Svetlana Borinskaya ::: Biography

GENOMICS AND BIOTECHNOLOGY:
SCIENCE AT THE BEGINNING OF THE THIRD MILLENIUM

The advances in 20th century biology which symbolize scientific progress in general are discoveries at the level of scientific sensations attracting great attention of the press and public. These include the following:
- The complete nucleotide sequence of the human genome has been deciphered;
- genes related to a range of diseases have been discovered;
- gene diagnostics and gene therapy methods have been developed basing on an understanding of the molecular mechanisms of disease development;
- transgenic animals and plants have been produced by directed integration of selected foreign genes into host genomes;
- animal cloning has been achieved.
These advances became possible due to the creation of principally new technologies of manipulation of genetic material, and the resultant discoveries considerably contributed to our understanding of the nature of living creatures and of the development of life on Earth, including human life.

This on-line version of the book "Biomediale. Contemporary Society and Genomic Culture" is not full. The unabridged edition can be purchased in printed form as anthology. Requests should be sent to: bulatov@ncca.koenig.ru (full information) or in written form: 236000, Russia, Kaliningrad, 18, Marx str., The National Publishing House “Yantarny Skaz”. Phone requests: Kaliningrad +7(0112)216251, Saint-Petersburg +7(812)3885881, Moscow +7(095)2867666. On-line bookshop (in Russian): http://www.yantskaz.ru. Full reference to this book: "Biomediale. Contemporary Society and Genomic Culture". Edited and curated by Dmitry Bulatov. The National Centre for Contemporary art (Kaliningrad branch, Russia), The National Publishing House “Yantarny Skaz”: Kaliningrad, 2004. ISBN 5-7406-0853-7

Scientific Studies and Discoveries
A brief history of the basic 'gene boom' discoveries can be started from the model of double-helical DNA structure developed in 1953 by James Watson and Francis Crick based on the X-ray plots obtained by Rosalind Franklin. In 1961 Sydney Brenner and Francis Jacob described the role of RNA, and at the end of the 1960s the efforts of several research groups resulted in deciphering of the universal genetic code, which is a nature-created vocabulary to translate the nucleotide sequence of RNA into an amino acid sequence of the protein being synthesized.
In 1970 the studies of Werner Arber and Hamilton Smith resulted in the discovery of restriction endonuclease enzymes that cleave DNA at certain strictly defined sites. The researches started to use restriction endonucleases for isolation of small fragments of interest from the extended DNA molecules. In 1973 genetic engineering was born: Stanley Cohen, Annie Chang, and Herbert W. Boyer produced the first chimeric DNA molecule by fusing two DNA fragments obtained from different organisms. Since then, scientists have been able to perform directed cleavage and fusion of the "Molecule of Life."
The procedures used to produce artificial DNA molecules in bacteria and yeast cells were developed. Basic molecular approaches were developed in the 1970s. Methods of sequencing DNA nucleotides were suggested by Frederick Sanger, Allan Maxam, and Walter Gilbert. H. Gobind Khorana developed procedures for the artificial synthesis of oligonucleotides, i.e., of short DNA chains of about several dozen nucleotides. An efficient procedure for the synthesis of artificial peptides was developed by Bruce Merrifield. It raised the possibility of synthesizing living cell DNA and proteins compounds (including those used for drugs in medicine) by request.
Gene technologies got powerful acceleration in the mid 80s after Kary B. Mullis invented the polymerase chain reaction (PCR), which enables production of a great quantity of the given DNA fragment in just a couple of hours. The PRC principle is so simple that geneticists were surprised that it had not been discovered earlier: all compounds involved in PCR were known a dozen years earlier. The PCR rapidly became a widely applied procedure in areas from advanced scientific research to new routine clinical tests designed to detect disease-related mutations in human DNA or to detect the presence of pathological microorganisms in the human body. The main part of the gene service market is composed of PCR diagnostics of sexually transmitted diseases. The introduction of PCR appeared to be of special importance in the diagnosis of tuberculosis. The growth of tuberculosis bacteria is very slow, and it takes up to one month to detect them with common biological methods. New technologies take just a few hours to determine not only the presence of these bacteria, but also their antibiotic resistance.
Many discoveries are based on careful and comprehensive research and scientific foresight, however some appeared as a happy incidence. For example, in their attempts to decipher the genetic code Marshall W. Nirenberg and J. Heinrich Matthaei used complex reactions with some control test tubes to which substances considered useless for inducing the required synthesis were added.
However, it was in these control test tubes where the key reaction was initiated, and this became a background for the subsequent rapid deciphering of the code.
Kary B. Mullis accidentally invented the polymerase chain reaction that allows one to reproduce given DNA fragments in great quantities. He was trying to develop a technology for quite a different purpose.
Almost all studies that were landmarks on the way of discoveries were awarded with Nobel Prize. Science rapidly passes the way from seemingly fantastic assumptions of researches to discoveries and technical solutions which go outside the laboratory to become a part of our everyday life.



