Aspects
of cancer pharmacogenomics include the consideration of the tumor
genome and the germline genome to make better decisions on cancer
treatment.
Cancer pharmacogenomics is the study of how variances in the genome influences an individual’s response to different cancer drug treatments. It is a subset of the broader field of pharmacogenomics, which is the area of study aimed at understanding how genetic variants influence drug efficacy and toxicity.
Cancer is a genetic disease where changes to genes can cause cells to grow and divide out of control. Each cancer can have a unique combination of genetic mutations,
and even cells within the same tumour may have different genetic
changes. In clinical settings, it has commonly been observed that the
same types and doses of treatment can result in substantial differences
in efficacy and toxicity across patients. Thus, the application of pharmacogenomics within the field of cancer
can offer key advantages for personalizing cancer therapy, minimizing
treatment toxicity, and maximizing treatment efficacy. This can include
choosing drugs that target specific mutations within cancer cells,
identifying patients at risk for severe toxicity to a drug, and
identifying treatments that a patient is most likely to benefit from.
Applying pharmacogenomics within cancer has considerable differences
compared to other complex diseases, as there are two genomes that need
to be considered - the germline and the tumour. The germline genome
considers inter-individual inherited genetic variations, and the tumour
genome considers any somatic mutations that accrue as a cancer evolves.
The accumulation of somatic mutations within the tumour genome
represents variation in disease, and plays a major role in understanding
how individuals will respond to treatments. Additionally, the germline
genome affects toxicity reactions to a specific treatment due to its
influence on drug exposure. Specifically, pharmacokinetic genes
participate in the inactivation and elimination of active compounds. Therefore, differences within the germline genome should also be considered.
Strategies
Advances
in cancer diagnostics and treatment have shifted the use of traditional
methods of physical examination, in vivo, and histopathological
analysis to assessment of cancer drivers, mutations, and targetable
genomic biomarkers.
There are an increasing number of genomic variants being studied and
identified as potential therapeutically actionable targets and drug
metabolism modifiers.
Thus, a patient's genomic information, in addition to information about
the patient's tumour, can be used to determine a personalized approach
to cancer treatment.
Cancer-driven DNA alterations
Cancer-driven
DNA alterations can include somatic DNA mutations and inherited DNA
variants. They are not a direct focus of pharmacogenomic studies, but
they can have an impact on pharmacogenomic strategies. These alterations can affect the pharmacokinetics and pharmacodynamics of metabolic pathways, making them potentially actionable drug-targets.
As whole-genome technologies continue to advance, there will be
increased opportunities to discover mutations and variants that are
involved in tumour progression, response to therapy, and drug-metabolism.
Polymorphism search
Candidate
polymorphism search refers to finding polymorphic DNA sequences within
specific genes that are candidates for certain traits. Within
pharmacogenomics, this method tries to resolve pharmacokinetic or
pharmacodynamic traits of a compound to a candidate polymorphism level. This type of information can contribute to selecting effective therapeutic strategies for a patient.
To understand the potential functional impact of a polymorphic DNA sequence, gene silencing
can be used. Previously, siRNAs have been commonly used to suppress
gene expressions, but more recently, siRNA have been suggested for use
in studying and developing therapeutics.
Another new method being applied is Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR). CRISPR, combined with the Cas9
enzyme, form the basis for the technology known as CRISPR-Cas9. This
system can recognize and cleave specific DNA sequences, and thus is a
powerful system for gene silencing purposes.
Pathway search
An
extension on the previous strategies is candidate pathway search. This
type of analysis considers a group of related genes, whose altered
function may have an effect on therapy, rather than solely focusing on
one gene. It can provide insight into additional information such as
gene-gene interactions, epistatic effects, or influences from cis-regulatory elements. These all contribute to understanding variations in drug efficacy and toxicity between patients.
Whole-Genome Strategies
Advancements in the cost and throughput of sequencing technologies is making it possible to perform whole-genome sequencing
at higher rates. The ability to perform whole-genome analysis for
cancer patients can aid in identifying markers of predisposition to drug
toxicity and efficacy.
Strategies for pharmacogenomic discovery using whole-genome sequences
include targeting frequently mutated gene stretches (known as hotspots)
to identify markers of prognostic and diagnostic significance, or
targeting specific genes that are known to be associated with a
particular disease.
Gene target examples
HER2
HER2
is an established therapeutic target within breast cancer, and the
activation of HER2 is observed in approximately 20% of breast cancers as
a result of overexpression. Trastuzumab,
the first HER2-targeted drug developed in 1990, interferes with HER2
signalling. In 2001, a study showed that adding trastuzumab to
chemotherapy improved overall survival in women with HER2-positive
metastatic breast cancer. Then, in 2005, it was shown that trastuzumab is effective as an adjuvant treatment in women with early-stage breast cancer.
Thus, trastuzumab has been a standard-of-care treatment in both
metastatic and early stage HER2-positive breast cancer cases. Many
genome sequencing studies have also revealed that other cancer tumours
had HER2 alterations, including overexpression, amplifications and other
mutations.
Because of this, there has been a lot of interest in studying the
efficacy of HER2-targeted therapies within a range of cancer types,
including bladder, colorectal, and gastro-esophageal.
