F) between July and August.[117] The winter, lasting from November to March, is relatively cool, with temperatures averaging around 13C (55F).[116] Winter also sees frequent showers and occasional snowfall in some western elevated areas.[116]

Over 2,000 plant species have been recorded in Jordan.[118] Many of the flowering plants bloom in the spring after the winter rains and the type of vegetation depends largely on the levels of precipitation. The mountainous regions in the northwest are clothed in forests, while further south and east the vegetation becomes more scrubby and transitions to steppe-type vegetation.[119] Forests cover 1.5 million dunums (1,500km2), less than 2% of Jordan, making Jordan among the world’s least forested countries, the international average being 15%.[120]

Plant species include, Aleppo pine, Sarcopoterium, Salvia dominica, black iris, Tamarix, Anabasis, Artemisia, Acacia, Mediterranean cypress and Phoenecian juniper.[121] The mountainous regions in the northwest are clothed in natural forests of pine, deciduous oak, evergreen oak, pistachio and wild olive.[122] Mammal and reptile species include, the long-eared hedgehog, Nubian ibex, wild boar, fallow deer, Arabian wolf, desert monitor, honey badger, glass snake, caracal, golden jackal and the roe deer, among others.[123][124][125] Bird include the hooded crow, Eurasian jay, lappet-faced vulture, barbary falcon, hoopoe, pharaoh eagle-owl, common cuckoo, Tristram’s starling, Palestine sunbird, Sinai rosefinch, lesser kestrel, house crow and the white-spectacled bulbul.[126]

Jordan is a unitary state under a constitutional monarchy. Jordan’s constitution, adopted in 1952 and amended a number of times since, is the legal framework that governs the monarch, government, bicameral legislature and judiciary.[127] The king retains wide executive and legislative powers from the government and parliament.[128] The king exercises his powers through the government that he appoints for a four-year term, which is responsible before the parliament that is made up of two chambers: the Senate and the House of Representatives. The judiciary is independent according to the constitution.[127]

The king is the head of state and commander-in-chief of the army. He can declare war and peace, ratify laws and treaties, convene and close legislative sessions, call and postpone elections, dismiss the government and dissolve the parliament.[127] The appointed government can also be dismissed through a majority vote of no confidence by the elected House of Representatives. After a bill is proposed by the government, it must be approved by the House of Representatives then the Senate, and becomes law after being ratified by the king. A royal veto on legislation can be overridden by a two-thirds vote in a joint session of both houses. The parliament also has the right of interpellation.[127]

The 65 members of the upper Senate are directly appointed by the king, the constitution mandates that they be veteran politicians, judges and generals who previously served in the government or in the House of Representatives.[129] The 130 members of the lower House of Representatives are elected through party-list proportional representation in 23 constituencies for a 4-year term.[130] Minimum quotas exist in the House of Representatives for women (15 seats, though they won 20 seats in the 2016 election), Christians (9 seats) and Circassians and Chechens (3 seats).[131]

Courts are divided into three categories: civil, religious, and special.[132] The civil courts deal with civil and criminal matters, including cases brought against the government.[132] The civil courts include Magistrate Courts, Courts of First Instance, Courts of Appeal,[132] High Administrative Courts which hear cases relating to administrative matters,[133] and the Constitutional Court which was set up in 2012 in order to hear cases regarding the constitutionality of laws.[134] Although Islam is the state religion, the constitution preserves religious and personal freedoms. Religious law only extends to matters of personal status such as divorce and inheritance in religious courts, and is partially based on Islamic Sharia law.[135] The special court deals with cases forwarded by the civil one.[136]

The capital city of Jordan is Amman, located in north-central Jordan.[9] Jordan is divided into 12 governorates (muhafazah) (informally grouped into three regions: northern, central, southern). These are subdivided into a total of 52 nawahi, which are further divided into neighbourhoods in urban areas or into towns in rural ones.[137]

The current monarch, Abdullah II, ascended to the throne in February 1999 after the death of his father Hussein. Abdullah re-affirmed Jordan’s commitment to the peace treaty with Israel and its relations with the United States. He refocused the government’s agenda on economic reform, during his first year. King Abdullah’s eldest son, Prince Hussein, is the current Crown Prince of Jordan.[138] The current prime minister is Omar Razzaz who received his position on 4 June 2018 after his predecessor’s austerity measures forced widespread protests.[139] Abdullah had announced his intentions of turning Jordan into a parliamentary system, where the largest bloc in parliament forms a government. However, the underdevelopment of political parties in the country have hampered such moves.[140] Jordan has around 50 political parties representing nationalist, leftist, Islamist, and liberal ideologies.[141] Political parties contested a fifth of the seats in the 2016 elections, the remainder belonging to independent politicians.[142]

