Ethical, Legal and Social Implications of the Human Genome Project
From the beginning, it has been understood that the Human Genome Project will have profound ethical, legal and social (ELS) implications; thus, between 3 and 5% of its budget has been devoted to the study of ELS issues. Ethical issues are generally defined as those raising questions concerning what is moral or right. Legal issues are those concerning the protections that laws or regulations should provide. Social issues are concerned with how events may affect society as a whole and individuals in society. Clearly, these aspects of the HGP and its possible outcomes are not independent of each other.
Many of the ELS implications are not new. The gene for Huntington’s disease was discovered in 1993, after a ten-year search following the localization of the gene to chromosome 4 in 1983. A test for the disease was developed soon after. Many of the questions currently being addressed by the ELS issues program of the HGP have, therefore, been familiar for many years to families afflicted with Huntington’s. As a result of the HGP, however, society as a whole will have to deal much more frequently with issues arising from knowledge of the human genome. Moreover, the implications may be less clear in the case of genes identified for diseases that have strong environmental aspects and involve interaction with many other genes.
1. The Existence of Genetic Information
The existence of genetic information with respect to individuals and the human population as a whole will have a profound impact on our day-to-day lives and may well change how we regard ourselves and one another.
The knowledge of predisposition to a certain disease and the ability to design "tailor made" therapies may greatly help in the treatment of disease. Already a company in Great Britain has applied for a patent on a device that can apparently detect different forms of over 2,500 genes said to be associated with traits including behaviour and intelligence.
It has been argued, however, that it is not proper, particularly at this juncture in history, to search for such knowledge. For example, some have pointed out that science has often been co-opted as a tool to accentuate racial differences and to defend racist practices. Given that humans are far from resolving issues of race, it is thought that information from the HGP, and such follow-up projects as the Human Genome Diversity Project, may have the potential to inflame racism in an already overly racist world.
Equally, some feel that if the goal of the HGP is to prevent disability and disease, increase life spans, decrease infant mortality, and increase intelligence, the money would be far better spent elsewhere. Given that we already know that environmental and social factors can influence such diseases as diabetes in aboriginal populations and drug addiction among the socially marginalized, some consider it unconscionable to dispense limited resources looking for genetic causes for these diseases.
The legal aspects of knowledge of the human genome are enormous. Already DNA evidence is being used as a powerful legal tool, particularly in exonerating wrongly accused individuals. Does this mean that the criminal system should be able to keep a bank of DNA information on anyone accused and/or convicted of a crime? Could the database be used for other purposes than simply identifying and eliminating suspects? A DNA database could contain much more information on individuals, both guilty and innocent, than does the current system of taking fingerprints.
On a more hypothetical note, should genes leading to a propensity for criminal activity be found, could they be used as prosecution or defence evidence in a trial? For instance, is a suspect who knows that he or she has a genetic disposition toward criminal behaviour and does nothing to avoid provoking such behaviour, guilty of a more serious crime than a suspect who is ignorant of having such a propensity? On the other hand, could genetic disposition be used as a defence on the grounds that the crime was really the fault of the gene, not the person?
When a patient tests positive for a gene linked to risk of disease, does the physician (or the patient) have a legal responsibility to inform the patients’ relatives of their own risks? Suppose a patient finds out that she has a genetic propensity for breast cancer, but neither she nor her doctor informs her relatives; would a relative who later developed that form of cancer be able to sue, on the grounds that the genetic information had not been disclosed?
Ensuring that the judge and jury in a trial are sufficiently educated to deal with these issues is yet another problem with which the legal system will have to deal.
On a larger social scale, knowledge of the human genome could be used to emphasize the similarities among all humans. The genetic differences between people within an identified group have already been shown to be greater than the differences between groups. In other words, people within an "ethnic" population are more different from each other than the group as a whole is different from other "ethnic" groups. This fact is unlikely, however, to deter those who wish to emphasize any ethnic differences that may be found.
On a more individual level, the results of the HGP might encourage people to view themselves as being wholly under the control of their genes. What has traditionally been viewed as the human spirit might in future be seen as limited by pre-programming at birth. Thus, though we cannot predict exactly how knowledge of the human genome will affect society, it could clearly have important consequences.
Individual decisions, such as choices with respect to mates and reproduction, could also be influenced by knowledge of genetic makeup. Awareness of personal genetic differences from a perceived norm might lead to confusion and uncertainty about the potential for disease, particularly in the absence of adequate professional consultation. Genetic analysis might reveal a myriad of genetic flaws that may or may not lead to disease, depending on what they are and how they interact with the environment. How will individuals select from a debilitating array of lifestyle choices, none of which has a certain outcome? Again, analysis of one’s own genetic makeup could reveal the genetic makeup of parents and siblings, including, for example, unsuspected information about paternity. How willing would people be to share this knowledge and, if they decided to withhold it, how would they be affected by living with the secret?
2. Ownership and Commercialization
On 11 November 1997, UNESCO passed its Universal Declaration on the Human Genome and Human Rights. Article 4 of the Declaration states that "The human genome in its natural state shall not give rise to financial gains." In most countries, however, DNA, when isolated from an individual, is not considered to be in its natural state and therefore can give rise to financial gain. One of the benefits of the HGP and genomics research in general is expected to be a thriving biotechnology industry with the potential, in the United States, to be worth $45 billion (U.S) by 2009. In most technological industries, innovation has been encouraged through the granting of patents on inventions.
Researchers who devise an invention that is useful, new, and unobvious are given approximately 20-year proprietary rights over its use. To be patentable, discoveries must involve some human intervention and inventiveness. In return for these rights, the inventor must make the invention public so that others may, at a price, use it to further their research.
For approximately 20 years, sequences of DNA that correspond to human genes have been claimed in patents. Conceptually, the string of DNA molecules is considered no different from other chemicals isolated from living organisms, such as penicillin, as long as it passes the tests for patentability (being new, useful, and unobvious).
For a number of reasons, some believe that human gene sequences should never be patentable. A fundamental, philosophical reason is the belief that the human genome, as an intrinsic part of every person, is a common heritage that all humans should share. This line of reasoning has led the Parliamentary Assembly of the Council of Europe to recommend that European Union countries renegotiate the agreed Directive that allows the patenting of human genes that are isolated from the body and applicable to industry, and specifically prohibit the patenting of human genes.
The World Trade Organization’s Trade Related Aspects of Intellectual Property Agreement includes some discussion on what member countries can exclude from patentability. Article 27(2) states that anything that is necessary to protect the "ordre public or morality" can be excluded, as long as the exemption is not made simply because it is prohibited by law. Section 27(3)(a) states that member countries may also exclude diagnostic, therapeutic and surgical methods for humans and animals. No specific clause would seem to prevent a member country from excluding the patentability of human genes. Canada’s Patent Act does not have an "ordre public" clause.
Some offer logistical reasons to explain why patents should not be extended to DNA sequences. They suggest that such patents, particularly on partial gene sequences, would inhibit innovation rather than encourage it, as the patent system is supposed to do. This could arise in a scenario, dubbed the "tragedy of the anticommons," in which numerous people and organizations held patents on different DNA sequences governing an overall biochemical pathway that could be the target for a medical treatment. To research that treatment, someone would have to negotiate for the rights to all the DNA sequences from all the respective owners; this might be so costly and onerous as to make further research unlikely. Pure researchers, who would not have the money, the time or the expertise for a complex series of transactions, would be the most severely affected. Others, however, refute this argument, citing the case of the computer industry. Patents on the various parts of computers certainly do not seem to have impeded the growth of that industry, though some might say that it has impeded innovation. Others point out that in the computer industry, the free flow of information has been a driving force behind such innovations as the GNU-Linux operating system.
It has also been suggested that DNA does not pass the tests for patentability on the ground that, since DNA exists in nature, knowledge of it is simply a discovery, not an invention. Therefore, while drugs should be patentable, the DNA sequence upstream from the target of the drug should not be. Moreover, it is said that many of the techniques used to isolate and manipulate DNA are now routine, and therefore the inventions are too obvious to be patentable.
In North America, the focus is more on what level of utility must be shown in order for genes to be patented, rather than on whether they are patentable at all. The Canadian Patent Act, as it is written, has for a long time been interpreted as meaning that genes are patentable material. A problem has arisen because many private companies have concentrated on sequencing genes in the hope of obtaining patents on a gene that may one day prove to be useful. Most of the genes sequenced by the HGP and private enterprises have as yet unknown functions; thus, applications are being made for DNA sequences that have no genuine utility. Since the sequences do encode a protein, some companies have gone so far as to claim that, at a minimum, the protein could be used for animal feed or in a molecular biological technique as a DNA probe. In one well known case in the United States, the company Human Genome Sciences obtained a patent on a gene that was subsequently discovered by a different researcher to be an entry portal through which the AIDS virus infects cells. Any future treatment of these cells that alters this entry portal will require royalties to be paid to Human Genome Sciences. While the Canadian Patent Act is similar to its U.S. equivalent, Canadian patenting procedures are generally more stringent with respect to the utility of the invention than are those in the United States, the country where the controversy is greatest. The U.S. Patent Office has recently announced that it will increase the stringency of the utility requirement for patenting DNA sequences.
Searching for medically useful, and therefore potentially profitable, genes also raises many ethical questions. Heritable disease patterns sometimes emerge in populations that have not mixed extensively with other populations; as a result, private companies are doing genetic exploration in such relatively isolated areas as Newfoundland, Iceland and certain tropical islands. In Iceland, a company called deCODE has been given the rights to produce a health sector database that will include genealogical, environmental, and molecular genetic information, along with the combined anonymized patient records of the country. In Newfoundland, political leaders are apparently coming to the conclusion that Newfoundlanders should maintain control over their unique genome. How to regulate the gene hunters without scaring off investment is a familiar problem to governments that already have experience with charging royalties and regulating natural resource operations. Gene "mining" companies, however, present a much more complex and emotional set of ethical issues than does the natural resources sector.
3. Genetic Treatment of Disease
From the outset, one of the defining goals of the HGP has been its potential for molecular medicine. The concept is that, once the functions of genes are known and we understand the effects of malfunctioning genes, we will be able to correct the problem either through the use of designer drugs or by replacing the faulty gene. It is the latter option that has created the most controversy.
There are two routes to replacing a faulty gene. The first route, germ line therapy, has the goal of replacing a harmful gene in a fertilized human egg with a properly functioning gene that would be passed on to future generations. The other route, somatic gene therapy, aims to replace the gene in target organs or tissues of an adult, so as to fix the symptoms in that individual but not in the next generation. Germ line therapy has the more profound ethical, legal and social implications.
As yet germ-line therapy in humans is not possible and some have argued that it will continue to be so for the foreseeable future. While this kind of therapy may be a long way off, it would bring, on the one hand, the hope of eradicating some genetic diseases but, on the other hand, the spectre of eugenics.
The eradication of disease through germ-line therapy might not seem, by itself, to raise many ethical questions. After all, humans have eradicated the smallpox virus from the world, why not diseases with genetic components? Do doctors not have the moral obligation to provide the very best treatment to their patients and would not the eradication of the disease be more cost effective in the long run than continually treating adults with somatic gene therapy? The main ethical problem arises in defining a "treatable" disease.
Some might say that eradication of a genetic disease for which there is no treatment and which is always fatal, should be pursued with all means possible. Others say that this would be the start of a slippery slope moving on toward the treatment of less obvious diseases and then to genetic enhancement. Some argue that if the technology is advanced in order to eradicate some diseases, it will inevitably be used by parents wishing to "enhance" their children, giving them the genes for raven black hair and blue eyes or athletic prowess. It was serious ethical concerns about genetic enhancement that prompted the Council of Europe to adopt the Convention for the Protection of Human Rights and Dignity of the Human Being with Regard to the Application of Biology and Medicine: Convention on Human Rights and Biomedicine. Article 13 of the Convention states that "an intervention seeking to modify the human genome may only be undertaken for preventive, diagnostic or therapeutic purposes and only if its aim is not to introduce any modification in the genome of any descendants." Article 11 of the UNESCO Universal Declaration on the Human Genome and Human Rights states that "practices which are contrary to human dignity, such as reproductive cloning of human beings, shall not be permitted." It is left to individual states, however, to define exactly what they believe these practices to be. Thus, while some countries, such as the signatories to the European Convention, may prohibit germ-line therapy, others may not. It is the existence of national differences in regulation of research on human embryos that has allowed controversial research to be performed, for example, in Singapore. Regulation has thus slowed down the progress of research but not prevented it.
Another ethical consideration with respect to germ-line therapy is defining what is normal, what is a disability, and what is a disease. Which of the genetic variations within a population ought to be eradicated, if any? In trying to eradicate a certain variation, are we demeaning those in the population who currently carry the gene?
Somatic gene therapy has its own, less controversial, set of ELS implications. These may be less ominous than eugenics but are of perhaps more immediate concern, given the more advanced state of the technology. Effectively, gene therapy involves the introduction of a properly functioning gene into target tissues in the hopes that it will be translated into a properly functioning protein, which will mask the malfunctioning protein. Often the new gene is placed into a modified virus, which is then introduced into a patient in the hope that the gene will be introduced into a tissue and properly expressed.
Such types of therapy, after much research on laboratory animals, have now reached the clinical trial stage. Unfortunately, what works for a mouse does not always work for a human being. In one highly publicized case, a patient, Jesse Gelsinger, was given an injection of a virus in the hope of introducing a protein into the liver. Mouse studies showed good absorption of the gene into the liver; however, the mouse has a much higher concentration of viral receptors on its liver cells than do humans. The virus did not absorb well into the human patient and, for still unknown reasons, created a massive immune response, causing the patient to die. The original plan for the trials had been to use the virus only on children in a coma caused by the lack of the particular liver enzyme; however, ethical and safety reviews caused the researchers to change the trial direction and use adults only. Many questions are now being asked regarding the ethics and scientific judgment of those performing such clinical trials. How well are "volunteer" patients informed of the possible risks and benefits? How objective are investigators who have equity in the companies that are funding the trials? One of the risks at this stage of gene therapy is the excessive public anticipation, created in part by some researchers, with respect to future benefits. This anticipation may turn to public distrust of science, if the benefits fail to be realized and problems such as that in the Gelsinger case continue to occur. Some clinical trials have shown positive results , and so there is still hope that somatic gene therapy will become a powerful medical tool.
4. Discrimination
One of the problems some fear might result from knowledge of the human genome is the emergence of a whole population of socially marginalized individuals, unable to obtain a job, a family, insurance, or health care and stigmatized by the rest of society. Insurance companies already insist that those identified at risk of Huntington’s disease must take a genetic test. If the results are positive, insurance is frequently refused. Insurance companies are on record as saying that if genetic information was available, they would use it in their risk assessment. In Canada, the refusal to insure a Huntington’s patient does not have dire consequences; in general, public insurance covers many aspects of care, though the level of care varies across the country and the coverage for pharmaceuticals is less clear. In countries without a public health insurance system, however, the plight of such a non-insured person can be a nightmare. Care may be available but finding it is very difficult. As more genetic tests become available, insurance is likely to be more and more expensive for those carrying what the insurance companies deem to be risky genes. The public insurance schemes may also start to feel the pressure for such genetic testing, and be forced to make policy decisions based on the funding available and the knowledge of genetic predisposition to disease within populations. Gene therapy is at the experimental stage at this point but will certainly be very expensive when it first comes into regular use. Who will pay for it? If not public insurance, will the therapy be available only to rich people, thus creating an ever widening gap between groups in society, based on both money and genetic inheritance?
Employers may also want access to genetic information. Some genes might reveal a susceptibility to environmental damage that was incompatible with a certain workplace environment. Employers might choose to screen out workers carrying that gene rather than trying to improve the environment. Individuals with genes associated with certain behavioural traits might also be excluded from the workplace.
Some action has already been taken to prevent the possibility of genetic discrimination. For example, President Bill Clinton has signed an executive order prohibiting federal departments and agencies from using genetic information in any hiring or promotion action. He has also endorsed an Act, introduced in 1999 by a Senator and a member of Congress, that would extend such protection to the private sector.
Wednesday, June 18, 2008
Ethical, Legal and Social Implications of the Human Genome Project
Ethical, Legal and Social Implications of the Human Genome Project
From the beginning, it has been understood that the Human Genome Project will have profound ethical, legal and social (ELS) implications; thus, between 3 and 5% of its budget has been devoted to the study of ELS issues. Ethical issues are generally defined as those raising questions concerning what is moral or right. Legal issues are those concerning the protections that laws or regulations should provide. Social issues are concerned with how events may affect society as a whole and individuals in society. Clearly, these aspects of the HGP and its possible outcomes are not independent of each other.
Many of the ELS implications are not new. The gene for Huntington’s disease was discovered in 1993, after a ten-year search following the localization of the gene to chromosome 4 in 1983. A test for the disease was developed soon after. Many of the questions currently being addressed by the ELS issues program of the HGP have, therefore, been familiar for many years to families afflicted with Huntington’s. As a result of the HGP, however, society as a whole will have to deal much more frequently with issues arising from knowledge of the human genome. Moreover, the implications may be less clear in the case of genes identified for diseases that have strong environmental aspects and involve interaction with many other genes.
1. The Existence of Genetic Information
The existence of genetic information with respect to individuals and the human population as a whole will have a profound impact on our day-to-day lives and may well change how we regard ourselves and one another.
The knowledge of predisposition to a certain disease and the ability to design "tailor made" therapies may greatly help in the treatment of disease. Already a company in Great Britain has applied for a patent on a device that can apparently detect different forms of over 2,500 genes said to be associated with traits including behaviour and intelligence.
