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specialization : Biotechnology Final report Genetic engineering of plants for the production of medicines Group 5: Iris Hensen Emanuel Casagrande Jan-Pieter Ploem Thibaut Gabriel Ilse Timmermans Genetic engineering of plants for the production of medicines ince the beginning of the earth, humans use plants. Plants exist even longer than humans and we are still not aware of all their opportunities. Scientists and people who are interested by these beautiful things present in the wild life try to understand how these plants operate. More and more, they discover a large variety of species and the different possibilities of each plant. Still, these days not all species of plants are discovered. Estimated, there are 380.000 different species of plants. S The development in science is also in progress and we are able to modify some genetic aspects. Geneticists are very advanced in the field of modifying DNA chain. They develop new techniques and methods every day to transfer genes from an organism to another. How does the genetic proces work? When were the techniques developed? Which are the bacteria used to develop genetic modification? Which medicines are the best: normal or genetic engineered medicines? Genetic engneering of plantsfor the production of medicines Table of contents Table of contents ..................................................................................................................................... 2 Summary ................................................................................................................................................. 3 Genetic engineering ................................................................................................................................ 4 What is genetic engineering? .............................................................................................................. 4 History.................................................................................................................................................. 4 Techniques .......................................................................................................................................... 4 Recombinant DNA-molecules ......................................................................................................... 4 Eukaryotic cloning and expression systems .................................................................................... 4 Genetic engineering of plants .................................................................................................................. 5 Transformation..................................................................................................................................... 5 Dicotyledonous plants ..................................................................................................................... 5 Monocotyledonous plants ................................................................................................................ 6 Hepatitis B ............................................................................................................................................... 7 Contagion and patho-genesis.............................................................................................................. 7 History.................................................................................................................................................. 7 Vaccines .................................................................................................................................................. 8 History.................................................................................................................................................. 8 New vaccines....................................................................................................................................... 8 How do they work? .............................................................................................................................. 8 Current vaccine ................................................................................................................................... 9 Tobacco and hepatitis B ...................................................................................................................... 9 Potatoes and hepatitis B .................................................................................................................... 10 Comparison genetic engineering medicines and normal medicines ..................................................... 11 conclusion .............................................................................................................................................. 11 References ............................................................................................................................................ 12 Figure list ............................................................................................................................................... 