The attitude to new technologies and discoveries is contradictory: these induce both great hope and serious fears.

The Human Genome Project
At the end of the 80s the idea of the possible deciphering of the whole human genetic information (genome) suggested by James Watson was considered absolutely fantastic. Skeptics argued that this task is technically unreal and, moreover, it would require unrealistic costs. However, thanks to Watson's scientific reputation and authority, in 1988 the Human Genome Project was started in the USA. James Watson was the first Head of this project, later the project was headed by Francis Collins. The Russian National Human Genome Program was started in 1989, it was initiated by Alexander Bayev, a member of the Russian Academy of Sciences, and supported by Mikhail Gorbachev. Russia thus became the second country that started a State Project of this type. National programs aiming to study the human genome were later started in more than 20 countries (the UK, Germany, France, Japan, China, etc.). The research within six larger projects is coordinated by The Human Genome Organization (HUGO) founded in 1988 at the first Conference on Mapping and Sequencing of the Human Genome in Cold Spring Harbor.
The initial value of the annual state financial support of the project in the USA and in Russia was 30 and 10 million dollars, respectively. At the end of the first step of the project in 2001 state funding in the USA was about 300 million dollars (no less financial support was provided by commercial organizations), while in Russia state funding of the National Human Genome Program in the dollar equivalent was only about $300,000.
In 2000-2001 the first step of the Human Genome Project was accomplished: the whole human DNA sequence had been obtained. The human genome contains 3 billion nucleotide pairs. It would take about 70 years (1 billion seconds) to look through a text of this size. Thirty years of research transformed DNA sequencing from a small-scale laboratory procedure into an industrial process, and modern sequencing centers resemble factories equipped with hundreds of automatic machines. Not only the human genome, but also the genomes of some animals, plants, and bacteria have been sequenced. The new branch of science dealing with the whole genomes was named genomics.

This on-line version of the book "Biomediale. Contemporary Society and Genomic Culture" is not full. The unabridged edition can be purchased in printed form as anthology. Requests should be sent to: bulatov@ncca.koenig.ru (full information) or in written form: 236000, Russia, Kaliningrad, 18, Marx str., The National Publishing House “Yantarny Skaz”. Phone requests: Kaliningrad +7(0112)216251, Saint-Petersburg +7(812)3885881, Moscow +7(095)2867666. On-line bookshop (in Russian): http://www.yantskaz.ru. Full reference to this book: "Biomediale. Contemporary Society and Genomic Culture". Edited and curated by Dmitry Bulatov. The National Centre for Contemporary art (Kaliningrad branch, Russia), The National Publishing House “Yantarny Skaz”: Kaliningrad, 2004. ISBN 5-7406-0853-7

A new method, named gene therapy, is being developed to cure diseases. Patients with genetic disorders receive genetic material to rescue the initial defects. This method remains rather far from widespread application; however, successful cases have already been reported. In 1990, W.F. Anderson, a geneticist from the USA, successfully applied gene therapy to cure a girl with a difficult innate disorder of the immune system. Considerable attention is deserved by the genetic studies as applied to cancer treatment. Malignant transformation can result from external factors (carcinogens, viruses) as well as from defects in the cellular genetic apparatus. Gene mutations that increase the risk of malignancies, e.g. breast cancer, were found. This allowed estimation of the risk of a certain cancer type. Gene therapy can prove efficient to cure malignancies. However, other directions are also being worked on, e.g. vaccines against cancer are being developed. Testing of the vaccine that prevents infection by papillomavirus (one of the main agents inducing cervical cancer) was started in 2001. If successful, the vaccine against cervical cancer will become available in the coming years. This form of cancer holds second place for occurrence in 20-30 year old females.
Transformation of external substances, such as drugs or food was also shown to depend on hereditary features of the human organism. The genes involved in these processes are named 'environmental control genes.' Combinations of variations of these genes can define success of the planned medical drug application, as well as the reaction to toxins. For example, females with certain combinations of mutations have ten times higher risk of breast cancer induced by smoking. One more example is the variable effect of the poisonous gas in Tokyo metro: the consequences regarding health depended on individual genetic parameters. Genetic tests can prove useful for selecting a profession. For example, the association between aniline dyes and bladder cancer risk is known since long ago. However, recently it was found that this serious 'industrial' disorder selectively affects individuals bearing certain gene combinations: control of foreign substance detoxification appears essential.