It has been argued, however, that it is not proper, particularly at this juncture in history, to search for such knowledge. For example, some have pointed out that science has often been co-opted as a tool to accentuate racial differences and to defend racist practices. Given that humans are far from resolving issues of race, it is thought that information from the HGP, and such follow-up projects as the Human Genome Diversity Project, may have the potential to inflame racism in an already overly racist world.
Equally, some feel that if the goal of the HGP is to prevent disability and disease, increase life spans, decrease infant mortality, and increase intelligence, the money would be far better spent elsewhere. Given that we already know that environmental and social factors can influence such diseases as diabetes in aboriginal populations and drug addiction among the socially marginalized, some consider it unconscionable to dispense limited resources looking for genetic causes for these diseases.
The legal aspects of knowledge of the human genome are enormous. Already DNA evidence is being used as a powerful legal tool, particularly in exonerating wrongly accused individuals. Does this mean that the criminal system should be able to keep a bank of DNA information on anyone accused and/or convicted of a crime? Could the database be used for other purposes than simply identifying and eliminating suspects? A DNA database could contain much more information on individuals, both guilty and innocent, than does the current system of taking fingerprints.
On a more hypothetical note, should genes leading to a propensity for criminal activity be found, could they be used as prosecution or defence evidence in a trial? For instance, is a suspect who knows that he or she has a genetic disposition toward criminal behaviour and does nothing to avoid provoking such behaviour, guilty of a more serious crime than a suspect who is ignorant of having such a propensity? On the other hand, could genetic disposition be used as a defence on the grounds that the crime was really the fault of the gene, not the person?
When a patient tests positive for a gene linked to risk of disease, does the physician (or the patient) have a legal responsibility to inform the patients’ relatives of their own risks? Suppose a patient finds out that she has a genetic propensity for breast cancer, but neither she nor her doctor informs her relatives; would a relative who later developed that form of cancer be able to sue, on the grounds that the genetic information had not been disclosed?
Ensuring that the judge and jury in a trial are sufficiently educated to deal with these issues is yet another problem with which the legal system will have to deal.
On a larger social scale, knowledge of the human genome could be used to emphasize the similarities among all humans. The genetic differences between people within an identified group have already been shown to be greater than the differences between groups. In other words, people within an "ethnic" population are more different from each other than the group as a whole is different from other "ethnic" groups. This fact is unlikely, however, to deter those who wish to emphasize any ethnic differences that may be found.
On a more individual level, the results of the HGP might encourage people to view themselves as being wholly under the control of their genes. What has traditionally been viewed as the human spirit might in future be seen as limited by pre-programming at birth. Thus, though we cannot predict exactly how knowledge of the human genome will affect society, it could clearly have important consequences.
Individual decisions, such as choices with respect to mates and reproduction, could also be influenced by knowledge of genetic makeup. Awareness of personal genetic differences from a perceived norm might lead to confusion and uncertainty about the potential for disease, particularly in the absence of adequate professional consultation. Genetic analysis might reveal a myriad of genetic flaws that may or may not lead to disease, depending on what they are and how they interact with the environment. How will individuals select from a debilitating array of lifestyle choices, none of which has a certain outcome? Again, analysis of one’s own genetic makeup could reveal the genetic makeup of parents and siblings, including, for example, unsuspected information about paternity. How willing would people be to share this knowledge and, if they decided to withhold it, how would they be affected by living with the secret?
2. Ownership and Commercialization
On 11 November 1997, UNESCO passed its Universal Declaration on the Human Genome and Human Rights. Article 4 of the Declaration states that "The human genome in its natural state shall not give rise to financial gains." In most countries, however, DNA, when isolated from an individual, is not considered to be in its natural state and therefore can give rise to financial gain. One of the benefits of the HGP and genomics research in general is expected to be a thriving biotechnology industry with the potential, in the United States, to be worth $45 billion (U.S) by 2009. In most technological industries, innovation has been encouraged through the granting of patents on inventions.
Researchers who devise an invention that is useful, new, and unobvious are given approximately 20-year proprietary rights over its use. To be patentable, discoveries must involve some human intervention and inventiveness. In return for these rights, the inventor must make the invention public so that others may, at a price, use it to further their research.
For approximately 20 years, sequences of DNA that correspond to human genes have been claimed in patents. Conceptually, the string of DNA molecules is considered no different from other chemicals isolated from living organisms, such as penicillin, as long as it passes the tests for patentability (being new, useful, and unobvious).
For a number of reasons, some believe that human gene sequences should never be patentable. A fundamental, philosophical reason is the belief that the human genome, as an intrinsic part of every person, is a common heritage that all humans should share. This line of reasoning has led the Parliamentary Assembly of the Council of Europe to recommend that European Union countries renegotiate the agreed Directive that allows the patenting of human genes that are isolated from the body and applicable to industry, and specifically prohibit the patenting of human genes.
The World Trade Organization’s Trade Related Aspects of Intellectual Property Agreement includes some discussion on what member countries can exclude from patentability. Article 27(2) states that anything that is necessary to protect the "ordre public or morality" can be excluded, as long as the exemption is not made simply because it is prohibited by law. Section 27(3)(a) states that member countries may also exclude diagnostic, therapeutic and surgical methods for humans and animals. No specific clause would seem to prevent a member country from excluding the patentability of human genes. Canada’s Patent Act does not have an "ordre public" clause.
Some offer logistical reasons to explain why patents should not be extended to DNA sequences. They suggest that such patents, particularly on partial gene sequences, would inhibit innovation rather than encourage it, as the patent system is supposed to do. This could arise in a scenario, dubbed the "tragedy of the anticommons," in which numerous people and organizations held patents on different DNA sequences governing an overall biochemical pathway that could be the target for a medical treatment. To research that treatment, someone would have to negotiate for the rights to all the DNA sequences from all the respective owners; this might be so costly and onerous as to make further research unlikely. Pure researchers, who would not have the money, the time or the expertise for a complex series of transactions, would be the most severely affected. Others, however, refute this argument, citing the case of the computer industry. Patents on the various parts of computers certainly do not seem to have impeded the growth of that industry, though some might say that it has impeded innovation. Others point out that in the computer industry, the free flow of information has been a driving force behind such innovations as the GNU-Linux operating system.
It has also been suggested that DNA does not pass the tests for patentability on the ground that, since DNA exists in nature, knowledge of it is simply a discovery, not an invention. Therefore, while drugs should be patentable, the DNA sequence upstream from the target of the drug should not be. Moreover, it is said that many of the techniques used to isolate and manipulate DNA are now routine, and therefore the inventions are too obvious to be patentable.
In North America, the focus is more on what level of utility must be shown in order for genes to be patented, rather than on whether they are patentable at all. The Canadian Patent Act, as it is written, has for a long time been interpreted as meaning that genes are patentable material. A problem has arisen because many private companies have concentrated on sequencing genes in the hope of obtaining patents on a gene that may one day prove to be useful. Most of the genes sequenced by the HGP and private enterprises have as yet unknown functions; thus, applications are being made for DNA sequences that have no genuine utility. Since the sequences do encode a protein, some companies have gone so far as to claim that, at a minimum, the protein could be used for animal feed or in a molecular biological technique as a DNA probe. In one well known case in the United States, the company Human Genome Sciences obtained a patent on a gene that was subsequently discovered by a different researcher to be an entry portal through which the AIDS virus infects cells. Any future treatment of these cells that alters this entry portal will require royalties to be paid to Human Genome Sciences. While the Canadian Patent Act is similar to its U.S. equivalent, Canadian patenting procedures are generally more stringent with respect to the utility of the invention than are those in the United States, the country where the controversy is greatest. The U.S. Patent Office has recently announced that it will increase the stringency of the utility requirement for patenting DNA sequences.
Searching for medically useful, and therefore potentially profitable, genes also raises many ethical questions. Heritable disease patterns sometimes emerge in populations that have not mixed extensively with other populations; as a result, private companies are doing genetic exploration in such relatively isolated areas as Newfoundland, Iceland and certain tropical islands. In Iceland, a company called deCODE has been given the rights to produce a health sector database that will include genealogical, environmental, and molecular genetic information, along with the combined anonymized patient records of the country. In Newfoundland, political leaders are apparently coming to the conclusion that Newfoundlanders should maintain control over their unique genome. How to regulate the gene hunters without scaring off investment is a familiar problem to governments that already have experience with charging royalties and regulating natural resource operations. Gene "mining" companies, however, present a much more complex and emotional set of ethical issues than does the natural resources sector.
3. Genetic Treatment of Disease
From the outset, one of the defining goals of the HGP has been its potential for molecular medicine. The concept is that, once the functions of genes are known and we understand the effects of malfunctioning genes, we will be able to correct the problem either through the use of designer drugs or by replacing the faulty gene. It is the latter option that has created the most controversy.
There are two routes to replacing a faulty gene. The first route, germ line therapy, has the goal of replacing a harmful gene in a fertilized human egg with a properly functioning gene that would be passed on to future generations. The other route, somatic gene therapy, aims to replace the gene in target organs or tissues of an adult, so as to fix the symptoms in that individual but not in the next generation. Germ line therapy has the more profound ethical, legal and social implications.
As yet germ-line therapy in humans is not possible and some have argued that it will continue to be so for the foreseeable future. While this kind of therapy may be a long way off, it would bring, on the one hand, the hope of eradicating some genetic diseases but, on the other hand, the spectre of eugenics.
The eradication of disease through germ-line therapy might not seem, by itself, to raise many ethical questions. After all, humans have eradicated the smallpox virus from the world, why not diseases with genetic components? Do doctors not have the moral obligation to provide the very best treatment to their patients and would not the eradication of the disease be more cost effective in the long run than continually treating adults with somatic gene therapy? The main ethical problem arises in defining a "treatable" disease.
Some might say that eradication of a genetic disease for which there is no treatment and which is always fatal, should be pursued with all means possible. Others say that this would be the start of a slippery slope moving on toward the treatment of less obvious diseases and then to genetic enhancement. Some argue that if the technology is advanced in order to eradicate some diseases, it will inevitably be used by parents wishing to "enhance" their children, giving them the genes for raven black hair and blue eyes or athletic prowess. It was serious ethical concerns about genetic enhancement that prompted the Council of Europe to adopt the Convention for the Protection of Human Rights and Dignity of the Human Being with Regard to the Application of Biology and Medicine: Convention on Human Rights and Biomedicine. Article 13 of the Convention states that "an intervention seeking to modify the human genome may only be undertaken for preventive, diagnostic or therapeutic purposes and only if its aim is not to introduce any modification in the genome of any descendants." Article 11 of the UNESCO Universal Declaration on the Human Genome and Human Rights states that "practices which are contrary to human dignity, such as reproductive cloning of human beings, shall not be permitted." It is left to individual states, however, to define exactly what they believe these practices to be. Thus, while some countries, such as the signatories to the European Convention, may prohibit germ-line therapy, others may not. It is the existence of national differences in regulation of research on human embryos that has allowed controversial research to be performed, for example, in Singapore. Regulation has thus slowed down the progress of research but not prevented it.
Another ethical consideration with respect to germ-line therapy is defining what is normal, what is a disability, and what is a disease. Which of the genetic variations within a population ought to be eradicated, if any? In trying to eradicate a certain variation, are we demeaning those in the population who currently carry the gene?
Somatic gene therapy has its own, less controversial, set of ELS implications. These may be less ominous than eugenics but are of perhaps more immediate concern, given the more advanced state of the technology. Effectively, gene therapy involves the introduction of a properly functioning gene into target tissues in the hopes that it will be translated into a properly functioning protein, which will mask the malfunctioning protein. Often the new gene is placed into a modified virus, which is then introduced into a patient in the hope that the gene will be introduced into a tissue and properly expressed.
Such types of therapy, after much research on laboratory animals, have now reached the clinical trial stage. Unfortunately, what works for a mouse does not always work for a human being. In one highly publicized case, a patient, Jesse Gelsinger, was given an injection of a virus in the hope of introducing a protein into the liver. Mouse studies showed good absorption of the gene into the liver; however, the mouse has a much higher concentration of viral receptors on its liver cells than do humans. The virus did not absorb well into the human patient and, for still unknown reasons, created a massive immune response, causing the patient to die. The original plan for the trials had been to use the virus only on children in a coma caused by the lack of the particular liver enzyme; however, ethical and safety reviews caused the researchers to change the trial direction and use adults only. Many questions are now being asked regarding the ethics and scientific judgment of those performing such clinical trials. How well are "volunteer" patients informed of the possible risks and benefits? How objective are investigators who have equity in the companies that are funding the trials? One of the risks at this stage of gene therapy is the excessive public anticipation, created in part by some researchers, with respect to future benefits. This anticipation may turn to public distrust of science, if the benefits fail to be realized and problems such as that in the Gelsinger case continue to occur. Some clinical trials have shown positive results , and so there is still hope that somatic gene therapy will become a powerful medical tool.
4. Discrimination
One of the problems some fear might result from knowledge of the human genome is the emergence of a whole population of socially marginalized individuals, unable to obtain a job, a family, insurance, or health care and stigmatized by the rest of society. Insurance companies already insist that those identified at risk of Huntington’s disease must take a genetic test. If the results are positive, insurance is frequently refused. Insurance companies are on record as saying that if genetic information was available, they would use it in their risk assessment. In Canada, the refusal to insure a Huntington’s patient does not have dire consequences; in general, public insurance covers many aspects of care, though the level of care varies across the country and the coverage for pharmaceuticals is less clear. In countries without a public health insurance system, however, the plight of such a non-insured person can be a nightmare. Care may be available but finding it is very difficult. As more genetic tests become available, insurance is likely to be more and more expensive for those carrying what the insurance companies deem to be risky genes. The public insurance schemes may also start to feel the pressure for such genetic testing, and be forced to make policy decisions based on the funding available and the knowledge of genetic predisposition to disease within populations. Gene therapy is at the experimental stage at this point but will certainly be very expensive when it first comes into regular use. Who will pay for it? If not public insurance, will the therapy be available only to rich people, thus creating an ever widening gap between groups in society, based on both money and genetic inheritance?
Employers may also want access to genetic information. Some genes might reveal a susceptibility to environmental damage that was incompatible with a certain workplace environment. Employers might choose to screen out workers carrying that gene rather than trying to improve the environment. Individuals with genes associated with certain behavioural traits might also be excluded from the workplace.
Some action has already been taken to prevent the possibility of genetic discrimination. For example, President Bill Clinton has signed an executive order prohibiting federal departments and agencies from using genetic information in any hiring or promotion action. He has also endorsed an Act, introduced in 1999 by a Senator and a member of Congress, that would extend such protection to the private sector.
From the beginning, it has been understood that the Human Genome Project will have profound ethical, legal and social (ELS) implications; thus, between 3 and 5% of its budget has been devoted to the study of ELS issues. Ethical issues are generally defined as those raising questions concerning what is moral or right. Legal issues are those concerning the protections that laws or regulations should provide. Social issues are concerned with how events may affect society as a whole and individuals in society. Clearly, these aspects of the HGP and its possible outcomes are not independent of each other.
Many of the ELS implications are not new. The gene for Huntington’s disease was discovered in 1993, after a ten-year search following the localization of the gene to chromosome 4 in 1983. A test for the disease was developed soon after. Many of the questions currently being addressed by the ELS issues program of the HGP have, therefore, been familiar for many years to families afflicted with Huntington’s. As a result of the HGP, however, society as a whole will have to deal much more frequently with issues arising from knowledge of the human genome. Moreover, the implications may be less clear in the case of genes identified for diseases that have strong environmental aspects and involve interaction with many other genes.
1. The Existence of Genetic Information
The existence of genetic information with respect to individuals and the human population as a whole will have a profound impact on our day-to-day lives and may well change how we regard ourselves and one another.
The knowledge of predisposition to a certain disease and the ability to design "tailor made" therapies may greatly help in the treatment of disease. Already a company in Great Britain has applied for a patent on a device that can apparently detect different forms of over 2,500 genes said to be associated with traits including behaviour and intelligence.
It has been argued, however, that it is not proper, particularly at this juncture in history, to search for such knowledge. For example, some have pointed out that science has often been co-opted as a tool to accentuate racial differences and to defend racist practices. Given that humans are far from resolving issues of race, it is thought that information from the HGP, and such follow-up projects as the Human Genome Diversity Project, may have the potential to inflame racism in an already overly racist world.
Equally, some feel that if the goal of the HGP is to prevent disability and disease, increase life spans, decrease infant mortality, and increase intelligence, the money would be far better spent elsewhere. Given that we already know that environmental and social factors can influence such diseases as diabetes in aboriginal populations and drug addiction among the socially marginalized, some consider it unconscionable to dispense limited resources looking for genetic causes for these diseases.
The legal aspects of knowledge of the human genome are enormous. Already DNA evidence is being used as a powerful legal tool, particularly in exonerating wrongly accused individuals. Does this mean that the criminal system should be able to keep a bank of DNA information on anyone accused and/or convicted of a crime? Could the database be used for other purposes than simply identifying and eliminating suspects? A DNA database could contain much more information on individuals, both guilty and innocent, than does the current system of taking fingerprints.
On a more hypothetical note, should genes leading to a propensity for criminal activity be found, could they be used as prosecution or defence evidence in a trial? For instance, is a suspect who knows that he or she has a genetic disposition toward criminal behaviour and does nothing to avoid provoking such behaviour, guilty of a more serious crime than a suspect who is ignorant of having such a propensity? On the other hand, could genetic disposition be used as a defence on the grounds that the crime was really the fault of the gene, not the person?