BRC-ABL
The majority of chronic myelogenous leukemia
cases are caused by a rearrangement between chromosomes 9 and 22. This
results in the fusion of the genes BCR and ABL. This atypical gene
fusion encodes for unregulated tyrosine kinase activity, which results
in the rapid and continuous division of white blood cells. Drugs known as tyrosine kinase inhibitors target BCR-ABL, and are the standard treatment for chronic myelogenous leukemia. Imatinib was the first tyrosine kinase inhibitor discovered with high specificity for targeting BCR-ABL.
However, after imatinib was used as the first-line therapy, several
BCR-ABL-dependent and BCR-ABL-independent mechanisms of resistance
developed. Thus, new second-line and third-line drugs have also been
developed to address new, mutated forms of BCR-ABL. These include dasatinib, nilotinib, bosutinib, and ponatinib.
Pharmacokinetic genes
Components of the pharmacodynamic influence of genes on drug exposure.
Cancer pharmacogenomics has also contributed to the understanding of
how pharmacokinetic genes affect the exposure to cancer drugs, which can
help predict patient sensitivity to treatment toxicity.
Some of these findings have been successfully translated into clinical
practice in the form of professional guidelines from the Clinical
Pharmacogenomics Implementation Consortium (CPIC) or other institutions.
TPMT
The TPMT gene
encodes for the thiopurine S-methyltransferase (TPMT) enzyme. It
participates in the S-methylation of thiopurine drugs, which include
6-mercaptopurine, 6-thioguanine, and Azathioprine.
The first two drugs are indicated for leukemias and lymphomas, while
Azathioprine is used in nonmalignant conditions such as Crohn’s disease.
These purine antimetabolites are activated in the form of thioguanine
nucleotides that affect DNA replication when incorporated into DNA.
This activation occurs through hypoxanthine phosphoribosyltransferase
to 6-thioguanosines (6-TGN), and the resulting antimetabolites are
inactivated by TPMT. It has been established that the TPMT
genotype of a patient can affect the levels of exposure to the active
metabolites, which has an impact in the treatment toxicity and efficacy.
Specifically, TPMT-deficient patients, such as those homozygous for the
*2 and *3 alleles, can experience myelosuppression up to pancytopenia. In a study on 1214 European Caucasian individuals, a trimodal distribution of TPMT genotypes was found, with 89.5% normal-to-high methylators, 9.9% intermediates, and 0.6% deficient methylators
CPIC guidelines recommend a dose reduction of 5-10% of the standard
dose and a lower frequency of application in individuals that are TPMT
poor metabolizers.
DPD
The dihydropyrimidine dehydrogenase (DPD) protein is responsible for the inactivation of more than 80% of the anticancer drug 5-Fluorouracil
(5-FU) in the liver. This drug is commonly used in colorectal cancer
treatment, and increased exposure to it can cause myelosuppression,
mucositis, neurotoxicity, hand-foot syndrome, and diarrhea. The genotype of DPYD (the gene that codes for DPD) has been linked to severe 5-FU toxicities in several studies summarized in meta-analyses. The CPIC has provided guidelines for implementation of DPYD
pharmacogenetics, indicating that homozygote carriers of low-activity
variants should be prescribed an alternative drug, while heterozygotes
should receive half of the normal dose.
UGT1A1
The UDP glucuronosyltransferase 1A1 (UGT1A1) is an hepatic enzyme involved in the glucoronidation of exogenous and endogenous substrates, such as bilirubin. There have been over 100 variants identified in UGT1A1 and some mutations are implicated Gilbert syndrome and Cringler-Najjar syndrome. Two variants in particular, UGT1A1*28 and UGT1A1*6, are associated with the pharmacogenomics of irinotecan chemotherapy. A UGT1A1*28 allele means the presence of 7 TA repeats in the promoter sequence of the gene, instead of the normal 6 repeats. The allele UGT1A1*6 is characterized by a SNP in exon 1.
Irinotecan is a prodrug used in the treatment of many solid tumours, including colorectal, pancreatic, and lung cancer. Irinotecan is metabolized into its active compound SN-38, which inhibits the enzyme topoisomerase-1, involved in DNA replication. This active metabolite is inactivated after glucoronidation, mainly performed by UGT1A1. High exposure to SN-38 can result in neutropenia and gastrointestinal toxicity. The decreased activity of UGT1A1 in UGT1A1*28 individuals has been found to increase exposure to the active compound and toxicity. For UGT1A1*6, this relationship is more controversial, with some studies finding it can predict irinotecan toxicity while others don’t.
Previous prospective studies for assessing the adequate dose of
irinotecan in Asians have supported the usage of lower doses in patients
with both of UGT1A1*28 and UGT1A1*6.
The results from these and other pharmacogenomics studies have been
translated into clinical guidelines from organizations in USA, Canada,
France, The Netherlands, and Europe. All of these institutions recommend a dose reduction in UGT1A1*28 patients.
Challenges
One
of the biggest challenges in using pharmacogenomics to study cancer is
the difficulty in conducting studies in humans. Drugs used for chemotherapy are too toxic to give to healthy individuals, which makes it difficult to perform genetic studies between related individuals.
Furthermore, some mutations occur at high frequencies, whereas others
occur at very low frequencies, so there is often a need to screen a
large number of patients in order to identify those with a particular
genetic marker. And, although genomic-driven analyses is effective for
stratifying patients and identifying possible treatment options, it is
often difficult for laboratories to get reimbursed for these genomic
sequencing tests. Thus, tracking clinical outcomes for patients whom
undergo sequencing is key to demonstrating both the clinical utility and
cost-effectiveness of pharmacogenomics within cancer.
