Pathogenes and development of man

The most palpable result of interaction between para­site/host populations is manifest in selection as a conse­quence of the mass death of infected hosts. The killer epidemics of the past decimated the inhabitants of vast territories to the extent of depopulation. Today infec­tious diseases continue to be in the lead as to the socioeconomic damage inflicted on humankind. Seven dis­eases (TB, AIDS/HIV, malaria, diarrheas, respiratory infections, virus hepatitis and measles) account for half of the deaths of small children and adolescents world­wide.

In the United States, for instance, the downtrend in the mortality rate had held on until the 1980s. However, it went up 58 percent in the following thirteen years due to the incidence of a "new" disease, AIDS/HIV, and "re-emerging" TB. The same uptrend has been regis­tered in Russia, too: the current growth in the death-rate began in 1991. The incidence of TB doubled in the seven subsequent years, and today it is killing twice as many people as all the other infections combined.

Dr. John Holdane, a British biologist (foreign hon­orary member of the USSR Academy of Sciences from 1942 to 1948) was the first to point at the cause-and-effect of such pathologies. He postulated in 1949 that infection as one of the basic selection pressures for evo­lution leads to genetic polymorphism in Homo sapiens. Hereby the organism inherits characters whose presence increases the survival rate or alleviates a disease. The lat­est discoveries in molecular biology demonstrate that the highest diversity is detected in genes responsible for protecting the organism against pathogenic agents. Thus, the histocompatibility system (an association of immune response genes) comprises about 2,000 allele variants.* In fact, not only interracial but also interethnic distinctions are conspicuous in the occurrence rate of particular specificities.

TB (tuberculosis) is thought to have been the main factor of genetic selection among Caucasoids (white men). The examination of remains found in burial tombs dating from the fifth to the third millennia B.C. reveals traces of bone TB-caused lesions. During the recent five centuries TB has triggered pandemics in Western Europe and North America. In the 17th and 18th centuries this disease killed 20 percent of white adults. The lethality rate continued high later on, too: over one billion people died of TB from 1850 to 1950. The TB incidence rate rose again from 1985 on after the TB causative agents had developed resistance to antibi­otics. Today every year as many as 1.9 men die of TB every year, largely due to the widespread circulation of strains with multiple drug resistance.

Another infectious disease, malaria, has played a major part in the development of man. According to some experts, blood groups antigens were formed in response to the malaria causative agents. The Negroid race was worst hit: living in the tropical belt, this race became the target of malaria-effected genetic selection. Yet specific anomalies have been identified among all races populating territories of the most violent outbreaks of the infection. Such characteristics are clearly distinct in the composition of blood. We know that oxygen takes hemoglobin to tissues from the respiratory organs, while carbon dioxide carries it from tissues to the respiratory organs (hemoglobin is part of erythrocytes, the red blood cells). But under the action of selection pressure, with malaria as agent, hereditary defects, the hemoglobinopathies, came into being-by way of protection against the disease.

People of West and Central Africa have developed a specific mutation, the absence of the Duffy factor in erythrocytes. Its carriers-and this is more than 98 percent of the population—are immuneable to one form of the disease, tertian fever (benign tertian malaria) since the protozoan Plasmodium vivax is incapable of getting into red blood cells devoid of, the above-mentioned factor. Thus far this is the only genetic anomaly caused by malaria pathogens, and its negative aftereffects have not been explained yet.

Thalassemias (Cooley's anemias) are yet another instance of mutation. This is a class of anemias caused by anomalies in genes coding for hemoglobin output. The higher incidence of this pathology in Europe has been found on the Mediterranean coast. It also occurs in Africa, in the Near and Middle East, on the Arabian Peninsula, in India, in Central and Southeast Asia, South China as well as on islands in the western Pacific all the way from the Philippines in the north to the Timor Sea in the south, and to New Guinea and Melanesia in the east. This hemoglobinopathy in homozygotes and heterozygotes alike halves the risk of malaria.

The lack of the enzyme glucoso-6-phosphate-dehy-drogenase (G6PD) was first identified as hemolysis (blood pathology characterized by the destruction of red blood cells with loss of hemoglobin) that sets in after the eating of legumes (French beans, peas and the like). This anomaly ensures 50 percent protection against the grave clinical form of tropical malaria. As shown by studies carried out at our research center, the percentage of cases afflicted with this pathology in the CIS countries (former Soviet republics) ranges from 3 percent in Moldova to 30 percent in Azerbaijan. The zone of G6PD deficiency concurs with the territory ravaged by tropical malaria in the past. The same peculiarities are shown in the other parts of the world.