When a patient tests positive for a gene linked to risk of disease, does the physician (or the patient) have a legal responsibility to inform the patients’ relatives of their own risks? Suppose a patient finds out that she has a genetic propensity for breast cancer, but neither she nor her doctor informs her relatives; would a relative who later developed that form of cancer be able to sue, on the grounds that the genetic information had not been disclosed?
Ensuring that the judge and jury in a trial are sufficiently educated to deal with these issues is yet another problem with which the legal system will have to deal.
On a larger social scale, knowledge of the human genome could be used to emphasize the similarities among all humans. The genetic differences between people within an identified group have already been shown to be greater than the differences between groups. In other words, people within an "ethnic" population are more different from each other than the group as a whole is different from other "ethnic" groups. This fact is unlikely, however, to deter those who wish to emphasize any ethnic differences that may be found.
On a more individual level, the results of the HGP might encourage people to view themselves as being wholly under the control of their genes. What has traditionally been viewed as the human spirit might in future be seen as limited by pre-programming at birth. Thus, though we cannot predict exactly how knowledge of the human genome will affect society, it could clearly have important consequences.
Individual decisions, such as choices with respect to mates and reproduction, could also be influenced by knowledge of genetic makeup. Awareness of personal genetic differences from a perceived norm might lead to confusion and uncertainty about the potential for disease, particularly in the absence of adequate professional consultation. Genetic analysis might reveal a myriad of genetic flaws that may or may not lead to disease, depending on what they are and how they interact with the environment. How will individuals select from a debilitating array of lifestyle choices, none of which has a certain outcome? Again, analysis of one’s own genetic makeup could reveal the genetic makeup of parents and siblings, including, for example, unsuspected information about paternity. How willing would people be to share this knowledge and, if they decided to withhold it, how would they be affected by living with the secret?
2. Ownership and Commercialization
On 11 November 1997, UNESCO passed its Universal Declaration on the Human Genome and Human Rights. Article 4 of the Declaration states that "The human genome in its natural state shall not give rise to financial gains." In most countries, however, DNA, when isolated from an individual, is not considered to be in its natural state and therefore can give rise to financial gain. One of the benefits of the HGP and genomics research in general is expected to be a thriving biotechnology industry with the potential, in the United States, to be worth $45 billion (U.S) by 2009. In most technological industries, innovation has been encouraged through the granting of patents on inventions.
Researchers who devise an invention that is useful, new, and unobvious are given approximately 20-year proprietary rights over its use. To be patentable, discoveries must involve some human intervention and inventiveness. In return for these rights, the inventor must make the invention public so that others may, at a price, use it to further their research.
For approximately 20 years, sequences of DNA that correspond to human genes have been claimed in patents. Conceptually, the string of DNA molecules is considered no different from other chemicals isolated from living organisms, such as penicillin, as long as it passes the tests for patentability (being new, useful, and unobvious).
For a number of reasons, some believe that human gene sequences should never be patentable. A fundamental, philosophical reason is the belief that the human genome, as an intrinsic part of every person, is a common heritage that all humans should share. This line of reasoning has led the Parliamentary Assembly of the Council of Europe to recommend that European Union countries renegotiate the agreed Directive that allows the patenting of human genes that are isolated from the body and applicable to industry, and specifically prohibit the patenting of human genes.
The World Trade Organization’s Trade Related Aspects of Intellectual Property Agreement includes some discussion on what member countries can exclude from patentability. Article 27(2) states that anything that is necessary to protect the "ordre public or morality" can be excluded, as long as the exemption is not made simply because it is prohibited by law. Section 27(3)(a) states that member countries may also exclude diagnostic, therapeutic and surgical methods for humans and animals. No specific clause would seem to prevent a member country from excluding the patentability of human genes. Canada’s Patent Act does not have an "ordre public" clause.
Some offer logistical reasons to explain why patents should not be extended to DNA sequences. They suggest that such patents, particularly on partial gene sequences, would inhibit innovation rather than encourage it, as the patent system is supposed to do. This could arise in a scenario, dubbed the "tragedy of the anticommons," in which numerous people and organizations held patents on different DNA sequences governing an overall biochemical pathway that could be the target for a medical treatment. To research that treatment, someone would have to negotiate for the rights to all the DNA sequences from all the respective owners; this might be so costly and onerous as to make further research unlikely. Pure researchers, who would not have the money, the time or the expertise for a complex series of transactions, would be the most severely affected. Others, however, refute this argument, citing the case of the computer industry. Patents on the various parts of computers certainly do not seem to have impeded the growth of that industry, though some might say that it has impeded innovation. Others point out that in the computer industry, the free flow of information has been a driving force behind such innovations as the GNU-Linux operating system.
It has also been suggested that DNA does not pass the tests for patentability on the ground that, since DNA exists in nature, knowledge of it is simply a discovery, not an invention. Therefore, while drugs should be patentable, the DNA sequence upstream from the target of the drug should not be. Moreover, it is said that many of the techniques used to isolate and manipulate DNA are now routine, and therefore the inventions are too obvious to be patentable.
In North America, the focus is more on what level of utility must be shown in order for genes to be patented, rather than on whether they are patentable at all. The Canadian Patent Act, as it is written, has for a long time been interpreted as meaning that genes are patentable material. A problem has arisen because many private companies have concentrated on sequencing genes in the hope of obtaining patents on a gene that may one day prove to be useful. Most of the genes sequenced by the HGP and private enterprises have as yet unknown functions; thus, applications are being made for DNA sequences that have no genuine utility. Since the sequences do encode a protein, some companies have gone so far as to claim that, at a minimum, the protein could be used for animal feed or in a molecular biological technique as a DNA probe. In one well known case in the United States, the company Human Genome Sciences obtained a patent on a gene that was subsequently discovered by a different researcher to be an entry portal through which the AIDS virus infects cells. Any future treatment of these cells that alters this entry portal will require royalties to be paid to Human Genome Sciences. While the Canadian Patent Act is similar to its U.S. equivalent, Canadian patenting procedures are generally more stringent with respect to the utility of the invention than are those in the United States, the country where the controversy is greatest. The U.S. Patent Office has recently announced that it will increase the stringency of the utility requirement for patenting DNA sequences.
Searching for medically useful, and therefore potentially profitable, genes also raises many ethical questions. Heritable disease patterns sometimes emerge in populations that have not mixed extensively with other populations; as a result, private companies are doing genetic exploration in such relatively isolated areas as Newfoundland, Iceland and certain tropical islands. In Iceland, a company called deCODE has been given the rights to produce a health sector database that will include genealogical, environmental, and molecular genetic information, along with the combined anonymized patient records of the country. In Newfoundland, political leaders are apparently coming to the conclusion that Newfoundlanders should maintain control over their unique genome. How to regulate the gene hunters without scaring off investment is a familiar problem to governments that already have experience with charging royalties and regulating natural resource operations. Gene "mining" companies, however, present a much more complex and emotional set of ethical issues than does the natural resources sector.
3. Genetic Treatment of Disease
From the outset, one of the defining goals of the HGP has been its potential for molecular medicine. The concept is that, once the functions of genes are known and we understand the effects of malfunctioning genes, we will be able to correct the problem either through the use of designer drugs or by replacing the faulty gene. It is the latter option that has created the most controversy.
There are two routes to replacing a faulty gene. The first route, germ line therapy, has the goal of replacing a harmful gene in a fertilized human egg with a properly functioning gene that would be passed on to future generations. The other route, somatic gene therapy, aims to replace the gene in target organs or tissues of an adult, so as to fix the symptoms in that individual but not in the next generation. Germ line therapy has the more profound ethical, legal and social implications.
As yet germ-line therapy in humans is not possible and some have argued that it will continue to be so for the foreseeable future. While this kind of therapy may be a long way off, it would bring, on the one hand, the hope of eradicating some genetic diseases but, on the other hand, the spectre of eugenics.
The eradication of disease through germ-line therapy might not seem, by itself, to raise many ethical questions. After all, humans have eradicated the smallpox virus from the world, why not diseases with genetic components? Do doctors not have the moral obligation to provide the very best treatment to their patients and would not the eradication of the disease be more cost effective in the long run than continually treating adults with somatic gene therapy? The main ethical problem arises in defining a "treatable" disease.
Some might say that eradication of a genetic disease for which there is no treatment and which is always fatal, should be pursued with all means possible. Others say that this would be the start of a slippery slope moving on toward the treatment of less obvious diseases and then to genetic enhancement. Some argue that if the technology is advanced in order to eradicate some diseases, it will inevitably be used by parents wishing to "enhance" their children, giving them the genes for raven black hair and blue eyes or athletic prowess. It was serious ethical concerns about genetic enhancement that prompted the Council of Europe to adopt the Convention for the Protection of Human Rights and Dignity of the Human Being with Regard to the Application of Biology and Medicine: Convention on Human Rights and Biomedicine. Article 13 of the Convention states that "an intervention seeking to modify the human genome may only be undertaken for preventive, diagnostic or therapeutic purposes and only if its aim is not to introduce any modification in the genome of any descendants." Article 11 of the UNESCO Universal Declaration on the Human Genome and Human Rights states that "practices which are contrary to human dignity, such as reproductive cloning of human beings, shall not be permitted." It is left to individual states, however, to define exactly what they believe these practices to be. Thus, while some countries, such as the signatories to the European Convention, may prohibit germ-line therapy, others may not. It is the existence of national differences in regulation of research on human embryos that has allowed controversial research to be performed, for example, in Singapore. Regulation has thus slowed down the progress of research but not prevented it.
Another ethical consideration with respect to germ-line therapy is defining what is normal, what is a disability, and what is a disease. Which of the genetic variations within a population ought to be eradicated, if any? In trying to eradicate a certain variation, are we demeaning those in the population who currently carry the gene?
Somatic gene therapy has its own, less controversial, set of ELS implications. These may be less ominous than eugenics but are of perhaps more immediate concern, given the more advanced state of the technology. Effectively, gene therapy involves the introduction of a properly functioning gene into target tissues in the hopes that it will be translated into a properly functioning protein, which will mask the malfunctioning protein. Often the new gene is placed into a modified virus, which is then introduced into a patient in the hope that the gene will be introduced into a tissue and properly expressed.
Such types of therapy, after much research on laboratory animals, have now reached the clinical trial stage. Unfortunately, what works for a mouse does not always work for a human being. In one highly publicized case, a patient, Jesse Gelsinger, was given an injection of a virus in the hope of introducing a protein into the liver. Mouse studies showed good absorption of the gene into the liver; however, the mouse has a much higher concentration of viral receptors on its liver cells than do humans. The virus did not absorb well into the human patient and, for still unknown reasons, created a massive immune response, causing the patient to die. The original plan for the trials had been to use the virus only on children in a coma caused by the lack of the particular liver enzyme; however, ethical and safety reviews caused the researchers to change the trial direction and use adults only. Many questions are now being asked regarding the ethics and scientific judgment of those performing such clinical trials. How well are "volunteer" patients informed of the possible risks and benefits? How objective are investigators who have equity in the companies that are funding the trials? One of the risks at this stage of gene therapy is the excessive public anticipation, created in part by some researchers, with respect to future benefits. This anticipation may turn to public distrust of science, if the benefits fail to be realized and problems such as that in the Gelsinger case continue to occur. Some clinical trials have shown positive results , and so there is still hope that somatic gene therapy will become a powerful medical tool.
4. Discrimination
One of the problems some fear might result from knowledge of the human genome is the emergence of a whole population of socially marginalized individuals, unable to obtain a job, a family, insurance, or health care and stigmatized by the rest of society. Insurance companies already insist that those identified at risk of Huntington’s disease must take a genetic test. If the results are positive, insurance is frequently refused. Insurance companies are on record as saying that if genetic information was available, they would use it in their risk assessment. In Canada, the refusal to insure a Huntington’s patient does not have dire consequences; in general, public insurance covers many aspects of care, though the level of care varies across the country and the coverage for pharmaceuticals is less clear. In countries without a public health insurance system, however, the plight of such a non-insured person can be a nightmare. Care may be available but finding it is very difficult. As more genetic tests become available, insurance is likely to be more and more expensive for those carrying what the insurance companies deem to be risky genes. The public insurance schemes may also start to feel the pressure for such genetic testing, and be forced to make policy decisions based on the funding available and the knowledge of genetic predisposition to disease within populations. Gene therapy is at the experimental stage at this point but will certainly be very expensive when it first comes into regular use. Who will pay for it? If not public insurance, will the therapy be available only to rich people, thus creating an ever widening gap between groups in society, based on both money and genetic inheritance?
Employers may also want access to genetic information. Some genes might reveal a susceptibility to environmental damage that was incompatible with a certain workplace environment. Employers might choose to screen out workers carrying that gene rather than trying to improve the environment. Individuals with genes associated with certain behavioural traits might also be excluded from the workplace.
Some action has already been taken to prevent the possibility of genetic discrimination. For example, President Bill Clinton has signed an executive order prohibiting federal departments and agencies from using genetic information in any hiring or promotion action. He has also endorsed an Act, introduced in 1999 by a Senator and a member of Congress, that would extend such protection to the private sector.
Human Genome Project
Human Genome Project - What is it?
The Human Genome Project, comprised of the U.S. Department of Energy and NIH Human Genome Programs, is the national coordinated effort to characterize all human genetic material by determining the complete sequence of DNA in the human genome. The Human Genome Project's ultimate goal is to discover and map all of the approximately 35,000 human genes and make them accessible for further biological study. To facilitate the future interpretation of human gene function, the Human Genome Project is also conducting parallel studies on the genetic makeup of other organisms.
Human Genome Project - The DNA Sequence Has Been Revealed
After years of multi-billion-dollar research, the Human Genome Project and Celera Genomics (a non-government biotechnology company) jointly announced drafts of the human genome sequence in 2000. By mid-2001, scientists associated with these ventures had presented the true nature and complexity of the digital code inherent in DNA. We now understand that there are approximately 35,000 genes in each human DNA molecule, comprised of approximately 3 billion chemical bases arranged in precise sequence. Even the DNA molecule for the single-celled bacterium, E. coli, contains enough information to fill all the books in any of the world's largest libraries. We now appreciate that the DNA structure is one of the greatest scientific discoveries of all time, only first discovered at its base level in 1953 by James Watson and Francis Crick.
Human Genome Project - What it Means for the 21st Century
As a result of the work of the Human Genome Project and other genetic scientists, including the recent media-hyped cloning of Dolly the sheep, we now realize that the possibilities of genetic manipulation are profound. With this awesome technological discovery comes dramatic potential for significant abuse. As such, we need to keep a careful eye on "science" and continually remind the popular culture that technology is not the supreme authority. Regardless of a person's DNA, every human being is a unique and special individual created by God. Genetic engineering seems to accept that our DNA is the entirety of who we are. In contrast, the Bible teaches that every person has a soul, separate and distinct from our genetic material. When a person dies, the soul continues to exist. Therefore, contrary to general scientific principles, we are more than a combination of genetic code and 17 naturally occurring organic elements. The Director of the Human Genome Project, Francis Collins, is a Christian who highlights the positive aspects of genetic research, "We have caught the first glimpse of our instruction book, previously known only to God." While this is an exciting statement, we must never lose sight of the fact that no matter how "smart" we get as a society, we are not God and should not put ourselves in a position to play God. Since we live in a post-modern society influenced more by humanism, materialism and moral relativism than by Judeo-christian values, we must keep careful tabs on the potential uses and abuses of human genetic engineering.
Human Genome Project - A Monstrous Final Thought
The Human Genome Project is a phenomenal undertaking. Unfortunately, it reminds us that some of the worst events in human history have occurred when technological expertise was united with spiritual emptiness. Mary Shelley, author of Frankenstein, explains it perfectly in the introduction to her famous book, "Frightful must it be; for supremely frightful would be the effect of any human endeavor to mock the stupendous mechanism of the Creator of the World."
The Human Genome Project - What is its Purpose?
The Human Genome Project was a 13-year project coordinated by the U.S. Department of Energy and the National Institute of Health. It completed its initial mission in 2003. The initial purpose or goals were to:
* identify all the approximately 20,000-25,000 genes in human DNA,
* determine the sequences of the 3 billion chemical base pairs that make up human DNA,
* store this information in databases,
* improve tools for data analysis,
* transfer related technologies to the private sector, and
* address the ethical, legal, and social issues (ELSI) that may arise from the project.
Identifying the sequences of the 3 billion chemical base pairs that make up human DNA was an enormous achievement of the Human Genome Project which some say is akin to developing the periodic table of elements. However, deriving meaningful knowledge from DNA sequence will define biological research through the coming decades and require the expertise and creativity of teams of biologists, chemists, engineers, and computational scientists, among others. Many research challenges remain in genetics even with the full human sequence in hand. Some of the application areas where specific goals (additional purposes) have been defined are as follows:
* Molecular Medicine
* Energy and Environmental Applications
* Risk Assessment
* Bioarchaeology, Anthropology, Evolution, and Human Migration
* DNA Forensics (Identification)
* Agriculture, Livestock, Breeding, and Bioprocessing
A short list of the many challenges (the purpose is to overcome these challenges) include the following:
* Gene number, exact locations, and functions
* Gene Regulation
* DNA sequence organization
* Chromosomal structure and organization
* Noncoding DNA types, amount, distribution, information content, and functions.