Another challenge is that cancer patients are often treated with
different combinations and dosages of drugs, so finding a large sample
of patients that have been treated the same way is rare. So, studying
the pharmacogenomics of a specific drug of interest is difficult, and,
because additional identical trials may not be feasible, it can be
difficult to replicate discoveries.
Furthermore, studies have shown that drug efficacy and toxicity
are likely multigenic traits. Since pathways contain multiple genes,
various combinations of driver mutations could promote tumour
progression. This can make it difficult to distinguish between functional driver mutations versus random, nonfunctional mutations.
Future
With
new tools and technologies continuing to develop, there are growing
opportunities to analyze cancer at the single-cell level. Corresponding
approaches with whole-genome sequencing can also be applied to
single-cell sequences and analyses. This level of pharmacogenomics has
implications in personalized medicine, as single-cell RNA sequencing and
genotyping can characterize subclones of the same tumour, and lead to the identification therapy-resistant cells, as well as their corresponding pathways.
As the ability to analyze and profile cancers continues to
improve, so will the therapies developed to treat them. And, with
increasing attention being given to whole-genome sequencing and
single-cell sequencing, there will be a growing amount of
pharmacogenomic data to analyze. These analyses will rely on new and
improved bioinformatics tools to help identify targetable genes and
pathways, to help select safer and more effect therapies for cancer
patients.
Territories colonized by European, American and Japanese powers since 1492
The historical phenomenon of colonization is one that stretches around the globe and across time. Ancient and medieval colonialism was practiced by the Phoenicians, the Greeks, the Turks, and the Arabs. Colonialism in the modern sense began with the "Age of Discovery", led by Portuguese, and then by the Spanish exploration of the Americas, the coasts of Africa, Southwest Asia which is also known as the Middle East, India, and East Asia. The Portuguese and Spanish empires were the first global empires
because they were the first to stretch across different continents,
covering vast territories around the globe. Between 1580 and 1640, the
two empires were both ruled by the Spanish monarchs in personal union. During the late 16th and 17th centuries, England, France and the Dutch Republic also established their own overseas empires, in direct competition with one another.
The end of the 18th and mid 19th century saw the first era of decolonization, when most of the European colonies in the Americas, notably those of Spain, New France and the 13 colonies, gained their independence from their metropole. The Kingdom of Great Britain (uniting Scotland and England), France, Portugal, and the Dutch turned their attention to the Old World, particularly South Africa, India and South East Asia, where coastal enclaves had already been established.
The second industrial revolution, in the 19th century, led to what has been termed the era of New Imperialism, when the pace of colonization rapidly accelerated, the height of which was the Scramble for Africa, in which Belgium, Germany and Italy were also participants.
There were deadly battles between colonizing states and
revolutions from colonized areas shaping areas of control and
establishing independent nations. During the 20th century, the colonies
of the defeated central powers in World War I were distributed amongst the victors as mandates, but it was not until the end of World War II that the second phase of decolonization began in earnest.
Periodisation
Colonial powers throughout history: most of them were European.
Some commentators identify three waves of European colonialism.
The three main countries in the first wave of European colonialism were Portugal, Spain and the early Ottoman Empire.
The Portuguese started the long age of European colonisation with the
conquest of Ceuta, Morocco in 1415, and the conquest and discovery of
other African territories and islands, this would also start the
movement known as the Age of Discoveries. The Ottomans conquered South Eastern Europe, the Middle East and much of Northern and Eastern Africa
between 1359 and 1653 - with the latter territories subjected to
colonial occupation, rather than traditional territorial conquest. The
Spanish and Portuguese launched the colonisation of the Americas, basing their territorial claims on the Treaty of Tordesillas of 1494. This treaty demarcated the respective spheres of influence of Spain and Portugal.
The expansion achieved by Spain and Portugal caught the attention of Britain, France and the Netherlands. The entrance of these three powers into the Caribbean and North America perpetuated European colonialism in these regions.
The second wave of European colonialism commenced with Britain's involvement in Asia in support of the British East India Company; other countries such as France, Portugal and the Netherlands also had involvement in European expansion in Asia.
The third wave ("New Imperialism") consisted of the Scramble for Africa regulated by the terms of the Berlin Conference
of 1884–1885. The conference effectively divided Africa among the
European powers. Vast regions of Africa came under the sway of Britain,
France, Germany, Portugal, Belgium, Italy and Spain.
Gilmartin argues that these three waves of colonialism were linked to capitalism. The first wave of European expansion involved exploring the world to find new revenue and perpetuating European feudalism. The second wave focused on developing the mercantile
capitalism system and the manufacturing industry in Europe. The last
wave of European colonialism solidified all capitalistic endeavours by
providing new markets and raw materials.
The Territorial changes of Russia happened by means of military conquest and by ideological and political unions over the centuries. This section covers (1533–1914).
After a period of political instability, 1598 to 1613 the Romanovs
came to power (1613) and the expansion-colonization process of the
Tsardom continued. While western Europe colonized the New World, Russia
expanded overland - to the east, north and south. This continued for
centuries; by the end of the 19th century, the Russian Empire reached from the Black Sea to the Pacific Ocean, and for some time included colonies in the Alaska (1732-1867) and a short-lived unofficial colony in Africa (1889) in present-day Djibouti.