Sickle-cell anemia (hemoglobin S disease or S-hemoglobinosis) is still another pathology caused by gene mutation. Today its victims survive up to the middle age (formerly, before present-day healthcare, they usually died in childhood). Hemoglobin S disease occuts throughout the African continent with the exception of southern Africa, along the southern and eastern coasts of the Mediterranean, on the Arabian and Indian Penin­sulas up to the eastern border of what is now Bangladesh. Children with hemoglobin S seldom die of tropical malaria, while those having the normal hemoglobin A perish ten times as often.

The connection between the occurrence rate of the hemoglobin S gene and the risk of the malaria infection is indirectly confirmed by comparative studies of Africa's aboriginals and Afro-Americans (Negroids) in the United States whose ancestors were brought to North America in the slave trade times. African Blacks show a much higher presence of the hemoglobin S gene. However, the occurrence of this gene among the' Afro-Americans of North America has been down, since there is no hazard of infection and selection pressure.

The above-cited examples of polymorphism are observed in populations hit hardest by malaria for cen­turies at least. As a consequence, even today 300 thou­sand to 1.5 million babies are born with bad forms of such congenital genetic anomalies. That is why the natives of northern Europe (except the Low Countries), of northern Asia, Australia, the Americas and islands of eastern Oceania, who have not been subjected to the pressure of this infection, are free from such anomalies.

Diseases to which African descendants show predispo­sition are also thought to be connected with the malaria-effected selection. For instance, Afro-Americans suc­cumb oftener to hypertension and show a higher content of iron in their organism.

In recent years the implication of polymorphism has been established in the clinical picture and characteris­tics of many infections. Likewise detected have been hereditary changes of the human genome which are responsible for resistance to AIDS/HIV or affecting the clinical symptoms of these diseases. Thus, deletion (chromosomal mutation) controlling synthesis of the chemokine receptor CCR5 (deletion designated as Δ32) is also assigned to mutations which in the homozygotic state can determine resistance to HIV infection. Among Caucasoids the mutant allele occurs at a rate of 12 to 18 percent in the heterozygotic state, and about 1 per­cent—in the homozygotic. This figure is significantly lower among other races (say, not above 2 percent for Afro-Americans). In our country the CCR5 A32 muta­tion is fairly common (among the ethnic Russians the heterozygotic genotype occurs in 17-24.4 percent of cases, and the homozygotic one—in 1-2 percent). This genotype provides 9.9 percent protection against the HIV infection in heterosexual contacts, transmission of the virus from mother to fetus or in blood transfusion.

The above facts confirm the hypotheses on the impor­tance of the selection-mediated effects of microorgan­isms on the evolution of the human genome. However, the impact of pathogens is not only restricted to the mod­ification of the biological characteristics of Homo sapiens. Acute infectious and parasitogenic diseases spilling over into epidemics affect the social and economic conditions and destinies of peoples and civilizations. Here are just a few examples, Tropical (falc iparum) malaria that hit the northern Mediterranean in the first century A.D. devas­tated the southern tip of the Apennine Peninsula, a region that had been developing with much success for nearly 1,000 years. Because of the infection hazard these dis­tricts of Italy had persisted desolate up to the onset of the 20th century. Traveling to the European continent in the beginning of the first millennium A.D., tropical malaria led to the rapid decay of the Hellenic civilization.

The spread of the Justinian plague in the 6th century A.D. finished off what remained of the Roman Empire. Smallpox, carried: by the Spanish conquistadors to America, undermined the Incan empire-in 1520 alone this disease kill more than 3 million American Indians. The import of syphilis by Columbus's sailors from the New World late in the 15th century and its propagation contributed to the twilight of the European Renaissance. The dysentery epidemic in the armies of Austria and Prussia advancing on the revolutionary Paris of 1794 compelled the troops incapacitated by diarrhea to fall back, which in no small measure helped save the French Revolution.

Just as dramatic are instances of social panic, as seen in the example of real or imaginary, epidemics of the last fifty years. The outbreak of cholera caused by El Tor vib­rio in Indonesia (1961) and in other regions of the globe resulted in an actual economic blockade of the countries involved. The first epidemic of the Ebola fever in Africa (Sudan, 1976) stalled air traffic there. Such kind of inad­equate "anti-epidemic" measures were also taken in respect of a "pneumonic plague" in India (1994), though no cases of that disease were actually reported. The same is true of the atypical pneumonia SARS (Severe Acute Respiratory Syndrome) said to have hit China, Viet Nam and other countries in 2003.