The purposes of the Human Genome Project and the ongoing effort to understand the relationship between the code and life is more than just a set of objectives, goals and challenges to overcome. The purpose also includes the significance and appropriateness of what is being done to our world and how it relates to our worldview and its values. The project team realized this and included an ethical, legal and social issues topic as part of their objectives and they spent about 3%-5% of their budget in this area. However, that doesn't mean they considered limiting the work to accommodate a Christian Theistic worldview that is opposite to the dominant naturalistic, humanistic worldview in the scientific community. In fact, they assumed that the theory of evolution is true and that God doesn't exist by including the study of evolution into their objectives.
It would seem that the most appropriate, significant and profound purpose of the Human Genome Project would be to identify if the evidence points to special creation or (macro) evolution. Zero percent of their budget went toward inferring or concluding what the data implied regarding the biggest question in the universe! Their naturalism presupposition compels them to conclude that macro evolution is true and that God does not exist. This, in part, has happened because of a redefinition of science.
The 1934 edition of Webster's New School dictionary in defining the word "science," "acknowledged truths and laws, especially as demonstrated by induction, experiment or observation." However, by 1983 the basic definition was changed as follows in the Webster's Collegiate dictionary; "knowledge concerning the physical world and its phenomena." Scientists have lost this fundamental understanding of the original purpose of science since its definition has now been altered. This (new) definition removes the idea that science is the search for truth, but only exists to identify and emphasize natural phenomena.
The Human Genome Project, comprised of the U.S. Department of Energy and NIH Human Genome Programs, is the national coordinated effort to characterize all human genetic material by determining the complete sequence of DNA in the human genome. The Human Genome Project's ultimate goal is to discover and map all of the approximately 35,000 human genes and make them accessible for further biological study. To facilitate the future interpretation of human gene function, the Human Genome Project is also conducting parallel studies on the genetic makeup of other organisms.
Human Genome Project - The DNA Sequence Has Been Revealed
After years of multi-billion-dollar research, the Human Genome Project and Celera Genomics (a non-government biotechnology company) jointly announced drafts of the human genome sequence in 2000. By mid-2001, scientists associated with these ventures had presented the true nature and complexity of the digital code inherent in DNA. We now understand that there are approximately 35,000 genes in each human DNA molecule, comprised of approximately 3 billion chemical bases arranged in precise sequence. Even the DNA molecule for the single-celled bacterium, E. coli, contains enough information to fill all the books in any of the world's largest libraries. We now appreciate that the DNA structure is one of the greatest scientific discoveries of all time, only first discovered at its base level in 1953 by James Watson and Francis Crick.
Human Genome Project - What it Means for the 21st Century
As a result of the work of the Human Genome Project and other genetic scientists, including the recent media-hyped cloning of Dolly the sheep, we now realize that the possibilities of genetic manipulation are profound. With this awesome technological discovery comes dramatic potential for significant abuse. As such, we need to keep a careful eye on "science" and continually remind the popular culture that technology is not the supreme authority. Regardless of a person's DNA, every human being is a unique and special individual created by God. Genetic engineering seems to accept that our DNA is the entirety of who we are. In contrast, the Bible teaches that every person has a soul, separate and distinct from our genetic material. When a person dies, the soul continues to exist. Therefore, contrary to general scientific principles, we are more than a combination of genetic code and 17 naturally occurring organic elements. The Director of the Human Genome Project, Francis Collins, is a Christian who highlights the positive aspects of genetic research, "We have caught the first glimpse of our instruction book, previously known only to God." While this is an exciting statement, we must never lose sight of the fact that no matter how "smart" we get as a society, we are not God and should not put ourselves in a position to play God. Since we live in a post-modern society influenced more by humanism, materialism and moral relativism than by Judeo-christian values, we must keep careful tabs on the potential uses and abuses of human genetic engineering.
Human Genome Project - A Monstrous Final Thought
The Human Genome Project is a phenomenal undertaking. Unfortunately, it reminds us that some of the worst events in human history have occurred when technological expertise was united with spiritual emptiness. Mary Shelley, author of Frankenstein, explains it perfectly in the introduction to her famous book, "Frightful must it be; for supremely frightful would be the effect of any human endeavor to mock the stupendous mechanism of the Creator of the World."
The Human Genome Project - What is its Purpose?
The Human Genome Project was a 13-year project coordinated by the U.S. Department of Energy and the National Institute of Health. It completed its initial mission in 2003. The initial purpose or goals were to:
* identify all the approximately 20,000-25,000 genes in human DNA,
* determine the sequences of the 3 billion chemical base pairs that make up human DNA,
* store this information in databases,
* improve tools for data analysis,
* transfer related technologies to the private sector, and
* address the ethical, legal, and social issues (ELSI) that may arise from the project.
Identifying the sequences of the 3 billion chemical base pairs that make up human DNA was an enormous achievement of the Human Genome Project which some say is akin to developing the periodic table of elements. However, deriving meaningful knowledge from DNA sequence will define biological research through the coming decades and require the expertise and creativity of teams of biologists, chemists, engineers, and computational scientists, among others. Many research challenges remain in genetics even with the full human sequence in hand. Some of the application areas where specific goals (additional purposes) have been defined are as follows:
* Molecular Medicine
* Energy and Environmental Applications
* Risk Assessment
* Bioarchaeology, Anthropology, Evolution, and Human Migration
* DNA Forensics (Identification)
* Agriculture, Livestock, Breeding, and Bioprocessing
A short list of the many challenges (the purpose is to overcome these challenges) include the following:
* Gene number, exact locations, and functions
* Gene Regulation
* DNA sequence organization
* Chromosomal structure and organization
* Noncoding DNA types, amount, distribution, information content, and functions.
The purposes of the Human Genome Project and the ongoing effort to understand the relationship between the code and life is more than just a set of objectives, goals and challenges to overcome. The purpose also includes the significance and appropriateness of what is being done to our world and how it relates to our worldview and its values. The project team realized this and included an ethical, legal and social issues topic as part of their objectives and they spent about 3%-5% of their budget in this area. However, that doesn't mean they considered limiting the work to accommodate a Christian Theistic worldview that is opposite to the dominant naturalistic, humanistic worldview in the scientific community. In fact, they assumed that the theory of evolution is true and that God doesn't exist by including the study of evolution into their objectives.
It would seem that the most appropriate, significant and profound purpose of the Human Genome Project would be to identify if the evidence points to special creation or (macro) evolution. Zero percent of their budget went toward inferring or concluding what the data implied regarding the biggest question in the universe! Their naturalism presupposition compels them to conclude that macro evolution is true and that God does not exist. This, in part, has happened because of a redefinition of science.
The 1934 edition of Webster's New School dictionary in defining the word "science," "acknowledged truths and laws, especially as demonstrated by induction, experiment or observation." However, by 1983 the basic definition was changed as follows in the Webster's Collegiate dictionary; "knowledge concerning the physical world and its phenomena." Scientists have lost this fundamental understanding of the original purpose of science since its definition has now been altered. This (new) definition removes the idea that science is the search for truth, but only exists to identify and emphasize natural phenomena.
Monday, June 16, 2008
Gel electrophoresis
Gel electrophoresis
Gel electrophoresis is a technique used for the separation of deoxyribonucleic acid, ribonucleic acid, or protein molecules using an electric current applied to a gel matrix.
It is usually performed for analytical purposes, but may be used as a preparative technique prior to use of other methods such as mass spectrometry, RFLP, PCR, cloning, DNA sequencing, or Southern blotting for further characterization.
Separation
The term "gel" in this instance refers to the matrix used to contain, then separate the target molecules. In most cases the gel is a crosslinked polymer whose composition and porosity is chosen based on the specific weight and composition of the target to be analyzed. When separating proteins or small nucleic acids (DNA, RNA, or oligonucleotides) the gel is usually composed of different concentrations of acrylamide and a cross-linker, producing different sized mesh networks of polyacrylamide. When separating larger nucleic acids (greater than a few hundred bases), the preferred matrix is purified agarose.
In both cases, the gel forms a solid, yet porous matrix. Acrylamide, in contrast to polyacrylamide, is a neurotoxin and must be handled using Good Laboratory Practices to avoid poisoning.
"Electrophoresis" refers to the electromotive force (EMF) that is used to move the molecules through the gel matrix. By placing the molecules in wells in the gel and applying an electric current, the molecules will move through the matrix at different rates, usually determined by mass, toward the positive anode if negatively charged or toward the negative cathode if positively charged.
Visualization
I Agarose gel prepared for DNA analysis - The first lane contains a DNA ladder for sizing, and the other four lanes show variously-sized DNA fragments that are present in some but not all of the samples.
After the electrophoresis is complete, the molecules in the gel can be stained to make them visible. Ethidium bromide, silver, or coomassie blue dye may be used for this process. Other methods may also be used to visualize the separation of the mixture's components on the gel. If the analyte molecules fluoresce under ultraviolet light, a photograph can be taken of the gel under ultraviolet lighting conditions. If the molecules to be separated contain radioactivity added for visibility, an autoradiogram can be recorded of the gel.
If several mixtures have initially been injected next to each other, they will run parallel in individual lanes. Depending on the number of different molecules, each lane shows separation of the components from the original mixture as one or more distinct bands, one band per component. Incomplete separation of the components can lead to overlapping bands, or to indistinguishable smears representing multiple unresolved components.
Bands in different lanes that end up at the same distance from the top contain molecules that passed through the gel with the same speed, which usually means they are approximately the same size. There are molecular weight size markers available that contain a mixture of molecules of known sizes. If such a marker was run on one lane in the gel parallel to the unknown samples, the bands observed can be compared to those of the unknown in order to determine their size. The distance a band travels is approximately inversely proportional to the logarithm of the size of the molecule.
Applications
Gel electrophoresis is used in forensics, molecular biology, genetics, microbiology and biochemistry. The results can be analyzed quantitatively by visualizing the gel with UV light and a gel imaging device. The image is recorded with a computer operated camera, and the intensity of the band or spot of interest is measured and compared against standard or markers loaded on the same gel. The measurement and analysis are mostly done with specialized software.
Depending on the type of analysis being performed, other techniques are often implemented in conjunction with the results of gel electrophoresis, providing a wide range of field-specific applications.
Nucleic acids
In the case of nucleic acids, the direction of migration, from negative to positive electrodes, is due to the naturally-occurring negative charge carried by their sugar-phosphate backbone.
Double-stranded DNA fragments naturally behave as long rods, so their migration through the gel is relative to their radius of gyration, or, for non-cyclic fragments, size. Single-stranded DNA or RNA tend to fold up into molecules with complex shapes and migrate through the gel in a complicated manner based on their tertiary structure. Therefore, agents that disrupt the hydrogen bonds, such as sodium hydroxide or formamide, are used to denature the nucleic acids and cause them to behave as long rods again.
Gel electrophoresis of large DNA or RNA is usually done by agarose gel electrophoresis. See the "Chain termination method" page for an example of a polyacrylamide DNA sequencing gel.
Proteins
SDS-PAGE autoradiography - The indicated proteins are present in different concentrations in the two samples.
Proteins, unlike nucleic acids, can have varying charges and complex shapes, therefore they may not migrate into the gel at similar rates, or at all, when placing a negative to positive EMF on the sample. Proteins therefore, are usually denatured in the presence of a detergent such as sodium dodecyl sulfate/sodium dodecyl phosphate (SDS/SDP) that coats the proteins with a negative charge. Generally, the amount of SDS bound is relative to the size of the protein (usually 1.4g SDS per gram of protein), so that the resulting denatured proteins have an overall negative charge, and all the proteins have a similar charge to mass ratio. Since denatured proteins act like long rods instead of having a complex tertiary shape, the rate at which the resulting SDS coated proteins migrate in the gel is relative only to its size and not its charge or shape.
Proteins are usually analyzed by sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE), by native gel electrophoresis, by quantitative preparative native continuous polyacrylamide gel electrophoresis (QPNC-PAGE), or by 2-D electrophoresis.
Gel electrophoresis is a technique used for the separation of deoxyribonucleic acid, ribonucleic acid, or protein molecules using an electric current applied to a gel matrix.
It is usually performed for analytical purposes, but may be used as a preparative technique prior to use of other methods such as mass spectrometry, RFLP, PCR, cloning, DNA sequencing, or Southern blotting for further characterization.
Separation
The term "gel" in this instance refers to the matrix used to contain, then separate the target molecules. In most cases the gel is a crosslinked polymer whose composition and porosity is chosen based on the specific weight and composition of the target to be analyzed. When separating proteins or small nucleic acids (DNA, RNA, or oligonucleotides) the gel is usually composed of different concentrations of acrylamide and a cross-linker, producing different sized mesh networks of polyacrylamide. When separating larger nucleic acids (greater than a few hundred bases), the preferred matrix is purified agarose.
In both cases, the gel forms a solid, yet porous matrix. Acrylamide, in contrast to polyacrylamide, is a neurotoxin and must be handled using Good Laboratory Practices to avoid poisoning.
"Electrophoresis" refers to the electromotive force (EMF) that is used to move the molecules through the gel matrix. By placing the molecules in wells in the gel and applying an electric current, the molecules will move through the matrix at different rates, usually determined by mass, toward the positive anode if negatively charged or toward the negative cathode if positively charged.
Visualization
I Agarose gel prepared for DNA analysis - The first lane contains a DNA ladder for sizing, and the other four lanes show variously-sized DNA fragments that are present in some but not all of the samples.
After the electrophoresis is complete, the molecules in the gel can be stained to make them visible. Ethidium bromide, silver, or coomassie blue dye may be used for this process. Other methods may also be used to visualize the separation of the mixture's components on the gel. If the analyte molecules fluoresce under ultraviolet light, a photograph can be taken of the gel under ultraviolet lighting conditions. If the molecules to be separated contain radioactivity added for visibility, an autoradiogram can be recorded of the gel.
If several mixtures have initially been injected next to each other, they will run parallel in individual lanes. Depending on the number of different molecules, each lane shows separation of the components from the original mixture as one or more distinct bands, one band per component. Incomplete separation of the components can lead to overlapping bands, or to indistinguishable smears representing multiple unresolved components.
Bands in different lanes that end up at the same distance from the top contain molecules that passed through the gel with the same speed, which usually means they are approximately the same size. There are molecular weight size markers available that contain a mixture of molecules of known sizes. If such a marker was run on one lane in the gel parallel to the unknown samples, the bands observed can be compared to those of the unknown in order to determine their size. The distance a band travels is approximately inversely proportional to the logarithm of the size of the molecule.
Applications
Gel electrophoresis is used in forensics, molecular biology, genetics, microbiology and biochemistry. The results can be analyzed quantitatively by visualizing the gel with UV light and a gel imaging device. The image is recorded with a computer operated camera, and the intensity of the band or spot of interest is measured and compared against standard or markers loaded on the same gel. The measurement and analysis are mostly done with specialized software.
Depending on the type of analysis being performed, other techniques are often implemented in conjunction with the results of gel electrophoresis, providing a wide range of field-specific applications.
Nucleic acids
In the case of nucleic acids, the direction of migration, from negative to positive electrodes, is due to the naturally-occurring negative charge carried by their sugar-phosphate backbone.
Double-stranded DNA fragments naturally behave as long rods, so their migration through the gel is relative to their radius of gyration, or, for non-cyclic fragments, size. Single-stranded DNA or RNA tend to fold up into molecules with complex shapes and migrate through the gel in a complicated manner based on their tertiary structure. Therefore, agents that disrupt the hydrogen bonds, such as sodium hydroxide or formamide, are used to denature the nucleic acids and cause them to behave as long rods again.
Gel electrophoresis of large DNA or RNA is usually done by agarose gel electrophoresis. See the "Chain termination method" page for an example of a polyacrylamide DNA sequencing gel.
Proteins
SDS-PAGE autoradiography - The indicated proteins are present in different concentrations in the two samples.
Proteins, unlike nucleic acids, can have varying charges and complex shapes, therefore they may not migrate into the gel at similar rates, or at all, when placing a negative to positive EMF on the sample. Proteins therefore, are usually denatured in the presence of a detergent such as sodium dodecyl sulfate/sodium dodecyl phosphate (SDS/SDP) that coats the proteins with a negative charge. Generally, the amount of SDS bound is relative to the size of the protein (usually 1.4g SDS per gram of protein), so that the resulting denatured proteins have an overall negative charge, and all the proteins have a similar charge to mass ratio. Since denatured proteins act like long rods instead of having a complex tertiary shape, the rate at which the resulting SDS coated proteins migrate in the gel is relative only to its size and not its charge or shape.
Proteins are usually analyzed by sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE), by native gel electrophoresis, by quantitative preparative native continuous polyacrylamide gel electrophoresis (QPNC-PAGE), or by 2-D electrophoresis.
Types of Gene Therapy
Types of Gene Therapy Explained
Gene therapy inserts genes into cells and tissues in order to treat diseases. It is mainly used for hereditary diseases. The inserted genes may seek to alter or replace faulty genes that are
responsible for the disease. There are two types of gene therapy; somatic gene therapy
(gene therapy that is used on adult cells) and germline gene therapy (gene therapy that targets egg and sperm cells).
Somatic - A Unique Type of Gene Therapy
Somatic gene therapy treats somatic cells by inserting an agent containing a modified gene (known as a vector) into a person's body. Somatic cells are cells that form the body and cannot produce offspring. Gene therapy, in its present stage, only treats somatic cells in humans. There are two types of somatic gene therapy, ex vivo and in vivo. Ex vivo modifies cells outsides the body and then transplants them back into the body. In vivo changes the cells while they are still in the body; Somatic gene therapy does not affect any offspring of the person being treated.