The acquisition of new territories, especially in the Caucasus, had an
invigorating effect on the rest of Russia. According to two Russian
historians:
the culture of Russia and that of the Caucasian peoples
interacted in a reciprocally beneficial manner. The turbulent tenor of
life in the Caucasus, the mountain peoples' love of freedom, and their
willingness to die for independence were felt far beyond the local
interaction of the Caucasian peoples and coresident Russians: they
injected a potent new spirit into the thinking and creative work of
Russia's progressives, strengthened the liberationist aspirations of
Russian writers and exiled Decembrists, and influenced distinguished Russian democrats, poets, and prose writers, including Alexander Griboyedov, Alexander Pushkin, Mikhail Lermontov, and Leo Tolstoy.
These writers, who generally supported the Caucasian fight for
liberation, went beyond the chauvinism of the colonial autocracy and
rendered the Caucasian peoples' cultures accessible to the Russian
intelligentsia. At the same time, Russian culture exerted an influence
on Caucasian cultures, bolstering positive aspects while weakening the
impact of the Caucasian peoples' reactionary feudalism and reducing the
internecine fighting between tribes and clans.
Expansion into Asia
The first stage to 1650 was an expansion eastward from the Urals to the Pacific.
Geographical expeditions mapped much of Siberia. The second stage from
1785 to 1830 looked south to the areas between the Black Sea and the
Caspian Sea. The key areas were Armenia and Georgia, with some better
penetration of the Ottoman Empire, and Persia. By 1829, Russia
controlled all of the Caucasus as shown in the Treaty of Adrianople
of 1829. The third era, 1850 to 1860, was a brief interlude jumping to
the East Coast, annexing the region from the Amur River to Manchuria.
The fourth era, 1865 to 1885 incorporated Turkestan, and the northern
approaches to India, sparking British fears of a threat to India in The Great Game.
Portuguese and Spanish exploration and colonization
Elmina Castle, Ghana, one in a chain of about fifty fortified factories to enforce Portuguese trade rule along the coast. View from the sea in 1668.
European colonization of both Eastern and Western Hemispheres
has its roots in Portuguese exploration. There were financial and
religious motives behind this exploration. By finding the source of the
lucrative spice trade,
the Portuguese could reap its profits for themselves. They would also
be able to probe the existence of the fabled Christian kingdom of Prester John, with an eye to encircling the Islamic Ottoman Empire,
itself gaining territories and colonies in Eastern Europe. The first
foothold outside of Europe was gained with the conquest of Ceuta in 1415. During the 15th century, Portuguese sailors discovered the Atlantic islands of Madeira, Azores, and Cape Verde, which were duly populated, and pressed progressively further along the west African coast until Bartolomeu Dias demonstrated it was possible to sail around Africa by rounding the Cape of Good Hope in 1488, paving the way for Vasco da Gama to reach India in 1498.
Portuguese successes led to Spanish financing of a mission by Christopher Columbus in 1492 to explore an alternative route to Asia, by sailing west. When Columbus eventually made landfall in the Caribbean Antilles
he believed he had reached the coast of India, and that the people he
encountered there were Indians with red skin. This is why Native Americans have been called Indians or red-Indians. In truth, Columbus had arrived on a continent
that was new to the Europeans, the Americas. After Columbus' first
trips, competing Spanish and Portuguese claims to new territories and
sea routes were solved with the Treaty of Tordesillas
in 1494, which divided the world outside of Europe in two areas of
trade and exploration, between the Iberian kingdoms of Castile and
Portugal along a north–south meridian, 370 leagues west of Cape Verde. According to this international agreement, the larger part of the Americas and the Pacific Ocean were open to Spanish exploration and colonization, while Africa, the Indian Ocean and most of Asia were assigned to Portugal.
The boundaries specified by the Treaty of Tordesillas were put to the test in 1521 when Ferdinand Magellan
and his Spanish sailors (among other Europeans), sailing for the
Spanish Crown became the first European to cross the Pacific Ocean, reaching Guam
and the Philippines, parts of which the Portuguese had already
explored, sailing from the Indian Ocean. The two by now global empires,
which had set out from opposing directions, had finally met on the other
side of the world. The conflicts that arose between both powers were
finally solved with the Treaty of Zaragoza
in 1529, which defined the areas of Spanish and Portuguese influence in
Asia, establishing the anti meridian, or line of demarcation on the
other side of the world.
During the 16th century the Portuguese continued to press both
eastwards and westwards into the Oceans. Towards Asia they made the
first direct contact between Europeans and the peoples inhabiting
present day countries such as Mozambique, Madagascar, Sri Lanka, Malaysia, Indonesia, East Timor
(1512), China, and finally Japan. In the opposite direction, the
Portuguese colonized the huge territory that eventually became Brasil,
and the Spanish conquistadores established the vast Viceroyalties of New Spain and Peru, and later of Río de la Plata (Argentina) and New Granada
(Colombia). In Asia, the Portuguese encountered ancient and well
populated societies, and established a seaborne empire consisting of
armed coastal trading posts along their trade routes (such as Goa, Malacca and Macau),
so they had relatively little cultural impact on the societies they
engaged. In the Western Hemisphere, the European colonization involved
the emigration of large numbers of settlers, soldiers and administrators
intent on owning land and exploiting the apparently primitive (as
perceived by Old World standards) indigenous peoples of the Americas.
The result was that the colonization of the New World was catastrophic:
native peoples were no match for European technology, ruthlessness, or
their diseases which decimated the indigenous population.
Map
indicating the territories colonized by the European powers over the
Americas in 1750 (mainly Spain, Portugal and France at the time).