According to Freedom House, Jordan is ranked as the 3rd freest Arab country, and as “partly free” in the Freedom in the World 2018 report.[143] The 2010 Arab Democracy Index from the Arab Reform Initiative ranked Jordan first in the state of democratic reforms out of 15 Arab countries.[144] Jordan ranked first among the Arab states and 78th globally in the Human Freedom Index in 2015,[145] and ranked 55th out of 175 countries in the Corruption Perceptions Index (CPI) issued by Transparency International in 2014, where 175th is most corrupt.[146] In the 2016 Press Freedom Index maintained by Reporters Without Borders, Jordan ranked 135th out of 180 countries worldwide, and 5th of 19 countries in the Middle East and North Africa region. Jordan’s score was 44 on a scale from 0 (most free) to 105 (least free). The report added “the Arab Spring and the Syrian conflict have led the authorities to tighten their grip on the media and, in particular, the Internet, despite an outcry from civil society”.[147] Jordanian media consists of public and private institutions. Popular Jordanian newspapers include Al Ghad and the Jordan Times. The two most-watched local TV stations are Ro’ya TV and Jordan TV.[148] Internet penetration in Jordan reached 76% in 2015.[149]

The first level subdivision in Jordan is the muhafazah or governorate. The governorates are divided into liwa or districts, which are often further subdivided into qda or sub-districts.[150] Control for each administrative unit is in a “chief town” (administrative centre) known as a nahia.[150]

The kingdom has followed a pro-Western foreign policy and maintained close relations with the United States and the United Kingdom. During the first Gulf War (1990), these relations were damaged by Jordan’s neutrality and its maintenance of relations with Iraq. Later, Jordan restored its relations with Western countries through its participation in the enforcement of UN sanctions against Iraq and in the Southwest Asia peace process. After King Hussein’s death in 1999, relations between Jordan and the Persian Gulf countries greatly improved.[151]

Jordan is a key ally of the USA and UK and, together with Egypt, is one of only two Arab nations to have signed peace treaties with Israel, Jordan’s direct neighbour.[152] Jordan views an independent Palestinian state with the 1967 borders, as part of the two-state solution and of supreme national interest.[153] The ruling Hashemite dynasty has had custodianship over holy sites in Jerusalem since 1924, a position re-inforced in the IsraelJordan peace treaty. Turmoil in Jerusalem’s Al-Aqsa mosque between Israelis and Palestinians created tensions between Jordan and Israel concerning the former’s role in protecting the Muslim and Christian sites in Jerusalem.[154]

Jordan is a founding member of the Organisation of Islamic Cooperation and of the Arab League.[155][156] It enjoys “advanced status” with the European Union and is part of the European Neighbourhood Policy (ENP), which aims to increase links between the EU and its neighbours.[157] Jordan and Morocco tried to join the Gulf Cooperation Council (GCC) in 2011, but the Gulf countries offered a five-year development aid programme instead.[158]

The first organised army in Jordan was established on 22 October 1920, and was named the “Arab Legion”. Jordan’s capture of the West Bank during the 1948 ArabIsraeli War proved that the Arab Legion, known today as the Jordan Armed Forces, was the most effective among the Arab troops involved in the war.[90] The Royal Jordanian Army, which boasts around 110,000 personnel, is considered to be among the most professional in the region, due to being particularly well-trained and organised.[90] The Jordanian military enjoys strong support and aid from the United States, the United Kingdom and France. This is due to Jordan’s critical position in the Middle East.[90] The development of Special Operations Forces has been particularly significant, enhancing the capability of the military to react rapidly to threats to homeland security, as well as training special forces from the region and beyond.[159] Jordan provides extensive training to the security forces of several Arab countries.[160]

There are about 50,000 Jordanian troops working with the United Nations in peacekeeping missions across the world. Jordan ranks third internationally in participation in U.N. peacekeeping missions,[161] with one of the highest levels of peacekeeping troop contributions of all U.N. member states.[162] Jordan has dispatched several field hospitals to conflict zones and areas affected by natural disasters across the region.[163]

In 2014, Jordan joined an aerial bombardment campaign by an international coalition led by the United States against the Islamic State as part of its intervention in the Syrian Civil War.[164] In 2015, Jordan participated in the Saudi Arabian-led military intervention in Yemen against the Shia Houthis and forces loyal to former President Ali Abdullah Saleh, who was deposed in the 2011 uprising.[165]