Applications of Somatic Gene Therapy
Somatic gene therapy has been used to treat genetic diseases and disorders. Scientists first used gene therapy on single-gene defects, like cystic fibrosis, hemophilia, muscular dystrophy, sickle cell anemia and ADA deficiency. Theoretically, these various types of gene therapy could be used to treat any disease that is caused from gene disorders. Some of the diseases that have been mentioned as possible candidates for somatic gene therapy include cancer, AIDS, Alzheimer's diseases, Lou Gehrig's disease, cardiovascular disease and arthritis.
Regulations in Somatic Gene Therapy
Legislation regarding somatic gene therapy varies from country to country and from state to state. Some countries limit the use of gene therapy to certain diseases, including diseases that may not be cured with other methods and that may cause an early death. Some countries require that any research that takes place follow certain regulations, including the establishment of committees and organizations to monitor. Many countries will require research to be approved by national or state committees that have been established to deal with somatic gene therapy research.
The use of somatic gene therapy is also usually subject to regulations, including approval by a committee set up for this purpose. Committees will often look at the probably benefits and harms. They will also ensure that the public is advised of any new research and applications and listen to their views on the subject.
Morals and ethics play an important role when it comes to certain types of gene therapy. Somatic gene therapy is not as affected by ethics when compared to the germline gene therapy. As somatic gene therapy only treats body cells, instead of reproduction cells, many people believe it does not compromise ethics as much as germline gene therapy, which treats egg and sperm cells and has the ability to affect future generations. However, there are some ethical concerns. Ethical standards vary from country to country. Some ethical organizations have released recommendations. These recommendations include:
Establishing a national ethics body in each country to look at somatic gene therapy;
Supporting somatic gene therapy research that follows the recommendations;
Asking researchers, organizations and governments to listen and respond to public concerns about gene therapy research;
Asking that research follow quality and safety controls.
Germline Gene Therapy
Germline gene therapy involves making changes to the cells that are used in the reproductive process. Germline gene manipulation can change sperm cells, oval or stem cells
precursors. In order for germline therapy to produce changes that will be transmitted to
offspring, the genes need to be inserted into chromosomes. Germline therapy has so far mainly been used in animals.
Germline Genetic Engineering and Specially Altered Animals
Germline genetic engineering has been used successfully to specially alter animals. When altered cells are implanted in a surrogate mother, the two types of cells in the hybrid blastocyst contribute to the final animal. This has been used to produce animals such as cows with elevated milk production, sheep that secrete a valuable hormone or enzyme in the udder, mice that have specific genes inactivated in order to analyze the gene's function and mice with a genetically engineered deficiency that is similar to human diseases.
Ethical Considerations in Germline Gene Therapy
Out of the two types of gene therapy, germline gene therapy poses the most ethical problems. Many people protest against the use of germline gene therapy in all scenarios, and the use of germline gene therapy moral in humans is a very contentious issue. Some people want this technology to be used in humans, so that certain diseases may be eradicated. Others believe that this sets some people up as "playing God" and opens the way to many future problems, including "designer babies" and the rejection of certain normal traits. It has only provoked questions about how it should be used and when it is ethical to use germline gene therapy. Germline gene therapy institutes are concerned with the ethical problems relating to germline gene therapy.
Differences between Somatic and Germline Gene Therapy
There is one main difference between somatic and germline gene therapy. Somatic gene therapy alters body cells and has no effect on the reproduction cells or any future offspring. Germline gene therapy, on the other hand, targets cells of the reproductive system and can be used to change the cells of future generations. Both types of gene therapy have ethical considerations.
Gene therapy inserts genes into cells and tissues in order to treat diseases. It is mainly used for hereditary diseases. The inserted genes may seek to alter or replace faulty genes that are
responsible for the disease. There are two types of gene therapy; somatic gene therapy
(gene therapy that is used on adult cells) and germline gene therapy (gene therapy that targets egg and sperm cells).
Somatic - A Unique Type of Gene Therapy
Somatic gene therapy treats somatic cells by inserting an agent containing a modified gene (known as a vector) into a person's body. Somatic cells are cells that form the body and cannot produce offspring. Gene therapy, in its present stage, only treats somatic cells in humans. There are two types of somatic gene therapy, ex vivo and in vivo. Ex vivo modifies cells outsides the body and then transplants them back into the body. In vivo changes the cells while they are still in the body; Somatic gene therapy does not affect any offspring of the person being treated.
Applications of Somatic Gene Therapy
Somatic gene therapy has been used to treat genetic diseases and disorders. Scientists first used gene therapy on single-gene defects, like cystic fibrosis, hemophilia, muscular dystrophy, sickle cell anemia and ADA deficiency. Theoretically, these various types of gene therapy could be used to treat any disease that is caused from gene disorders. Some of the diseases that have been mentioned as possible candidates for somatic gene therapy include cancer, AIDS, Alzheimer's diseases, Lou Gehrig's disease, cardiovascular disease and arthritis.
Regulations in Somatic Gene Therapy
Legislation regarding somatic gene therapy varies from country to country and from state to state. Some countries limit the use of gene therapy to certain diseases, including diseases that may not be cured with other methods and that may cause an early death. Some countries require that any research that takes place follow certain regulations, including the establishment of committees and organizations to monitor. Many countries will require research to be approved by national or state committees that have been established to deal with somatic gene therapy research.
The use of somatic gene therapy is also usually subject to regulations, including approval by a committee set up for this purpose. Committees will often look at the probably benefits and harms. They will also ensure that the public is advised of any new research and applications and listen to their views on the subject.
Morals and ethics play an important role when it comes to certain types of gene therapy. Somatic gene therapy is not as affected by ethics when compared to the germline gene therapy. As somatic gene therapy only treats body cells, instead of reproduction cells, many people believe it does not compromise ethics as much as germline gene therapy, which treats egg and sperm cells and has the ability to affect future generations. However, there are some ethical concerns. Ethical standards vary from country to country. Some ethical organizations have released recommendations. These recommendations include:
Establishing a national ethics body in each country to look at somatic gene therapy;
Supporting somatic gene therapy research that follows the recommendations;
Asking researchers, organizations and governments to listen and respond to public concerns about gene therapy research;
Asking that research follow quality and safety controls.
Germline Gene Therapy
Germline gene therapy involves making changes to the cells that are used in the reproductive process. Germline gene manipulation can change sperm cells, oval or stem cells
precursors. In order for germline therapy to produce changes that will be transmitted to
offspring, the genes need to be inserted into chromosomes. Germline therapy has so far mainly been used in animals.
Germline Genetic Engineering and Specially Altered Animals
Germline genetic engineering has been used successfully to specially alter animals. When altered cells are implanted in a surrogate mother, the two types of cells in the hybrid blastocyst contribute to the final animal. This has been used to produce animals such as cows with elevated milk production, sheep that secrete a valuable hormone or enzyme in the udder, mice that have specific genes inactivated in order to analyze the gene's function and mice with a genetically engineered deficiency that is similar to human diseases.
Ethical Considerations in Germline Gene Therapy
Out of the two types of gene therapy, germline gene therapy poses the most ethical problems. Many people protest against the use of germline gene therapy in all scenarios, and the use of germline gene therapy moral in humans is a very contentious issue. Some people want this technology to be used in humans, so that certain diseases may be eradicated. Others believe that this sets some people up as "playing God" and opens the way to many future problems, including "designer babies" and the rejection of certain normal traits. It has only provoked questions about how it should be used and when it is ethical to use germline gene therapy. Germline gene therapy institutes are concerned with the ethical problems relating to germline gene therapy.
Differences between Somatic and Germline Gene Therapy
There is one main difference between somatic and germline gene therapy. Somatic gene therapy alters body cells and has no effect on the reproduction cells or any future offspring. Germline gene therapy, on the other hand, targets cells of the reproductive system and can be used to change the cells of future generations. Both types of gene therapy have ethical considerations.
Gene Therapy
What is gene therapy?
Genes, which are carried on chromosomes, are the basic physical and functional units of heredity. Genes are specific sequences of bases that encode instructions on how to make proteins. Although genes get a lot of attention, it’s the proteins that perform most life functions and even make up the majority of cellular structures. When genes are altered so that the encoded proteins are unable to carry out their normal functions, genetic disorders can result.
Gene therapy is a technique for correcting defective genes responsible for disease development. Researchers may use one of several approaches for correcting faulty genes:
A normal gene may be inserted into a nonspecific location within the genome to replace a nonfunctional gene. This approach is most common.
An abnormal gene could be swapped for a normal gene through homologous recombination.
The abnormal gene could be repaired through selective reverse mutation, which returns the gene to its normal function.
The regulation (the degree to which a gene is turned on or off) of a particular gene could be altered.
How does gene therapy work?
In most gene therapy studies, a "normal" gene is inserted into the genome to replace an "abnormal," disease-causing gene. A carrier molecule called a vector must be used to deliver the therapeutic gene to the patient's target cells. Currently, the most common vector is a virus that has been genetically altered to carry normal human DNA. Viruses have evolved a way of encapsulating and delivering their genes to human cells in a pathogenic manner. Scientists have tried to take advantage of this capability and manipulate the virus genome to remove disease-causing genes and insert therapeutic genes.
Target cells such as the patient's liver or lung cells are infected with the viral vector. The vector then unloads its genetic material containing the therapeutic human gene into the target cell. The generation of a functional protein product from the therapeutic gene restores the target cell to a normal state.
Some of the different types of viruses used as gene therapy vectors:
Retroviruses - A class of viruses that can create double-stranded DNA copies of their RNA genomes. These copies of its genome can be integrated into the chromosomes of host cells. Human immunodeficiency virus (HIV) is a retrovirus.
Adenoviruses - A class of viruses with double-stranded DNA genomes that cause respiratory, intestinal, and eye infections in humans. The virus that causes the common cold is an adenovirus.
Adeno-associated viruses - A class of small, single-stranded DNA viruses that can insert their genetic material at a specific site on chromosome 19.
Herpes simplex viruses
- A class of double-stranded DNA viruses that infect a particular cell type, neurons. Herpes simplex virus type 1 is a common human pathogen that causes cold sores.
Besides virus-mediated gene-delivery systems, there are several nonviral options for gene delivery. The simplest method is the direct introduction of therapeutic DNA into target cells. This approach is limited in its application because it can be used only with certain tissues and requires large amounts of DNA.
Another nonviral approach involves the creation of an artificial lipid sphere with an aqueous core. This liposome, which carries the therapeutic DNA, is capable of passing the DNA through the target cell's membrane.
Therapeutic DNA also can get inside target cells by chemically linking the DNA to a molecule that will bind to special cell receptors. Once bound to these receptors, the therapeutic DNA constructs are engulfed by the cell membrane and passed into the interior of the target cell. This delivery system tends to be less effective than other options.
Researchers also are experimenting with introducing a 47th (artificial human) chromosome into target cells. This chromosome would exist autonomously alongside the standard 46 --not affecting their workings or causing any mutations. It would be a large vector capable of carrying substantial amounts of genetic code, and scientists anticipate that, because of its construction and autonomy, the body's immune systems would not attack it. A problem with this potential method is the difficulty in delivering such a large molecule to the nucleus of a target cell.
What is the current status of gene therapy research?
The Food and Drug Administration (FDA) has not yet approved any human gene therapy product for sale. Current gene therapy is experimental and has not proven very successful in clinical trials. Little progress has been made since the first gene therapy clinical trial began in 1990. In 1999, gene therapy suffered a major setback with the death of 18-year-old Jesse Gelsinger. Jesse was participating in a gene therapy trial for ornithine transcarboxylase deficiency (OTCD). He died from multiple organ failures 4 days after starting the treatment. His death is believed to have been triggered by a severe immune response to the adenovirus carrier.
Another major blow came in January 2003, when the FDA placed a temporary halt on all gene therapy trials using retroviral vectors in blood stem cells. FDA took this action after it learned that a second child treated in a French gene therapy trial had developed a leukemia-like condition. Both this child and another who had developed a similar condition in August 2002 had been successfully treated by gene therapy for X-linked severe combined immunodeficiency disease (X-SCID), also known as "bubble baby syndrome."
FDA's Biological Response Modifiers Advisory Committee (BRMAC) met at the end of February 2003 to discuss possible measures that could allow a number of retroviral gene therapy trials for treatment of life-threatening diseases to proceed with appropriate safeguards. In April of 2003 the FDA eased the ban on gene therapy trials using retroviral vectors in blood stem cells.
Genes, which are carried on chromosomes, are the basic physical and functional units of heredity. Genes are specific sequences of bases that encode instructions on how to make proteins. Although genes get a lot of attention, it’s the proteins that perform most life functions and even make up the majority of cellular structures. When genes are altered so that the encoded proteins are unable to carry out their normal functions, genetic disorders can result.
Gene therapy is a technique for correcting defective genes responsible for disease development. Researchers may use one of several approaches for correcting faulty genes:
A normal gene may be inserted into a nonspecific location within the genome to replace a nonfunctional gene. This approach is most common.
An abnormal gene could be swapped for a normal gene through homologous recombination.
The abnormal gene could be repaired through selective reverse mutation, which returns the gene to its normal function.
The regulation (the degree to which a gene is turned on or off) of a particular gene could be altered.
How does gene therapy work?
In most gene therapy studies, a "normal" gene is inserted into the genome to replace an "abnormal," disease-causing gene. A carrier molecule called a vector must be used to deliver the therapeutic gene to the patient's target cells. Currently, the most common vector is a virus that has been genetically altered to carry normal human DNA. Viruses have evolved a way of encapsulating and delivering their genes to human cells in a pathogenic manner. Scientists have tried to take advantage of this capability and manipulate the virus genome to remove disease-causing genes and insert therapeutic genes.
Target cells such as the patient's liver or lung cells are infected with the viral vector. The vector then unloads its genetic material containing the therapeutic human gene into the target cell. The generation of a functional protein product from the therapeutic gene restores the target cell to a normal state.
Some of the different types of viruses used as gene therapy vectors:
Retroviruses - A class of viruses that can create double-stranded DNA copies of their RNA genomes. These copies of its genome can be integrated into the chromosomes of host cells. Human immunodeficiency virus (HIV) is a retrovirus.
Adenoviruses - A class of viruses with double-stranded DNA genomes that cause respiratory, intestinal, and eye infections in humans. The virus that causes the common cold is an adenovirus.
Adeno-associated viruses - A class of small, single-stranded DNA viruses that can insert their genetic material at a specific site on chromosome 19.
Herpes simplex viruses
- A class of double-stranded DNA viruses that infect a particular cell type, neurons. Herpes simplex virus type 1 is a common human pathogen that causes cold sores.
Besides virus-mediated gene-delivery systems, there are several nonviral options for gene delivery. The simplest method is the direct introduction of therapeutic DNA into target cells. This approach is limited in its application because it can be used only with certain tissues and requires large amounts of DNA.
Another nonviral approach involves the creation of an artificial lipid sphere with an aqueous core. This liposome, which carries the therapeutic DNA, is capable of passing the DNA through the target cell's membrane.
Therapeutic DNA also can get inside target cells by chemically linking the DNA to a molecule that will bind to special cell receptors. Once bound to these receptors, the therapeutic DNA constructs are engulfed by the cell membrane and passed into the interior of the target cell. This delivery system tends to be less effective than other options.
Researchers also are experimenting with introducing a 47th (artificial human) chromosome into target cells. This chromosome would exist autonomously alongside the standard 46 --not affecting their workings or causing any mutations. It would be a large vector capable of carrying substantial amounts of genetic code, and scientists anticipate that, because of its construction and autonomy, the body's immune systems would not attack it. A problem with this potential method is the difficulty in delivering such a large molecule to the nucleus of a target cell.
What is the current status of gene therapy research?
The Food and Drug Administration (FDA) has not yet approved any human gene therapy product for sale. Current gene therapy is experimental and has not proven very successful in clinical trials. Little progress has been made since the first gene therapy clinical trial began in 1990. In 1999, gene therapy suffered a major setback with the death of 18-year-old Jesse Gelsinger. Jesse was participating in a gene therapy trial for ornithine transcarboxylase deficiency (OTCD). He died from multiple organ failures 4 days after starting the treatment. His death is believed to have been triggered by a severe immune response to the adenovirus carrier.
Another major blow came in January 2003, when the FDA placed a temporary halt on all gene therapy trials using retroviral vectors in blood stem cells. FDA took this action after it learned that a second child treated in a French gene therapy trial had developed a leukemia-like condition. Both this child and another who had developed a similar condition in August 2002 had been successfully treated by gene therapy for X-linked severe combined immunodeficiency disease (X-SCID), also known as "bubble baby syndrome."
FDA's Biological Response Modifiers Advisory Committee (BRMAC) met at the end of February 2003 to discuss possible measures that could allow a number of retroviral gene therapy trials for treatment of life-threatening diseases to proceed with appropriate safeguards. In April of 2003 the FDA eased the ban on gene therapy trials using retroviral vectors in blood stem cells.
Hybridoma Technology
Hybridoma Technology
A hybridoma is a hybrid cell produced by injecting a specific antigen into a mouse, collecting an antibody-producing cell from the mouse's spleen, and fusing it with a long-lived cancerous immune cell called a myeloma cell. Individual hybridoma cells are cloned and tested to find those that produce the desired antibody. Their many identical daughter clones will secrete, over a long period of time, millions of identical copies of made-to-order "monoclonal" antibodies.
Thanks to hybridoma technology, scientists are now able to make large quantities of specific antibodies.
