Genome Research Will Save Millions in Developing. World WHO Report Calls for Genetic Medicine Benefits for All

Released simultaneously from Washington, DC, Toronto and London

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(Dr. Barry Bloom, Dean of Harvard School of Public Health and Dr. Tikki Pang of the WHO, will be available for interviews April 30, 2002. Please, call 703-820-2244 to schedule time of the interview)

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Genetic research has the potential to lead to major medical advances within 3-5 years against such killer diseases as malaria, tuberculosis and HIV/AIDS, potentially saving millions of lives, especially in the developing world, the World Health Organization (WHO) says in a major new report on the impact of genomics.

The WHO report, entitled Genomics and World Health, also makes a major contribution to the debate on the ethics of genome research, covering a wide array of themes, from using DNA tests to select the sex of children to the need to ensure that poor countries are not left out of the coming medical advances.

The report strongly endorses the recommendation of the Commission on Macroeconomics and Health to create a Global Health Research Fund, a new central organization for research and development with an initial US$ 1.5 billion, which would be available through peer-reviewed application, to every country. It argues that a second US$ 1.5 billion should be made available to institutions which are working on new vaccine and drug development for HIV/AIDS, tuberculosis and malaria.

“Genome research, if we handle it correctly, can change the world for all health care,” says Dr. Gro Harlem Brundtland, WHO Director-General. “In particular, it has the potential to allow developing countries to leap frog decades of medical development and bring their citizens greatly improved care and modern methods in the much more immediate future.”

A team of 14 internationally prominent doctors, medical researchers and ethicists in both developed and developing countries, coordinated by Dr. Tikki Pang, WHO Director, Research Policy & Cooperation, developed the 241-page Genomics and World Health Report over a 12 month period.

The report was issued on behalf of WHO’s Advisory Committee on Health Research (ACHR), the organization’s highest level scientific advisory body. Based on a wide-ranging consultative process, the report details the latest advances in genome research, explains how this research could result in medical advances against many diseases, including those pandemic in poor countries, warns about potential risks of such research and makes recommendations on how the fruits of this research can be brought to the developing world.

“This is the first ever report to put genomic research in a global perspective,” says Sir David Weatherall, lead writer of the report, professor at Oxford University’s Weatherall Institute of Molecular Medicine and a pioneering researcher in molecular genetics, hematology, pathology and clinical medicine. “The report anticipates how the global community could use genetics to attack the unfinished agenda of infectious diseases such as malaria, TB and HIV/AIDS that are still killing so many in the developing world, and eventually the diseases that are crippling the health care systems of all countries, like heart disease, diabetes and cancer.”

In recent years, scientists have succeeded in sequencing the entire human genome, which contains between 28,000 and 40,000 genes — lengths of DNA that carry the information required for every biological function of all living creatures. Researchers are also mapping the genomes of some important pathogens, disease vectors and plants.

Such research involves large-scale creation and utilization of databases through a high level of automation, and therefore requires major capital investment. This has mostly limited research to the rich industrial nations, although Brazil, China, India and Cuba are notable exceptions. These achievements should allow other researchers to develop both preventative and treatment techniques that have pinpoint accuracy for a wide range of afflictions.

Commenting on the report, Dr. Peter A. Singer, Director of University of Toronto’s Joint Centre for Bioethics said “Developing nations are in danger of being left out of the benefits of genomic research, like they were left behind in the computer revolution of the 1980s and 90s, resulting in the so-called ‘digital divide’. Genomics and related technologies should be used to narrow the existing unethical inequities in global health. The report is an important first step towards this goal.”

“The whole thrust of the report is that we will not change medical practice overnight by this new technology,” Dr. Weatherall says. “However, the long-term possibilities are such that developing countries, as well as developed countries, must prepare themselves for this new technology and carefully explore its possibilities.”

DNA research is underway on a number of projects that can improve health care in developing countries, with some projects already yielding results. Among the research mentioned in the report are:

• Creating a new designer mosquito that cannot carry the malaria parasite, one of the biggest killers in the developing world. The United Nations Development Programme/World Bank/ World Health Organization Special Programme for Research and Training in Tropical Diseases (TDR) is conducting research with an international consortium to map the genome of the Anopheles gambiae mosquito, which could be finished by the end of 2002. Once completed, scientists believe they can manipulate the mosquito’s DNA so that the parasite, which the mosquito currently transfers to humans when it feeds on their blood, will no longer be able to live and multiply in the insect. This mosquito would then be introduced into malaria-pandemic countries and would eventually dominate the region through cross breeding.

“We have tried everything against malaria, without real success,” says Dr. Pang “This new process gives us the ability to modify the mosquito’s genetic makeup, though we must continue with all other programs, such as vaccine development and bednets treated with biodegradable pyrethroid insecticide. This new alternative is only possible because of DNA sequencing.”