13 Genetic engneering of plantsfor the production of medicines Summary Genetic engineering refers to all techniques that transfer genes from one organism to another, to produce new or modified organisms. The most used general technique is the recombinant DNAtechnique. There also plant specific techniques like transformation by A. tumefaciens. With these techniques, medicines can be made out of normal plants by modify them. An example from this ‘genetic medicine’ is the hepatitis B vaccine made from genetic modified tobacco plants or potatoes. Hepatitis B is an infectious illness caused by a virus which infects the liver of humans and causes an inflammation. The virus is spread through the blood through the body. Then , if the immune system doesn’t response as it should be, chronic infection can arise. Better is prevent hepatitis B by making vaccines to help the immune system. They contain living weakened or dead micro-organisms. These micro-organisms will encourage the immune response without making people sick. Thanks to the recombinant DNA-technique, the tobacco plants or potatoes can used for making a hepatitis B vaccine. By bringing a foreign gene in the tobacco or potato, the plant will start to make antibodies against it. Then the plant can be eaten or making a pill from it, so it’s an oral vaccine. These days, the vaccine against hepatitis B made from tobacco plants or potatoes is only tested on mice. So now is proved that making medicines from genetic modified plants is very useful, they will slowly conquer the medicine world. 3 Genetic engneering of plantsfor the production of medicines Genetic engineering somes. A vector is cut with the same restriction-endonucleases as the frag-ment. This clutch What is engineering? can be made permanently by another en-zyme: DNA-ligase. genetic Everyone knows Dolly the sheep, the first cloned fullgrown animal in the world. For a lot of people, it was the first acquaintance with genetic engineering. This was in 1996, but genetic engineering existed even before then. Genetic engineering refers to all techniques that artificially move or transfer genes from one organism to another, to produce new or modified organisms. The target material is the deoxyribonucleic acid (DNA) molecule found in all living cells of organisms, where genetic information is stored. (J.Craig Venter Institute 2004) History Genetic Engineering first appeared in 1972, nineteen years after the discovery of the DNA structure. It was Paul Berg, an American scientist, who produced the first DNA-recombinant molecule. Recombinant DNA is a type of DNA that is artificially created by inserting a strand or more of DNA into a different set of DNA. These DNA have different origins, they come from other organisms. Later, in 1976 Recombinant DNA is a type of DNA that is artificially created by inserting a strand or more of DNA into a different set of DNA. These DNA have different origins, they come from other organisms. bred the first genetic modified mice. 10 years after the mice, scientists modify the first crop, a gene-altered tobacco. These days, genetic modification is one of the most important subjects in the biotechnology (E.Wirix 2010;J.Craig Venter Institute 2004) Afterwards, the recombinant DNA-molecule will be inserted in a living host cell where it replicates (cloning). Techniques Recombinant DNA-molecules When a DNA-molecule consists of DNA coming from different sources is called a recombinant DNA-molecule. Genetic modification can be applied in bacteria, plants and in animals. The process in plants will be described more in detail in chapter 2. Restriction-endonucleases (cutting enzymes) cut the genomic DNA in little fragments. This enzymes recognize DNA-sequences from 4 to 8 nucleotides long present in the target DNA molecule. So, a certain DNA-molecule will always be cut in the same way by a certain restriction-enzym. (E.Wirix 2010) After the cutting, we end up with restriction-fragments. The most restriction-endonucleases split the DNA in a certain way that the fragments have a single-stranded piece at the 3’ or 5’ end. These ends are called the ‘sticky ends’. Each fragment will be inserted in a carrier molecule, which is called a vector. A vector can be: a plasmid, bacteriophages, viruses or little artificial chromo- Simple version of recombinant DNA technique (national health museum 2010) (E.Wirix 2010) Eukaryotic cloning and expression systems These days, it’s possible to develop recombinant DNAmolecules which will be inserted in the genome of multicellular organisms. When a zygote transforms with the strange DNA, it will develop in an organism which contains the recombinant DNA in all cells. If we breed with these organisms we can get transgenic organisms, which contain the recombinant DNA in all his cells. Plant specific techniques like transformation will be explained in the next chapter. (E.Wirix 2010) Zygote a term to refer to the cell in a state between the fusion of two haploid nuclei during fertilization until the first cleavage. 