A hybridoma is a hybrid cell produced by injecting a specific antigen into a mouse, collecting an antibody-producing cell from the mouse's spleen, and fusing it with a long-lived cancerous immune cell called a myeloma cell. Individual hybridoma cells are cloned and tested to find those that produce the desired antibody. Their many identical daughter clones will secrete, over a long period of time, millions of identical copies of made-to-order "monoclonal" antibodies.
Thanks to hybridoma technology, scientists are now able to make large quantities of specific antibodies.
Animal Biotechnology
Animal Biotechnology
Animal biotechnology is the application of scientific and engineering principles to the processing or production of materials by animals or aquatic species to provide goods and services (NRC 2003). Examples of animal biotechnology include generation of transgenic animals or transgenic fish (animals or fish with one or more genes introduced by human intervention), using gene knockout technology to generate animals in which a specific gene has been inactivated, production of nearly identical animals by somatic cell nuclear transfer (also referred to as clones), or production of infertile aquatic species.
Transgenics
Since the early 1980s, methods have been developed and refined to generate transgenic animals or transgenic aquatic species. For example, transgenic livestock and transgenic aquatic species have been generated with increased growth rates, enhanced lean muscle mass, enhanced resistance to disease or improved use of dietary phosphorous to lessen the environmental impacts of animal manure. Transgenic poultry, swine, goats, and cattle also have been produced that generate large quantities of human proteins in eggs, milk, blood, or urine, with the goal of using these products as human pharmaceuticals. Examples of human pharmaceutical proteins include enzymes, clotting factors, albumin, and antibodies. The major factor limiting widespread use of transgenic animals in agricultural production systems is the relatively inefficient rate (success rate less than 10 percent) of production of transgenic animals. CSREES has supported research projects to generate transgenic animals or transgenic aquatic species with enhanced production or health traits.
Gene Knockout Technology
Animal biotechnology also can knock out or inactivate a specific gene. Knockout technology creates a possible source of replacement organs for humans. The process of transplanting cells, tissues, or organs from one species to another is referred to as “xenotransplantation.” Currently, the pig is the major animal being considered as a xenotransplant donor to humans. Unfortunately, pig cells and human cells are not immunologically compatible. Pig cells express a carbohydrate epitope (alpha1, 3 galactose) on their surface that is not normally found on human cells. Humans will generate antibodies to this epitope, which will result in acute rejection of the xenograft. Genetic engineering is used to knock out or inactivate the pig gene (alpha1, 3 galactosyl transferase) that attaches this carbohydrate epitope on pig cells. Other examples of knockout technology in animals include inactivation of the prion-related peptide (PRP) gene that may generate animals resistant to diseases associated with prions (bovine spongiform encephalopathy [BSE], Creutzfeldt-Jakob Disease [CJD], scrapie, etc.). Most of the funding for these types of projects is conducted by private companies or in academic laboratories supported by the National Institutes of Health. Research projects designed to provide basic information regarding mechanisms associated with gene knockout technology are supported by CSREES.
Somatic Cell Nuclear Transfer
Another application of animal biotechnology is the use of somatic cell nuclear transfer to produce multiple copies of animals that are nearly identical copies of other animals (transgenic animals, genetically superior animals, or animals that produce high quantities of milk or have some other desirable trait, etc.). This process has been referred to as cloning. To date, somatic cell nuclear transfer has been used to clone cattle, sheep, pigs, goats, horses, mules, cats, rats, and mice. The technique involves culturing somatic cells from an appropriate tissue (fibroblasts) from the animal to be cloned. Nuclei from the cultured somatic cells are then microinjected into an enucleated oocyte obtained from another individual of the same or a closely related species. Through a process that is not yet understood, the nucleus from the somatic cell is reprogrammed to a pattern of gene expression suitable for directing normal development of the embryo. After further culture and development in vitro, the embryos are transferred to a recipient female and ultimately will result in the birth of live offspring. The success rate for propagating animals by nuclear transfer is often less than 10 percent and depends on many factors, including the species, source of the recipient ova, cell type of the donor nuclei, treatment of donor cells prior to nuclear transfer, the techniques employed for nuclear transfer, etc. CSREES has supported research projects to obtain a better understanding of the basic cellular mechanisms associated with nuclear reprogramming.
Production of Infertile Aquatic Species. In aquaculture production systems, some species are not indigenous to a given area and can pose an ecological risk to native species should the foreign species escape confinement and enter the natural ecosystem. Generation of large populations of sterile fish or mollusks is one potential solution to this problem. Techniques have been developed to alter the chromosome complement to render individual fish and mollusks infertile. For example, triploid individuals (with three, instead of two, sets of chromosomes) have been generated by using various procedures to interfere with the final step in meiosis (extrusion of the second polar body). Timed application of high or low temperatures, various chemicals, or high hydrostatic pressure to newly fertilized eggs has been effective in producing triploid individuals. At a later time, the first cell division of the zygote can be suppressed to produce a fertile tetraploid individual (four sets of chromosomes). Tetraploids can then be mated with normal diploids to produce large numbers of infertile triploids. Unfortunately, in a commercial production system, it is often difficult to obtain sterilization of 100 percent of the individuals; thus, alternative methods are needed to ensure reproductive confinement of transgenic fish. Another technique that is being developed for finfish is to farm monosex fish stocks. Monosex populations can be produced by gender reversal and progeny testing to identify XX males for producing all female stocks or YY males for producing all male stocks. CSREES has supported research projects to alter the chromosome content or produce monosex populations of genetically engineered fish or mollusks.
As with any new technology, animal biotechnology faces a variety of uncertainties, safety issues and potential risks. For example, concerns have been raised regarding: the use of unnecessary genes in constructs used to generate transgenic animals, the use of vectors with the potential to be transferred or to otherwise contribute sequences to other organisms, the potential effects of genetically modified animals on the environment, the effects of the biotechnology on the welfare of the animal, and potential human health and food safety concerns for meat or animal products derived from animal biotechnology. Before animal biotechnology will be used widely by animal agriculture production systems, additional research will be needed to determine if the benefits of animal biotechnology outweigh these potential risks. The USDA Biotechnology Risk Assessment Grants program supports environmental risk assessment research projects on genetically engineered animals. In addition, the NRI Animal Protection program supports research projects to determine the effects of genetic modification on the health and well-being of the animal.
Advances in animal biotechnology have been facilitated by recent progress in sequencing and analyzing animal genomes, identification of molecular markers (microsatellites, expressed sequence tags [ESTs], quantitative trait loci [QTLs], etc.) and a better understanding of the mechanisms that regulate gene expression.
Animal biotechnology is the application of scientific and engineering principles to the processing or production of materials by animals or aquatic species to provide goods and services (NRC 2003). Examples of animal biotechnology include generation of transgenic animals or transgenic fish (animals or fish with one or more genes introduced by human intervention), using gene knockout technology to generate animals in which a specific gene has been inactivated, production of nearly identical animals by somatic cell nuclear transfer (also referred to as clones), or production of infertile aquatic species.Transgenics
Since the early 1980s, methods have been developed and refined to generate transgenic animals or transgenic aquatic species. For example, transgenic livestock and transgenic aquatic species have been generated with increased growth rates, enhanced lean muscle mass, enhanced resistance to disease or improved use of dietary phosphorous to lessen the environmental impacts of animal manure. Transgenic poultry, swine, goats, and cattle also have been produced that generate large quantities of human proteins in eggs, milk, blood, or urine, with the goal of using these products as human pharmaceuticals. Examples of human pharmaceutical proteins include enzymes, clotting factors, albumin, and antibodies. The major factor limiting widespread use of transgenic animals in agricultural production systems is the relatively inefficient rate (success rate less than 10 percent) of production of transgenic animals. CSREES has supported research projects to generate transgenic animals or transgenic aquatic species with enhanced production or health traits.
Gene Knockout Technology
Animal biotechnology also can knock out or inactivate a specific gene. Knockout technology creates a possible source of replacement organs for humans. The process of transplanting cells, tissues, or organs from one species to another is referred to as “xenotransplantation.” Currently, the pig is the major animal being considered as a xenotransplant donor to humans. Unfortunately, pig cells and human cells are not immunologically compatible. Pig cells express a carbohydrate epitope (alpha1, 3 galactose) on their surface that is not normally found on human cells. Humans will generate antibodies to this epitope, which will result in acute rejection of the xenograft. Genetic engineering is used to knock out or inactivate the pig gene (alpha1, 3 galactosyl transferase) that attaches this carbohydrate epitope on pig cells. Other examples of knockout technology in animals include inactivation of the prion-related peptide (PRP) gene that may generate animals resistant to diseases associated with prions (bovine spongiform encephalopathy [BSE], Creutzfeldt-Jakob Disease [CJD], scrapie, etc.). Most of the funding for these types of projects is conducted by private companies or in academic laboratories supported by the National Institutes of Health. Research projects designed to provide basic information regarding mechanisms associated with gene knockout technology are supported by CSREES.
Somatic Cell Nuclear Transfer
Another application of animal biotechnology is the use of somatic cell nuclear transfer to produce multiple copies of animals that are nearly identical copies of other animals (transgenic animals, genetically superior animals, or animals that produce high quantities of milk or have some other desirable trait, etc.). This process has been referred to as cloning. To date, somatic cell nuclear transfer has been used to clone cattle, sheep, pigs, goats, horses, mules, cats, rats, and mice. The technique involves culturing somatic cells from an appropriate tissue (fibroblasts) from the animal to be cloned. Nuclei from the cultured somatic cells are then microinjected into an enucleated oocyte obtained from another individual of the same or a closely related species. Through a process that is not yet understood, the nucleus from the somatic cell is reprogrammed to a pattern of gene expression suitable for directing normal development of the embryo. After further culture and development in vitro, the embryos are transferred to a recipient female and ultimately will result in the birth of live offspring. The success rate for propagating animals by nuclear transfer is often less than 10 percent and depends on many factors, including the species, source of the recipient ova, cell type of the donor nuclei, treatment of donor cells prior to nuclear transfer, the techniques employed for nuclear transfer, etc. CSREES has supported research projects to obtain a better understanding of the basic cellular mechanisms associated with nuclear reprogramming.
Production of Infertile Aquatic Species. In aquaculture production systems, some species are not indigenous to a given area and can pose an ecological risk to native species should the foreign species escape confinement and enter the natural ecosystem. Generation of large populations of sterile fish or mollusks is one potential solution to this problem. Techniques have been developed to alter the chromosome complement to render individual fish and mollusks infertile. For example, triploid individuals (with three, instead of two, sets of chromosomes) have been generated by using various procedures to interfere with the final step in meiosis (extrusion of the second polar body). Timed application of high or low temperatures, various chemicals, or high hydrostatic pressure to newly fertilized eggs has been effective in producing triploid individuals. At a later time, the first cell division of the zygote can be suppressed to produce a fertile tetraploid individual (four sets of chromosomes). Tetraploids can then be mated with normal diploids to produce large numbers of infertile triploids. Unfortunately, in a commercial production system, it is often difficult to obtain sterilization of 100 percent of the individuals; thus, alternative methods are needed to ensure reproductive confinement of transgenic fish. Another technique that is being developed for finfish is to farm monosex fish stocks. Monosex populations can be produced by gender reversal and progeny testing to identify XX males for producing all female stocks or YY males for producing all male stocks. CSREES has supported research projects to alter the chromosome content or produce monosex populations of genetically engineered fish or mollusks.
As with any new technology, animal biotechnology faces a variety of uncertainties, safety issues and potential risks. For example, concerns have been raised regarding: the use of unnecessary genes in constructs used to generate transgenic animals, the use of vectors with the potential to be transferred or to otherwise contribute sequences to other organisms, the potential effects of genetically modified animals on the environment, the effects of the biotechnology on the welfare of the animal, and potential human health and food safety concerns for meat or animal products derived from animal biotechnology. Before animal biotechnology will be used widely by animal agriculture production systems, additional research will be needed to determine if the benefits of animal biotechnology outweigh these potential risks. The USDA Biotechnology Risk Assessment Grants program supports environmental risk assessment research projects on genetically engineered animals. In addition, the NRI Animal Protection program supports research projects to determine the effects of genetic modification on the health and well-being of the animal.
Advances in animal biotechnology have been facilitated by recent progress in sequencing and analyzing animal genomes, identification of molecular markers (microsatellites, expressed sequence tags [ESTs], quantitative trait loci [QTLs], etc.) and a better understanding of the mechanisms that regulate gene expression.
DNA, RNA and Protein Synthesis
DNA
DNA molecules are incredibly long, but also very thin. One DNA molecule from the chromosome of a mammal may be about 1 m long when unraveled. However, it has to fit in a nucleus of some 5-6 orders of magnitude smaller and is folded up in chromosomes in a highly organized manner. DNA is a linear polymer that is composed of four different building blocks, the nucleotides. It is in the sequence of the nucleotides in the polymers where the genetic information carried by chromosomes is located. Each nucleotide is composed of three parts: (1) a nitrogenous base known as purine (adenine (A) and guanine (G)) or pyrimidine (cytosine (C) and thymine (T)); (2) a sugar, deoxyribose; and (3) a phosphate group (see pp. 20-22 of Molecular Biotechnology for molecular structures of DNA and its components). The nitrogenous base determines the identity of the nucleotide, and individual nucleotides are often referred to by their base (A, C, G, or T). One DNA strand can be up to several hundred million nucleotides in length. T can form a hydrogen bond with A, and C with G; two DNA strands wind together in an antiparallel fashion in a double-helix.
Inside the cell, the DNA acts like an "instruction manual": in its sequence, it provides all the information needed to function, but the actual work of translating the information into a medium that can be used directly by the cell is done by RNA, ribonucleic acid. The structural difference with DNA is that RNA contains a -OH group both at the 2' and 3' position of the ribose ring, whereas DNA (which stands, in fact, for deoxy-RNA) lacks such a hydroxy group at the 2' position of the ribose. See http://www.ch.cam.ac.uk/magnus/molecules/nucleic/sugars.html. The same bases can be attached to the ribose group in RNA as occur in DNA, with the exception that in RNA thymine does not occur, and is replaced by uracil, which has an H-group instead of a methyl group at the C-5 position of the pyrimidine. The molecular structures of uracil and thymine are compared at http://www.ch.cam.ac.uk/magnus/molecules/nucleic/bases.html. The RNA has three functions: (a) it serves as the messenger that tells the cell (the ribosomes) what protein to make (messenger RNA; mRNA); (b) it serves as part of the structure of the ribosome, the protein/RNA complex that synthesizes proteins according to the information presented by the mRNA (ribosomal RNA; rRNA); and (c) it functions to bring amino acids (the constituents of the proteins) to the ribosome when a specific amino acid "is called for" by the information on the mRNA to be put in into the protein that is being synthesized; this RNA is called transfer RNA (tRNA).
An important point of emphasis should be that all vegetative cells of one organism contain the same genetic information. Upon division, each daughter cell obtains an "exact" copy of the DNA of the parent (see http://accessexcellence.org/AB/GG/dna_replicating.html). However, the specific genes that are expressed at specific times may be very different between different tissues. These differences in gene expression allow for the regulation of development of the organism, and for the development of different tissues. For the most part, DNA-binding proteins (encoded by the DNA) play an important role in the regulation of expression of genes encoded on the DNA. A very important "chicken-and-egg" problem.....
RNAs
The messenger RNA (mRNA) serves as an intermediate between DNA and protein. Parts of the DNA are "transcribed" into transcripts (single-stranded RNA molecules) that are processed to mRNA. In prokaryotes the transcript generally does not need to be processed, and can serve as mRNA right away. Transcription starts at a specific site on the DNA called a promoter. Each gene or operon has its own promoter(s). Transcription ends at a terminator sequence on the DNA. The transcripts usually are 300-50,000 nucleotides long, and contain the information to make protein. In eukaryotes (organisms with cells containing a nucleus; in fact, any higher organism) generally the transcripts needs to be processed before they can serve as a blueprint for a protein. The processing involves the removal of intervening sequences (introns) in the gene. The introns may be anywhere between 50 and 10,000 nucleotides in length.
The coding regions of the mRNA are called exons. There may be up to 100 introns in a single gene. The introns are spliced out by small ribonucleoprotein particles (consisting of RNA and protein), which appear to pull the two ends of the intron together. However, there are also introns that splice out without the need of a protein: the RNA sequence itself appears to contain sufficient information to know where to splice out the intron. In addition to the removal of introns, a poly-A sequence is added to the 3’ end of the transcript. The processed transcript is the mRNA, and the information in the mRNA can be used to be "translated" into a protein of specific sequence. However, in prokaryotes introns are rare and mRNA generally does not get processed before translation.
The intron splicing process provides an opportunity to increase the amount of usable genetic information without increasing the genome size of the organism: Alternative splicing of a particular transcript can occur. Alternative splicing means that introns may be recognized in different ways in different molecules of the same primary transcript, and the result is that one gene can give rise to different mRNAs and thereby to different proteins. Note that this process is largely limited to eukaryotes as introns in prokaryotes are rare.
Ribosomal RNAs (rRNAs) are essential components of an important part of the protein synthesis machinery: the ribosomes. In addition to rRNA, there are some 70 different proteins in a ribosome. There are hundreds of copies of rRNA genes per genome, thus making the production of lots of rRNA possible. There are four different rRNAs, each with a different size. Each ribosome contains one molecule of each of the four rRNA types. In prokaryotes, ribosomes bind to the mRNA close to the translation start site. This ribosome binding site is referred to as the Shine-Dalgarno sequence or as the ribosome recognition element. In eukaryotes, ribosomes bind at the 5' end of the mRNA and scan down the mRNA until they encounter a suitable start codon.