As characteristically happens in any colonialism, European or not,
previous or subsequent, both Spain and Portugal profited handsomely from
their newfound overseas colonies: the Spanish from gold and silver from
mines such as Potosí and Zacatecas in New Spain, the Portuguese from the huge markups they enjoyed as trade intermediaries, particarlarly during the NanbanJapan trade period. The influx of precious metals to the Spanish monarchy's coffers allowed it to finance costly religious wars
in Europe which ultimately proved its economic undoing: the supply of
metals was not infinite and the large inflow caused inflation and debt,
and subsequently affected the rest of Europe.
Northern European challenges to the Iberian hegemony
It
was not long before the exclusivity of Iberian claims to the Americas
was challenged by other up and coming European powers, primarily the
Netherlands, France and England: the view taken by the rulers of these
nations is epitomized by the quotation attributed to Francis I of France
demanding to be shown the clause in Adam's will excluding his authority
from the New World. This challenge initially took the form of piratical
attacks (such as those by Francis Drake) on Spanish treasure fleets or coastal settlements.
Later the Northern European countries began establishing settlements of
their own, primarily in areas that were outside of Spanish interests,
such as what is now the eastern seaboard of the United States and
Canada, or islands in the Caribbean, such as Aruba, Martinique and Barbados, that had been abandoned by the Spanish in favour of the mainland and larger islands.
Whereas Spanish colonialism was based on the religious conversion and exploitation of local populations via encomiendas
(many Spaniards emigrated to the Americas to elevate their social
status, and were not interested in manual labour), Northern European
colonialism was bolstered by those emigrating for religious reasons (for
example, the Mayflower
voyage). The motive for emigration was not to become an aristocrat or
to spread one's faith but to start a new society afresh, structured
according to the colonists wishes. The most populous emigration of the
17th century was that of the English, who after a series of wars with
the Dutch and French came to dominate the Thirteen Colonies on the eastern coast of the present day United States and other colonies such as Newfoundland and Rupert's Land in what is now Canada.
However, the English, French and Dutch were no more averse to
making a profit than the Spanish and Portuguese, and whilst their areas
of settlement in the Americas proved to be devoid of the precious metals
found by the Spanish, trade in other commodities and products that
could be sold at massive profit in Europe provided another reason for
crossing the Atlantic, in particular furs from Canada, tobacco and
cotton grown in Virginia
and sugar in the islands of the Caribbean and Brazil. Due to the
massive depletion of indigenous labour, plantation owners had to look
elsewhere for manpower for these labour-intensive crops. They turned to
the centuries-old slave trade of west Africa and began transporting
Africans across the Atlantic on a massive scale – historians estimate
that the Atlantic slave trade
brought between 10 and 12 million black African slaves to the New
World. The islands of the Caribbean soon came to be populated by slaves
of African descent, ruled over by a white minority of plantation owners
interested in making a fortune and then returning to their home country
to spend it.
Role of companies in early colonialism
From
its very outset, Western colonialism was operated as a joint
public-private venture. Columbus' voyages to the Americas were partially
funded by Italian investors, but whereas the Spanish state maintained a
tight rein on trade with its colonies (by law, the colonies could only
trade with one designated port in the mother country and treasure was
brought back in special convoys), the English, French and Dutch granted what were effectively trade monopolies to joint-stock companies such as the East India Companies and the Hudson's Bay Company.
Imperial Russia
had no state sponsored expeditions or colonization in the Americas, but
did charter the first Russian joint-stock commercial enterprise, the Russian America Company, which did sponsor those activities in its territories.
In May 1498, the Portuguese set foot in Kozhikode in Kerala, making them the first Europeans to sail to India. Rivalry among reigning European powers saw the entry of the Dutch, English, French, Danish and others. The kingdoms of India were gradually taken over by the Europeans and indirectly controlled by puppet rulers. In 1600, Queen Elizabeth I accorded a charter, forming the East India Company to trade with India and eastern Asia. The English landed in India in Surat in 1612. By the 19th century, they had assumed direct and indirect control over most of India.
After the conclusion of the Seven Years' War
in 1763, Britain had emerged as the world's dominant power, but found
itself mired in debt and struggling to finance the Navy and Army
necessary to maintain a global empire. The British Parliament's
attempt to raise taxes from North American colonists raised fears among
the Americans that their rights as "Englishmen", and particularly their
rights of self-government, were in danger.
From 1765, a series of disputes with Parliament over taxation led to the American Revolution, first to informal committees of correspondence among the colonies, then to coordinated protest and resistance, with an important event in 1770, the Boston Massacre. A standing army was formed by the United Colonies, and independence was declared by the Second Continental Congress
on 4 July 1776. A new nation was born, the United States of America,
and all royal officials were expelled. On their own the Patriots
captured a British Invasion army and France recognized the new nation,
formed military alliance, declared war on Britain, and left the
superpower without any major ally. The American War of Independence continued until 1783, when the Treaty of Paris
was signed. Britain recognised the sovereignty of the United States
over the territory bounded by the British possessions to the North, Florida to the South, and the Mississippi River to the west.
France and the Haitian Revolution (1791–1804)
The Haitian Revolution, a slave revolt led by Toussaint L'Ouverture in the French colony of Saint-Domingue, established Haïti as a free, black republic, the first of its kind. Haiti became the second independent nation that was a former European colony in the Western Hemisphere
after the United States. Africans and people of African ancestry freed
themselves from slavery and colonization by taking advantage of the
conflict among whites over how to implement the reforms of the French Revolution in this slave society. Although independence was declared in 1804, it was not until 1825 that it was formally recognized by King Charles X of France.