By decoding our biological structure and learning to alter it, we gain power over our own evolution. In the photo: Dr. Michael West, the president and CEO of Advanced Cell Technology (Worcester, Massachusetts).

Bacteria and Genomics
Genomic study of other organisms, primarily bacteria, is no less important then studies of the human genome. Compared with the human genome, the bacterial genome is very small, and this allows testing of new gene technologies. The complete genome of bacterium Haemophilus influenzae was sequenced in 1995. This work was a test of the procedure suggested by Craig Venter and used by him later for human genome sequencing. Venter created several private companies that competed (quite successfully!) with the worldwide scientific community for the work on human genome sequencing. Structural analysis of bacterial genes provides a lot of valuable information, both fundamental (theoretical evaluation of living matter functioning) and practical (applications in biotechnology and medicine). For example, the minimal number of genes required to support cell life under optimal conditions was estimated as a bit higher than 250. The smallest known bacterium contains 500 genes, while most bacteria have 1000 - 4000 genes. Deciphering of genomes for pathological bacteria allows identification of their metabolism peculiarities in order to develop specific antibiotics directed against the given bacterium, but not against normal human microflora or the human itself; this is essential to avoid after-effects. Human susceptibility and resistance to infection also depends on the genes. For example, some mutations preventing AIDS infection or providing considerable slow-down of AIDS development have been found.



Not only medicine uses the results of human genome studies. Among the areas of practical application is DNA identification of a person and DNA relationship testing.

Comparative and Functional Genomics
As found based on the whole human nucleotide sequence, the human genome contains about 30,000-40,000 genes. However, these genes are much more complex than bacterial ones. Human genes (as well as the genes of other complex organisms) contain the path of development from the first division of the egg up to the last breath ending human life. The fate of a cell, i.e. its further transformation into an epithelial cell, neuron, leukocyte or erythrocyte is determined by the function of certain gene groups within a given cell. The main part of the gene is normally inactive. It is turned off, and special signals are needed to make it start working.
In a normal cell subsequent turning on and off of various gene groups is surprisingly well coordinated, as if it was controlled by an invisible conductor. In fact, each cell has its own 'gene accord' that defines cell specificity. Conductor genes which transfer signals to other genes are known as regulatory genes, or "master genes."
Interesting results on gene activity changes in the process of development were obtained using model animals with already sequenced genomes: the fruit fly Drosophila, mouse, and a nematode worm. It was shown, for example, that the speech-related gene found in the human is very similar to the murine gene which functions at one of the embryonic development stages involved in brain formation. Experiments on mice suggest that that the function of the human gene is similar, and its mutations should affect normal brain development.
The research of the "postgenomic era" that started after deciphering of the whole genome nucleotide sequences aims to identify complete sets of RNAs synthesis in various cells and tissues, to identify all respective proteins and biochemical reactions. It is supposed that these tasks will be under extensive study during the coming decades.

