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Wednesday, April 15, 2020

World Health Organization

From Wikipedia, the free encyclopedia

World Health Organization
Emblem of the United Nations.svg
World Health Organization Logo.svg
AbbreviationWHO
Formation7 April 1948
TypeUnited Nations specialised agency
Legal statusActive
HeadquartersGeneva, Switzerland
Head
Tedros Adhanom
(Director-General)
Soumya Swaminathan
(deputy Director-General)
Jane Ellison
(deputy Director-General)
Peter Salama
(deputy Director-General)
Parent organization
United Nations Economic and Social Council
Websitewww.who.int

The World Health Organization (WHO) is a specialized agency of the United Nations responsible for international public health. It is part of the U.N. Sustainable Development Group. The WHO Constitution, which establishes the agency's governing structure and principles, states its main objective as ensuring "the attainment by all peoples of the highest possible level of health." It is headquartered in Geneva, Switzerland, with six semi-autonomous regional offices and 150 field offices worldwide.

The WHO was established in 7 April 1948, which is commemorated as World Health Day. The first meeting of the World Health Assembly (WHA), the agency's governing body, took place on 24 July 1948. The WHO incorporated the assets, personnel, and duties of the League of Nations' Health Organisation and the Office International d'Hygiène Publique, including the International Classification of Diseases. Its work began in earnest in 1951 following a significant infusion of financial and technical resources.

The WHO's broad mandate includes advocating for universal healthcare, monitoring public health risks, coordinating responses to health emergencies, and promoting human health and well being. It provides technical assistance to countries, sets international health standards and guidelines, and collects data on global health issues through the World Health Survey. Its flagship publication, the World Health Report, provides expert assessments of global health topics and health statistics on all nations. The WHO also serves as a forum for summits and discussions on health issues.

The WHO has played a leading role in several public health achievements, most notably the eradication of smallpox, the near-eradication of polio, and the development of an Ebola vaccine. Its current priorities include communicable diseases, particularly HIV/AIDS, Ebola, malaria and tuberculosis; non-communicable diseases such as heart disease and cancer; healthy diet, nutrition, and food security; occupational health; and substance abuse.

The WHA, composed of representatives from all 194 member states, serves as the agency's supreme decision-making body. It also elects and advises an Executive Board made up of 34 health specialists. The WHA convenes annually and is responsible for selecting the Director-General, setting goals and priorities, and approving the WHO's budget and activities. The current Director-General is Tedros Adhanom, former Health Minister and Foreign Minister of Ethiopia, who began his five-year term on 1 July 2017.

The WHO relies on assessed and voluntary contributions from member states and private donors for funding. As of 2018, it has a budget of over $4.2 billion, most of which comes from voluntary contributions from member states.

History and development

Origins

The International Sanitary Conferences, originally held on 23 June 1851, were the first predecessors of the WHO. A series of 14 conferences that lasted from 1851 to 1938, the International Sanitary Conferences worked to combat many diseases, chief among them cholera, yellow fever, and the bubonic plague. The conferences were largely ineffective until the seventh, in 1892; when an International Sanitary Convention that dealt with cholera was passed.

Five years later, a convention for the plague was signed. In part as a result of the successes of the Conferences, the Pan-American Sanitary Bureau (1902), and the Office International d'Hygiène Publique (1907) were soon founded. When the League of Nations was formed in 1920, they established the Health Organization of the League of Nations. After World War II, the United Nations absorbed all the other health organizations, to form the WHO.

Establishment

During the 1945 United Nations Conference on International Organization, Szeming Sze, a delegate from the Republic of China, conferred with Norwegian and Brazilian delegates on creating an international health organization under the auspices of the new United Nations. After failing to get a resolution passed on the subject, Alger Hiss, the Secretary General of the conference, recommended using a declaration to establish such an organization. Sze and other delegates lobbied and a declaration passed calling for an international conference on health. The use of the word "world", rather than "international", emphasized the truly global nature of what the organization was seeking to achieve. The constitution of the World Health Organization was signed by all 51 countries of the United Nations, and by 10 other countries, on 22 July 1946. It thus became the first specialized agency of the United Nations to which every member subscribed. Its constitution formally came into force on the first World Health Day on 7 April 1948, when it was ratified by the 26th member state.

The first meeting of the World Health Assembly finished on 24 July 1948, having secured a budget of US$5 million (then GB£1,250,000) for the 1949 year. Andrija Štampar was the Assembly's first president, and G. Brock Chisholm was appointed Director-General of WHO, having served as Executive Secretary during the planning stages. Its first priorities were to control the spread of malaria, tuberculosis and sexually transmitted infections, and to improve maternal and child health, nutrition and environmental hygiene. Its first legislative act was concerning the compilation of accurate statistics on the spread and morbidity of disease. The logo of the World Health Organization features the Rod of Asclepius as a symbol for healing.

Operational history of WHO

Three former directors of the Global Smallpox Eradication Programme read the news that smallpox had been globally eradicated, 1980
 
1947: The WHO established an epidemiological information service via telex, and by 1950 a mass tuberculosis inoculation drive using the BCG vaccine was under way.
1955: The malaria eradication programme was launched, although it was later altered in objective. 1955 saw the first report on diabetes mellitus and the creation of the International Agency for Research on Cancer.
1958: Viktor Zhdanov, Deputy Minister of Health for the USSR, called on the World Health Assembly to undertake a global initiative to eradicate smallpox, resulting in Resolution WHA11.54. At this point, 2 million people were dying from smallpox every year.
1966: The WHO moved its headquarters from the Ariana wing at the Palace of Nations to a newly constructed HQ elsewhere in Geneva.
1967: The WHO intensified the global smallpox eradication by contributing $2.4 million annually to the effort and adopted a new disease surveillance method. The initial problem the WHO team faced was inadequate reporting of smallpox cases. WHO established a network of consultants who assisted countries in setting up surveillance and containment activities. The WHO also helped contain the last European outbreak in Yugoslavia in 1972. After over two decades of fighting smallpox, the WHO declared in 1979 that the disease had been eradicated – the first disease in history to be eliminated by human effort.
1967: The WHO launched the Special Programme for Research and Training in Tropical Diseases and the World Health Assembly voted to enact a resolution on Disability Prevention and Rehabilitation, with a focus on community-driven care.
1974: The Expanded Programme on Immunization and the control programme of onchocerciasis was started, an important partnership between the Food and Agriculture Organization (FAO), the United Nations Development Programme (UNDP), and the World Bank.
1977: The first list of essential medicines was drawn up, and a year later the ambitious goal of "Health For All" was declared.
1986: The WHO began its global programme on HIV/AIDS. Two years later preventing discrimination against sufferers was attended to and in 1996 UNAIDS was formed.
1988: The Global Polio Eradication Initiative was established.
1998: WHO's Director-General highlighted gains in child survival, reduced infant mortality, increased life expectancy and reduced rates of "scourges" such as smallpox and polio on the fiftieth anniversary of WHO's founding. He, did, however, accept that more had to be done to assist maternal health and that progress in this area had been slow.
2000: The Stop TB Partnership was created along with the UN's formulation of the Millennium Development Goals.
2001: The measles initiative was formed, and credited with reducing global deaths from the disease by 68% by 2007.
2002: The Global Fund to Fight AIDS, Tuberculosis and Malaria was drawn up to improve the resources available.
2006: The organization endorsed the world's first official HIV/AIDS Toolkit for Zimbabwe, which formed the basis for global prevention, treatment, and support the plan to fight the AIDS pandemic.

Overall focus

The WHO's Constitution states that its objective "is the attainment by all people of the highest possible level of health".

The WHO fulfills this objective through its functions as defined in its Constitution: (a) To act as the directing and coordinating authority on international health work; (b) To establish and maintain effective collaboration with the United Nations, specialized agencies, governmental health administrations, professional groups and such other organizations as may be deemed appropriate; (c) To assist Governments, upon request, in strengthening health services; (d) To furnish appropriate technical assistance and, in emergencies, necessary aid upon the request or acceptance of Governments; (e) To provide or assist in providing, upon the request of the United Nations, health services and facilities to special groups, such as the peoples of trust territories; (f) To establish and maintain such administrative and technical services as may be required, including epidemiological and statistical services; (g) to stimulate and advance work to eradicate epidemic, endemic and other diseases; (h) To promote, in co-operation with other specialized agencies where necessary, the prevention of accidental injuries; (i) To promote, in co-operation with other specialized agencies where necessary, the improvement of nutrition, housing, sanitation, recreation, economic or working conditions and other aspects of environmental hygiene; (j) To promote co-operation among scientific and professional groups which contribute to the advancement of health; (k) To propose conventions, agreements and regulations, and make recommendations with respect to international health matters and to perform.