Spain and the Wars of Independence in Latin America
The gradual decline of Spain as an imperial power throughout the 17th century was hastened by the War of the Spanish Succession
(1701–14), as a result of which it lost its European imperial
possessions. The death knell for the Spanish Empire in the Americas was
Napoleon's invasion of the Iberian peninsula in 1808. With the
installation of his brother Joseph
on the Spanish throne, the main tie between the metropole and its
colonies in the Americas, the Spanish monarchy, had been cut, leading
the colonists to question their continued subordination to a declining
and distant country. With an eye on the events of the American
Revolution forty years earlier, revolutionary leaders began bloody wars
of independence against Spain, whose armies were ultimately unable to
maintain control. By 1831, Spain had been ejected from the mainland of
the Americas, leaving a collection of independent republics that
stretched from Chile and Argentina in the south to Mexico in the north.
Spain's colonial possessions were reduced to Cuba, Puerto Rico, the Philippines and a number of small islands in the Pacific, all of which she was to lose to the United States in the 1898 Spanish–American War or sell to Germany shortly thereafter.
Portugal and Brazil
Brazil
was the only country in Latin America to gain its independence without
bloodshed. The invasion of Portugal by Napoleon in 1808 had forced King João VI
to escape to Brazil and establish his court in Rio de Janeiro. For
thirteen years, Portugal was ruled from Brazil (the only instance of
such a reversal of roles between colony and metropole) until his return
to Portugal in 1821. His son, Dom Pedro,
was left in charge of Brazil and in 1822 he declared independence from
Portugal and himself the Emperor of Brazil. Unlike Spain's former
colonies which had abandoned the monarchy in favour of republicanism,
Brazil therefore retained its links with its monarchy, the House of Braganza.
Vasco da Gama's maritime success to discover for Europeans a new sea route to India in 1498 paved the way for direct Indo-European commerce. The Portuguese soon set up trading-posts in Goa, Daman, Diu and Bombay. The next to arrive were the Dutch, the English—who set up a trading-post in the west-coast port of Surat
in 1619—and the French. The internal conflicts among Indian Kingdoms
gave opportunities to the European traders to gradually establish
political influence and appropriate lands. Although these continental
European powers were to control various regions of southern and eastern
India during the ensuing century, they would eventually lose all their
territories in India to the British, with the exception of the French
outposts of Pondicherry and Chandernagore, the Dutch port in Travancore, and the Portuguese colonies of Goa, Daman, and Diu.
The English East India Company had been given permission by the Mughal emperor Jahangir in 1617 to trade in India. Gradually the company's increasing influence led the de jure Mughal emperor Farrukh Siyar to grant them dastaks or permits for duty-free trade in Bengal in 1717. The Nawab of BengalSiraj Ud Daulah, the de facto ruler of the Bengal province, opposed British attempts to use these permits. This led to the Battle of Plassey in 1757, in which the armies of the East India Company, led by Robert Clive,
defeated the Nawab's forces. This was the first political foothold with
territorial implications that the British had acquired in India. Clive
was appointed by the company as its first Governor of Bengal in 1757. This was combined with British victories over the French at Madras, Wandiwash and Pondicherry that, along with wider British successes during the Seven Years' War, reduced French influence in India. After the Battle of Buxar in 1764, the company acquired the civil rights of administration in Bengal from the Mughal Emperor Shah Alam II;
it marked the beginning of its formal rule, which was to engulf
eventually most of India and extinguish the Moghul rule and dynasty
itself in less than a century.
The East India Company monopolized the trade of Bengal. They introduced a land taxation system called the Permanent Settlement which introduced a feudal-like structure (See Zamindar)
in Bengal. By the 1850s, the East India Company controlled most of the
Indian sub-continent, which included present-day Pakistan and Bangladesh. Their policy was sometimes summed up as Divide and Rule, taking advantage of the enmity festering between various princely states and social and religious groups.
The first major movement against the British Company's high handed rule resulted in the Indian Rebellion of 1857,
also known as the "Indian Mutiny" or "Sepoy Mutiny" or the "First War
of Independence". After a year of turmoil, and reinforcement of the East
India Company's troops with British soldiers, the Company overcame the
rebellion. The nominal leader of the uprising, the last Mughal emperor Bahadur Shah Zafar,
was exiled to Burma, his children were beheaded and the Moghul line
abolished. In the aftermath all power was transferred from the East
India Company to the British Crown,
which began to administer most of India as a colony; the company's
lands were controlled directly and the rest through the rulers of what
it called the Princely states. There were 565 princely states when the Indian subcontinent gained independence from Britain in August 1947.
During period of the British Raj, famines in India, often attributed to El Nino droughts and failed government policies, were some of the worst ever recorded, including the Great Famine of 1876–78, in which 6.1 million to 10.3 million people died and the Indian famine of 1899–1900, in which 1.25 to 10 million people died. The Third Plague Pandemic
started in China in the middle of the 19th century, spreading plague to
all inhabited continents and killing 10 million people in India alone. Despite persistent diseases and famines, however, the population of the Indian subcontinent, which stood at about 125 million in 1750, had reached 389 million by 1941.