Jordan’s law enforcement is under the purview of the Public Security Directorate (which includes approximately 50,000 persons) and the General Directorate of Gendarmerie, both of which are subordinate to the country’s Ministry of Interior. The first police force in the Jordanian state was organised after the fall of the Ottoman Empire on 11 April 1921.[166] Until 1956 police duties were carried out by the Arab Legion and the Transjordan Frontier Force. After that year the Public Safety Directorate was established.[166] The number of female police officers is increasing. In the 1970s, it was the first Arab country to include females in its police force.[167] Jordan’s law enforcement was ranked 37th in the world and 3rd in the Middle East, in terms of police services’ performance, by the 2016 World Internal Security and Police Index.[11][168]

Jordan is classified by the World Bank as an “upper-middle income” country.[169] However, approximately 14.4% of the population lives below the national poverty line on a longterm basis (as of 2010[update]),[169] while almost a third fell below the national poverty line during some time of the yearknown as transient poverty.[170] The economy, which boasts a GDP of $39.453 billion (as of 2016[update]),[4] grew at an average rate of 8% per annum between 2004 and 2008, and around 2.6% 2010 onwards.[17] GDP per capita rose by 351% in the 1970s, declined 30% in the 1980s, and rose 36% in the 1990scurrently $5,092 per capita.[171] The Jordanian economy is one of the smallest economies in the region, and the country’s populace suffers from relatively high rates of unemployment and poverty.[17]

Jordan’s economy is relatively well diversified. Trade and finance combined account for nearly one-third of GDP; transportation and communication, public utilities, and construction account for one-fifth, and mining and manufacturing constitute nearly another fifth. Despite plans to expand the private sector, the state remains the dominant force in Jordan’s economy.[16] Net official development assistance to Jordan in 2009 totalled USD 761 million; according to the government, approximately two-thirds of this was allocated as grants, of which half was direct budget support.[172]

The official currency is the Jordanian dinar, which is pegged to the IMF’s special drawing rights (SDRs), equivalent to an exchange rate of 1 US$ 0.709 dinar, or approximately 1 dinar 1.41044 dollars.[173] In 2000, Jordan joined the World Trade Organization and signed the JordanUnited States Free Trade Agreement, thus becoming the first Arab country to establish a free trade agreement with the United States. Jordan enjoys advanced status with the EU, which has facilitated greater access to export to European markets.[174] Due to slow domestic growth, high energy and food subsidies and a bloated public-sector workforce, Jordan usually runs annual budget deficits.[175]

The Great Recession and the turmoil caused by the Arab Spring have depressed Jordan’s GDP growth, damaging trade, industry, construction and tourism.[17] Tourist arrivals have dropped sharply since 2011.[176] Since 2011, the natural gas pipeline in Sinai supplying Jordan from Egypt was attacked 32 times by Islamic State affiliates. Jordan incurred billions of dollars in losses because it had to substitute more expensive heavy-fuel oils to generate electricity.[177] In November 2012, the government cut subsidies on fuel, increasing its price.[178] The decision, which was later revoked, caused large scale protests to break out across the country.[175][176]

Jordan’s total foreign debt in 2011 was $19 billion, representing 60% of its GDP. In 2016, the debt reached $35.1 billion representing 93% of its GDP.[106] This substantial increase is attributed to effects of regional instability causing: decrease in tourist activity; decreased foreign investments; increased military expenditure; attacks on Egyptian pipeline; the collapse of trade with Iraq and Syria; expenses from hosting Syrian refugees and accumulated interests from loans.[106] According to the World Bank, Syrian refugees have cost Jordan more than $2.5 billion a year, amounting to 6% of the GDP and 25% of the government’s annual revenue.[179] Foreign aid covers only a small part of these costs, 63% of the total costs are covered by Jordan.[180] An austerity programme was adopted by the government which aims to reduce Jordan’s debt-to-GDP ratio to 77 percent by 2021.[181] The programme succeeded in preventing the debt from rising above 95% in 2018.[182]

The proportion of well-educated and skilled workers in Jordan is among the highest in the region in sectors such as ICT and industry, due to a relatively modern educational system. This has attracted large foreign investments to Jordan and has enabled the country to export its workforce to Persian Gulf countries.[14] Flows of remittances to Jordan grew rapidly, particularly during the end of the 1970s and 1980s, and remains an important source of external funding.[183] Remittances from Jordanian expatriates were $3.8 billion in 2015, a notable rise in the amount of transfers compared to 2014 where remittances reached over $3.66 billion listing Jordan as fourth largest recipient in the region.[184]