It's a paradox: periodic epidemics excite but a fleeting "interest" among the public. Policy-makers and even top healthcare officials close their eyes to the socioeconomic role of infectious diseases as the prime cause of, mass incapacitation and premature death of people the world over and do not allocate essential funds for combating this hazard jeopardizing the very existence of humanity.

Well aware of the primary role of causative pathogenic agents and the fact of interspecific competition between microorganisms and man, we cannot afford to pin hopes on consecutive adaptation of Homo sapiens as a biologi­cal species in the context of the Darwin-Wallace theory. Millions and millions of lives will have to be sacrificed in epidemics and in the struggle for survival, as it has hap­pened time and again. Dr. Joshua Lederberg, a US geneticist (Nobel Prize, 1958), had a point when he said that in the race for survival with microbial genes our weapon should be human intelligence, not the natural selection of our genes.

5. Bio – shield

This far Russia is not ready to address biohazards, Academician Mikhail Paltsev, rector of the Moskov Medical Academy and chairman of the Russian Health Ministry Exspert Board, says. He was one of the organizers of the Second International Conference “Molecylar Medicine and Biosafety”. The conference, attended by Russia’s leading virologists, as well as representatives from the U.S Department of Health and Human Servises and the State Department, discussed, among other things, the threat of bird flu in the world.

Is bird flu a real bio – threat?

Bird flu exists, and it affects people – mainly those who eat raw poultry. This far there has not been a single proven case of bird flu transmission from person to person. Should this happen, there will he a serious epidemic. The danger lies in the so – called antigenetic drift, when genetic information is exchanged between ordinary flu and bird flu viruses, and the human virus acquires bird – flu characteristics. This new virus can evolve within the organism of a person who has contracted common flu and bird flu simultaneously. This virus will spread through the air. So there are two ways of protection – common vaccines, to reduce the number of ordinary flu cases, and special vaccines.

Will a vaccine be developed by the tune an epidemic begins?

Nobody knows when the bird – to – human species barrier will be crossed or whether it will be crossed at all. Science is so far unable either to provide an accurate forecast or to prevent a dangerous situation. Maybe there is still enough time or maybe there is not, so a vaccine must be developed as a matter of – urgency – 3 % ere is no doubt that it will be eventually created. The flu viris strain has been isolated, and work is in progress in many countries, including Russia. The problem is to launch its production if an epidemic strikes, and produce the vaccine in sufficient quantities.

There have been reports in the media that bird – flu drigs have been developed. Is this true?

As far as I know, there is no proven prescription against this particular disease. Such a drug has to be tested on a large number of people, while there are only a few dozens [of such people] at this stage. Tyis is not enough to prove that a drug is effective.

Substantial investments into biology are required to develop new drugs, vaccines, and other means of protection against bio – threats. How is this field of science being financed, compared to others?

It is very difficult to make any comparisons here since there are no reliable figures in Russia, but the level of funding is rlenrly insufficient. Here is just one example: Russia has not been producing its own antibiotics for the past two years, while this is one of the main indicators of the status of bio – technology in any country. Any civilized state is supposed to produce them in sufficient quantities sience they are the main protection against infections. An ongoing congress on biotechnology dramatized the bio – tech crisis in Russia. Just like 40 years ago, science in Russia is dominated by physics and nuclear engineering. In other countres, investment in bio – technology has been growing exponentially with the correlation between the biological science and all other science reaching 50:50. In Russia, biology has a very low priority. This is why Russia is extremely vulnerable to bio – threats and is completely dependent on import. Whereas nuclear security matters have been more or less resolved, the bio – threat has not as yet been fully appreciated. A biosafety doctrine was signed by the president two years ago, but nothing has changed since then. It was also announced that a national biosafety program was being prepared, but it has yet to materialize. Russian state and government officials do not understand that bio – threats, both natural and man – made, are growing every day and that we do not have effective systems to counteract them.

How should a biosafety system be built?

First of all, there should be permanent monitoring and forecasting of bio-threats. As soon as the United States was faced with bio-terrorism, funding of bio-terror research programs increased sharply. Whereas before 2002, about $40 million a year was provided, in 2002 through 2005, it was $1.8 billion a year (plus about $700 million via the Center for Disease Control and Prevention). A network of laboratories was created, constantly monitoring the appearance and movement of all dangerous bacteria, viruses and genetically modified organisms (GMO). Furthermore, there should be a well-developed vaccine production industry. In Russia, this industry needs serious modernization. As is known, flu vaccines are based on chicken embryos, but is there a guarantee that they are not affected by a bird flu virus and that we will not create a dangerous mix in a laboratory? Vaccines should be produced without the use of living matter. Russia only has projects and patents in this field.