Like the other European colonists, the French began their
colonisation via commercial activities, starting with the establishment
of a factory in Surat in 1668. The French started to settle down in
India in 1673, beginning with the purchase of land at Chandernagore from
the Mughal Governor of Bengal, followed by the acquisition of
Pondicherry from the Sultan of Bijapur the next year. Both became the
centres of the maritime commercial activities that the French conducted
in India.
The French also had trading posts in Mahe, Karikal and Yanaom. Similar
to the situation in Tahiti and Martinique, the French colonial
administrative area was insular, but, in India, the French authority was
isolated on the peripheries of a British-dominated territory.
By the early eighteenth century, the French had become the chief
European rivals of the British. During the eighteenth century, it was
highly possible for the Indian subcontinent to have succumbed to French
control, but the defeat inflicted on them in the Seven Years War
(1756–1763) permanently curtailed French ambitions. The Treaty of Paris
of 1763 restored the original five to the French while making it clear
that France could not expand its control beyond these areas.
The beginning of the Portuguese occupation of India can be traced
back to the arrival of Vasco da Gama near Calicut on 20 May 1498. Soon
after this, other explorers, traders and missionaries followed. By 1515,
the Portuguese were the strongest naval power in the Indian Ocean and
the Malabar Coast was dominated by them.
The policy and ideology of European colonial expansion between the 1870s (circa opening of Suez Canal and Second Industrial Revolution) and the outbreak of World War I in 1914 are often characterised as the "New Imperialism."
The period is distinguished by an unprecedented pursuit of what has
been termed "empire for empire's sake," aggressive competition for
overseas territorial acquisitions and the emergence in colonising
countries of doctrines of racial superiority which denied the fitness of
subjugated peoples for self-government.
During this period, Europe's powers added nearly 8,880,000 square miles (23,000,000 km2)
to their overseas colonial possessions. As it was mostly unoccupied by
the Western powers as late as the 1880s, Africa became the primary
target of the "new" imperialist expansion (known as the Scramble for Africa),
although conquest took place also in other areas — notably south-east
Asia and the East Asian seaboard, where Japan joined the European
powers' scramble for territory.
The Berlin Conference
(1884–1885) mediated the imperial competition among Britain, France and
Germany, defining "effective occupation" as the criterion for
international recognition of colonial claims and codifying the
imposition of direct rule, accomplished usually through armed force.
In Germany, rising pan-Germanism was coupled to imperialism in the Alldeutsche Verband
("Pangermanic League"), which argued that Britain's world power
position gave the British unfair advantages on international markets,
thus limiting Germany's economic growth and threatening its security.
Asking whether colonies paid, economic historian Grover Clark
argues an emphatic "No!" He reports that in every case the support
cost, especially the military system necessary to support and defend the
colonies outran the total trade they produced. Apart from the British
Empire, they were not favored destinations for the immigration of
surplus populations.
Africa was the target of the third wave of European colonialism, after that of the Americas and Asia. Many European statesmen and industrialists wanted to accelerate the Scramble for Africa, securing colonies before they strictly needed them. As a champion of Realpolitik, Bismarck
disliked colonies and thought they were a waste of time, but his hand
was forced by pressure from both the elites and the general population
which considered the colonization a necessity for German prestige.
German colonies in Togoland, Samoa, South-West Africa and New Guinea
had corporate commercial roots, while the equivalent German-dominated
areas in East Africa and China owed more to political motives. The
British also took an interest in Africa, using the East Africa Company
to take over what are now Kenya and Uganda. The British crown formally
took over in 1895 and renamed the area the East Africa Protectorate.
Leopold II of Belgium personally owned the Congo Free State
from 1885 to 1908, When round after round of international scandal
regarding the abusive treatment of native workers forced the Belgium
government to take full ownership and responsibility. The Dutch Empire continued to hold the Dutch East Indies, which was one of the few profitable overseas colonies.
Imperialism also took place in Burma, Indonesia (Netherlands East
Indies), Malaya and the Philippines. Burma had been under British rule
for nearly a hundred years, however, it was always considered an
“imperial backwater”. This accounts for the fact that Burma does not
have an obvious colonial legacy and is not a part of the Commonwealth.
In the beginning, in the mid-1820s, Burma was administered from Penang
in Britain's Straits Settlements. However, it was soon brought within
British India, of which it remained a part until 1937.
Burma was governed as a province of India, not considered very
important, and barely any accommodation was made to Burmese political
culture or sensitivities. As reforms began to move India towards
independence, Burma was simply dragged along.
The colonial map was redrawn following the defeat of the German Empire and the Ottoman Empire after the World War I (1914–18). Colonies from the defeated empires were transferred to the newly founded League of Nations, which itself redistributed it to the victorious powers as "mandates". The secret 1916 Sykes-Picot Agreement partitioned the Middle East between Britain and France. French mandates included Syria and Lebanon, whilst the British were granted Iraq and Palestine. The bulk of the Arabian peninsula became the independent Kingdom of Saudi Arabia in 1922. The discovery of the world's largest easily accessible crude oil deposits led to an influx of Western oil companies
that dominated the region's economies until the 1970s, and making the
emirs of the oil states immensely rich, enabling them to consolidate
their hold on power and giving them a stake in preserving Western
hegemony over the region. During the 1920 and 1930s Iraq, Syria and Egypt
moved towards independence, although the British and French did not
formally depart the region until they were forced to do so after World
War II.
For Japan, the second half of the nineteenth century was a period of
internal turmoil succeeded by a period of rapid development.