As of 2012, the WHO has defined its role in public health as follows:
  • providing leadership on matters critical to health and engaging in partnerships where joint action is needed;
  • shaping the research agenda and stimulating the generation, translation, and dissemination of valuable knowledge;
  • setting norms and standards and promoting and monitoring their implementation;
  • articulating ethical and evidence-based policy options;
  • providing technical support, catalysing change, and building sustainable institutional capacity; and
  • monitoring the health situation and assessing health trends.
  • CRVS (civil registration and vital statistics) to provide monitoring of vital events (birth, death, wedding, divorce).

Communicable diseases

The 2012–2013 WHO budget identified 5 areas among which funding was distributed. Two of those five areas related to communicable diseases: the first, to reduce the "health, social and economic burden" of communicable diseases in general; the second to combat HIV/AIDS, malaria and tuberculosis in particular.

As of 2015, the World Health Organization has worked within the UNAIDS network and strives to involve sections of society other than health to help deal with the economic and social effects of HIV/AIDS. In line with UNAIDS, WHO has set itself the interim task between 2009 and 2015 of reducing the number of those aged 15–24 years who are infected by 50%; reducing new HIV infections in children by 90%; and reducing HIV-related deaths by 25%.

During the 1970s, WHO had dropped its commitment to a global malaria eradication campaign as too ambitious, it retained a strong commitment to malaria control. WHO's Global Malaria Programme works to keep track of malaria cases, and future problems in malaria control schemes. As of 2012, the WHO was to report as to whether RTS,S/AS01, were a viable malaria vaccine. For the time being, insecticide-treated mosquito nets and insecticide sprays are used to prevent the spread of malaria, as are antimalarial drugs – particularly to vulnerable people such as pregnant women and young children.

Between 1990 and 2010, WHO's help has contributed to a 40% decline in the number of deaths from tuberculosis, and since 2005, over 46 million people have been treated and an estimated 7 million lives saved through practices advocated by WHO. These include engaging national governments and their financing, early diagnosis, standardising treatment, monitoring of the spread and effect of tuberculosis and stabilising the drug supply. It has also recognized the vulnerability of victims of HIV/AIDS to tuberculosis.

In 1988, WHO launched the Global Polio Eradication Initiative to eradicate polio. It has also been successful in helping to reduce cases by 99% since which partnered WHO with Rotary International, the US Centers for Disease Control and Prevention (CDC), the United Nations Children's Fund (UNICEF), and smaller organizations. As of 2011, it has been working to immunize young children and prevent the re-emergence of cases in countries declared "polio-free". In 2017, a study was conducted where why Polio Vaccines may not be enough to eradicate the Virus & conduct new technology. Polio is now on the verge of extinction, thanks to a Global Vaccination Drive. the World Health Organization (WHO) stated the eradication programme has saved millions from deadly disease.

Non-communicable diseases

Another of the thirteen WHO priority areas is aimed at the prevention and reduction of "disease, disability and premature deaths from chronic noncommunicable diseases, mental disorders, violence and injuries, and visual impairment". The Division of Noncommunicable Diseases for Promoting Health through the Life-course Sexual and Reproductive Health has published the magazine, Entre Nous, across Europe since 1983.

Environmental health

The WHO estimates that 12.6 million people died as a result of living or working in an unhealthy environment in 2012 – this accounts for nearly 1 in 4 of total global deaths. Environmental risk factors, such as air, water and soil pollution, chemical exposures, climate change, and ultraviolet radiation, contribute to more than 100 diseases and injuries. This can result in a number of pollution-related diseases.
  • 2018 (30 October – 1 November) : 1 WHO's first global conference on air pollution and health (Improving air quality, combatting climate change – saving lives) ; organized in collaboration with UN Environment, World Meteorological Organization (WMO) and the secretariat of the UN Framework Convention on Climate Change (UNFCCC)

Life course and life style

WHO works to "reduce morbidity and mortality and improve health during key stages of life, including pregnancy, childbirth, the neonatal period, childhood and adolescence, and improve sexual and reproductive health and promote active and healthy aging for all individuals".

It also tries to prevent or reduce risk factors for "health conditions associated with use of tobacco, alcohol, drugs and other psychoactive substances, unhealthy diets and physical inactivity and unsafe sex".

The WHO works to improve nutrition, food safety and food security and to ensure this has a positive effect on public health and sustainable development.

In April 2019, the WHO released new recommendations stating that children between the ages of two and five should spend no more than one hour per day engaging in sedentary behavior in front of a screen and that children under two should not be permitted any sedentary screen time.

Surgery and trauma care

The World Health Organization promotes road safety as a means to reduce traffic-related injuries. It has also worked on global initiatives in surgery, including emergency and essential surgical care, trauma care, and safe surgery. The WHO Surgical Safety Checklist is in current use worldwide in the effort to improve patient safety.

Emergency work

The World Health Organization's primary objective in natural and man-made emergencies is to coordinate with member states and other stakeholders to "reduce avoidable loss of life and the burden of disease and disability."

On 5 May 2014, WHO announced that the spread of polio was a world health emergency – outbreaks of the disease in Asia, Africa, and the Middle East were considered "extraordinary".

On 8 August 2014, WHO declared that the spread of Ebola was a public health emergency; an outbreak which was believed to have started in Guinea had spread to other nearby countries such as Liberia and Sierra Leone. The situation in West Africa was considered very serious.

On 30 January 2020, the WHO declared the 2019-20 coronavirus pandemic was a Public Health Emergency of International Concern (PHEIC).

Health policy

WHO addresses government health policy with two aims: firstly, "to address the underlying social and economic determinants of health through policies and programmes that enhance health equity and integrate pro-poor, gender-responsive, and human rights-based approaches" and secondly "to promote a healthier environment, intensify primary prevention and influence public policies in all sectors so as to address the root causes of environmental threats to health".

The organization develops and promotes the use of evidence-based tools, norms and standards to support member states to inform health policy options. It oversees the implementation of the International Health Regulations, and publishes a series of medical classifications; of these, three are over-reaching "reference classifications": the International Statistical Classification of Diseases (ICD), the International Classification of Functioning, Disability and Health (ICF) and the International Classification of Health Interventions (ICHI). Other international policy frameworks produced by WHO include the International Code of Marketing of Breast-milk Substitutes (adopted in 1981),[55] Framework Convention on Tobacco Control (adopted in 2003) the Global Code of Practice on the International Recruitment of Health Personnel (adopted in 2010) as well as the WHO Model List of Essential Medicines and its pediatric counterpart

In terms of health services, WHO looks to improve "governance, financing, staffing and management" and the availability and quality of evidence and research to guide policy. It also strives to "ensure improved access, quality and use of medical products and technologies". WHO – working with donor agencies and national governments – can improve their use of and their reporting about their use of research evidence.

Governance and support

The remaining two of WHO's thirteen identified policy areas relate to the role of WHO itself:
  • "to provide leadership, strengthen governance and foster partnership and collaboration with countries, the United Nations system, and other stakeholders in order to fulfill the mandate of WHO in advancing the global health agenda"; and
  • "to develop and sustain WHO as a flexible, learning organization, enabling it to carry out its mandate more efficiently and effectively".

Partnerships

The WHO along with the World Bank constitute the core team responsible for administering the International Health Partnership (IHP+). The IHP+ is a group of partner governments, development agencies, civil society, and others committed to improving the health of citizens in developing countries. Partners work together to put international principles for aid effectiveness and development co-operation into practice in the health sector.

The organization relies on contributions from renowned scientists and professionals to inform its work, such as the WHO Expert Committee on Biological Standardization, the WHO Expert Committee on Leprosy, and the WHO Study Group on Interprofessional Education & Collaborative Practice.


WHO also aims to improve access to health research and literature in developing countries such as through the HINARI network.

WHO collaborates with the Global Fund to fight AIDS, Tuberculosis and Malaria, UNITAID, and the United States President's Emergency Plan for AIDS Relief to spearhead and fund the development of HIV programs. 

WHO created the Civil Society Reference Group on HIV, which brings together other networks that are involved in policy making and the dissemination of guidelines. 

WHO, a sector of the United Nations, partners with UNAIDS to contribute to the development of HIV responses in different areas of the world. 

WHO facilitates technical partnerships through the Technical Advisory Committee on HIV, which they created to develop WHO guidelines and policies.

In 2014, WHO released the Global Atlas of Palliative Care at the End of Life in a joint publication with the Worldwide Hospice Palliative Care Alliance, an affiliated NGO working collaboratively with the WHO to promote palliative care in national and international health policy

Public health education and action

Each year, the organization marks World Health Day and other observances focusing on a specific health promotion topic. World Health Day falls on 7 April each year, timed to match the anniversary of WHO's founding. Recent themes have been vector-borne diseases (2014), healthy ageing (2012) and drug resistance (2011).


As part of the United Nations, the World Health Organization supports work towards the Millennium Development Goals. Of the eight Millennium Development Goals, three – reducing child mortality by two-thirds, to reduce maternal deaths by three-quarters, and to halt and begin to reduce the spread of HIV/AIDS – relate directly to WHO's scope; the other five inter-relate and affect world health.