6. «Super-tough» bugs to improve cancer research

Almost-indestructible microbes that survive and thrive in hot sulphuric acid pools as well as freezing polar terrain are being studied by space sci­entists because the organisms rep­resent the type of life most likely to be found elsewhere in the solar sys­tem.

The "super-tough" bug research is expected to improve our understand­ing of the origin of life and, eventu­ally, reveal whether life is confined to our planet or is distributed more widely.

And in similar work elsewhere, sci­entists at a top university in United Kingdom are making good progress with much more down-to-earth stud­ies after focusing on this incredibly strong family of microbes - called Archaea.

These almost immortal minute creatures have many similarities to humans in the way they replicate and repair their DNA, shedding new light on the workings of the human body. Because of their extreme lifestyle, Archaea proteins are very robust and often easier to study than the equiva­lent human proteins.

A research team at the University of St. Andrews, Scotland, recently made a startling advance relevant to human diseases and they are continuing to es­tablish if it could prove to be a useful weapon in the fight against cancer.

Led by Professor Malcolm White, the team at the Centre for Biomolecular Sciences at St Andrews made the discovery while investigat­ing proteins - called helicases - that separate strands of the genetic ma­terial DNA.

Helicases are vital for the replica­tion and repair of DNA (deoxyribo­nucleic acid); defects in these pro­teins can lead to increased rates of cancer In humans.

The team found that a family of helicases important for the avoidance of breast and skin cancer incorporates a cluster of iron and sulphur atoms. This "Iron-sulphur cluster" is essential for the activity of the helicases, and mutations in humans that prevent the cluster forming _tare known to lead to severe cases of early onset cancer.

Professor White paid tribute to the Association for International Cancer Research for funding the study and added: "Iron is very important in the body but no-one had suspected this link with DNA repair. The discovery was only possible because we inves­tigated a simple model organism - it would have been very difficult to study the human proteins. This emphasises the need for basic research as part of our efereto understand and com­bat cancer."

He added: "Credit must also go to the student who made the discovery, Ms. Jana Rudolf. She has now been funded by the charity Cancer Research UK to continue her studies."

It was in 2002 that Professor White discovered that archaea have unex­pected similarities to humans. He ex­plained: "Because the archaea are so simple they are much easier to study, SO that is really our reason for work­ing with them. They only have 3,000 genes whereas we have well over 30,000 genes.

"The other main point is that this work changes the way we think about these so-called 'primitive' forms of life - they may be more sophisticated than we had thought and, therefore, more similar to man."

Many archaeans are extremophiles. Some live at very high temperatures, often above 100 degrees Celsius, and are found in geysers and around "black smokers" - volcanic chimneys rising from the seabed. Others are found in very cold habitats or in highly saline, acidic or alkaline water.

Other archaeans are mesophiles and have been found in environments such as marshland, sewage, sea water and soil. Many methanogenic archaea are found in the digestive tracts of animals such as ruminants, termites and humans. Archaea are usually harmless to other organisms and none is known to cause disease.

Professor White said that the work had only been possible because re­searchers could pool theit expertise in research centres such as the Centre for Biomolecular Sciences, where scien­tists from different disciplines are brought together in world-class labo­ratories with state-of-the-art equipment.

At the biomolecular sciences cen­tre, Professor White is renowned as an expert on archaea proteins that are ideally suited for structural stud­ies. Describing his work in more de­tail, he said: "ONA is subjected to continual assault by a variety of chemical, enzymatic and environmen­tal factors, and must be repaired ac­curately and swiftly to maintain the in­tegrity of the genome. Multiple re­pair pathways have evolved to fulfil this role, including nucleotide exci­sion repair and homologous recom­bination.

"We are studying these pathways in the archaea - a group of prokaryotes that represent a third domain of life, distinct from both eukaryotes and bacteria. Archaeal information processing pathways (for example transcription, translation, DNA repli­cation) are good models for the equivalent, more complex pathways in eukaryotes.

"We ' are identifying and characterising archaeal proteins im­portant for DNA repair and recombi­nation, using a multi-disciplinary ap­proach that includes biochemical, bio­physical, molecular biological and genetic techniques, with the aim of defining the relevant components and mechanisms- This work will yield insights to the equivalent processes in eukaryotes, including humans, that are essential for the avoidance of cell death and carcinogenesis," he added.

The School of Chemistry provides an outstanding environment for re­search and study. Chemical research has a long and distinguished history at St. Andrews. In recent years, sev­eral named prizes of the Royal Soci­ety of Chemistry have been awarded to current members of the school.