Transfer RNA (tRNA) carries amino acids to the ribosomes, to enable the ribosomes to put this amino acid on the protein that is being synthesized as an elongating chain of amino acid residues, using the information on the mRNA to "know" which amino acid should be put on next. For each kind of amino acid, there is a specific tRNA that will recognize the amino acid and transport it to the protein that is being synthesized, and tag it on to the protein once the information on the mRNA calls for it.
All tRNAs have the same general shape, sort of resembling a clover leaf. Parts of the molecule fold back in characteristic loops, which are held in shape by nucleotide-pairing between different areas of the molecule. There are two parts of the tRNA that are of particular importance: the aminoacyl attachment site and the anticodon. The aminoacyl attachment site is the site at which the amino acid is attached to the tRNA molecule. Each type of tRNA specifically binds only one type of amino acid. The anticodon (three bases) of the tRNA base-pairs with the appropriate mRNA codon at the mRNA-ribosome complex. This temporarily binds the tRNA to the mRNA, allowing the amino acid carried by the tRNA to be incorporated into the polypeptide in its proper place. Thus, the sequence of the codon (three bases) in the mRNA dictates the amino acid to be put in in the protein at a specific site. The "dictionary" of codons coding for amino acids is called the genetic code. A summary of the amino acids that the 64 possible codons encode can be found at http://molbio.info.nih.gov/molbio/desk.html (choose "Table of Standard Genetic Code" for a codon table, and "Amino Acid Structure and Properties" for information regarding the amino acids). The three codons for which there is no matching tRNA (UAA, UGA, and UAG) serve as "stop-translation" signals at which the ribosome falls off.
Protein synthesis
After having discussed DNA and the various RNAs, the stage has been set for protein synthesis. The basic reaction of protein synthesis is the controlled formation of a peptide bond between two amino acids. This reaction is repeated many times, as each amino acid in turn is added to the growing polypeptide. Protein synthesis starts when the mRNA binds to a small ribosomal subunit near a AUG sequence in the mRNA. The AUG codon is called start codon, since it codes for the first amino acid (a methionine) to be made of the protein. The AUG codon base-pairs with the anticodon of tRNA carrying methionine. A large ribosomal subunit binds to the complex, and the reactions of protein synthesis itself can begin. The aminoacyl-tRNA to be called for next is determined by the next codon (the next three bases) on the mRNA. Each amino acid is coded for by one or more (up to six) codons. Of course, it would be more straightforward to have each amino acid coded for by only one codon, but nature appears to have chosen a more complex route. The reason for this in part is that there are 20 different amino acids, and 4x4x4=64 different combinations possible in a codon. When the ribosome reaches one of the three codons for which there is no matching tRNA, the ribosome falls off and the synthesized protein is released. The degeneracy of the genetic code for certain amino acids could have a function in regulation of translation; any idea how? The process of protein synthesis has been summarized on pages 34-38 of Molecular Biotechnology, and can also be found on the web at http://accessexcellence.org/AB/GG/protein_synthesis.html translation (in conjunction with transcription) and http://accessexcellence.org/AB/GG/dna_molecule.html.
Amino acids represent quite a broad spectrum of different chemical structures. The web address http://www.ch.cam.ac.uk/magnus/molecules/amino/ provides the structure of all amino acids. With the generation of a protein with a specific amino acid sequence using essentially the genetic information present in the DNA, the link between genetic and functional information is complete.
DNA molecules are incredibly long, but also very thin. One DNA molecule from the chromosome of a mammal may be about 1 m long when unraveled. However, it has to fit in a nucleus of some 5-6 orders of magnitude smaller and is folded up in chromosomes in a highly organized manner. DNA is a linear polymer that is composed of four different building blocks, the nucleotides. It is in the sequence of the nucleotides in the polymers where the genetic information carried by chromosomes is located. Each nucleotide is composed of three parts: (1) a nitrogenous base known as purine (adenine (A) and guanine (G)) or pyrimidine (cytosine (C) and thymine (T)); (2) a sugar, deoxyribose; and (3) a phosphate group (see pp. 20-22 of Molecular Biotechnology for molecular structures of DNA and its components). The nitrogenous base determines the identity of the nucleotide, and individual nucleotides are often referred to by their base (A, C, G, or T). One DNA strand can be up to several hundred million nucleotides in length. T can form a hydrogen bond with A, and C with G; two DNA strands wind together in an antiparallel fashion in a double-helix.
Inside the cell, the DNA acts like an "instruction manual": in its sequence, it provides all the information needed to function, but the actual work of translating the information into a medium that can be used directly by the cell is done by RNA, ribonucleic acid. The structural difference with DNA is that RNA contains a -OH group both at the 2' and 3' position of the ribose ring, whereas DNA (which stands, in fact, for deoxy-RNA) lacks such a hydroxy group at the 2' position of the ribose. See http://www.ch.cam.ac.uk/magnus/molecules/nucleic/sugars.html. The same bases can be attached to the ribose group in RNA as occur in DNA, with the exception that in RNA thymine does not occur, and is replaced by uracil, which has an H-group instead of a methyl group at the C-5 position of the pyrimidine. The molecular structures of uracil and thymine are compared at http://www.ch.cam.ac.uk/magnus/molecules/nucleic/bases.html. The RNA has three functions: (a) it serves as the messenger that tells the cell (the ribosomes) what protein to make (messenger RNA; mRNA); (b) it serves as part of the structure of the ribosome, the protein/RNA complex that synthesizes proteins according to the information presented by the mRNA (ribosomal RNA; rRNA); and (c) it functions to bring amino acids (the constituents of the proteins) to the ribosome when a specific amino acid "is called for" by the information on the mRNA to be put in into the protein that is being synthesized; this RNA is called transfer RNA (tRNA).
An important point of emphasis should be that all vegetative cells of one organism contain the same genetic information. Upon division, each daughter cell obtains an "exact" copy of the DNA of the parent (see http://accessexcellence.org/AB/GG/dna_replicating.html). However, the specific genes that are expressed at specific times may be very different between different tissues. These differences in gene expression allow for the regulation of development of the organism, and for the development of different tissues. For the most part, DNA-binding proteins (encoded by the DNA) play an important role in the regulation of expression of genes encoded on the DNA. A very important "chicken-and-egg" problem.....
RNAs
The messenger RNA (mRNA) serves as an intermediate between DNA and protein. Parts of the DNA are "transcribed" into transcripts (single-stranded RNA molecules) that are processed to mRNA. In prokaryotes the transcript generally does not need to be processed, and can serve as mRNA right away. Transcription starts at a specific site on the DNA called a promoter. Each gene or operon has its own promoter(s). Transcription ends at a terminator sequence on the DNA. The transcripts usually are 300-50,000 nucleotides long, and contain the information to make protein. In eukaryotes (organisms with cells containing a nucleus; in fact, any higher organism) generally the transcripts needs to be processed before they can serve as a blueprint for a protein. The processing involves the removal of intervening sequences (introns) in the gene. The introns may be anywhere between 50 and 10,000 nucleotides in length.The coding regions of the mRNA are called exons. There may be up to 100 introns in a single gene. The introns are spliced out by small ribonucleoprotein particles (consisting of RNA and protein), which appear to pull the two ends of the intron together. However, there are also introns that splice out without the need of a protein: the RNA sequence itself appears to contain sufficient information to know where to splice out the intron. In addition to the removal of introns, a poly-A sequence is added to the 3’ end of the transcript. The processed transcript is the mRNA, and the information in the mRNA can be used to be "translated" into a protein of specific sequence. However, in prokaryotes introns are rare and mRNA generally does not get processed before translation.
The intron splicing process provides an opportunity to increase the amount of usable genetic information without increasing the genome size of the organism: Alternative splicing of a particular transcript can occur. Alternative splicing means that introns may be recognized in different ways in different molecules of the same primary transcript, and the result is that one gene can give rise to different mRNAs and thereby to different proteins. Note that this process is largely limited to eukaryotes as introns in prokaryotes are rare.
Ribosomal RNAs (rRNAs) are essential components of an important part of the protein synthesis machinery: the ribosomes. In addition to rRNA, there are some 70 different proteins in a ribosome. There are hundreds of copies of rRNA genes per genome, thus making the production of lots of rRNA possible. There are four different rRNAs, each with a different size. Each ribosome contains one molecule of each of the four rRNA types. In prokaryotes, ribosomes bind to the mRNA close to the translation start site. This ribosome binding site is referred to as the Shine-Dalgarno sequence or as the ribosome recognition element. In eukaryotes, ribosomes bind at the 5' end of the mRNA and scan down the mRNA until they encounter a suitable start codon.
Transfer RNA (tRNA) carries amino acids to the ribosomes, to enable the ribosomes to put this amino acid on the protein that is being synthesized as an elongating chain of amino acid residues, using the information on the mRNA to "know" which amino acid should be put on next. For each kind of amino acid, there is a specific tRNA that will recognize the amino acid and transport it to the protein that is being synthesized, and tag it on to the protein once the information on the mRNA calls for it.
All tRNAs have the same general shape, sort of resembling a clover leaf. Parts of the molecule fold back in characteristic loops, which are held in shape by nucleotide-pairing between different areas of the molecule. There are two parts of the tRNA that are of particular importance: the aminoacyl attachment site and the anticodon. The aminoacyl attachment site is the site at which the amino acid is attached to the tRNA molecule. Each type of tRNA specifically binds only one type of amino acid. The anticodon (three bases) of the tRNA base-pairs with the appropriate mRNA codon at the mRNA-ribosome complex. This temporarily binds the tRNA to the mRNA, allowing the amino acid carried by the tRNA to be incorporated into the polypeptide in its proper place. Thus, the sequence of the codon (three bases) in the mRNA dictates the amino acid to be put in in the protein at a specific site. The "dictionary" of codons coding for amino acids is called the genetic code. A summary of the amino acids that the 64 possible codons encode can be found at http://molbio.info.nih.gov/molbio/desk.html (choose "Table of Standard Genetic Code" for a codon table, and "Amino Acid Structure and Properties" for information regarding the amino acids). The three codons for which there is no matching tRNA (UAA, UGA, and UAG) serve as "stop-translation" signals at which the ribosome falls off.
Protein synthesis
After having discussed DNA and the various RNAs, the stage has been set for protein synthesis. The basic reaction of protein synthesis is the controlled formation of a peptide bond between two amino acids. This reaction is repeated many times, as each amino acid in turn is added to the growing polypeptide. Protein synthesis starts when the mRNA binds to a small ribosomal subunit near a AUG sequence in the mRNA. The AUG codon is called start codon, since it codes for the first amino acid (a methionine) to be made of the protein. The AUG codon base-pairs with the anticodon of tRNA carrying methionine. A large ribosomal subunit binds to the complex, and the reactions of protein synthesis itself can begin. The aminoacyl-tRNA to be called for next is determined by the next codon (the next three bases) on the mRNA. Each amino acid is coded for by one or more (up to six) codons. Of course, it would be more straightforward to have each amino acid coded for by only one codon, but nature appears to have chosen a more complex route. The reason for this in part is that there are 20 different amino acids, and 4x4x4=64 different combinations possible in a codon. When the ribosome reaches one of the three codons for which there is no matching tRNA, the ribosome falls off and the synthesized protein is released. The degeneracy of the genetic code for certain amino acids could have a function in regulation of translation; any idea how? The process of protein synthesis has been summarized on pages 34-38 of Molecular Biotechnology, and can also be found on the web at http://accessexcellence.org/AB/GG/protein_synthesis.html translation (in conjunction with transcription) and http://accessexcellence.org/AB/GG/dna_molecule.html.
Amino acids represent quite a broad spectrum of different chemical structures. The web address http://www.ch.cam.ac.uk/magnus/molecules/amino/ provides the structure of all amino acids. With the generation of a protein with a specific amino acid sequence using essentially the genetic information present in the DNA, the link between genetic and functional information is complete.
Traditional Biotechnology Vs New Biotechnology
Traditional Biotechnology
Traditional biotechnology refers to a number of ancient ways of using living organisms to make new products or modify existing ones. In its broadest definition, traditional biotechnology can be traced back to human's transition from hunter-gatherer to farmer. As farmers, humans collected wild plants and cultivated them and the best yielding strains were selected for growing the following seasons.
As humans discovered more plant varieties and traits or characteristics, they gradually became adept at breeding specific plant varieties over several years and sometimes generations, to obtain desired traits such as disease resistance, better taste and higher yield. With the domestication of animals, ancient farmers applied the same breeding techniques to obtain desired traits among animals over generations.
Centuries ago, people accidentally discovered how to make use of natural processes that occur all the time within living cells. Although they had no scientific explanation for the processes, they applied the results they saw to their domestic lives. They discovered, for example, that food matures in a way that changes its taste and content, and makes it less perishable. Hence, through a process later called fermentation, flour dough becomes leavened in the making of bread, grape juice becomes wine, and milk stored in bags made from camels' stomachs turns into cheese.
Through trial and error and later through advances in technology, people learned to control these processes and make large quantities of biotechnology products. Advances in science enabled the transfer of these mostly domestic techniques into industrial applications and the discovery of new techniques. Examples of traditional biotechnology techniques include selective breeding, hybridization and fermentation.
Modern Biotechnology
Modern biotechnology refers to a number of techniques that involve the intentional manipulation of genes, cells and living tissue in a predictable and controlled manner to generate changes in the genetic make-up of an organism or produce new tissue. Examples of these techniques include: recombinant DNA techniques (rDNA or genetic engineering), tissue culture and mutagenesis.
Modern biotechnology began with the 1953 discovery of the structure of deoxyribonucleic acid (DNA) and the way genetic information is passed from generation to generation. This discovery was made possible by the earlier discovery of genes (discrete, independent units that transmit traits from parents to offspring) by Gregor Mendel. These discoveries laid the groundwork for the transition from traditional to modern biotechnology. They made it possible to produce desired changes in an organism through the direct manipulation of its genes in a controlled and less time-consuming fashion in comparison to traditional biotechnology techniques. These discoveries, coupled with advances in technology and science (such as biochemistry and physiology), opened up the possibilities for new applications of biotechnology which were unknown with traditional forms.
Traditional biotechnology refers to a number of ancient ways of using living organisms to make new products or modify existing ones. In its broadest definition, traditional biotechnology can be traced back to human's transition from hunter-gatherer to farmer. As farmers, humans collected wild plants and cultivated them and the best yielding strains were selected for growing the following seasons.
As humans discovered more plant varieties and traits or characteristics, they gradually became adept at breeding specific plant varieties over several years and sometimes generations, to obtain desired traits such as disease resistance, better taste and higher yield. With the domestication of animals, ancient farmers applied the same breeding techniques to obtain desired traits among animals over generations.
Centuries ago, people accidentally discovered how to make use of natural processes that occur all the time within living cells. Although they had no scientific explanation for the processes, they applied the results they saw to their domestic lives. They discovered, for example, that food matures in a way that changes its taste and content, and makes it less perishable. Hence, through a process later called fermentation, flour dough becomes leavened in the making of bread, grape juice becomes wine, and milk stored in bags made from camels' stomachs turns into cheese.
Through trial and error and later through advances in technology, people learned to control these processes and make large quantities of biotechnology products. Advances in science enabled the transfer of these mostly domestic techniques into industrial applications and the discovery of new techniques. Examples of traditional biotechnology techniques include selective breeding, hybridization and fermentation.
Modern Biotechnology
Modern biotechnology refers to a number of techniques that involve the intentional manipulation of genes, cells and living tissue in a predictable and controlled manner to generate changes in the genetic make-up of an organism or produce new tissue. Examples of these techniques include: recombinant DNA techniques (rDNA or genetic engineering), tissue culture and mutagenesis.Modern biotechnology began with the 1953 discovery of the structure of deoxyribonucleic acid (DNA) and the way genetic information is passed from generation to generation. This discovery was made possible by the earlier discovery of genes (discrete, independent units that transmit traits from parents to offspring) by Gregor Mendel. These discoveries laid the groundwork for the transition from traditional to modern biotechnology. They made it possible to produce desired changes in an organism through the direct manipulation of its genes in a controlled and less time-consuming fashion in comparison to traditional biotechnology techniques. These discoveries, coupled with advances in technology and science (such as biochemistry and physiology), opened up the possibilities for new applications of biotechnology which were unknown with traditional forms.
Saturday, June 14, 2008
Applications of biotechnology
Applications
Biotechnology has applications in four major industrial areas, including health care (medical), crop production and agriculture, non food (industrial) uses of crops and other products (e.g. biodegradable plastics, vegetable oil, biofuels), and environmental uses.
For example, one application of biotechnology is the directed use of organisms for the manufacture of organic products (examples include beer and milk products). Another example is using naturally present bacteria by the mining industry in bioleaching. Biotechnology is also used to recycle, treat waste, clean up sites contaminated by industrial activities (bioremediation), and also to produce biological weapons.
A series of derived terms have been coined to identify several branches of biotechnology, for example:
Red biotechnology is applied to medical processes. Some examples are the designing of organisms to produce antibiotics, and the engineering of genetic cures through genomic manipulation.
A rose plant that began as cells grown in a tissue culture
Green biotechnology is biotechnology applied to agricultural processes. An example would be the selection and domestication of plants via micropropagation. Another example is the designing of transgenic plants to grow under specific environmental conditions or in the presence (or absence) of certain agricultural chemicals. One hope is that green biotechnology might produce more environmentally friendly solutions than traditional industrial agriculture. An example of this is the engineering of a plant to express a pesticide, thereby eliminating the need for external application of pesticides. An example of this would be Bt corn. Whether or not green biotechnology products such as this are ultimately more environmentally friendly is a topic of considerable debate.