Data handling and publications

The World Health Organization works to provide the needed health and well-being evidence through a variety of data collection platforms, including the World Health Survey covering almost 400,000 respondents from 70 countries, and the Study on Global Aging and Adult Health (SAGE) covering over 50,000 persons over 50 years old in 23 countries. The Country Health Intelligence Portal (CHIP), has also been developed to provide an access point to information about the health services that are available in different countries. The information gathered in this portal is used by the countries to set priorities for future strategies or plans, implement, monitor, and evaluate it. 

The WHO has published various tools for measuring and monitoring the capacity of national health systems and health workforces. The Global Health Observatory (GHO) has been the WHO's main portal which provides access to data and analyses for key health themes by monitoring health situations around the globe.

The WHO Assessment Instrument for Mental Health Systems (WHO-AIMS), the WHO Quality of Life Instrument (WHOQOL), and the Service Availability and Readiness Assessment (SARA) provide guidance for data collection. Collaborative efforts between WHO and other agencies, such as through the Health Metrics Network, also aim to provide sufficient high-quality information to assist governmental decision making. WHO promotes the development of capacities in member states to use and produce research that addresses their national needs, including through the Evidence-Informed Policy Network (EVIPNet). The Pan American Health Organization (PAHO/AMRO) became the first region to develop and pass a policy on research for health approved in September 2009.

On 10 December 2013, a new WHO database, known as MiNDbank, went online. The database was launched on Human Rights Day, and is part of WHO's QualityRights initiative, which aims to end human rights violations against people with mental health conditions. The new database presents a great deal of information about mental health, substance abuse, disability, human rights, and the different policies, strategies, laws, and service standards being implemented in different countries. It also contains important international documents and information. The database allows visitors to access the health information of WHO member states and other partners. Users can review policies, laws, and strategies and search for the best practices and success stories in the field of mental health.

The WHO regularly publishes a World Health Report, its leading publication, including an expert assessment of a specific global health topic. Other publications of WHO include the Bulletin of the World Health Organization, the Eastern Mediterranean Health Journal (overseen by EMRO), the Human Resources for Health (published in collaboration with BioMed Central), and the Pan American Journal of Public Health (overseen by PAHO/AMRO).

In 2016, the World Health Organization drafted a global health sector strategy on HIV. In the draft, the World Health Organization outlines its commitment to ending the AIDS epidemic by the year 2030 with interim targets for the year 2020. To make achievements towards these targets, the draft lists actions that countries and the WHO can take, such as a commitment to universal health coverage, medical accessibility, prevention and eradication of disease, and efforts to educate the public. Some notable points made in the draft include addressing gender inequity where females are nearly twice as likely as men to get infected with HIV and tailoring resources to mobilized regions where the health system may be compromised due to natural disasters, etc. Among the points made, it seems clear that although the prevalence of HIV transmission is declining, there is still a need for resources, health education, and global efforts to end this epidemic.

Structure

The World Health Organization is a member of the United Nations Development Group.

Membership

Countries by World Health Organization membership status

As of 2016, the WHO has 194 member states: all of the member states of the United Nations except for Liechtenstein, plus the Cook Islands and Niue. (A state becomes a full member of WHO by ratifying the treaty known as the Constitution of the World Health Organization.) As of 2013, it also had two associate members, Puerto Rico and Tokelau. Several other countries have been granted observer status. Palestine is an observer as a "national liberation movement" recognized by the League of Arab States under United Nations Resolution 3118. The Holy See also attends as an observer, as does the Order of Malta.
WHO member states appoint delegations to the World Health Assembly, WHO's supreme decision-making body. All UN member states are eligible for WHO membership, and, according to the WHO website, "other countries may be admitted as members when their application has been approved by a simple majority vote of the World Health Assembly". The World Health Assembly is attended by delegations from all member states, and determines the policies of the organization. 

The executive board is composed of members technically qualified in health, and gives effect to the decisions and policies of the World Health Assembly. In addition, the UN observer organizations International Committee of the Red Cross and International Federation of Red Cross and Red Crescent Societies have entered into "official relations" with WHO and are invited as observers. In the World Health Assembly, they are seated alongside the other NGOs.

World Health Assembly and Executive Board

WHO Headquarters in Geneva

The World Health Assembly (WHA) is the legislative and supreme body of WHO. Based in Geneva, it typically meets yearly in May. It appoints the Director-General every five years and votes on matters of policy and finance of WHO, including the proposed budget. It also reviews reports of the Executive Board and decides whether there are areas of work requiring further examination. The Assembly elects 34 members, technically qualified in the field of health, to the Executive Board for three-year terms. The main functions of the Board are to carry out the decisions and policies of the Assembly, to advise it and to facilitate its work. The current chairman of the executive board is Dr. Assad Hafeez.

Director-General

The head of the organization is the Director-General, elected by the World Health Assembly. The term lasts for 5 years, and Directors-General are typically appointed in May, when the Assembly meets. The current Director-General is Dr. Tedros Adhanom Ghebreyesus, who was appointed on 1 July 2017.

Global institutions

Apart from regional, country and liaison offices, the World Health Assembly has also established other institutions for promoting and carrying on research.

Regional offices

Map of the WHO's regional offices and their respective operating regions.
  Africa; HQ: Brazzaville, Republic of Congo
  Western Pacific; HQ: Manila, Philippines
  Eastern Mediterranean; HQ: Cairo, Egypt
  South East Asia; HQ: New Delhi, India
  Europe; HQ: Copenhagen, Denmark
  Americas; HQ: Washington D.C., US

The regional divisions of WHO were created between 1949 and 1952, and are based on article 44 of the WHO's constitution, which allowed the WHO to "establish a [single] regional organization to meet the special needs of [each defined] area". Many decisions are made at regional level, including important discussions over WHO's budget, and in deciding the members of the next assembly, which are designated by the regions.

Each region has a regional committee, which generally meets once a year, normally in the autumn. Representatives attend from each member or associative member in each region, including those states that are not full members. For example, Palestine attends meetings of the Eastern Mediterranean Regional office. Each region also has a regional office. Each regional office is headed by a director, who is elected by the Regional Committee. The Board must approve such appointments, although as of 2004, it had never over-ruled the preference of a regional committee. The exact role of the board in the process has been a subject of debate, but the practical effect has always been small. Since 1999, Regional directors serve for a once-renewable five-year term, and typically take their position on 1 February.

Each regional committee of the WHO consists of all the Health Department heads, in all the governments of the countries that constitute the Region. Aside from electing the regional director, the regional committee is also in charge of setting the guidelines for the implementation, within the region, of the health and other policies adopted by the World Health Assembly. The regional committee also serves as a progress review board for the actions of WHO within the Region.

The regional director is effectively the head of WHO for his or her region. The RD manages and/or supervises a staff of health and other experts at the regional offices and in specialized centres. The RD is also the direct supervising authority – concomitantly with the WHO Director-General – of all the heads of WHO country offices, known as WHO Representatives, within the region.

Regional offices of WHO
Region Headquarters Notes Website
Africa Brazzaville, Republic of the Congo AFRO includes most of Africa, with the exception of Egypt, Sudan, Djibouti, Tunisia, Libya, Somalia and Morocco (all fall under EMRO). The Regional Director is Dr. Matshidiso Moeti, a Botswanan national. (Tenure: – present). AFRO
Europe Copenhagen, Denmark EURO includes all of Europe (except Liechtenstein) Israel, and all of the former USSR. The Regional Director is Dr. Zsuzsanna Jakab, a Hungarian national (Tenure: 2010 – present). EURO
South-East Asia New Delhi, India North Korea is served by SEARO. The Regional Director is Dr. Poonam Khetrapal Singh, an Indian national (Tenure: 2014 – present). SEARO
Eastern Mediterranean Cairo, Egypt The Eastern Mediterranean Regional Office serves the countries of Africa that are not included in AFRO, as well as all countries in the Middle East except for Israel. Pakistan is served by EMRO. The Regional Director is Dr. Ahmed Al-Mandhari, an Omani national (Tenure: 2018 – present). EMRO
Western Pacific Manila, the Philippines WPRO covers all the Asian countries not served by SEARO and EMRO, and all the countries in Oceania. South Korea is served by WPRO. The Regional Director is Dr. Shin Young-soo, a South Korean national (Tenure: 2009 – present). WPRO
The Americas Washington, D.C., United States Also known as the Pan American Health Organization (PAHO), and covers the Americas. The WHO Regional Director is Dr. Carissa F. Etienne, a Dominican national (Tenure: 2013 – present). AMRO

Employees

The WHO employs 8,500 people in 147 countries to carry out its principles. In support of the principle of a tobacco-free work environment, the WHO does not recruit cigarette smokers. The organization has previously instigated the Framework Convention on Tobacco Control in 2003.

Goodwill Ambassadors

The WHO operates "Goodwill Ambassadors"; members of the arts, sports, or other fields of public life aimed at drawing attention to WHO's initiatives and projects. There are currently five Goodwill Ambassadors (Jet Li, Nancy Brinker, Peng Liyuan, Yohei Sasakawa and the Vienna Philharmonic Orchestra) and a further ambassador associated with a partnership project (Craig David).