4 Genetic engneering of plantsfor the production of medicines Genetic engineering of plants Genetic engineering is a technique used to introduce desired traits into a chosen organism. To achieve this the scientist has to insert a specific gene which will encode for a protein that is responsible for the expression of a certain defined trait. This insertion followed by the expression of a new feature is called ‘Transformation’. It is possible to transform plants due to their totipotent nature. A new plant can grow from a single cell. This means that if an isolated cell is adjusted, all the cells of the new plant will have the new gene. Since all the cells will be copies of the adjusted cell. Some examples of new traits are: herbicide tolerance, drought tolerance, resistance to pathogens and insects. But it is also possible to insert a gene that is responsible for higher nutrition values or for the production of certain products that can be of interest. The gene used to introduce the traits can be of any origin. There is only one condition, the trait has to be compatible with the host organism. Totipotency The ability to regenerate from a single cell to become a full grown plant. To be certain that the plant is a modified organism the desired transgene will be accompanied by a herbicide/antibiotic re- sistance inducing gene. This is a control mechanism which will be used after the transformation. By adding the herbicide or the antibiotic, to which the modified plant should be resistant, to the nutrition medium the scientist can check if the transformation worked because only the plants with the right gene will be able to grow. The first generation of transformed plants has to be grown on a gel-like medium on a petri dish, It is easier to control the environment and the growth factors in which the transformation can take place and allows the cell to regenerate. Further generations could be cultivated on the field. This however is not yet commonly approved by law. There are severe rules on the cultivation of modified plants. Within Europe the gmo has to undergo a risk assessment before the cultivation can be approved. (J.A.Thompson 2009) Transformation To insert this transgene in the DNA of the plant the scientist can chose between a few techniques, one more favourable than the other. There is a difference between the insertion of a gene in dicotyledonous and monocotyledonous plants. Dicotyledonous plants There are a few techniques used to insert a gene in the genome of the plant. (J.A.Thompson 2009) Transformation tumefaciens by A. There is more and more progress in the world of plant genetic manipulation, but we still use an older method with A. tumefaciens. Agrobacterium tumefaciens(International Microbial Ecology 2002) Society for This still is a major method of choice for trans-forming plant cells. Despite these progresses, we always work on this bacteria to get a better understanding of the mechanism of gene transfer . A lot of important cereals have now been transformed using A. tumefaciens. These plants have been transformed to gain a higher tolerance against certain herbicides or a higher nutrition value. (Newell, 2000) A. tumefaciens seems to be the best discovery to realize DNA implantation into plant genomes. Bacterial vectors such as Eschericia coli have already been used successfully as vectors in microbiology (Kikkert et al., 1999) ; that is now extended to the world of botany. These techniques have been applied on several plants, such as lettuce (Curtis, 1995), rice (Hiei, 1997) and tomatoes (Tzfira et al., 2002). This proves 5 Genetic engneering of plantsfor the production of medicines that methods with direct gene transfer, are not the only way for transforming important crop plants (Newell, 2000). The transformation by A. Tumefaciens permits insertion of specific DNA-sequences into the plant’s genome. This is a good reason to choose this method when compared with other methods (see below) although the success rate is not 100% (Gheysen et al., 1998). There are however some valid arguments against the validity of A. tumefaciens mediated transformation. Dicotyledonous plants are plants which develop from two cotyledons in the seed. They can be recognized by the branching veins in their leaves. Dicots of commercial value include many horticultural plants such as petunias, and crops such as tobacco, tomatoes, cotton, soybean and potatoes. Tobacco, due to its ease of transformation, initially became the workhorse of plant genetic engineering, but more recently the common wall or thale cress, Arabidopsis thaliana, has become very popular. It has the advantage of not requiring tissue culture during its transformation. Tomatoes have been transformed to delay their ripening, cotton to insect resistance and herbicide tolerance, soybeans to improved oil quality and herbicide tolerance, and potatoes to resist viruses. Other methods For many years the only alternative to A. tumefaciensmediated transformation was the direct uptake of naked DNA by plant protoplasts, achieved by electroporation or mediated by polyethylene glycol (PEG). These methods depend on the ability of plants to regenerate from protoplasts, which varies considerably between species. For example, there are many parameters to be successful with PEG technique (such as ion concentration, molecular weight and concentration of PEG, physical configuration of nucleic acid,…). Linearized double-stranded plasmid DNA molecules are