Jordan is ranked as having the 35th best infrastructure in the world, one of the highest rankings in the developing world, according to the 2010 World Economic Forum’s Index of Economic Competitiveness. This high infrastructural development is necessitated by its role as a transit country for goods and services to Palestine and Iraq. Palestinians use Jordan as a transit country due to the Israeli restrictions and Iraqis use Jordan due to the instability in Iraq.[185]

According to data from the Jordanian Ministry of Public Works and Housing, as of 2011[update], the Jordanian road network consisted of 2,878km (1,788mi) of main roads; 2,592km (1,611mi) of rural roads and 1,733km (1,077mi) of side roads. The Hejaz Railway built during the Ottoman Empire which extended from Damascus to Mecca will act as a base for future railway expansion plans. Currently, the railway has little civilian activity; it is primarily used for transporting goods. A national railway project is currently undergoing studies and seeking funding sources.[186]

Jordan has three commercial airports, all receiving and dispatching international flights. Two are in Amman and the third is in Aqaba, King Hussein International Airport. Amman Civil Airport serves several regional routes and charter flights while Queen Alia International Airport is the major international airport in Jordan and is the hub for Royal Jordanian, the flag carrier. Queen Alia International Airport expansion was completed in 2013 with new terminals costing $700 million, to handle over 16 million passengers annually.[187] It is now considered a state-of-the-art airport and was awarded ‘the best airport by region: Middle East’ for 2014 and 2015 by Airport Service Quality (ASQ) survey, the world’s leading airport passenger satisfaction benchmark programme.[188]

The Port of Aqaba is the only port in Jordan. In 2006, the port was ranked as being the “Best Container Terminal” in the Middle East by Lloyd’s List. The port was chosen due to it being a transit cargo port for other neighbouring countries, its location between four countries and three continents, being an exclusive gateway for the local market and for the improvements it has recently witnessed.[189]

The tourism sector is considered a cornerstone of the economy, being a large source of employment, hard currency and economic growth. In 2010, there were 8 million visitors to Jordan. The majority of tourists coming to Jordan are from European and Arab countries.[15] The tourism sector in Jordan has been severely affected by regional turbulence.[190] The most recent blow to the tourism sector was caused by the Arab Spring, which scared off tourists from the entire region. Jordan experienced a 70% decrease in the number of tourists from 2010 to 2016.[191] Tourist numbers started to recover as of 2017.[191]

According to the Ministry of Tourism and Antiquities, Jordan is home to around 100,000 archaeological and tourist sites.[192] Some very well preserved historical cities include Petra and Jerash, the former being Jordan’s most popular tourist attraction and an icon of the kingdom.[191] Jordan is part of the Holy Land and has several biblical attractions that attract pilgrimage activities. Biblical sites include: Al-Maghtasa traditional location for the Baptism of Jesus, Mount Nebo, Umm ar-Rasas, Madaba and Machaerus.[193] Islamic sites include shrines of the prophet Muhammad’s companions such as ‘Abd Allah ibn Rawahah, Zayd ibn Harithah and Muadh ibn Jabal.[194] Ajlun Castle built by Muslim Ayyubid leader Saladin in the 12th century AD during his wars with the Crusaders, is also a popular tourist attraction.[8]

Modern entertainment and recreation in urban areas, mostly in Amman, also attract tourists. Recently, the nightlife in Amman, Aqaba and Irbid has started to emerge and the number of bars, discos and nightclubs is on the rise.[195] Alcohol is widely available in tourist restaurants, liquor stores and even some supermarkets.[196] Valleys like Wadi Mujib and hiking trails in different parts of the country attract adventurers. Moreover, seaside recreation is present on the shores of Aqaba and the Dead Sea through several international resorts.[197]

Jordan has been a medical tourism destination in the Middle East since the 1970s. A study conducted by Jordan’s Private Hospitals Association found that 250,000 patients from 102 countries received treatment in Jordan in 2010, compared to 190,000 in 2007, bringing over $1 billion in revenue. Jordan is the region’s top medical tourism destination, as rated by the World Bank, and fifth in the world overall.[198] The majority of patients come from Yemen, Libya and Syria due to the ongoing civil wars in those countries. Jordanian doctors and medical staff have gained experience in dealing with war patients through years of receiving such cases from various conflict zones in the region.[199] Jordan also is a hub for natural treatment methods in both Ma’in Hot Springs and the Dead Sea. The Dead Sea is often described as a ‘natural spa’. It contains 10 times more salt than the average ocean, which makes it impossible to sink in. The high salt concentration of the Dead Sea has been proved as being therapeutic for many skin diseases. The uniqueness of this lake attracts several Jordanian and foreign vacationers, which boosted investments in the hotel sector in the area.[200] The Jordan Trail, a 650km (400mi) hiking trail stretching the entire country from north to south, crossing several of Jordan’s attractions was established in 2015.[201] The trail aims to revive the Jordanian tourism sector.[201]