DNA as a Forensic Instrument
Not only medicine uses the results of human genome studies. Among the areas of practical application is DNA identification of a person and DNA relationship testing. DNA profiling is used in forensic tests, including criminal cases.
These methods are used in criminalistics to identify offenders by biological marks found at the crime scene or on the suspect. This direction of research was started by the works of Alec Jeffreys, who found that human DNA has unique personal features which allow one to definitely tell whether a certain person produced the material collected as biological samples (hair, skin fragments, blood, saliva, sperm). This method named the 'DNA fingerprint' was first used in the UK to prove guilty the murderer of two 15-year-old girls. An analogous procedure of DNA similarity testing allows paternity identification (a rather frequent procedure in civil actions) or identification of any blood relationship between two individuals. The DNA analysis is currently applied for criminalistic and forensic testing all over the world.
For example, a National DNA Database for forensic DNA profiling exists in the UK. DNA samples are taken from any person arrested for an indictable offence (similarly to fingerprinting long in use), and the results are stored in a computer-assisted database. At present, the UK National DNA Database contains descriptions of hundreds of thousands of DNA samples. These were used to assist in thousands of criminal cases. Since most crimes are committed by recidivists, this data base helps to obtain matches unique to the crime scene, and also scene to scene matches using biological samples collected at the scene of these indictable offences. It is important to note, that upon acquittal all personal information is deleted.
Methods of DNA identification and forensic profiling were applied in some well-known cases: identification of the remains of the family of the Russian Emperor Nikolai I, the case of O.J. Simpson, and the case of President Clinton and Monica Lewinsky.
DNA data banks are created in the USA for the purposes of DNA-identification of military personnel. The DNA profile identifies a person much more efficiently than the hand-worn identification tag.

History in Our Genes
Similarity in genetic parameters allows relationship testing not only for individuals, but also for entire ethnic groups. Genetic diversity of the world populations is used to reconstruct the history of the human as a biological species. Combined with archaeological, ethnographic, historical, and linguistic data, DNA studies are used for dating the events of the history of the human population.
Different groups of geneticists arrived at the conclusion that the contemporary human originated in Africa and then spread through the whole world. The concept of African origin is contradictory to the earlier concept of multi-region origins that suggests independent transformation of our ancestor species Homo erectus into Homo sapiens in several regions of the world. The deceptive arguments in the debate were provided by DNA analysis. DNA studies allowed reconstruction of the main stages of history.
The genetic diversity of modern human populations was used to estimate the abundance of the ancestor population common to all modern humans. The ancestor population of about 10,000 people lived in Africa more than 100,000 years ago. The first migration waves of the contemporary human started from Africa and were directed to Australia through Asia (50-60,000 years ago) and to Europe (40-50,000 years ago). Later, Paleolithic Europeans pressed by the glacier several times moved back to the South and South-East, probably sometimes even returning back to Africa.
For some time our ancestors in Europe lived side by side with the Neanderthals, who became extinct about 30,000 years ago. Svante Paabo was the first geneticist who succeeded in isolating DNA from bone remains of the Neanderthals. Comparison of these samples of ancient DNA with DNA of the modern human has shown that the Neanderthals formed a separate biological species though were closely related to the human. No genetic traces of hybridization (if any took place) of human ancestors and the Neanderthals were found.

This on-line version of the book "Biomediale. Contemporary Society and Genomic Culture" is not full. The unabridged edition can be purchased in printed form as anthology. Requests should be sent to: bulatov@ncca.koenig.ru (full information) or in written form: 236000, Russia, Kaliningrad, 18, Marx str., The National Publishing House “Yantarny Skaz”. Phone requests: Kaliningrad +7(0112)216251, Saint-Petersburg +7(812)3885881, Moscow +7(095)2867666. On-line bookshop (in Russian): http://www.yantskaz.ru. Full reference to this book: "Biomediale. Contemporary Society and Genomic Culture". Edited and curated by Dmitry Bulatov. The National Centre for Contemporary art (Kaliningrad branch, Russia), The National Publishing House “Yantarny Skaz”: Kaliningrad, 2004. ISBN 5-7406-0853-7

Some chips possess the analytical capacity of well-equipped laboratories, while they are no bigger than the palm of the hand. Microchips of various types have been developed for environmental monitoring, detection of infectious agents in samples from patients and from the environment (there are chips which can detect bacteriological weapons application in only 30 minutes). Systems are developed to rapidly identify the presence of drugs in human blood. Complex tests can be run outside the laboratory, and the personnel do not need to be highly qualified. At present, the microchips are already used in scientific research, medicine, pharmacology, environment control, and many other areas.




During the past decades biologists learnt to manipulate not only genes, but also whole cells.