Country and liaison offices

The World Health Organization operates 150 country offices in six different regions. It also operates several liaison offices, including those with the European Union, United Nations and a single office covering the World Bank and International Monetary Fund. It also operates the International Agency for Research on Cancer in Lyon, France, and the WHO Centre for Health Development in Kobe, Japan. Additional offices include those in Pristina; the West Bank and Gaza; the US-Mexico Border Field Office in El Paso; the Office of the Caribbean Program Coordination in Barbados; and the Northern Micronesia office. There will generally be one WHO country office in the capital, occasionally accompanied by satellite-offices in the provinces or sub-regions of the country in question. 

The country office is headed by a WHO Representative (WR). As of 2010, the only WHO Representative outside Europe to be a national of that country was for the Libyan Arab Jamahiriya ("Libya"); all other staff were international. WHO Representatives in the Region termed the Americas are referred to as PAHO/WHO Representatives. In Europe, WHO Representatives also serve as Head of Country Office, and are nationals with the exception of Serbia; there are also Heads of Country Office in Albania, the Russian Federation, Tajikistan, Turkey, and Uzbekistan. The WR is member of the UN system country team which is coordinated by the UN System Resident Coordinator

The country office consists of the WR, and several health and other experts, both foreign and local, as well as the necessary support staff. The main functions of WHO country offices include being the primary adviser of that country's government in matters of health and pharmaceutical policies.

Financing and partnerships

The WHO is financed by contributions from member states and outside donors. As of 2012, the largest annual assessed contributions from member states came from the United States ($110 million), Japan ($58 million), Germany ($37 million), United Kingdom ($31 million) and France ($31 million). The combined 2012–2013 budget has proposed a total expenditure of $3,959 million, of which $944 million (24%) will come from assessed contributions. This represented a significant fall in outlay compared to the previous 2009–2010 budget, adjusting to take account of previous underspends. Assessed contributions were kept the same. Voluntary contributions will account for $3,015 million (76%), of which $800 million is regarded as highly or moderately flexible funding, with the remainder tied to particular programmes or objectives.

In recent years, the WHO's work has involved increasing collaboration with external bodies. As of 2002, a total of 473 non-governmental organizations (NGO) had some form of partnership with WHO. There were 189 partnerships with international NGOs in formal "official relations" – the rest being considered informal in character. Partners include the Bill and Melinda Gates Foundation and the Rockefeller Foundation.

U.S. contributions to the WHO are funded through the U.S. State Department’s account for Contributions to International Organizations (CIO). In the budget requests for fiscal years 2020 and 2021, the Trump administration asked to halve funding for the WHO.

In April 2020, President Donald Trump announced that his administration would be halting funding to the WHO. Funds previously earmarked for the WHO would be on hold for 60-90 days pending an investigation into WHO's handling of the COVID-19 pandemic, particularly in respect to the organization's purported relationship with China.

Controversies

IAEA – Agreement WHA 12–40

Alexey Yablokov (left) and Vassili Nesterenko (farthest right) protesting in front of the World Health Organization headquarters in Geneva, Switzerland in 2008.
 
Demonstration on Chernobyl disaster day near WHO in Geneva

In 1959, the WHO signed Agreement WHA 12–40 with the International Atomic Energy Agency (IAEA). Reading of this document (clause 3) can result in the understanding that the IAEA is able to prevent the WHO from conducting research or work on some areas. The agreement states that the WHO recognizes the IAEA as having responsibility for peaceful nuclear energy without prejudice to the roles of the WHO of promoting health. The following paragraph adds:


The nature of this statement has led some groups and activists including Women in Europe for a Common Future to claim that the WHO is restricted in its ability to investigate the effects on human health of radiation caused by the use of nuclear power and the continuing effects of nuclear disasters in Chernobyl and Fukushima. They believe WHO must regain what they see as independence. IndependentWHO held a weekly vigil from 2007–2017 in front of WHO headquarters. However, as pointed out by Foreman in clause 2 it states: 

Ebola and HIV experimentation

It has been alleged that the WHO was aware of a Dr. Hilary Koprowski, a doctor allegedly performing research on AIDS and Ebola by deceiving and infecting Africans with a faux polio vaccine. It was estimated that over a million Africans were infected from 1954 to 1957. However, his work having been the cause of any disease has been refuted.

Roman Catholic Church and AIDS

In 2003, the WHO denounced the Roman Curia's health department's opposition to the use of condoms, saying: "These incorrect statements about condoms and HIV are dangerous when we are facing a global pandemic which has already killed more than 20 million people, and currently affects at least 42 million." As of 2009, the Catholic Church remains opposed to increasing the use of contraception to combat HIV/AIDS. At the time, the World Health Assembly President, Guyana's Health Minister Leslie Ramsammy, has condemned Pope Benedict's opposition to contraception, saying he was trying to "create confusion" and "impede" proven strategies in the battle against the disease.

Intermittent preventive therapy

The aggressive support of the Bill & Melinda Gates Foundation for intermittent preventive therapy of malaria triggered a memo from the former WHO malaria chief Akira Kochi.

Diet and sugar intake

Some of the research undertaken or supported by WHO to determine how people's lifestyles and environments are influencing whether they live in better or worse health can be controversial, as illustrated by a 2003 joint WHO/FAO report on nutrition and the prevention of chronic non-communicable disease, which recommended that free sugars should form no more than 10% of a healthy diet. The report led to lobbying by the sugar industry against the recommendation, to which the WHO/FAO responded by including the following statement in the report: "The Consultation recognized that a population goal for free sugars of less than 10% of total energy is controversial". It also stood by its recommendation based upon its own analysis of scientific studies. In 2014, WHO reduced recommended free sugars levels by half and said that free sugars should make up no more than 5% of a healthy diet.

2009 swine flu pandemic

In 2007, the WHO organized work on pandemic influenza vaccine development through clinical trials in collaboration with many experts and health officials. A pandemic involving the H1N1 influenza virus was declared by the then Director-General Margaret Chan in April 2009. Margret Chan declared in 2010 that the H1N1 has moved into the post-pandemic period.

By the post-pandemic period critics claimed the WHO had exaggerated the danger, spreading "fear and confusion" rather than "immediate information". Industry experts countered that the 2009 pandemic had led to "unprecedented collaboration between global health authorities, scientists and manufacturers, resulting in the most comprehensive pandemic response ever undertaken, with a number of vaccines approved for use three months after the pandemic declaration. This response was only possible because of the extensive preparations undertaken during the last decade".

2013–2016 Ebola outbreak and reform efforts

Following the 2014 Ebola outbreak in West Africa, the organization was heavily criticized for its bureaucracy, insufficient financing, regional structure, and staffing profile.

An internal WHO report on the Ebola response pointed to underfunding and the lack of "core capacity" in health systems in developing countries as the primary weaknesses of the existing system. At the annual World Health Assembly in 2015, Director-General Margaret Chan announced a $100 million Contingency Fund for rapid response to future emergencies, of which it had received $26.9 million by April 2016 (for 2017 disbursement). WHO has budgeted an additional $494 million for its Health Emergencies Programme in 2016–17, for which it had received $140 million by April 2016.

The program was aimed at rebuilding WHO capacity for direct action, which critics said had been lost due to budget cuts in the previous decade that had left the organization in an advisory role dependent on member states for on-the-ground activities. In comparison, billions of dollars have been spent by developed countries on the 2013–2016 Ebola epidemic and 2015–16 Zika epidemic.

FCTC implementation database

The WHO has a Framework Convention on Tobacco implementation database which is one of the few mechanisms to help enforce compliance with the FCTC. However, there have been reports of numerous discrepancies between it and national implementation reports on which it was built. As researchers Hoffman and Rizvi report "As of July 4, 2012, 361 (32·7%) of 1104 countries' responses were misreported: 33 (3·0%) were clear errors (e.g., database indicated “yes” when report indicated “no”), 270 (24·5%) were missing despite countries having submitted responses, and 58 (5·3%) were, in our opinion, misinterpreted by WHO staff".

IARC controversies

The World Health Organization sub-department, the International Agency for Research on Cancer (IARC), has been criticized for the way it analyses the tendency of certain substances and activities to cause cancer and for having a politically motivated bias when it selects studies for its analysis. Ed Yong, a British science journalist, has criticized the agency and its "confusing" category system for misleading the public. Marcel Kuntz, a French director of research at the French National Centre for Scientific Research, criticized the agency for its classification of potentially carcinogenic substances. He claimed that this classification did not take into account the extent of exposure: for example, red meat is qualified as probably carcinogenic, but the quantity of consumed red meat at which it could become dangerous is not specified.

Controversies have erupted multiple times when the IARC has classified many things as Class 2a (probable carcinogens) or 2b (possible carcinogen), including cell phone signals, glyphosate, drinking hot beverages, and working as a barber.