By Richard Maino

7. World leading research at biomedical centre

A unique collaboration of com­mercial, academic and clinical enter­prises - that's how to describe the Centre for Biomedical Research that is expected to open in 2006.

Seen as a flagship development for Scotland and a leading project for biomedical research, the Centre for Biomedical Research (CBR) is housed on a high quality campus de­velopment near the new Edinburgh Royal Infirmary, a five-star teaching hospital.

The University of Edinburgh's Medical School and Institute for Medical Cell Biology will also be based on the bioscience park built at a cost of 200 million pounds.

"The CBR will bring together world-leading commercial research and development, healthcare delivery, academic research and medical train­ing in an inclusive, optimized envi­ronment said a spokesman for Scottish Enterprise, the organization promoting inward Investment.

"Organizations within the park will have a truly dynamic scientific com­munity on their doorstep. For most companies and scientists Involved in biomedicine, the attraction of working closely with academic exper­tise and clinical practice Is hard to beat. In particular, they will benefit from the research expertise of the University of Edinburgh, recognized as 'world-class' in a number of specialisms including life sciences and medicine."

The CBR Is a public/private part­nership valued at one billion pounds. The centre cost seven million pounds to build and equip and aims to posi­tion Edinburgh as one of the world's top ten areas for biomedical invest­ment. The CBR will also seek to en­tice world-class life science compa­nies and attract and retain scientists and researchers- Furthermore, it plans to encourage the commercialisation of new ideas.

The project is expected to create 6,000 jobs, contribute up to 440 mil­lion pounds annually to the economy and is one of Scottish Enterprise's flagship projects for the coming years.

A range of laboratory and office space will be available, from start-up incubator units to flexible multi-user spaces and strategic sites for single biomedical companies. A variety of facilities will be shared between com­mercial, academic and health service-related research organizations, provid­ing a natural environment for collabo­ration and networking.

In addition, organizations will have access to scientific-support facilities and intensive business-de­velopment support. Plans are also in hand to create conferencing/ meeting facilities, restaurant, nurs­ery and recreation facilities within the vicinity of the park.

The Centre for Biomedical Research is part of the Edinburgh Sci­ence Triangle (EST). The EST project brings together new teaching hospi­tals, health services, academics and the bio-pharmaceutical industry to commercialise leading-edge re­search. An estimated 30 spin-out companies and 120 business start­ups are to be generated by the EST.

The super-campus is already home to more than 3,300 world-class re­searchers and includes companies such as leading anti-cancer therapy company Viragen. The EST will rank alongside Cambridge and London as a top UK research region and is on track to be recognized as atop ten area of science and technology ex­cellence in Europe.

The CBR will help establish Edinburgh as one of the globe's top ten centres for biomedical research, positioning itself with such well-respected institutions as Biosquare in Boston, Mission Bay in San Francisco, Biopolis in Singapore and Kobe.

Professor Shin Ichi Nishikawa is deputy director of the Riken Centre for Developmental Biology in Kobe. He is one of the world's most recognised researchers in blood stem cells, and believes the links with Scotland's academic and business community could unlock huge poten­tial.

Particular biomedical research strengths there lie in cardiovascular science, reproductive biology, inflam­matory cell biology, infectious dis­eases, stem cell and advanced imag­ing.

Professor Nishikawa said: "When you work together the process is much smoother. Edinburgh has enor­mous potential and can continue its growth in world-leading research in the field of stem cells and there is mu­tual opportunity for Edinburgh and Kobe."

According to the government body UK Trade & Investment there has never been a better time to invest in the UK healthcare indus­try. The home of many key scien­tific and medical discoveries and in­ventions, the UK remains at the fore­front of research and development (R&O).

Indeed, many investors have es­tablished R&D centres in the UK to take advantage of the, outstanding individuals and facilities.available: Universities form the hub around which centres of research excellence are created, offering a range of fa­cilities to support development such as clinical trials laboratories.

Many multinational corporations have formed strategic partnerships with universities, spin-out companies or contract research teams In the UK. They go to the UK because of its long and highly successful R&D record. It offers skilled research, institutional support, a high-class academic environment, multi disciplinary networking, industrial links and government fi­nancing.

The UK's 100 universities and many research centres are busy working on new developments. That is why hun­dreds of the world's leading indus­trial players have based their own R&D centres there, linking them to UK aca­demic and research teams skilled in scientific and technological innova­tion.

By Richard Maino

Дата добавления: 2015-10-30