Jordan is the world’s second poorest country in terms of water resources per capita, and scarce water resources were aggravated by the influx of Syrian refugees.[202] Water from Disi aquifer and ten major dams historically played a large role in providing Jordan’s need for fresh water.[203] The Jawa Dam in northeastern Jordan, which dates back to the fourth millennium BC, is the world’s oldest dam.[204] The Dead Sea is receding at an alarming rate. Multiple canals and pipelines were proposed to reduce its recession, which had begun causing sinkholes. The Red SeaDead Sea Water Conveyance project, carried out by Jordan, will provide water to the country and to Israel and Palestine, while the brine will be carried to the Dead Sea to help stabilise its levels. The first phase of the project is scheduled to begin in 2018 and to be completed in 2021.[205]

Natural gas was discovered in Jordan in 1987, however, the estimated size of the reserve discovered was about 230 billion cubic feet, a minuscule quantity compared with its oil-rich neighbours. The Risha field, in the eastern desert beside the Iraqi border, produces nearly 35 million cubic feet of gas a day, which is sent to a nearby power plant to generate a small amount of Jordan’s electricity needs.[206] This led to a reliance on importing oil to generate almost all of its electricity. Regional instability over the decades halted oil and gas supply to the kingdom from various sources, making it incur billions of dollars in losses. Jordan built a liquified natural gas port in Aqaba in 2012 to temporarily substitute the supply, while formulating a strategy to rationalize energy consumption and to diversify its energy sources. Jordan receives 330 days of sunshine per year, and wind speeds reach over 7m/s in the mountainous areas, so renewables proved a promising sector.[207] King Abdullah inaugurated large-scale renewable energy projects in the 2010s including: the 117 MW Tafila Wind Farm, the 53 MW Shams Ma’an and the 103 MW Quweira solar power plants, with several more projects planned. By early 2018, it was reported that more than 500 MW of renewable energy projects had been completed, contributing to 7% of Jordan’s electricity up from 3% in 2011, while 93% was generated from gas.[208] After having initially set the percentage of renewable energy Jordan aimed to generate by 2020 at 10%, the government announced in 2018 that it sought to beat that figure and aim for 20%.[209] A report by pv magazine described Jordan as the Middle East’s “solar powerhouse”.[210]

Jordan has the 5th largest oil-shale reserves in the world, which could be commercially exploited in the central and northwestern regions of the country.[211] Official figures estimate the kingdom’s oil shale reserves at more than 70 billion tonnes. The extraction of oil-shale had been delayed a couple of years due to technological difficulties; and the relatively higher costs.[212] The government overcame the difficulties and in 2017 laid the groundbreaking for the Attarat Power Plant, a $2.2 billion oil shale-dependent power plant that is expected to generate 470 MW after it is completed in 2020.[213] Jordan also aims to benefit from its large uranium reserves by tapping nuclear energy. The original plan involved constructing two 1000 MW reactors but has been scrapped due to financial constraints.[214] Currently, the country’s Atomic Energy Commission is considering building small modular reactors instead, whose capacities hover below 500 MW and can provide new water sources through desalination. In 2018, the Commission announced that Jordan was in talks with multiple companies to build the country’s first commercial nuclear plant, a Helium-cooled reactor that is scheduled for completion by 2025.[215] Phosphate mines in the south have made Jordan one of the largest producers and exporters of the mineral in the world.[216]

Jordan’s well developed industrial sector, which includes mining, manufacturing, construction, and power, accounted for approximately 26% of the GDP in 2004 (including manufacturing, 16.2%; construction, 4.6%; and mining, 3.1%). More than 21% of Jordan’s labor force was employed in industry in 2002. In 2014, industry accounted for 6% of the GDP.[217] The main industrial products are potash, phosphates, cement, clothes, and fertilisers. The most promising segment of this sector is construction. Petra Engineering Industries Company, which is considered to be one of the main pillars of Jordanian industry, has gained international recognition with its air-conditioning units reaching NASA.[218] Jordan is now considered to be a leading pharmaceuticals manufacturer in the MENA region led by Jordanian pharmaceutical company Hikma.[219]

Jordan’s military industry thrived after the King Abdullah Design and Development Bureau (KADDB) defence company was established by King Abdullah II in 1999, to provide an indigenous capability for the supply of scientific and technical services to the Jordanian Armed Forces, and to become a global hub in security research and development. It manufactures all types of military products, many of which are presented at the bi-annually held international military exhibition SOFEX. In 2015, KADDB exported $72 million worth of industries to over 42 countries.[220]