Taiwanese membership and participation

Between 2009 and 2016 Taiwan was allowed to attend WHO meetings and events as an observer but was forced to stop due to renewed pressure from China.

Political pressure from China has led to Taiwan being barred from membership of the WHO and other UN-affiliated organizations, and in 2017 to 2020 the WHO refused to allow Taiwanese delegates to attend the WHO annual assembly. On multiple occasions Taiwanese journalists have been denied access to report on the assembly.

In May 2018, the WHO denied access to its annual assembly by Taiwanese media reportedly due to demands from China. Later in May 172 members of the United States House of Representatives wrote to the Director-General of the World Health Organization to argue for Taiwan's inclusion as an observer at the WHA. The United States, Japan, Germany, and Australia all support Taiwan's inclusion in WHO.

Pressure to allow Taiwan to participate in WHO increased as a result of the 2019–2020 coronavirus pandemic with Taiwan's exclusion from emergency meetings concerning the outbreak bringing a rare united front from Taiwan's diverse political parties. Taiwan's main opposition party, the KMT, expressed their anger at being excluded arguing that disease respects neither politics nor geography. China once again dismissed concerns over Taiwanese inclusion with the Foreign Minister claiming that no-one cares more about the health and wellbeing of the Taiwanese people than China's central government. During the outbreak Canadian Prime Minister Justin Trudeau voiced his support for Taiwan's participation in WHO, as did Japanese Prime Minister Shinzo Abe. In January 2020 the European Union, a WHO observer, backed Taiwan's participation in WHO meetings related to the coronavirus pandemic as well as their general participation.

In a 2020 interview, assistant director-general Bruce Aylward appeared to dodge a question about Taiwan and when the question was repeated, the connection was "cut off" blaming internet connection issues. When the video chat was restarted, he was asked another question about Taiwan but he claimed to have already answered the question and formally ended the interview.

Taiwan’s effective response to the coronavirus outbreak has bolstered its case for WHO membership. Taiwan’s response to the outbreak has been praised by a number of experts.

Travel expenses

According to The Associated Press, the WHO routinely spends about $200 million a year on travel expenses, more than it spends to tackle mental health problems, HIV/AIDS, Tuberculosis, and Malaria combined. In 2016, Margaret Chan, Director-General of WHO from November 2006 to June 2017, stayed in a $1000-per-night hotel room while visiting West Africa.

Robert Mugabe's role as a goodwill ambassador

On 21 October 2017, the Director-General Tedros Adhanom Ghebreyesus appointed former Zimbabwean president Robert Mugabe as a WHO Goodwill Ambassador to help promote the fight against non-communicable diseases. The appointment address praised Mugabe for his commitment to public health in Zimbabwe.

The appointment attracted widespread condemnation and criticism in WHO member states and international organizations due to Robert Mugabe's poor record on human rights and presiding over a decline in Zimbabwe's public health. Due to the outcry, the following day the appointment was revoked.

2019–20 COVID-19 pandemic

The WHO's handling of the epidemic has come under criticism amidst what has been described as the agency's "diplomatic balancing act" between "China and China's critics," including scrutiny of the relationship between the agency and Chinese authorities. Initial concerns included the observation that while WHO relies upon data provided and filtered by member states, China has had a "historical aversion to transparency and sensitivity to international criticism". While the WHO and some world leaders have praised the Chinese government's transparency in comparison to the 2003 SARS outbreak, others including John Mackenzie of the WHO's emergency committee and Anne Schuchat of the US' CDC have shown skepticism, suggesting that China's official tally of cases and deaths may be an underestimation. David Heymann, professor of infectious disease epidemiology at the London School of Hygiene and Tropical Medicine, said in response to skepticism on transparency that "China has been very transparent and open in sharing its data … they’re sharing it very well and they opened up all of their files with the WHO present."

In response to the criticisms, Director-General Tedros has stated that China "doesn't need to be asked to be praised. China has done many good things to slow down the virus. The whole world can judge. There is no spinning here," and further stating that "I know there is a lot of pressure on WHO when we appreciate what China is doing but because of pressure we should not fail to tell the truth, we don't say anything to appease anyone. It's because it's the truth." Amid the pandemic, African leaders expressed support for the WHO, with the African Union saying the organization had done "good work" and Nigerian President Muhammadu Buhari calling for "global solidarity".

Some observers have said the WHO is unable to risk antagonizing the Chinese government, as otherwise the agency would not have been able to stay informed on the domestic state of the outbreak and influence response measures there, after which there would have "likely have been a raft of articles criticizing the WHO for needlessly offending China at a time of crisis and hamstringing its own ability to operate." Through this, experts such as Dr. David Nabarro have defended this strategy in order "to ensure Beijing's co-operation in mounting an effective global response to the outbreak". Osman Dar, director of the One Health Project at the Chatham House Centre on Global Health Security defended the WHO's conduct, stating that the same pressure was one "that UN organisations have always had from the advanced economies."

The inclusion of the "Taiwan region" in the WHO's daily situation reports, which resulted in Taiwan receiving the same WHO "very high" risk rating as the mainland despite only a having a relatively small number of cases on the ROC-governed island has led to protests by Taiwan who says that the rating has led to it receiving travel bans as a result. Further concerns regarding Taiwan's non-member status in the WHO has been on the effect this has on increasing Taiwan's vulnerability in the case of an outbreak in the region without proper channels to the WHO. In response, the WHO has said that they "have Taiwanese experts involved in all of our consultations ... so they're fully engaged and fully aware of all of the developments in the expert networks."

The controversy was furthered when Canadian WHO epidemiologist Bruce Aylward, head of the WHO's 2019–20 COVID-19 response team, refused to answer questions from RTHK reporter Yvonne Tong about Taiwan's response to the pandemic and inclusion in the WHO, leading to accusations about China's political influence over the international organization.

On 14 April 2020, United States President Donald Trump announced that he would stop United States funding of the WHO while reviewing its role in what he described as “severely mismanaging and covering up the spread of the coronavirus.” A week earlier, at a press briefing, Trump had criticized the WHO for "missing the call" on the coronavirus pandemic and had threatened to withhold U.S. funding to the organization; on the same day, he also tweeted a complaint that China benefits disproportionately from the WHO, saying that "the WHO really blew it." The U.S. Congress had already allocated about $122 million to WHO for 2020, and Trump had previously proposed in the White House's 2021 budget request to reduce WHO funding to $58 million.

Traditional medicine

WHO has been moving toward acceptance and integration of traditional medicine and traditional Chinese medicine (TCM). In 2022, the new International Statistical Classification of Diseases and Related Health Problems, ICD-11, will attempt to enable classifications from traditional medicine to be integrated with classifications from evidence-based medicine. This and other support of WHO for such practices has been criticized by the medical and scientific community, due to lack of evidence and the risk of endangering wildlife hunted for traditional remedies. A WHO spokesman said that the inclusion was "not an endorsement of the scientific validity of any Traditional Medicine practice or the efficacy of any Traditional Medicine intervention."

World headquarters

The seat of the organization is in Geneva, Switzerland. It was designed by Swiss architect Jean Tschumi and inaugurated in 1966. In 2017, the organization launched an international competition to redesign and extend its headquarters.

Gene ontology

From Wikipedia, the free encyclopedia
 
The Gene Ontology

Content
DescriptionResource with controlled vocabulary to describe the function of genes and gene products
Access
Websitegeneontology.org

The Gene Ontology (GO) is a major bioinformatics initiative to unify the representation of gene and gene product attributes across all species. More specifically, the project aims to: 1) maintain and develop its controlled vocabulary of gene and gene product attributes; 2) annotate genes and gene products, and assimilate and disseminate annotation data; and 3) provide tools for easy access to all aspects of the data provided by the project, and to enable functional interpretation of experimental data using the GO, for example via enrichment analysis. GO is part of a larger classification effort, the Open Biomedical Ontologies, being one of the Initial Candidate Members of the OBO Foundry.

Whereas gene nomenclature focuses on gene and gene products, the Gene Ontology focuses on the function of the genes and gene products. The GO also extends the effort by using markup language to make the data (not only of the genes and their products but also of curated attributes) machine readable, and to do so in a way that is unified across all species (whereas gene nomenclature conventions vary by biological taxon).

Terms and ontology

From a practical view, an ontology is a representation of something we know about. "Ontologies" consist of representations of things that are detectable or directly observable, and the relationships between those things. There is no universal standard terminology in biology and related domains, and term usages may be specific to a species, research area or even a particular research group. This makes communication and sharing of data more difficult. The Gene Ontology project provides an ontology of defined terms representing gene product properties. The ontology covers three domains:
Each GO term within the ontology has a term name, which may be a word or string of words; a unique alphanumeric identifier; a definition with cited sources; and an ontology indicating the domain to which it belongs. Terms may also have synonyms, which are classed as being exactly equivalent to the term name, broader, narrower, or related; references to equivalent concepts in other databases; and comments on term meaning or usage. The GO ontology is structured as a directed acyclic graph, and each term has defined relationships to one or more other terms in the same domain, and sometimes to other domains. The GO vocabulary is designed to be species-neutral, and includes terms applicable to prokaryotes and eukaryotes, single and multicellular organisms

GO is not static, and additions, corrections and alterations are suggested by, and solicited from, members of the research and annotation communities, as well as by those directly involved in the GO project. For example, an annotator may request a specific term to represent a metabolic pathway, or a section of the ontology may be revised with the help of community experts (e.g.). Suggested edits are reviewed by the ontology editors, and implemented where appropriate. 