expressed and integrated most efficiently. Now the most widely used alternative to transformation by A. tumefaciens is biolistics. Other techniques exists, including pollen co-cultivation, microinjection of somatic embryos and liposome fusion with protoplasts. (J.A.Thompson 2009) Monocotyledonous plants These plants require a different approach to insert a gene. Transformation by A. tumefaciens This method is used less frequently but when it can be used it is the preferred technique. The problem here is that some important monocots, such as: maize, rice and wheat are resistant to A. tumefaciens and cannot be transformed. There have been some efforts to alter the A. tumefaciens to make it able to infect these monocots. Until now the greatest success has been with rice. (J.A.Thompson) Biolistic transformation “This technique of particle bombardment, or biolistics, is the most versatile and effective way of creating many transgenic plant species, including elite lines.” When this technique is used, an isolated DNA-fragment has to be coated on a metal particle. Currently gold and tungsten are often used metals because of their inert nature. The coated particles are shot into the cell with a gene gun, a biolistic device driven by a gas, Helium for example. When the particles pass through the cell there is a chance that the new gene will be introduced in the genome of the plant. Previous tests had a success rate of 54%. This chance is dependent on several factors like humidity, duration temperature, composition of the chosen particle and the form of the used DNA-fragment. Modifying plants The actual genetic modification, the transfer of foreign genes in the plants own genome is done by following the next few steps. - Mapping = Finding + isolating the gene responsible for the desired characteristics PCR = copying the isolated gene Transformation = transfer and insertion of the gene Creation of a new plant for the modified tissue Verification: o Does the gene work? o Is the gene inherited by the progeny of the plant? 6 Genetic engneering of plantsfor the production of medicines Hepatitis B Hepatitis B is an infectious illness caused by hepatitis B virus which infects the liver of primates, including humans, and causes an inflammation called hepatitis. The hepatitis B virus infects the liver of the human's body and causes an inflammation.(Soucaze M. 2009) Originally known as "serum hepatitis", the disease has caused epidemics in parts of Asia and Africa, and it is endemic in China. About a third of the world's population, more than 2 billion people, have been infected with the hepatitis B virus. This includes 350 million chronic carriers of the virus. There’s no relationship between Hepatitis A and C with B. (LCI 2008) Contagion genesis and patho- Hepatitis B is spread mainly by exposure to infected blood or body secretions. In infected individuals, the virus can be found in the blood, semen, vaginal fluid, breast milk, and saliva. Hepatitis B is not spread through food, water, or by casual contact. Hepatitis B also may be spread from infected mothers to their babies at birth (so-called 'vertical'transmission) After entering, the Hepatitis B virus is spread through the blood through the body. By adherence to specific sensors the virus is incorporated in liver cell but doesn’t damage these. The immunological response of the immunocompetent host to presence of the Hepatitis B virus, determines the clinical picture. Cells that fulfill humoral and cellular processes of the immune system and also contain the virus antigen, are removed.. As a result of a strong immune response at the acute stage, an acute hepatitis can show up. If the immune response reacts as needed, the virus is managed. When the immune system doesn’t response as needed, a chronic infection cangarise. The incubation period lasts 4 weeks to 6 months (usually 2 to 3 months). The variation depends on the amount of virus in the inoculum, the route of infection and host factors such as host immunity. (LCI 2008;Nettleman M. et al. 2010;Renaldo E. and ph D. 2000) History In 1885, a number of cases of ' Serumhepatitis’ were located in Bremen (Germany) after being administered the variola vaccine (that contained human lymph) to workers. Just in the years forty and fifty of the previous century a clear distinction was made between 'serumhepatitis' and 'contagious Jaundice' on the basis of transmission experiments. In search of genetic differences, scientists in 1965 found a particular protein in blood of Aboriginals that they called ' Australian-antigen'. This proved to be the later hepatitis B surface antigen (HBsAg). The introduction of safe effective vaccines (plasma-prepared in 1983, and DNA Transmission experiments Experiment that examines the transfer of an infectious disease from one infected individual to a susceptible individual. vaccines in 1986) have increased the possibilities for worldwide suppression of hepatitis b virus (HBV) to introduce vaccination programs on child age. 7 illustration of hepatitis B virus (university of washington 2008) Genetic engneering of plantsfor the production of medicines Vaccines Our immune system has the important task to defend the body. It attacks the pathogens and