Cloning: Molecules and Animals
During the past decades biologists learnt to manipulate not only genes, but also whole cells. Special attention is attracted by cloning. Cloning (from the Greek word "klon": a branch, a shoot) is an exact reproduction of a given living object in a given number of copies. This term is used to define two completely different processes: cloning of DNA fragments (i.e., producing identical copies) and cloning of cells from an adult organism (i.e., producing a group of cells of the same genotype).
Cloning of DNA fragments is widely used in molecular genetics, since a small fragment (about one hundred or one thousand nucleotide pairs) is much easier to study than the whole chromosome. For this purpose, the studied DNA fragment is introduced into bacterial cells. Cloned DNA fragments are used in biotechnology to produce various products. For example, a human gene encoding interferon (a protein which protects the human body from viruses) was introduced into bacterial cells, and bacteria produce large amounts of human protein for medical applications. This is a much more efficient technology that the earlier procedure of interferon isolation from donor blood.
The first animal cloning experiments were performed at the beginning of the 50s in the USA by embryologists Robert Briggs and Thomas King. They transferred the nucleus of a mature frog cell into the ovule after the original ovule nucleus was removed. Similar experiments were preformed somewhat earlier in Russia by Georgy Lopashev, but his results were never published because of the prosecution of Russian geneticists in the Stalin era. John Gurdon from the UK successfully improved this method, obtaining tadpoles from 1-2% eggs with the transplanted nucleus. Other eggs produced defective embryos, and some showed no development at all: damage resulting from nucleus transplantation was rather severe. If it was possible to clone a frog, why not try other animals?
In 1997 a sensational report from the laboratory of Ian Willmut (Edinburgh, Scotland) announced the development of a method to clone animals. The experiments were run using sheep. A nucleus from the mammary gland of an adult sheep was transferred to the ovule with nucleus removed, then the egg was activated by electric shock. The embryos were placed in the uterus of the foster-mother to develop until birth. Only one of the 236 experiments was successful, and resulted in the birth of the famous sheep Dolly. Cloning of other mammals was reported some time later: a cow, a goat, a mouse, and a pig.
Scientists consider it technically possible to clone a human, however this induces moral, ethical and judicial problems. However, even in the case of successful cloning it is impossible to obtain a personality completely identical to the donor of the nucleus. It is impossible even to produce an organism with biological properties completely identical to those of the initial one: this would require exact reproduction of conditions for fetus development and birth. Any speculation about the mass production of super-geniuses or super-dutiful soldiers is nonsense. Any possibilities realized through cloning will in any case remain within the potential of the human as a biological species.
The reports on animal cloning and information on successful attempts at human cloning (they appear from time to time, but have not yet been proved) attract great public interest. As demonstrated by surveying of the Progress Educational Trust, London, UK, in Europe about 90% of respondents had heard about the sheep Dolly, while only about 50% knew about already practically applied and much more important gene diagnostics and gene therapy. Surveys in Russia gave similar results. It seems that non-specialists associate cloning with a sort of reincarnation. This produces fears like those demonstrated by participants of the student manifestation in Berkley in 1973 at the International Genetic Congress. The students tried to declare a boycott against scientists, charging them with attempts to clone Lenin, Hitler, Stalin, or Mao Tze Tung. These fears mainly originate from a lack of information. Living cells are essential to clone an individual. After death the DNA becomes damaged and can be used only to clone separate fragments, but by no means to produce a genetically identical organism.

Genetically Modified Plants
None of the kingdoms of living organisms was deprived of attention from a genomic perspective. Not only humans, animals and bacteria were carefully studied or subjected to attempts at improvement, but also plants. A great advance in biotechnology is the production of genetically modified plants, including transgenic plants containing genes from other organisms. Gene manipulation allow rapid production of plant varieties adapted to given climatic conditions, resistant to pests, allowing for long storage of fruit. The cautious attitude of consumers toward genetically modified products is in part explained by the rather recent introduction into practice and by the fact that the results of long-term experiments are not yet available (though all products undergo profound complex control and the technology of their creation by itself assures no danger to humans). Lack of public information plays a considerable role. As shown by the afore-mentioned surveys by the Progress Educational Trust, at least one third of the total population thinks that genetically modified tomatoes contain genes, while unmodified tomatoes do not.
Of particular interest are genetically produced plants capable of synthesizing vitamins or drugs. These plants can be used in medical practice. For example, 'golden rice' produces vitamin A, consequently, growing golden rice in countries where rice is the main source of nutrition would rescue thousands of people from blindness caused by vitamin A deficiency.