The GO ontology and annotation files are freely available from the GO website in a number of formats, or can be accessed online using the GO browser AmiGO. The Gene Ontology project also provides downloadable mappings of its terms to other classification systems.

Example term

id: GO:0000016
name: lactase activity
ontology: molecular_function
def: "Catalysis of the reaction: lactose + H2O=D-glucose + D-galactose." [EC:3.2.1.108]
synonym: "lactase-phlorizin hydrolase activity" BROAD [EC:3.2.1.108]
synonym: "lactose galactohydrolase activity" EXACT [EC:3.2.1.108]
xref: EC:3.2.1.108
xref: MetaCyc:LACTASE-RXN
xref: Reactome:20536
is_a: GO:0004553 ! hydrolase activity, hydrolyzing O-glycosyl compounds

Annotation

Genome annotation encompasses the practice of capturing data about a gene product, and GO annotations use terms from the GO ontology to do so. Annotations from GO curators are integrated and disseminated on the GO website, where they can be downloaded directly or viewed online using AmiGO. In addition to the gene product identifier and the relevant GO term, GO annotations have at least the following data: The reference used to make the annotation (e.g. a journal article); An evidence code denoting the type of evidence upon which the annotation is based; The date and the creator of the annotation

Supporting information, depending on GO term and evidence used and supplementary information, such as the conditions the function is observed under, may also be included in a GO annotation.

The evidence code comes from a controlled vocabulary of codes, the Evidence Code Ontology, covering both manual and automated annotation methods. For example, Traceable Author Statement (TAS) means a curator has read a published scientific paper and the metadata for that annotation bears a citation to that paper; Inferred from Sequence Similarity (ISS) means a human curator has reviewed the output from a sequence similarity search and verified that it is biologically meaningful. Annotations from automated processes (for example, remapping annotations created using another annotation vocabulary) are given the code Inferred from Electronic Annotation (IEA). In 2010, over 98% of all GO annotations were inferred computationally, not by curators, but as of July 2, 2019, only about 30% of all GO annotations were inferred computationally. As these annotations are not checked by a human, the GO Consortium considers them to be marginally less reliable and they are commonly to higher level, less detailed terms. Full annotation data sets can be downloaded from the GO website. To support the development of annotation, the GO Consortium provides workshops and mentors new groups of curators and developers.

Many machine learning algorithms have been designed and implemented to predict Gene Ontology annotations.

Example annotation

Gene product: Actin, alpha cardiac muscle 1, UniProtKB:P68032
GO term: heart contraction ; GO:0060047 (biological process)
Evidence code: Inferred from Mutant Phenotype (IMP)
Reference: PMID 17611253
Assigned by: UniProtKB, June 6, 2008

Tools

There are a large number of tools available both online and to download that use the data provided by the GO project. The vast majority of these come from third parties; the GO Consortium develops and supports two tools, AmiGO and OBO-Edit.

AmiGO is a web-based application that allows users to query, browse and visualize ontologies and gene product annotation data. It also has a BLAST tool, tools allowing analysis of larger data sets, and an interface to query the GO database directly.

AmiGO can be used online at the GO website to access the data provided by the GO Consortium, or can be downloaded and installed for local use on any database employing the GO database schema (e.g.). It is free open source software and is available as part of the go-dev software distribution.

OBO-Edit is an open source, platform-independent ontology editor developed and maintained by the Gene Ontology Consortium. It is implemented in Java, and uses a graph-oriented approach to display and edit ontologies. OBO-Edit includes a comprehensive search and filter interface, with the option to render subsets of terms to make them visually distinct; the user interface can also be customized according to user preferences. OBO-Edit also has a reasoner that can infer links that have not been explicitly stated, based on existing relationships and their properties. Although it was developed for biomedical ontologies, OBO-Edit can be used to view, search and edit any ontology. It is freely available to download.

Consortium

The Gene Ontology Consortium is the set of biological databases and research groups actively involved in the gene ontology project. This includes a number of model organism databases and multi-species protein databases, software development groups, and a dedicated editorial office.

History

The Gene Ontology was originally constructed in 1998 by a consortium of researchers studying the genomes of three model organisms: Drosophila melanogaster (fruit fly), Mus musculus (mouse), and Saccharomyces cerevisiae (brewer's or baker's yeast). Many other Model Organism Databases have joined the Gene Ontology Consortium, contributing not only annotation data, but also contributing to the development of the ontologies and tools to view and apply the data. Many major plant, animal and microorganism databases make a contribution towards this project. As of July 2019, the GO contains 44,945 terms; there are 6,408,283 annotations to 4,467 different biological organisms. There is a significant body of literature on the development and use of the GO, and it has become a standard tool in the bioinformatics arsenal. Their objectives have three aspects: building gene ontology, assigning ontology to gene/gene products and developing software and databases for the first two objects.

Several analyses of the Gene Ontology using formal, domain-independent properties of classes (the metaproperties) are also starting to appear. For instance, an ontological analysis of biological ontologies see.

Functional genomics

From Wikipedia, the free encyclopedia
 
Functional genomics is a field of molecular biology that attempts to describe gene (and protein) functions and interactions. Functional genomics make use of the vast data generated by genomic and transcriptomic projects (such as genome sequencing projects and RNA sequencing). Functional genomics focuses on the dynamic aspects such as gene transcription, translation, regulation of gene expression and protein–protein interactions, as opposed to the static aspects of the genomic information such as DNA sequence or structures. A key characteristic of functional genomics studies is their genome-wide approach to these questions, generally involving high-throughput methods rather than a more traditional “gene-by-gene” approach.

Deep mutational scan of the RNA recognition motif(RRM2) of a yeast PolyA binding protein (Pab1)

Definition and goals of functional genomics

In order to understand functional genomics it is important to first define function. In their paper Graur et al. define function in two possible ways. These are "Selected effect" and "Causal Role". The "Selected Effect" function refers to the function for which a trait(DNA, RNA, protein etc.) is selected for. The "Causal role" function refers to the function that a trait is sufficient and necessary for. Functional genomics usually tests the "Causal role" definition of function. 

The goal of functional genomics is to understand the function of genes or proteins, eventually all components of a genome. The term functional genomics is often used to refer to the many technical approaches to study an organism's genes and proteins, including the "biochemical, cellular, and/or physiological properties of each and every gene product" while some authors include the study of nongenic elements in their definition. Functional genomics may also include studies of natural genetic variation over time (such as an organism's development) or space (such as its body regions), as well as functional disruptions such as mutations. 

The promise of functional genomics is to generate and synthesize genomic and proteomic knowledge into an understanding of the dynamic properties of an organism. This could potentially provide a more complete picture of how the genome specifies function compared to studies of single genes. Integration of functional genomics data is often a part of systems biology approaches.

Techniques and applications

Functional genomics includes function-related aspects of the genome itself such as mutation and polymorphism (such as single nucleotide polymorphism (SNP) analysis), as well as the measurement of molecular activities. The latter comprise a number of "-omics" such as transcriptomics (gene expression), proteomics (protein production), and metabolomics. Functional genomics uses mostly multiplex techniques to measure the abundance of many or all gene products such as mRNAs or proteins within a biological sample. A more focused functional genomics approach might test the function of all variants of one gene and quantify the effects of mutants by using sequencing as a readout of activity. Together these measurement modalities endeavor to quantitate the various biological processes and improve our understanding of gene and protein functions and interactions.

At the DNA level

Genetic interaction mapping

Systematic pairwise deletion of genes or inhibition of gene expression can be used to identify genes with related function, even if they do not interact physically. Epistasis refers to the fact that effects for two different gene knockouts may not be additive; that is, the phenotype that results when two genes are inhibited may be different from the sum of the effects of single knockouts.

DNA/Protein interactions

Proteins formed by the translation of the mRNA (messenger RNA, a coded information from DNA for protein synthesis) play a major role in regulating gene expression. To understand how they regulate gene expression it is necessary to identify DNA sequences that they interact with. Techniques have been developed to identify sites of DNA-protein interactions. These include Chip-sequencing, CUT&RUN sequencing and Calling Cards.

DNA accessibility assays

Assays have been developed to identify regions of the genome that are accessible. These regions of open chromatin are candidate regulatory regions. These assays include ATAC-seq, DNase-Seq and FAIRE-Seq.