eliminates them. Where the defense fails, a vaccine is the solution. A vaccine is a treatment that encourage a immune response without making the human sick. Most vaccines are administered in the form of a shot or a liquid that is consumed by mouth. However, some vaccines are inhaled as aerosols or powders. (Rijkers G. et al. 2009) New vaccines History Recently we see more and more the appearance of new vaccines in the pharmaceutical market. The improvement of classical biochemistry, recombinant DNA technology, peptide synthesis, molecular genetics and protein purification has laid the foundations for the development of new, genetically modified vaccines. New vaccines have a lot of advantages, but they have also disadvantages. The vaccine exists longer than the most people think. In 1800, Edward Jenner was the first one who experimented with terms like immunology and vaccination. He saw that milkmaids, which had smallpox infection from cows by milking cows, received no human smallpox. Jenner thought that people could made immune to the human smallpox by infect them first with cow smallpox. His way of thinking was right. But the people were suspicious. However, after Jenner his results, a big vaccination campaign was set. In the fifties, doctors started to vaccinate children against diphtheria, whooping-cough, tetanus and polio. These days, 95% of the Belgian children is vaccinated. A vaccine helps the immune system to defend the body(Fitandwell's weblog 2008;Kroosduiker 2009) First, the new generation vaccines, would be cheaper, safer, fewer side effects and more effective. But a disadvantage of live vaccines is to ensure that the virus is sufficiently attenuated to not cause disease but still respond to the immune system to produce these antigens. Another disadvantage is the possibility that the vaccine virus can recombine with other viral strain. (Rijkers G., Kroese M., & Kallenberg M. 2009) How do they work? The vaccines can be made of living weakened or dead microorganisms. With dead microorganisms it’s important that the antigen, against which the protective immune response must be formed, stays intact. Examples of working vaccines that exists of dead microorganisms are the bacteria Bordetella pertussis, Salmonella typhi and Vibrio cholera. The living weakened microorganisms form more powerful vaccines than the vaccines made of dead micro-organisms. Weakening or attenuating means that by different techniques a variant has been made with strong reduced malignance. Attenuating can be reached by high temperatures, bred micro-organisms in another animal species or by recombinant techniques. With recombinant techniques it’s possible to use microorganisms from other animal species and put relevant antigens into it for the vaccine. After this they put the microorganism in other animal species. There’re a two reasons that a living weakened microorganisms vaccine is more effective than vaccines made of dead micro-organisms. First of all, the micro-organism can multiply itself and confront the immune system with a higher dose that’s longer present. A second reason is that in case of viral living vaccines the naturally target cells can be infected. Of course, dead viruses can’t infect the host cell 8 Genetic engneering of plantsfor the production of medicines and multiply themselves. So the immune response that’s been caused by vaccines made of living micro-organisms is better to compare with the natural immune response. However, living weakening vaccines are discouraged by patients with a less strong defense because a potential danger provides that attenuated micro-organisms go back to their not-attenuated situation. It gets back to the originally malignance. Examples of living weakened vaccines are parotitis viruses, measles viruses and rubella virus. If it’s known to which part from a micro-organisms the protective immune responds, there’s a possibility to use only this antigen in the vaccine. These vaccines are called subunitvaccines. Examples of this vaccine is the hepatitis B and tetanustoxoïd vaccine. category of “subunit vaccines.” The gene encoding the hepatitis B surface antigen (HBsAg) is expressed in yeast cells grown by fermentation; the cells are broken, the protein is collected, and the HBsAg is caused to refold by chemical treatment to yield virus-like particles that can be formulated for injection. However, it is technology-intensive so it’s very expensive. Tobacco and hepatitis B The Tobacco plant, is a perennial herbaceous plant that’s only found in cultivation. It commercially grows in a lot of countries to be processed into tobacco. The tobacco plant is easy to recognize at his pink flowers and big leaves. (Anon 2008) Now the different ways of making vaccines are known, The next question is how to make them from modified plants like the tobacco and potato. This will be discussed in the next chapter. (Rijkers G., Kroese M., & Kallenberg M. 2009) Vaccines There are 2 types of vaccines: - Injection vaccines Oral vaccines Oral vaccines are taken by the mouth and it is this type of vaccine that can be produced by plants. Current vaccine The existing vaccine to prevent HBV infection is a biotechnology product that falls in the The tobacco