  • Rapid identification of a class of anti-malarial drugs that have the potential to be effective against multi-drug–resistant parasites, as well as being inexpensive and stable. A combination of malaria parasite DNA sequencing, bioinformatics (use of computer technology to store, analyze and interpret biological data-), and data mining (searching for comparative genomic data) have been instrumental in the creation of these drugs.
  • Two new types of vaccines derived from genetic research have been developed against tuberculosis, which is spreading in both developing and developed countries. Clinical trials of one of these vaccines has already started. It uses a combination of bacillus Calmette-Guérin (BCG) and a booster consisting of a vaccinia virus (a virus commonly used as a vector for microbial genes) engineered to produce antigen 85, a protein that is synthesized by the tuberculosis bacterium, Mycobacterium tuberculosis. Another promising vaccine is derived from the observation that the intra-muscular injection of a fragment of DNA encoding a so-called heat shock protein from a bacterium that is related to M. tuberculosis, protects mice from the disease and, remarkably, seems to cure those that have been infected.
  • The diagnosis of leishmaniasis and dengue fever, both pandemic in some Latin American countries, has already been improved by the use of polymerase chain reaction techniques — one of the basic techniques in DNA research. Eva Harris of the Sustainable Sciences Institute in San Francisco, California has conducted pioneering research that has documented that when implemented in Nicaragua, Ecuador, and Guatemala, techniques such as PCR and non-radioactive DNA probes are more rapid, sensitive, specific, versatile, safer, and less costly than prevailing methods for detection of pathogenic organisms.
  • Cuba has developed a meningitis B vaccine at the Carlos J. Finlay Institute, attesting to the potential of biotechnology in developing countries. The United States, despite its economic embargo against Cuba, has made a specific exemption and is willing to import the new vaccine. This vaccine is being tested in the United Kingdom and has been exported and licensed to at least a dozen other countries.
  • Clinical trials have begun in Nairobi, Kenya and Oxford, UK, of a DNA-based AIDS vaccine candidate designed specifically for Africa. The vaccine was developed through collaboration between the Universities of Nairobi and Oxford and the International AIDS Vaccine Initiative. The vaccine was derived from the observation that some prostitutes in Nairobi develop strong cellular immune responses and do not develop HIV infection despite repeated exposure.
  • Scientists are using DNA technology to produce vaccines that can be incorporated into potatoes and other vegetables, and fruits, against hepatitis B, cholera, measles, and human papilloma virus (associated with cervical cancer, a common malignancy in women in sub-Saharan Africa), allowing the vaccines to be ingested as part of a meal. Because they do not require refrigeration, plant-based edible vaccines are cheaper than conventional vaccines and could be grown or freeze-dried and shipped anywhere.

Hepatitis B has infected 2 billion people worldwide and is associated with hepatocellular carcinoma, which is among the top three causes of cancer-related death in men in sub-Saharan Africa, most of Asia, and the Pacific. Scientists believe they can prevent the disease from spreading by using DNA research to produce hepatitis B surface antigen in transgenic (a fertile animal or plant that carries an introduced gene in its germ line), plants for oral immunization. A human trial of a recombinant hepatitis B vaccine that has been incorporated into potatoes has begun.

  • A candidate vaccine for Plasmodium vivax, the main type of malaria in India, has been identified by a recent collaborative effort between Indian researchers at the International Centre for Genetic Engineering and Biotechnology in New Delhi and the Malaria Vaccine Initiative. The research was partly funded by the Bill and Melinda Gates Foundation through the Program for Appropriate Technology in Health. The vaccine will be developed by Bharat Biotech International of Hyderabad, India.

India is increasingly investing in genomics and bio-technology: The Indian Department of Bio-technology recently announced that it would spend US$85 million on genomics over the next 5 years, mainly in medical research, and the renowned Indian Institute of Technology has just established a new School of Bioscience and Bioengineering.

  • Pharmacogenetics may save lives and valuable health care resources in developing countries by identifying populations who will respond favorably to therapeutics; there is preliminary evidence for this in relation to certain anti-HIV drugs in West Africa. If confirmed, this finding could save money and lives through proper drug selection. Based on genomic information of humans, scientists believe that they could one day tailor specific treatments to suit the individual — ‘the right drug for the right patient.’ In this way, doctors could minimize the adverse side effects associated with many treatments based on knowledge about how an individual will/may respond to a particular drug.

“The importance of this WHO report is to make clear that while most of the incentives to develop new drugs and vaccines are appealing to the markets in the industrialized world, there are enormous opportunities to apply knowledge of the genome to diseases of the poorest people as well, and that we all have a responsibility to help make those opportunities into realities,” says Professor Barry R. Bloom, Dean of the Harvard University School of Public Health and a member of the Committee which prepared the WHO report.