Science and technology is the country’s fastest developing economic sector. This growth is occurring across multiple industries, including information and communications technology (ICT) and nuclear technology. Jordan contributes 75% of the Arabic content on the Internet.[222] In 2014, the ICT sector accounted for more than 84,000 jobs and contributed to 12% of the GDP. More than 400 companies are active in telecom, information technology and video game development. There are 600 companies operating in active technologies and 300 start-up companies.[222]

Nuclear science and technology is also expanding. The Jordan Research and Training Reactor, which began working in 2016, is a 5 MW training reactor located at the Jordan University of Science and Technology in Ar Ramtha.[223] The facility is the first nuclear reactor in the country and will provide Jordan with radioactive isotopes for medical usage and provide training to students to produce a skilled workforce for the country’s planned commercial nuclear reactors.[223]

Jordan was also selected as the location for the Synchrotron-Light for Experimental Science and Applications in the Middle East (SESAME) facility, supported by UNESCO and CERN.[224] This particle accelerator that was opened in 2017 will allow collaboration between scientists from various rival Middle Eastern countries.[224] The facility is the only particle accelerator in the Middle East, and one of only 60 synchrotron radiation facilities in the world.[224]

The 2015 census showed Jordan’s population to be 9,531,712 (Female: 47%; Males: 53%). Around 2.9 million (30%) were non-citizens, a figure including refugees, and illegal immigrants.[3] There were 1,977,534 households in Jordan in 2015, with an average of 4.8 persons per household (compared to 6.7 persons per household for the census of 1979).[3] The capital and largest city of Jordan is Amman, which is one of the world’s oldest continuously inhabited cities and one of the most liberal in the Arab world.[226] The population of Amman was 65,754 in 1946, but came to be over 4 million in 2015.

Arabs make up about 98% of the population. The rest 2% is attributed to other ethnic groups such as Circassians, and Armenians and other minorities.[17] About 84.1% of the population live in urban towns and cities.[17]

Jordan is a home to 2,175,491 Palestinian refugees as of December 2016; most of them, but not all, were granted Jordanian citizenship.[227] The first wave of Palestinian refugees arrived during the 1948 ArabIsraeli War and peaked in the 1967 Six-Day War and the 1990 Gulf War. In the past, Jordan had given many Palestinian refugees citizenship, however recently Jordanian citizenship is given only in rare cases. 370,000 of these Palestinians live in UNRWA refugee camps.[227] Following the capture of the West Bank by Israel in 1967, Jordan revoked the citizenship of thousands of Palestinians to thwart any attempt to permanently resettle from the West Bank to Jordan. West Bank Palestinians with family in Jordan or Jordanian citizenship were issued yellow cards guaranteeing them all the rights of Jordanian citizenship if requested.[228]

Up to 1,000,000 Iraqis came to Jordan following the Iraq War in 2003,[229] and most of them have returned. In 2015, their number in Jordan was 130,911. Many Iraqi Christians (Assyrians/Chaldeans) however settled temporarily or permanently in Jordan.[230] Immigrants also include 15,000 Lebanese who arrived following the 2006 Lebanon War.[231] Since 2010, over 1.4 million Syrian refugees have fled to Jordan to escape the violence in Syria.[3] The kingdom has continued to demonstrate hospitality, despite the substantial strain the flux of Syrian refugees places on the country. The effects are largely affecting Jordanian communities, as the vast majority of Syrian refugees do not live in camps. The refugee crisis effects include competition for job opportunities, water resources and other state provided services, along with the strain on the national infrastructure.[13]

In 2007, there were up to 150,000 Assyrian Christians; most are Eastern Aramaic speaking refugees from Iraq.[232] Kurds number some 30,000, and like the Assyrians, many are refugees from Iraq, Iran and Turkey.[233] Descendants of Armenians that sought refuge in the Levant during the 1915 Armenian Genocide number approximately 5,000 persons, mainly residing in Amman.[234] A small number of ethnic Mandeans also reside in Jordan, again mainly refugees from Iraq.[235] Around 12,000 Iraqi Christians have sought refuge in Jordan after the Islamic State took the city of Mosul in 2014.[236] Several thousand Libyans, Yemenis and Sudanese have also sought asylum in Jordan to escape instability and violence in their respective countries.[13] The 2015 Jordanian census recorded that there were 1,265,000 Syrians, 636,270 Egyptians, 634,182 Palestinians, 130,911 Iraqis, 31,163 Yemenis, 22,700 Libyans and 197,385 from other nationalities residing in the country.[3]