plant can be recognized at his pink flowers and big leaves (Kroosduiker 2009) The first ever experimental immunogenic protein that was produced in plants, was the hepatitis B vaccine in tobacco. Since 1989, antibodies (also called plantibodies) can be produced by plants. This give a lot of possibilities in the passive immunotherapy. Passive immunotherapy means that the human body doesn’t make the antibodies by itself, but they are administered from outside. For the production of antibodies against Hepatitis B in tobacco, first the plant must have the Hepatitis B surface antigen. This is a protein that is present on the surface of the virus. Therefore, recombinant hepatitis B surface antigen must be inserted in the plant. This can happen with the help of a bacteria, in this case ‘Agrobacterium tumefaciens’ which is a natural carrier of the Ti-plasmid. This means that Tiplasmid is a vector. The Hepatitis B surface antigen will be inserted in the Ti-plasmid and forms a recombinant hepatitis B surface antigen. Now, they put the antigen in the tobacco plant. The plant brings the recombinant antigen at expression so the plant will start making a lot of antibodies, which are abbreviated antiHBsAg, to defend himself against this recombinant hepatitis B surface antigen. After this process, the leaves of the plant will be harvested and the antibodies will be extracted from the leaves. Then the antiHBsAg will be cleaned and are now ready to made in to vaccine. These days, the vaccine is only tested in mice by exposed them to smoke from the recombinant tobacco plant. T-cells, or also called the T lymphocytes, belong to a group of white blood cells which play an important role in the immune response. They were obtained from mice primed with the Perennial herbaceous plant A perennial plant is a plant that lives for more than two years A herbaceous plant is a plant that has leaves and stems that die down at the end of the growing season to the soil level 9 Genetic engneering of plantsfor the production of medicines tobacco-derived recombinant hepatitis B surface antigenic peptide that represents part of the determinant of hepatitis B surface antigen. The mice were administer tobacco smoke for 3 days, 18 weeks or 28 weeks. Mice exposed to smoke for 3 days or 18 weeks produced a reduction in the magnitude and the duration of the primary immune response. Mice exposed to smoke for 28 weeks have a better immune response. The results prove that tobacco smoke extracts stimulated immune responses to tobacco leaf antigens in mice. Because, the test on mice was very successful (the mice become immune for hepatitis B), the next big step is testing the vaccine on humans. (Diederick 2010;G.B.Sunil KumarT. et al. 2007;I.Smets 2010;M.Keulenmans 2008;Ross I. 2008) Potatoes and hepatitis B The potato or Solanum tuberosum is a starchy tuber originally from South America. It’s cultivated all over the world, and more than thousand varieties are known but only a fraction of this number are cultivated commercially. Most of all, the potato is used as food, but in these days full of techniques, the potato has a new goal. They are used to produce medicines. (S.E.Smith 2010) If you have the choice between a needle in your arm and a few lunches of (raw) potato chips containing a vaccine, which would you prefer? The oral immunogenicity (how strong it provokes an immune response) of hepatitis B recombinant surface antigen (HBsAg) produced in yeast, which is a traditional way to produce the medicine , is compared to the hepatitis B recombinant surface antigen in transgenic potatoes (not cooked or processed). Just like the tobacco, Ti-plasmids from the bacteria Agrobacterium tumefaciens are used to bring the HBsAg in the potato plant so that the potato create antibodies. But in this case, they don’t extract the antibodies, they leave them in the raw potato. Scientists hope that by eating raw potatoes, you’re vaccinated against hepatitis B. So the scientists fed mice three doses of raw potatoes containing the hepatitis B surface antigen (HBsAg) and also gave them cholera toxin. Cholera toxin is an oral adjuvant, which is used to increase immune responses. After three weeks, the mice developed antibodies against hepatitis B; this response declined within weeks. But when the mice were injected with a low dose of a commercial vaccine at this point ("low" meaning not enough to make them immune), the antibodies came back to very high levels. Thus, the potato vaccine had probably created memory cells that the injection activated. Transgenic plant material containing HBsAg gave the best response in mice (Best induction of a primary immune response in mice and preparation of an additional booster injection of HBsAg). Protective levels of 10 milliunits/ml antibody is ach- ieved when the transgenic HBsAg mice were fed with the HBsAg-transgenic potatoes produced HBsAg and you also get a strong long lasting secondary antibody response. The advantage of oral vaccines are that it’s easy to use and there’s a better control of intake. There’s also a better immune response at the level of mucosa, which is important for pathogens that enter enteric, respiration, or sexual systems. They stimulate the humoral immunity