At the RNA level

Microarrays

Microarrays measure the amount of mRNA in a sample that corresponds to a given gene or probe DNA sequence. Probe sequences are immobilized on a solid surface and allowed to hybridize with fluorescently labeled “target” mRNA. The intensity of fluorescence of a spot is proportional to the amount of target sequence that has hybridized to that spot, and therefore to the abundance of that mRNA sequence in the sample. Microarrays allow for identification of candidate genes involved in a given process based on variation between transcript levels for different conditions and shared expression patterns with genes of known function.

SAGE

Serial analysis of gene expression (SAGE) is an alternate method of analysis based on RNA sequencing rather than hybridization. SAGE relies on the sequencing of 10–17 base pair tags which are unique to each gene. These tags are produced from poly-A mRNA and ligated end-to-end before sequencing. SAGE gives an unbiased measurement of the number of transcripts per cell, since it does not depend on prior knowledge of what transcripts to study (as microarrays do).

RNA sequencing

RNA sequencing has taken over microarray and SAGE technology in recent years, as noted in 2016, and has become the most efficient way to study transcription and gene expression. This is typically done by next-generation sequencing.

A subset of sequenced RNAs are small RNAs, a class of non-coding RNA molecules that are key regulators of transcriptional and post-transcriptional gene silencing, or RNA silencing. Next generation sequencing is the gold standard tool for non-coding RNA discovery, profiling and expression analysis.

Massively Parallel Reporter Assays (MPRAs)

Massively parallel reporter assays is a technology to test the cis-regulatory activity of DNA sequences. MPRAs use a plasmid with a synthetic cis-regulatory element upstream of a promoter driving a synthetic gene such as Green Fluorescent Protein. A library of cis-regulatory elements is usually tested using MPRAs, a library can contain from hundreds to thousands of cis-regulatory elements. The cis-regulatory activity of the elements is assayed by using the downstream reporter activity. The activity of all the library members is assayed in parallel using barcodes for each cis-regulatory element. One limitation of MPRAs is that the activity is assayed on a plasmid and may not capture all aspects of gene regulation observed in the genome.

STARR-seq

STARR-seq is a technique similar to MPRAs to assay enhancer activity of randomly sheared genomic fragments. In the original publication, randomly sheared fragments of the Drosophila genome were placed downstream of a minimal promoter. Candidate enhancers amongst the randomly sheared fragments will transcribe themselves using the minimal promoter. By using sequencing as a readout and controlling for input amounts of each sequence the strength of putative enhancers are assayed by this method.

Perturb-seq

Overview of Perturb-seq workflow

Perturb-seq couples CRISPR mediated gene knockdowns with single-cell gene expression. Linear models are used to calculate the effect of the knockdown of a single gene on the expression of multiple genes.

At the protein level

Yeast two-hybrid system

A yeast two-hybrid screening (Y2H) tests a "bait" protein against many potential interacting proteins ("prey") to identify physical protein–protein interactions. This system is based on a transcription factor, originally GAL4, whose separate DNA-binding and transcription activation domains are both required in order for the protein to cause transcription of a reporter gene. In a Y2H screen, the "bait" protein is fused to the binding domain of GAL4, and a library of potential "prey" (interacting) proteins is recombinantly expressed in a vector with the activation domain. In vivo interaction of bait and prey proteins in a yeast cell brings the activation and binding domains of GAL4 close enough together to result in expression of a reporter gene. It is also possible to systematically test a library of bait proteins against a library of prey proteins to identify all possible interactions in a cell.

AP/MS

Affinity purification and mass spectrometry (AP/MS) is able to identify proteins that interact with one another in complexes. Complexes of proteins are allowed to form around a particular “bait” protein. The bait protein is identified using an antibody or a recombinant tag which allows it to be extracted along with any proteins that have formed a complex with it. The proteins are then digested into short peptide fragments and mass spectrometry is used to identify the proteins based on the mass-to-charge ratios of those fragments.

Deep Mutational Scanning

In Deep mutational scanning every possible amino acid change in a given protein is first synthesized. The activity of each of these protein variants is assayed in parallel using barcodes for each variant. By comparing the activity to the wild-type protein, the effect of each mutation is identified. While it is possible to assay every possible single amino-acid change due to combinatorics two or more concurrent mutations are hard to test. Deep Mutational scanning experiments have also been used to infer protein structure and protein-protein interactions.

Loss-of-function techniques

Mutagenesis

Gene function can be investigated by systematically “knocking out” genes one by one. This is done by either deletion or disruption of function (such as by insertional mutagenesis) and the resulting organisms are screened for phenotypes that provide clues to the function of the disrupted gene.

RNAi

RNA interference (RNAi) methods can be used to transiently silence or knock down gene expression using ~20 base-pair double-stranded RNA typically delivered by transfection of synthetic ~20-mer short-interfering RNA molecules (siRNAs) or by virally encoded short-hairpin RNAs (shRNAs). RNAi screens, typically performed in cell culture-based assays or experimental organisms (such as C. elegans) can be used to systematically disrupt nearly every gene in a genome or subsets of genes (sub-genomes); possible functions of disrupted genes can be assigned based on observed phenotypes.

CRISPR screens

An example of a CRISPR loss-of-function screen.
 
CRISPR-Cas9 has been used to delete genes in a multiplexed manner in cell-lines. Quantifying the amount of guide-RNAs for each gene before and after the experiment can point towards essential genes. If a guide-RNA disrupts an essential gene it will lead to the loss of that cell and hence there will be a depletion of that particular guide-RNA after the screen. In a recent CRISPR-cas9 experiment in mammalian cell-lines, around 2000 genes were found to be essential in multiple cell-lines. Some of these genes were essential in only one cell-line. Most of genes are part of multi-protein complexes. This approach can be used to identify synthetic lethality by using the appropriate genetic background. CRISPRi and CRISPRa enable loss-of-function and gain-of-function screens in a similar manner. CRISPRi identified ~2100 essential genes in the K562 cell-line. CRISPR deletion screens have also been used to identify potential regulatory elements of a gene. For example, a technique called ScanDel was published which attempted this approach. The authors deleted regions outside a gene of interest(HPRT1 involved in a Mendelian disorder) in an attempt to identify regulatory elements of this gene. Gassperini et al. did not identify any distal regulatory elements for HPRT1 using this approach, however such approaches can be extended to other genes of interest.

Functional annotations for genes

Genome annotation

Putative genes can be identified by scanning a genome for regions likely to encode proteins, based on characteristics such as long open reading frames, transcriptional initiation sequences, and polyadenylation sites. A sequence identified as a putative gene must be confirmed by further evidence, such as similarity to cDNA or EST sequences from the same organism, similarity of the predicted protein sequence to known proteins, association with promoter sequences, or evidence that mutating the sequence produces an observable phenotype.

Rosetta stone approach

The Rosetta stone approach is a computational method for de-novo protein function prediction. It is based on the hypothesis that some proteins involved in a given physiological process may exist as two separate genes in one organism and as a single gene in another. Genomes are scanned for sequences that are independent in one organism and in a single open reading frame in another. If two genes have fused, it is predicted that they have similar biological functions that make such co-regulation advantageous.

Bioinformatics methods for Functional genomics

Because of the large quantity of data produced by these techniques and the desire to find biologically meaningful patterns, bioinformatics is crucial to analysis of functional genomics data. Examples of techniques in this class are data clustering or principal component analysis for unsupervised machine learning (class detection) as well as artificial neural networks or support vector machines for supervised machine learning (class prediction, classification). Functional enrichment analysis is used to determine the extent of over- or under-expression (positive- or negative- regulators in case of RNAi screens) of functional categories relative to a background sets. Gene ontology based enrichment analysis are provided by DAVID and gene set enrichment analysis (GSEA), pathway based analysis by Ingenuity and Pathway studio and protein complex based analysis by COMPLEAT.

An overview of a phydms workflow
 
New computational methods have been developed for understanding the results of a deep mutational scanning experiment. 'phydms' compares the result of a deep mutational scanning experiment to a phylogenetic tree. This allows the user to infer if the selection process in nature applies similar constraints on a protein as the results of the deep mutational scan indicate. This may allow an experimenter to choose between different experimental conditions based on how well they reflect nature. Deep mutational scanning has also been used to infer protein-protein interactions. The authors used a thermodynamic model to predict the effects of mutations in different parts of a dimer. Deep mutational structure can also be used to infer protein structure. Strong positive epistasis between two mutations in a deep mutational scan can be indicative of two parts of the protein that are close to each other in 3-D space. This information can then be used to infer protein structure. A proof of principle of this approach was shown by two groups using the protein GB1.

Results from MPRA experiments have required machine learning approaches to interpret the data. A gapped k-mer SVM model has been used to infer the kmers that are enriched within cis-regulatory sequences with high activity compared to sequences with lower activity. These models provide high predictive power. Deep learning and random forest approaches have also been used to interpret the results of these high-dimensional experiments. These models are beginning to help develop a better understanding of non-coding DNA function towards gene-regulation.