“This report addresses broadly two sets of ethical issues,” says Prof. Dan Brock of Brown University and another of the report’s writers. “The first is the enormous health care inequality between the two worlds of rich nations and poor ones. The WHO wants much more than genetic advances not just exacerbating differences between these two worlds but rather helping to reduce them. We have to recognize that the potential does exist for exacerbating health care differences because scientists tend to focus on the needs of the developed world. Therefore, one task the report recommends is seeking ways for the WHO to help to direct genetic research for the needs of the poor living in the developing world.”

Mapping the Genome

In June 2000, both Celera Genomics, a private company, and the International Human Genome Mapping Consortium, funded by governments and charities in several countries, announced the completion of “working drafts” of the human genome sequence, that is the order of the three billion bases that constitute the human genetic make-up. Over the next few years it will be necessary to complete the sequence analysis by closing gaps and resolving various ambiguities. This “finishing” process has already been more or less accomplished for chromosomes 21 and 22 and should be completed for the remainder of the genome by 2003.

“It is now believed that the information generated by genomics will, in the long term, have major benefits for the prevention, diagnosis and management of many diseases which hitherto have been difficult or impossible to control,” the report says. “These include communicable and genetic diseases, together with other common killers or causes of chronic ill-health, including cardiovascular disease, cancer, diabetes, the major psychoses, dementia, rheumatic disease, asthma, and many others.”

“I would like the WHO to send this report not only to health ministers and policy makers, but also to ministers of finance, ministers of science and technology and even heads of state, so that they can see where investments must be made,” says another main report contributor, Dr. Zulfiqar A. Bhutta, the Husein Lalji Dewraj Professor of Pediatrics & Child Health at the Aga Khan University in Karachi, Pakistan. “The report should also be widely distributed among members of academia so that they will have a basis to lobby with government ministers for proper health care and research investments.”

“Developing nations also need to anticipate social and ethical problems that could arise from new genomics research and applications, and set up the infrastructure to address these problems. One way for a country to do this is to establish an independent advisory panel consisting of scientists, ethicists, representatives of civil society groups, as well as lay people,” says another of the report’s writers, Dr. Chee Heng Leng, Associate Professor at the Department of Community Health, at the Universiti Putra Malaysia. “This panel should be able to chart the direction for the country, for example, in advising on what laws or ethical guidelines need to be set up to safeguard the interests of vulnerable groups or individuals, or on the issues that require public education to be carried out. This panel should be independent of government, and able to command the respect of the general population.”

First DNA Benefits Within Five Years

The very first practical uses deriving from genome research could come within 3-5 years in much more rapid and accurate diagnostic testing for many diseases. “Currently, many tests for these diseases are ambiguous, take a considerable amount of time, and are even hazardous to the laboratory workers performing them” says WHO’s Dr. Pang. “Polymerase chain reaction (PCR) technology, derived from genetic research, can vastly improve diagnostic testing.”

The key to DNA amplification is to use primer molecules, which are short pieces of DNA that can be manufactured in a laboratory. For optimal design and use of primers, scientists need to know the entire DNA sequence of any pathogen.

Primer molecules for malaria, for example, will only bind to specific regions of malaria DNA, which will also be the case for primers for all other diseases. These molecules will amplify by a million times the ability to identify the presence of pathogens in a blood sample. So scientists and doctors will have an entire battery of primers for infectious diseases. Importantly, and in contrast to conventional methods, scientists would need just a small sample of blood or other fluids and tissues to then undertake the testing.

A whole industry to manufacture primers molecules exists, the report says. Scientists would be sure that they are getting a definitive diagnosis, while some present tests are ambiguous in how they are interpreted. It will also cut length of time needed to identify a disease causing a particular illness.

“Further down the road, scientists should be able to identify what is the Achilles heel of every virus or bacteria and then design drugs to attack that weakness,” says Dr. Pang. “In the past drugs are designed to attack diseases in a hit or miss way, through trial and error, We think it might work; we test, if it doesn’t work, we modify and improve it using a largely empirical approach until it is proven effective, but it can take many years or even decades.”

DNA medicine would bring a much more rational approach and improve efficiency and reduce costs, which is especially important in developing countries. Multinational drug companies say that it costs them an average of US$500 million and 12 years of research and testing to get a single drug onto the market.

It is now believed that the information generated by genomics will, in the long-term, have major benefits for the prevention, diagnosis and management of many diseases that hitherto have been difficult or impossible to control. These include causes of chronic ill health, including cardiovascular disease, cancer, diabetes, the major psychoses, dementia, rheumatic disease, asthma, and many others.