that is based on antibodies. And because the tradition vaccine is very expensive : edible crops can be produced at low cost and can spot out in areas where the vaccine is needed. The next step will be to test the effects of the potato hepatitis vaccine in humans. This testing has already been done with edible vaccines against the Norwalk virus and against pathogenic forms of E.coli, which both cause diarrhea. Ultimately, a cheap plant vaccine for hepatitis B could help the two billion people who are infected, many of them in developing countries. (C.J.Arntzen 2001;G.B.Sunil KumarT., R.Ganapathi, & V.A.Bapat 2007) A simple potato can prevent a infectious illness like Hepatitis B. (Drent E. 2010) 10 Genetic engneering of plantsfor the production of medicines Comparison medicines genetic engineering Genetic engineering medicines Controversial Cheaper Intake by food possible The table shows us some comparisons of genetic engineering medicines and normal medicines. But the subject genetic engineering is nowadays very controversial. Genetics, used in medicine can also be dangerous. Scientists have to be careful because by trying to cure a disease, they can also increase the risk of upgrading a more dangerous one. For example, if they introduce a gene which will eliminate a medicines and normal Normal medicines People think it’s more safe Expensive Only intake by pills, injections disease, this gene could also make another disease stronger. But the genetic engineering medicines that are officially on the market are well tested and safe. The normal medicines are more expensive because of the highly priced chemicals used for processing the medicines. For genetic engineering medicines you also need to process but the materials that are used are very cheap. Plants and bacteria can be easy cultivated. Than the intake of medicines. The normal medicines, that we mostly now, are oral in taken by pills or injections. The genetic engineering medicines allows the intake by food. Because of the two last advantages for genetic engineering medicines it’s a great opportunity for solving vaccine shortage and the scarcity of medicines in the whole world. conclusion As shown above the genetic engineering medicines have more advantages than normal medicines. But it’s still a controversial subject. The techniques are not yet 100% developed, but are already used in different continents. It’s mostly practiced in America and less in Europe. Though, a lot of scientists are working on it. Genetic engineering medicines are mostly used in America, but Europe is following (Spök A. 2008) Genetic engineering medicines are also cheap. So it will help moving forward the third world countries. Especially the hepatitis B vaccine will reduce the number of liver infections. In this article are two plants discussed but there are a lot of different plants that can be used. A lot of different plants can be used for making the medicines.(Spök A. 2008) 11 Genetic engneering of plantsfor the production of medicines References Tabaksplant. 2008. Ref Type: Online Source C.J.Arntzen. Oral immunization with hepatitis B surface antigen expressed in transgenic plants . 2001. Ref Type: Online Source Diederick. Biotechnologie. 2010. Ref Type: Unpublished Work Drent E. Kook workshop voor particulieren. 2010. Ref Type: Online Source E.Wirix 2010, "Biotechnologie," In Van Gen tot Populatie, deel 1. Fitandwell's weblog. The hidden dangers of vaccination. 24-6-2008. Ref Type: Online Source G.B.Sunil KumarT., R.Ganapathi, & V.A.Bapat 2007, Production of Hepatitis B Surface Antigen in Recombinant Plant Systems: An Update. I.Smets. Biotechnologie Planten. 2010. Ref Type: Slide International Society for Microbial Ecology. Agrobacterium tumefaciens Mediated Gene Transfer. 2002. Ref Type: Online Source J.A.Thompson 2009, Genetic Engineering of plants. J.Craig Venter Institute. Genetics and Genomics Timeline. 2004. Ref Type: Online Source Kroosduiker. Tabaksveldje. 26-7-2009. Ref Type: Online Source LCI 2008. Hepatitis B. M.Keulenmans. De terugkeer van tabak. nwt . 2008. Ref Type: Magazine Article national health museum. Recombinant DNA technique. 2010. Genetic engneering of plantsfor the production of medicines Ref Type: Art Work Nettleman M., MD, MS, & l Mortada M. Hepatitis B. 2010. Ref Type: Online Source Renaldo E. & ph D. 2000. Genetically modified organism: it's implications to food safety and consumers protection. Rijkers G., Kroese M., & Kallenberg M. 2009. Immunologie. Ross I. 2008. Medicinal plants of the world. S.E.Smith. What's a potato? 8-9-2010. Ref Type: Online Source Soucaze M. Liver diseases. 2009. Ref Type: Online Source Spök A. Pharma plants: Status report. 2008. Ref Type: Online Source Figure list Kroosduiker. Tabaksveldje. 26-7-2009. Ref Type: Online Source healty lifestyle. info on herbal pills and plants. 2009. Ref Type: Online Source Drent E. Kook workshop voor particulieren. 2010. Ref Type: Online Source Fitandwell's weblog. The hidden dangers of vaccination. 24-6-2008. Ref Type: Online Source International Society for Microbial Ecology. Agrobacterium tumefaciens Mediated Gene Transfer. 2002. Ref Type: Online Source national health museum. Recombinant DNA technique. 2010. Ref Type: Art Work