After being closed for centuries to Western influence, Japan was forced
by the United States to open itself to the West during the Meiji Era
(1868–1912), characterized by swift modernization and borrowings from
European culture (in law, science, etc.) This, in turn, helped make
Japan the modern power that it is now, which was symbolized as soon as
the 1904–1905 Russo-Japanese War:
this war marked the first victory of an Asian power against a European
imperial power, and led to widespread fears among European populations.
During the first part of the 20th century, while China was still subject
to various European imperialisms, Japan became an imperialist power,
conquering what it called a "Greater East Asia Co-Prosperity Sphere".
With the final revision of treaties in 1894, Japan may be
considered to have joined the family of nations on a basis of equality
with the western states. From this same time imperialism became a
dominant motive in Japanese policy.
Japan ruled over and governed Korea and Taiwan from 1895 when the Treaty of Shimonoseki was concluded to 1945 when Japan was defeated. In 1910, Korea was formally annexed to the Japanese Empire. According to the Korean, The Japanese colonization of Korea was particularly brutal, even by 20th-century standards. This brutal colonization included the use of Korean "comfort women" who were forced to serve as sex slaves in Japanese Army brothels.
In 1931 Japanese army units based in Manchuria seized control of the region and created the puppet state of Manchukuo.
Full-scale war with China followed in 1937, drawing Japan toward an
overambitious bid for Asian hegemony (Greater East Asia Co-Prosperity
Sphere), which ultimately led to defeat and the loss of all its overseas
territories after World War II (see Japanese expansionism and Japanese
nationalism). As in Korea, the Japanese treatment of the Chinese people
was particularly brutal as exemplified by the Nanjing Massacre.
Anticolonialist movements had begun to gain momentum after the close
of World War I, which had seen colonial troops fight alongside those of
the metropole, and U.S. President Woodrow Wilson's speech on the Fourteen Points. However, it was not until the end of World War II that they were fully mobilised. British Prime Minister Winston Churchill and U.S. President Franklin D. Roosevelt's 1941 Atlantic Charter
declared that the signatories would "respect the right of all peoples
to choose the form of government under which they will live". Though
Churchill subsequently claimed this applied only to those countries
under Nazi occupation, rather than the British Empire, the words were
not so easily retracted: for example, the legislative assembly of
Britain's most important colony, India, passed a resolution stating that
the Charter should apply to it too.
In 1945, the United Nations (UN) was founded when 50 nations signed the UN Charter,
which included a statement of its basis in the respect for the
principle of equal rights and self-determination of peoples. In 1952,
demographer Alfred Sauvy coined the term "Third World" in reference to the French Third Estate. The expression distinguished nations that aligned themselves with neither the West nor the Soviet Bloc during the Cold War.
In the following decades, decolonization would strengthen this group
which began to be represented at the United Nations. The Third World's
first international move was the 1955 Bandung Conference, led by Jawaharlal Nehru for India, Gamal Abdel Nasser for Egypt and Josip Broz Tito for Yugoslavia. The Conference, which gathered 29 countries representing over half the world's population, led to the creation of the Non-Aligned Movement in 1961.
World map of colonization at the end of the Second World War in 1945
Although the U.S. had first opposed itself to colonial empires, the
Cold War concerns about Soviet influence in the Third World caused it to
downplay its advocacy of popular sovereignty and decolonization. France
thus received financial support in the First Indochina War (1946–54) and the U.S. did not interfere in the Algerian War of Independence
(1954–62). Decolonization itself was a seemingly unstoppable process.
In 1960, after a number countries gained independence, the UN had
reached 99 members states: the decolonization of Africa was almost complete. In 1980, the UN had 154 member states, and in 1990, after Namibia's independence, 159 states. Hong Kong and Macau transferred sovereignty to China in 1997 and 1999 finally marked the end of European colonial era.
Role of Soviet Union and China
The Soviet Union
was a main supporter of decolonization movements and communist parties
across the world that denounced imperialism and colonization. While the Non-Aligned Movement, created in 1961 following the Bandung 1955 Conference, was supposedly neutral, the "Third World" being opposed to both the "First" and the "Second" Worlds, geopolitical
concerns, as well as the refusal of the U.S. to support decolonization
movements against its NATO European allies, led the national liberation
movements to look increasingly toward the East. However, China's
appearance on the world scene, under the leadership of Mao Zedong,
created a rupture between the Soviet and Chinese factions in Communist
parties around the world, all of which opposed imperialism. Cuba, with Soviet financing, send combat troops to help left-wing independence movements in Angola and Mozambique.
Globally, the non-aligned movement, led by Jawaharlal Nehru (India), Josip Broz Tito (Yugoslavia) and Gamal Abdel Nasser
(Egypt) tried to create a block of nations powerful enough to be
dependent on neither the United States nor the Soviet Union, but finally
tilted towards the Soviet Union, while smaller independence movements,
both by strategic necessity and ideological choice, were supported
either by Moscow or by Beijing. Few independence movements were totally
independent from foreign aid. In 1960s and 1970s, Leonid Brezhnev and Mao Zedong gave influential support to those newly African governments which many became one-party socialist states.
Postcolonialism
is a term used to recognise the continued and troubling presence and
influence of colonialism within the period we designate as
after-the-colonial. It refers to the ongoing effects that colonial
encounters, dispossession and power have in shaping the familiar
structures (social, political, spatial, uneven global interdependencies)
of the present world. Postcolonialism, in itself, questions the end of
colonialism.