Combined with archaeological, ethnographic, historical, and linguistic data, DNA studies are used for dating the events of the history of the human population.

The Future of Genomic Medicine
In the opinion of Francis Collins, Head of the USA genomic projects, in 30-40 years the public medical service will be based on advances in genomics: cancer, diabetes, and hypertension will be successfully overcome, and gene products corresponding to those produced by the organism to fight disease will be available as drugs. It is hard to tell whether genes will be sold in drug stores together with pills and liquid medicines, and we do not know what new unexpected discoveries will change the world image we got used to. It is evident, however, that gene technologies have already entered the life of the contemporary human. Educational programs and wide-scale discussions of ethical, legal, and social issues in practical genomics and biotechnology are essential for the understanding and productive application of new scientific discoveries by the modern human society.

Translated from Russian by Ekaterina Gupalo.

Notes:
* Phenylketonuria is an inherited metabolic disease leading to severe mental disorders. (Editor's note)
** Cystic fibrosis is an inherited disease affecting the airway, the gastrointestinal tract, the ducts of the pancreas, the bile ducts of the liver and the male urogenital tract. It alters the chemical properties of mucus; instead of protecting tissues from harm, the abnormal mucus obstructs the ducts and airways, causing tissue damage. (Editor's note)
*** See: "Computational Genomics: from the Wet Lab to Computer and back", by Michael Gelfand, this issue. (Editor's note)





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COLOPHON

CONTENTS:

I. LABORATORY: science and technology

Svetlana Borinskaya. Genomics and Biotechnology: Science at the Beginning of the Third Millennium.

Mikhail Gelfand. Computational Genomics: from the Wet Lab to Computer and Back.

Irina Grigorjan, Vsevolod Makeev. Biochips and Industrial Biology.

Valery Shumakov, Alexander Tonevitsky. Xenotransplantation as a Scientific and Ethic Problem.

Abraham Iojrish. Legal Aspects of Gene Engineering.

Pavel Tishchenko. Genomics: New Science in the New Cultural Situation.
II. FORUM: society and genomic culture

Eugene Thacker. Darwin's Waiting Room.

Critical Art Ensemble. The Promissory Rhetoric of Biotechnology in the Public Sphere.

SubRosa. Sex and Gender in the Biotech Century.

Ricardo Dominguez. Nano-Fest Destiny 3.0: Fragments from the Post-Biotech Era.

Birgit Richard. Clones and Doppelgangers. Multiplications and Reproductions of the Self in Film.

Sven Druehl. Chimaera Phylogeny: From Antiquity to the Present.
III. TOPOLOGY: from biopolitics to bioaesthetics

Boris Groys. Art in the Age of Biopolitics.

Stephen Wilson. Art and Science as Cultural Acts.

Melentie Pandilovski. On the Phenomenology of Consciousness, Technology, and Genetic Culture.

Roy Ascott. Interactive Art: Doorway to the Post-Biological Culture.
IV. INTERACTION CODE: artificial life

Mark Bedau. Artificial Life Illuminates Human Hyper-creativity.

Louis Bec. Artificial Life under Tension.

Alan Dorin. Virtual Animals in Virtual Environments.

Christa Sommerer, Laurent Mignonneau. The Application of Artificial Life to Interactive Computer Installations.
V. MODERN THEATRE: ars genetica

George Gessert. A History of Art Involving DNA.

Kathleen Rogers. The Imagination of Matter.

Brandon Ballengee. The Origins of Artificial Selection.

Marta de Menezes. The Laboratory as an Art Studio.

Adam Zaretsky. Workhorse Zoo Art and Bioethics Quiz.
VI. IMAGE TECHNOLOGY: ars chimaera

Joe Davis. Monsters, Maps, Signals and Codes.

David Kremers. The Delbruck Paradox. Version 3.0.

Eduardo Kac. GFP Bunny.

Dmitry Bulatov. Ars Chimaera.

Valery Podoroga. Rene Descartes and Ars Chimaera.
VII. METABOLA: tissue culture and art

Ionat Zurr. Complicating Notions of Life - Semi-Living Entities.

Oron Catts. Fragments of Designed Life - the Wet Palette of Tissue Engineering.
VIII. P.S.

Dmitry Prigov. Speaking of Unutterable.

Wet art gallery

Biographies

Bibliography

Webliography

Glossary


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