There are around 1.2 million illegal, and 500,000 legal, migrant workers in the kingdom.[237] Thousands of foreign women, mostly from the Middle East and Eastern Europe, work in nightclubs, hotels and bars across the kingdom.[238][239][240] American and European expatriate communities are concentrated in the capital, as the city is home to many international organizations and diplomatic missions.[196]

Sunni Islam is the dominant religion in Jordan. Muslims make up about 95% of the country’s population; in turn, 93% of those self-identify as Sunnis.[241] There are also a small number of Ahmadi Muslims,[242] and some Shiites. Many Shia are Iraqi and Lebanese refugees.[243] Muslims who convert to another religion as well as missionaries from other religions face societal and legal discrimination.[244]

Jordan contains some of the oldest Christian communities in the world, dating as early as the 1st century AD after the crucifixion of Jesus Christ.[245] Christians today make up about 4% of the population,[246] down from 20% in 1930, though their absolute number has grown.[12] This is due to high immigration rates of Muslims into Jordan, higher emigration rates of Christians to the west and higher birth rates for Muslims.[247] Jordanian Christians number around 250,000, all of whom are Arabic-speaking, according to a 2014 estimate by the Orthodox Church. The study excluded minority Christian groups and the thousands of western, Iraqi and Syrian Christians residing in Jordan.[246] Christians are exceptionally well integrated in the Jordanian society and enjoy a high level of freedom. [248] Christians traditionally occupy two cabinet posts, and are reserved 9 seats out of the 130 in the parliament.[249] The highest political position reached by a Christian is deputy prime minister, currently held by Rajai Muasher.[250] Christians are also influential in media.[251] Smaller religious minorities include Druze, Bah’s and Mandaeans. Most Jordanian Druze live in the eastern oasis town of Azraq, some villages on the Syrian border, and the city of Zarqa, while most Jordanian Bah’s live in the village of Adassiyeh bordering the Jordan Valley.[252] It is estimated that 1,400 Mandaeans live in Amman, they came from Iraq after the 2003 invasion fleeing persecution.[253]

The official language is Modern Standard Arabic, a literary language taught in the schools.[254] Most Jordanians natively speak one of the non-standard Arabic dialects known as Jordanian Arabic. Jordanian Sign Language is the language of the deaf community. English, though without official status, is widely spoken throughout the country and is the de facto language of commerce and banking, as well as a co-official status in the education sector; almost all university-level classes are held in English and almost all public schools teach English along with Standard Arabic.[254] Chechen, Circassian, Armenian, Tagalog, and Russian are popular among their communities.[255] French is offered as an elective in many schools, mainly in the private sector.[254] German is an increasingly popular language; it has been introduced at a larger scale since the establishment of the German-Jordanian University in 2005.[256]

Many institutions in Jordan aim to increase cultural awareness of Jordanian Art and to represent Jordan’s artistic movements in fields such as paintings, sculpture, graffiti and photography.[257] The art scene has been developing in the past few years[258] and Jordan has been a haven for artists from surrounding countries.[259] In January 2016, for the first time ever, a Jordanian film called Theeb was nominated for the Academy Awards for Best Foreign Language Film.[260]

The largest museum in Jordan is The Jordan Museum. It contains much of the valuable archaeological findings in the country, including some of the Dead Sea Scrolls, the Neolithic limestone statues of ‘Ain Ghazal and a copy of the Mesha Stele.[261] Most museums in Jordan are located in Amman including The Children’s Museum Jordan, The Martyr’s Memorial and Museum and the Royal Automobile Museum. Museums outside Amman include the Aqaba Archaeological Museum.[262] The Jordan National Gallery of Fine Arts is a major contemporary art museum located in Amman.[262]

Music in Jordan is now developing with a lot of new bands and artists, who are now popular in the Middle East. Artists such as Omar Al-Abdallat, Toni Qattan, Diana Karazon and Hani Metwasi have increased the popularity of Jordanian music.[263] The Jerash Festival is an annual music event that features popular Arab singers.[263] Pianist and composer Zade Dirani has gained wide international popularity.[264] There is also an increasing growth of alternative Arabic rock bands, who are dominating the scene in the Arab World, including: El Morabba3, Autostrad, JadaL, Akher Zapheer and Aziz Maraka.[265]