Consortium projects focused on Functional Genomics

The ENCODE project

The ENCODE (Encyclopedia of DNA elements) project is an in-depth analysis of the human genome whose goal is to identify all the functional elements of genomic DNA, in both coding and noncoding regions. Important results include evidence from genomic tiling arrays that most nucleotides are transcribed as coding transcripts, noncoding RNAs, or random transcripts, the discovery of additional transcriptional regulatory sites, further elucidation of chromatin-modifying mechanisms.

The Genotype-Tissue Expression (GTEx) project

Samples used and eQTLs discovered in GTEx v6
 
The GTEx project is a human genetics project aimed at understanding the role of genetic variation in shaping variation in the transcriptome across tissues. The project has collected a variety of tissue samples (> 50 different tissues) from more than 700 post-mortem donors. This has resulted in the collection of >11,000 samples. GTEx has helped understand the tissue-sharing and tissue-specificity of EQTLs.

Java Card

From Wikipedia, the free encyclopedia
 
Java Card refers to a software technology that allows Java-based applications (applets) to be run securely on smart cards and similar small memory footprint devices. Java Card is the tiniest of Java platforms targeted for embedded devices. Java Card gives the user the ability to program the devices and make them application specific. It is widely used in SIM cards (used in GSM mobile phones) and ATM cards. The first Java Card was introduced in 1996 by Schlumberger's card division which later merged with Gemplus to form Gemalto. Java Card products are based on the Java Card Platform specifications developed by Sun Microsystems (later a subsidiary of Oracle Corporation). Many Java card products also rely on the GlobalPlatform specifications for the secure management of applications on the card (download, installation, personalization, deletion).

The main design goals of the Java Card technology are portability and security.

Portability

Java Card aims at defining a standard smart card computing environment allowing the same Java Card applet to run on different smart cards, much like a Java applet runs on different computers. As in Java, this is accomplished using the combination of a virtual machine (the Java Card Virtual Machine), and a well-defined runtime library, which largely abstracts the applet from differences between smart cards. Portability remains mitigated by issues of memory size, performance, and runtime support (e.g. for communication protocols or cryptographic algorithms).

Security

Java Card technology was originally developed for the purpose of securing sensitive information stored on smart cards. Security is determined by various aspects of this technology:
Data encapsulation
Data is stored within the application, and Java Card applications are executed in an isolated environment (the Java Card VM), separate from the underlying operating system and hardware.
Applet Firewall
Unlike other Java VMs, a Java Card VM usually manages several applications, each one controlling sensitive data. Different applications are therefore separated from each other by an applet firewall which restricts and checks access of data elements of one applet to another.
Cryptography
Commonly used symmetric key algorithms like DES, Triple DES, AES, and asymmetric key algorithms such as RSA, elliptic curve cryptography are supported as well as other cryptographic services like signing, key generation and key exchange.
Applet
The applet is a state machine which processes only incoming command requests and responds by sending data or response status words back to the interface device.

Design

At the language level, Java Card is a precise subset of Java: all language constructs of Java Card exist in Java and behave identically. This goes to the point that as part of a standard build cycle, a Java Card program is compiled into a Java class file by a Java compiler; the class file is post-processed by tools specific to the Java Card platform. 

However, many Java language features are not supported by Java Card (in particular types char, double, float and long; the transient qualifier; enums; arrays of more than one dimension; finalization; object cloning; threads). Further, some common features of Java are not provided at runtime by many actual smart cards (in particular type int, which is the default type of a Java expression; and garbage collection of objects).

Bytecode

Java Card bytecode run by the Java Card Virtual Machine is a functional subset of Java 2 bytecode run by a standard Java Virtual Machine but with a different encoding to optimize for size. A Java Card applet thus typically uses less bytecode than the hypothetical Java applet obtained by compiling the same Java source code. This conserves memory, a necessity in resource constrained devices like smart cards. As a design tradeoff, there is no support for some Java language features (as mentioned above), and size limitations. Techniques exist for overcoming the size limitations, such as dividing the application's code into packages below the 64 KiB limit.

Library and runtime

Standard Java Card class library and runtime support differs a lot from that in Java, and the common subset is minimal. For example, the Java Security Manager class is not supported in Java Card, where security policies are implemented by the Java Card Virtual Machine; and transients (non-persistent, fast RAM variables that can be class members) are supported via a Java Card class library, while they have native language support in Java.

Specific features

The Java Card runtime and virtual machine also support features that are specific to the Java Card platform:
Persistence
With Java Card, objects are by default stored in persistent memory (RAM is very scarce on smart cards, and it is only used for temporary or security-sensitive objects). The runtime environment as well as the bytecode have therefore been adapted to manage persistent objects.
Atomicity
As smart cards are externally powered and rely on persistent memory, persistent updates must be atomic. The individual write operations performed by individual bytecode instructions and API methods are therefore guaranteed atomic, and the Java Card Runtime includes a limited transaction mechanism.
Applet isolation
The Java Card firewall is a mechanism that isolates the different applets present on a card from each other. It also includes a sharing mechanism that allows an applet to explicitly make an object available to other applets.

Development

Coding techniques used in a practical Java Card program differ significantly from those used in a Java program. Still, that Java Card uses a precise subset of the Java language speeds up the learning curve, and enables using a Java environment to develop and debug a Java Card program (caveat: even if debugging occurs with Java bytecode, make sure that the class file fits the limitation of Java Card language by converting it to Java Card bytecode; and test in a real Java Card smart card early on to get an idea of the performance); further, one can run and debug both the Java Card code for the application to be embedded in a smart card, and a Java application that will be in the host using the smart card, all working jointly in the same environment.

Versions

Oracle has released several Java Card platform specifications and is providing SDK tools for application development. Usually smart card vendors implement just a subset of algorithms specified in Java Card platform target and the only way to discover what subset of specification is implemented is to test the card.
  • Version 3.1 (17.12.2018)
    • Added configurable key pair generation support, named elliptic curves support, new algorithms and operations support, additional AES modes and Chinese algorithms.
  • Version 3.0.5 (03.06.2015)
    • Oracle SDK: Java Card Classic Development Kit 3.0.5u1 (03.06.2015)
    • Added support for Diffie-Hellman modular exponentiation, Domain Data Conservation for Diffie-Hellman, Elliptic Curve and DSA keys, RSA-3072, SHA3, plain ECDSA, AES CMAC, AES CTR.
  • Version 3.0.4 (06.08.2011)
    • Oracle SDK: Java Card Classic Development Kit 3.0.4 (06.11.2011)
    • Added support for DES MAC8 ISO9797.
  • Version 3.0.1 (15.06.2009)
    • Oracle SDK: Java Card Development Kit 3.0.3 RR (11.11.2010)
    • Added support for SHA-224, SHA-2 for all signature algorithms.
  • Version 2.2.2 (03.2006)
    • Oracle SDK: Java Card Development Kit 2.2.2 (03.2006)
    • Added support for SHA-256, SHA-384, SHA-512, ISO9796-2, HMAC, Korean SEED MAC NOPAD, Korean SEED NOPAD.
  • Version 2.2.1 (10.2003)
    • Oracle SDK: Java Card Development Kit 2.2.1 (10.2003)
  • Version 2.2 (11.2002)
    • Added support for AES cryptography key encapsulation, CRC algorithms, Elliptic Curve Cryptography key encapsulation,Diffie-Hellman key exchange using ECC, ECC keys for binary polynomial curves and for prime integer curves, AES, ECC and RSA with variable key lengths.
  • Version 2.1.1 (18.05.2000)
    • Oracle SDK: Java Card Development Kit 2.1.2 (05.04.2001)
    • Added support for RSA without padding.
  • Version 2.1 (07.06.1999)

Java Card 3.0

The version 3.0 of the Java Card specification (draft released in March 2008) is separated in two editions: the Classic Edition and the Connected Edition.
  • The Classic Edition (currently at version 3.0.5 released in June 2015) is an evolution of the Java Card Platform version 2 (which last version 2.2.2 was released in March 2006), which supports traditional card applets on resource-constrained devices such as Smart Cards. Older applets are generally compatible with newer Classic Edition devices, and applets for these newer devices can be compatible with older devices if not referring to new library functions. Smart Cards implementing Java Card Classic Edition have been security-certified by multiple vendors, and are commercially available.
  • The Connected Edition (currently at version 3.0.2 released in December 2009) aims to provide a new virtual machine and an enhanced execution environment with network-oriented features. Applications can be developed as classic card applets requested by APDU commands or as servlets using HTTP to support web-based schemes of communication (HTML, REST, SOAP ...) with the card. The runtime uses a subset of the Java (1.)6 bytecode, without Floating Point; it supports volatile objects (garbage collection), multithreading, inter-application communications facilities, persistence, transactions, card management facilities ... As of 2017 there has been little adoption in commercially available Smart Cards, so much that reference to Java Card (including in the present Wikipedia page) often implicitly excludes the Connected Edition.

Representation of a Lie group

From Wikipedia, the free encyclopedia https://en.wikipedia.org/wiki/Representation_of_a_Lie_group...