“A prime example is the world epidemic of insulin-resistant (type 2) diabetes, which is an extremely important risk factor for vascular disease,” the report says. “Although accurate epidemiological data are difficult to obtain, it appears that this disease is reaching frequencies of between 20 percent and 70 percent in many populations and that the global figure of affected people will rise from the current figure of 150 million to 300 million by 2025. At the same time, hypertension and vascular disease are rapidly increasing problems in various African, Asian and Caribbean countries. Indeed, the picture that is emerging is that many of the developing countries that are struggling to improve basic standards of nutrition and hygiene, and that are attempting to control the problems of communicable disease, are then finding themselves facing an unusually high frequency of these major causes of morbidity and mortality in adult life.”

Genetic Research and Ethics

The report carries the first ever global examination of the role that ethics should play in genetic research and genetic medicine.

The report warns that the planned development of large-scale genetic databases offers a series of hazards and ethical issues which have not been previously encountered. It says that there is still considerable controversy about the desirability of establishing databases of this type and there are many ambiguities regarding access and control. Concerns are focused on the potential harm to individuals, groups and communities.

Individual risks: Concerns for the individual arise from access to genetic information, both by individuals themselves and by third parties. The latter might include health insurance companies, government bodies, or the legal profession and police. Hence a great deal of attention is being paid to the questions of confidentiality and access to these databases. Although much effort is being put into protecting individuals there are still possibilities for the misuse of the databases.

Country risks: Some ethicists have suggested that genetic research based on collections may stigmatize particular groups of individuals or even entire countries. Concerns about commercial exploitation without adequate compensation exist as well. Also, because scientific research depends on freedom of access to samples and information, the commercial ownership of these databases may have a deleterious effect on genetic research.

Developing country risks: Another major issue regarding large-scale databases is that some developing countries are establishing collections of this type, often at the behest of companies from the developed world. Because of the lack of appropriate regulatory and ethical bodies in some of these developing countries these problems become much more serious and the dangers of inequitable commercial exploitation are even more acute.

Criminal data base risks: Many countries now have DNA databases containing DNA from convicted criminals. The use of DNA testing for forensic purposes also raises a number of important issues that have yet to be settled, which include:

  • Should DNA testing be compulsory for those being investigated for criminal activities?
  • How long should samples be stored in databases?
  • Should members of the public be asked to donate DNA for “elimination” purposes?

Currently a United States National Commission is studying these complex issues.

“It is not certain whether individuals who donate DNA samples for these databases are fully aware of the potential risks involved, and it is even less clear whether some of the arrangements that have been made with the private sector, which is becoming increasingly involved in these enterprises, are adequately controlled,” the report says. “It is also not apparent how information, particularly unexpected findings, will be handled in these large population studies and how these DNA samples will be used above and beyond the stated aims of those who are establishing the databases.”

Another ethical problem deals with decisions families may make regarding children as a result of DNA research. “These concerns are based on the notion that in our attempts to help families or individuals with a genetic disease we may increase the number of deleterious genes in the human gene pool,” the report says. “Preventing parents who are carrying the same genetic defect from reproducing, and hence having affected children, will tend to interfere with the normal evolutionary mechanism for reducing the frequency of deleterious genes within a population.”

Recommendations

The report says that it is vital to maintain a balance in medical research between genomics and more traditional and well-tried approaches of clinical practice, public health and clinical and epidemiological research and says that genomic research will only yield its full potential if it is integrated alongside these disciplines. These recommendations include:

  • Strong support for the recommendation of the Commission on Macroeconomics and Health to create of a Global Health Research Fund, a new central organization for research and development with an initial US$ 1.5 billion, which would be available through peer-reviewed application, to every country.
  • Endorsement of the Macroeconomics Commission’s proposal for a second US$ 1.5 billion should be made available to institutions which are working on new vaccine and drug development for HIV/AIDS, tuberculosis and malaria.
  • To support its Member States, the report says that WHO should develop the capability to examine advances in genomics for their potential for health care, and disseminate this information to governments quickly.
  • The WHO should develop the mechanisms required to evaluate such advances in comparison with more conventional approaches to medical research and development, especially with regard to their likely cost-effectiveness and value to particular populations and environments within Member States.
  • To develop clinical genetic services, based on easily transferable and well-tried clinical applications of DNA technology, which could provide immediate benefits to health care in many developing Member States.
  • WHO should play a major role in providing technical assistance to Member States to aid them in establishing centers for clinical genetics and genetic research programs targeted to their particular health problems, through supporting regional meetings, the establishment of collaborative training programs between developed and developing countries, and the development of local networking.
  • WHO should ensure that countries develop capacity to evaluate the ethical implications of genomics and also engage in public education at all levels.

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To get the full report, visit the WHO home page at http://www.who.int

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