Football is the most popular sport in Jordan.[196] The national football team has improved in recent years, though it has yet to qualify for the World Cup.[262] In 2013, Jordan spurned the chance to play at the 2014 World Cup when they lost to Uruguay during inter-confederation play-offs. This was the highest that Jordan had advanced in the World Cup qualifying rounds since 1986.[266] The women’s football team is also gaining reputation,[267] and in March 2016 ranked 58th in the world.[268] Jordan hosted the 2016 FIFA U-17 Women’s World Cup, the first women’s sports tournament in the Middle East.[269]

Less common sports are gaining popularity. Rugby is increasing in popularity, a Rugby Union is recognised by the Jordan Olympic Committee which supervises three national teams.[270] Although cycling is not widespread in Jordan, the sport is developing rapidly as a lifestyle and a new way to travel especially among the youth.[271] In 2014, a NGO Make Life Skate Life completed construction of the 7Hills Skatepark, the first skatepark in the country located in Downtown Amman.[272] Jordan’s national basketball team is participating in various international and Middle Eastern tournaments. Local basketball teams include: Al-Orthodoxi Club, Al-Riyadi, Zain, Al-Hussein and Al-Jazeera.[273]

As the 8th largest producer of olives in the world, olive oil is the main cooking oil in Jordan.[274] A common appetizer is hummus, which is a puree of chick peas blended with tahini, lemon, and garlic. Ful medames is another well-known appetiser. A typical worker’s meal, it has since made its way to the tables of the upper class. A typical Jordanian meze often contains koubba maqliya, labaneh, baba ghanoush, tabbouleh, olives and pickles.[275] Meze is generally accompanied by the Levantine alcoholic drink arak, which is made from grapes and aniseed and is similar to ouzo, rak and pastis. Jordanian wine and beer are also sometimes used. The same dishes, served without alcoholic drinks, can also be termed “muqabbilat” (starters) in Arabic.[196]

The most distinctive Jordanian dish is mansaf, the national dish of Jordan. The dish is a symbol for Jordanian hospitality and is influenced by the Bedouin culture. Mansaf is eaten on different occasions such as funerals, weddings and on religious holidays. It consists of a plate of rice with meat that was boiled in thick yogurt, sprayed with pine nuts and sometimes herbs. As an old tradition, the dish is eaten using one’s hands, but the tradition is not always used.[275] Simple fresh fruit is often served towards the end of a Jordanian meal, but there is also dessert, such as baklava, hareeseh, knafeh, halva and qatayef, a dish made specially for Ramadan. In Jordanian cuisine, drinking coffee and tea flavoured with na’na or meramiyyeh is almost a ritual.[276]

Life expectancy in Jordan was around 74.8 years in 2017.[17] The leading cause of death is cardiovascular diseases, followed by cancer.[278] Childhood immunization rates have increased steadily over the past 15 years; by 2002 immunisations and vaccines reached more than 95% of children under five.[279] In 1950, Water and sanitation was available to only 10% of the population, while in 2015 reached 98% of Jordanians.[280]

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Jordan – The New York Times

The Hashemite Kingdom of Jordan is a relatively young, politically liberal Arab state in the Middle East. Once the home of ancient biblical kingdoms and outpost of several powerful foreign empires, Jordan fell under Ottoman Empire control in 1516, where it remained until the British took over governorship at the end of World War I. In 1946, Jordan won its independence, establishing a constitutional monarchy under the rule of King Abdullah I.

From 1953 until 1999, Jordan was governed by Abdullah Is grandson King Hussein, who sought to maintain a political balancing act between the many countries and territories that Jordan borders Israel, Iraq, Saudi Arabia, Syria and the West Bank. During this time, Husseins government often clashed with Jordans large Palestinian population, many of whom resented his annexation of the West Bank in the 1948 Arab-Israeli War and refusal to fight for an independent Palestinian state. Concurrently, Hussein also traded hostilities with Israel, culminating in the 1967 Six-Day War in which Jordan lost its claim to the West Bank. In 1994, Hussein signed a peace treaty with Israel, officially ending the war between the two countries.

Husseins son Abdullah II, who took the throne in 1999 after his fathers death, has pledged to work toward a more open government and to ease restrictions on public expression that were tamped down during Husseins long reign. During the 2010-12 Arab Spring, Abdullah II responded to protesters in capital of Amman and elsewhere by putting into place modest democratic reforms, bypassing the violent upheavals that toppled other rulers in neighboring countries. Abdullah IIs government, following the nations pro-Western foreign policy and international peace efforts, continues to be a key ally to the United States and, in 2013, welcomed news that Jordan was elected a non-permanent member of the United Nations Security Council. Since the start of Syrias civil war in 2011, Abdullahs government has also struggled with massive influx of Syrian refugees, who have strained Jordans already limited resources.

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Jordan – The New York Times