White biotechnology, also known as industrial biotechnology, is biotechnology applied to industrial processes. An example is the designing of an organism to produce a useful chemical. Another example is the using of enzymes as industrial catalysts to either produce valuable chemicals or destroy hazardous/polluting chemicals. White biotechnology tends to consume less in resources than traditional processes used to produce industrial goods.
Blue biotechnology is a term that has been used to describe the marine and aquatic applications of biotechnology, but its use is relatively rare.
The investments and economic output of all of these types of applied biotechnologies form what has been described as the bioeconomy.
Bioinformatics is an interdisciplinary field which addresses biological problems using computational techniques, and makes the rapid organization and analysis of biological data possible. The field may also be referred to as computational biology, and can be defined as, "conceptualizing biology in terms of molecules and then applying informatics techniques to understand and organize the information associated with these molecules, on a large scale." Bioinformatics plays a key role in various areas, such as functional genomics, structural genomics, and proteomics, and forms a key component in the biotechnology and pharmaceutical sector.
Medicine
In medicine, modern biotechnology finds promising applications in such areas as
pharmacogenomics;
drug production;
genetic testing; and
gene therapy.
Pharmacogenomics
DNA Microarray chip -- Some can do as many as a million blood tests at once
Main article: Pharmacogenomics
Pharmacogenomics is the study of how the genetic inheritance of an individual affects his/her body’s response to drugs. It is a coined word derived from the words “pharmacology” and “genomics”. It is hence the study of the relationship between pharmaceuticals and genetics. The vision of pharmacogenomics is to be able to design and produce drugs that are adapted to each person’s genetic makeup.
Pharmacogenomics results in the following benefits:
1. Development of tailor-made medicines. Using pharmacogenomics, pharmaceutical companies can create drugs based on the proteins, enzymes and RNA molecules that are associated with specific genes and diseases. These tailor-made drugs promise not only to maximize therapeutic effects but also to decrease damage to nearby healthy cells.
2. More accurate methods of determining appropriate drug dosages. Knowing a patient’s genetics will enable doctors to determine how well his/ her body can process and metabolize a medicine. This will maximize the value of the medicine and decrease the likelihood of overdose.
3. Improvements in the drug discovery and approval process. The discovery of potential therapies will be made easier using genome targets. Genes have been associated with numerous diseases and disorders. With modern biotechnology, these genes can be used as targets for the development of effective new therapies, which could significantly shorten the drug discovery process.
4. Better vaccines. Safer vaccines can be designed and produced by organisms transformed by means of genetic engineering. These vaccines will elicit the immune response without the attendant risks of infection. They will be inexpensive, stable, easy to store, and capable of being engineered to carry several strains of pathogen at once.
Pharmaceutical products
Computer-generated image of insulin hexamers highlighting the threefold symmetry, the zinc ions holding it together, and the histidine residues involved in zinc binding.
Most traditional pharmaceutical drugs are relatively simple molecules that have been found primarily through trial and error to treat the symptoms of a disease or illness. Biopharmaceuticals are large biological molecules known as proteins and these usually target the underlying mechanisms and pathways of a malady (but not always, as is the case with using insulin to treat type 1 diabetes mellitus, as that treatment merely addresses the symptoms of the disease, not the underlying cause which is autoimmunity); it is a relatively young industry. They can deal with targets in humans that may not be accessible with traditional medicines. A patient typically is dosed with a small molecule via a tablet while a large molecule is typically injected.
Small molecules are manufactured by chemistry but larger molecules are created by living cells such as those found in the human body: for example, bacteria cells, yeast cells, animal or plant cells.
Modern biotechnology is often associated with the use of genetically altered microorganisms such as E. coli or yeast for the production of substances like synthetic insulin or antibiotics. It can also refer to transgenic animals or transgenic plants, such as Bt corn. Genetically altered mammalian cells, such as Chinese Hamster Ovary (CHO) cells, are also used to manufacture certain pharmaceuticals. Another promising new biotechnology application is the development of plant-made pharmaceuticals.
Biotechnology is also commonly associated with landmark breakthroughs in new medical therapies to treat hepatitis B, hepatitis C, cancers, arthritis, haemophilia, bone fractures, multiple sclerosis, and cardiovascular disorders. The biotechnology industry has also been instrumental in developing molecular diagnostic devices than can be used to define the target patient population for a given biopharmaceutical. Herceptin, for example, was the first drug approved for use with a matching diagnostic test and is used to treat breast cancer in women whose cancer cells express the protein HER2.
Modern biotechnology can be used to manufacture existing medicines relatively easily and cheaply. The first genetically engineered products were medicines designed to treat human diseases. To cite one example, in 1978 Genentech developed synthetic humanized insulin by joining its gene with a plasmid vector inserted into the bacterium Escherichia coli. Insulin, widely used for the treatment of diabetes, was previously extracted from the pancreas of abattoir animals (cattle and/or pigs). The resulting genetically engineered bacterium enabled the production of vast quantities of synthetic human insulin at relatively low cost, although the cost savings was used to increase profits for manufacturers, not passed on to consumers or their healthcare providers. According to a 2003 study undertaken by the International Diabetes Federation (IDF) on the access to and availability of insulin in its member countries, synthetic 'human' insulin is considerably more expensive in most countries where both synthetic 'human' and animal insulin are commercially available: e.g. within European countries the average price of synthetic 'human' insulin was twice as high as the price of pork insulin. Yet in its position statement, the IDF writes that "there is no overwhelming evidence to prefer one species of insulin over another" and "[modern, highly-purified] animal insulins remain a perfectly acceptable alternative.
Modern biotechnology has evolved, making it possible to produce more easily and relatively cheaply human growth hormone, clotting factors for hemophiliacs, fertility drugs, erythropoietin and other drugs.[12] Most drugs today are based on about 500 molecular targets. Genomic knowledge of the genes involved in diseases, disease pathways, and drug-response sites are expected to lead to the discovery of thousands more new targets
Genetic testing
Gel electrophoresis
Genetic testing involves the direct examination of the DNA molecule itself. A scientist scans a patient’s DNA sample for mutated sequences.
There are two major types of gene tests. In the first type, a researcher may design short pieces of DNA (“probes”) whose sequences are complementary to the mutated sequences. These probes will seek their complement among the base pairs of an individual’s genome. If the mutated sequence is present in the patient’s genome, the probe will bind to it and flag the mutation. In the second type, a researcher may conduct the gene test by comparing the sequence of DNA bases in a patient’s gene to disease in healthy individuals or their progeny.
Genetic testing is now used for:
Determining sex
Carrier screening, or the identification of unaffected individuals who carry one copy of a gene for a disease that requires two copies for the disease to manifest
Prenatal diagnostic screening
Newborn screening
Presymptomatic testing for predicting adult-onset disorders
Presymptomatic testing for estimating the risk of developing adult-onset cancers
Confirmational diagnosis of symptomatic individuals
Forensic/identity testing
Some genetic tests are already available, although most of them are used in developed countries. The tests currently available can detect mutations associated with rare genetic disorders like cystic fibrosis, sickle cell anemia, and Huntington’s disease. Recently, tests have been developed to detect mutation for a handful of more complex conditions such as breast, ovarian, and colon cancers. However, gene tests may not detect every mutation associated with a particular condition because many are as yet undiscovered, and the ones they do detect may present different risks to different people and populations.
Controversial questions
The bacterium E. coli is routinely genetically engineered.
Several issues have been raised regarding the use of genetic testing:
1. Absence of cure. There is still a lack of effective treatment or preventive measures for many diseases and conditions now being diagnosed or predicted using gene tests. Thus, revealing information about risk of a future disease that has no existing cure presents an ethical dilemma for medical practitioners.
2. Ownership and control of genetic information. Who will own and control genetic information, or information about genes, gene products, or inherited characteristics derived from an individual or a group of people like indigenous communities? At the macro level, there is a possibility of a genetic divide, with developing countries that do not have access to medical applications of biotechnology being deprived of benefits accruing from products derived from genes obtained from their own people. Moreover, genetic information can pose a risk for minority population groups as it can lead to group stigmatization.
At the individual level, the absence of privacy and anti-discrimination legal protections in most countries can lead to discrimination in employment or insurance or other misuse of personal genetic information. This raises questions such as whether genetic privacy is different from medical privacy.
3. Reproductive issues. These include the use of genetic information in reproductive decision-making and the possibility of genetically altering reproductive cells that may be passed on to future generations. For example, germline therapy forever changes the genetic make-up of an individual’s descendants. Thus, any error in technology or judgment may have far-reaching consequences. Ethical issues like designer babies and human cloning have also given rise to controversies between and among scientists and bioethicists, especially in the light of past abuses with eugenics.
4. Clinical issues. These center on the capabilities and limitations of doctors and other health-service providers, people identified with genetic conditions, and the general public in dealing with genetic information.
5. Effects on social institutions. Genetic tests reveal information about individuals and their families. Thus, test results can affect the dynamics within social institutions, particularly the family.
6. Conceptual and philosophical implications regarding human responsibility, free will vis-à-vis genetic determinism, and the concepts of health and disease.
Gene therapy
Main article: Gene therapy
Gene therapy using an Adenovirus vector. A new gene is inserted into an adenovirus vector, which is used to introduce the modified DNA into a human cell. If the treatment is successful, the new gene will make a functional protein.
Gene therapy may be used for treating, or even curing, genetic and acquired diseases like cancer and AIDS by using normal genes to supplement or replace defective genes or to bolster a normal function such as immunity. It can be used to target somatic (i.e., body) or germ (i.e., egg and sperm) cells. In somatic gene therapy, the genome of the recipient is changed, but this change is not passed along to the next generation. In contrast, in germline gene therapy, the egg and sperm cells of the parents are changed for the purpose of passing on the changes to their offspring.
There are basically two ways of implementing a gene therapy treatment:
1. Ex vivo, which means “outside the body” – Cells from the patient’s blood or bone marrow are removed and grown in the laboratory. They are then exposed to a virus carrying the desired gene. The virus enters the cells, and the desired gene becomes part of the DNA of the cells. The cells are allowed to grow in the laboratory before being returned to the patient by injection into a vein.
2. In vivo, which means “inside the body” – No cells are removed from the patient’s body. Instead, vectors are used to deliver the desired gene to cells in the patient’s body.
Currently, the use of gene therapy is limited. Somatic gene therapy is primarily at the experimental stage. Germline therapy is the subject of much discussion but it is not being actively investigated in larger animals and human beings.
As of June 2001, more than 500 clinical gene-therapy trials involving about 3,500 patients have been identified worldwide. Around 78% of these are in the United States, with Europe having 18%. These trials focus on various types of cancer, although other multigenic diseases are being studied as well. Recently, two children born with severe combined immunodeficiency disorder (“SCID”) were reported to have been cured after being given genetically engineered cells.
Gene therapy faces many obstacles before it can become a practical approach for treating disease. At least four of these obstacles are as follows:
1. Gene delivery tools. Genes are inserted into the body using gene carriers called vectors. The most common vectors now are viruses, which have evolved a way of encapsulating and delivering their genes to human cells in a pathogenic manner. Scientists manipulate the genome of the virus by removing the disease-causing genes and inserting the therapeutic genes. However, while viruses are effective, they can introduce problems like toxicity, immune and inflammatory responses, and gene control and targeting issues.
2. Limited knowledge of the functions of genes. Scientists currently know the functions of only a few genes. Hence, gene therapy can address only some genes that cause a particular disease. Worse, it is not known exactly whether genes have more than one function, which creates uncertainty as to whether replacing such genes is indeed desirable.
3. Multigene disorders and effect of environment. Most genetic disorders involve more than one gene. Moreover, most diseases involve the interaction of several genes and the environment. For example, many people with cancer not only inherit the disease gene for the disorder, but may have also failed to inherit specific tumor suppressor genes. Diet, exercise, smoking and other environmental factors may have also contributed to their disease.
4. High costs. Since gene therapy is relatively new and at an experimental stage, it is an expensive treatment to undertake. This explains why current studies are focused on illnesses commonly found in developed countries, where more people can afford to pay for treatment. It may take decades before developing countries can take advantage of this technology.
Human Genome Project
DNA Replication image from the Human Genome Project (HGP)
The Human Genome Project is an initiative of the U.S. Department of Energy (“DOE”) that aims to generate a high-quality reference sequence for the entire human genome and identify all the human genes.
The DOE and its predecessor agencies were assigned by the U.S. Congress to develop new energy resources and technologies and to pursue a deeper understanding of potential health and environmental risks posed by their production and use. In 1986, the DOE announced its Human Genome Initiative. Shortly thereafter, the DOE and National Institutes of Health developed a plan for a joint Human Genome Project (“HGP”), which officially began in 1990.
The HGP was originally planned to last 15 years. However, rapid technological advances and worldwide participation accelerated the completion date to 2003 (making it a 13 year project). Already it has enabled gene hunters to pinpoint genes associated with more than 30 disorders
Biotechnology has applications in four major industrial areas, including health care (medical), crop production and agriculture, non food (industrial) uses of crops and other products (e.g. biodegradable plastics, vegetable oil, biofuels), and environmental uses.
For example, one application of biotechnology is the directed use of organisms for the manufacture of organic products (examples include beer and milk products). Another example is using naturally present bacteria by the mining industry in bioleaching. Biotechnology is also used to recycle, treat waste, clean up sites contaminated by industrial activities (bioremediation), and also to produce biological weapons.
A series of derived terms have been coined to identify several branches of biotechnology, for example:
Red biotechnology is applied to medical processes. Some examples are the designing of organisms to produce antibiotics, and the engineering of genetic cures through genomic manipulation.
A rose plant that began as cells grown in a tissue culture
Green biotechnology is biotechnology applied to agricultural processes. An example would be the selection and domestication of plants via micropropagation. Another example is the designing of transgenic plants to grow under specific environmental conditions or in the presence (or absence) of certain agricultural chemicals. One hope is that green biotechnology might produce more environmentally friendly solutions than traditional industrial agriculture. An example of this is the engineering of a plant to express a pesticide, thereby eliminating the need for external application of pesticides. An example of this would be Bt corn. Whether or not green biotechnology products such as this are ultimately more environmentally friendly is a topic of considerable debate.
White biotechnology, also known as industrial biotechnology, is biotechnology applied to industrial processes. An example is the designing of an organism to produce a useful chemical. Another example is the using of enzymes as industrial catalysts to either produce valuable chemicals or destroy hazardous/polluting chemicals. White biotechnology tends to consume less in resources than traditional processes used to produce industrial goods.
Blue biotechnology is a term that has been used to describe the marine and aquatic applications of biotechnology, but its use is relatively rare.
The investments and economic output of all of these types of applied biotechnologies form what has been described as the bioeconomy.
Bioinformatics is an interdisciplinary field which addresses biological problems using computational techniques, and makes the rapid organization and analysis of biological data possible. The field may also be referred to as computational biology, and can be defined as, "conceptualizing biology in terms of molecules and then applying informatics techniques to understand and organize the information associated with these molecules, on a large scale." Bioinformatics plays a key role in various areas, such as functional genomics, structural genomics, and proteomics, and forms a key component in the biotechnology and pharmaceutical sector.
Medicine
In medicine, modern biotechnology finds promising applications in such areas as
pharmacogenomics;
drug production;
genetic testing; and
gene therapy.
Pharmacogenomics
DNA Microarray chip -- Some can do as many as a million blood tests at once
Main article: Pharmacogenomics
Pharmacogenomics is the study of how the genetic inheritance of an individual affects his/her body’s response to drugs. It is a coined word derived from the words “pharmacology” and “genomics”. It is hence the study of the relationship between pharmaceuticals and genetics. The vision of pharmacogenomics is to be able to design and produce drugs that are adapted to each person’s genetic makeup.
Pharmacogenomics results in the following benefits:
1. Development of tailor-made medicines. Using pharmacogenomics, pharmaceutical companies can create drugs based on the proteins, enzymes and RNA molecules that are associated with specific genes and diseases. These tailor-made drugs promise not only to maximize therapeutic effects but also to decrease damage to nearby healthy cells.
2. More accurate methods of determining appropriate drug dosages. Knowing a patient’s genetics will enable doctors to determine how well his/ her body can process and metabolize a medicine. This will maximize the value of the medicine and decrease the likelihood of overdose.
3. Improvements in the drug discovery and approval process. The discovery of potential therapies will be made easier using genome targets. Genes have been associated with numerous diseases and disorders. With modern biotechnology, these genes can be used as targets for the development of effective new therapies, which could significantly shorten the drug discovery process.
4. Better vaccines. Safer vaccines can be designed and produced by organisms transformed by means of genetic engineering. These vaccines will elicit the immune response without the attendant risks of infection. They will be inexpensive, stable, easy to store, and capable of being engineered to carry several strains of pathogen at once.
Pharmaceutical products
Computer-generated image of insulin hexamers highlighting the threefold symmetry, the zinc ions holding it together, and the histidine residues involved in zinc binding.
Most traditional pharmaceutical drugs are relatively simple molecules that have been found primarily through trial and error to treat the symptoms of a disease or illness. Biopharmaceuticals are large biological molecules known as proteins and these usually target the underlying mechanisms and pathways of a malady (but not always, as is the case with using insulin to treat type 1 diabetes mellitus, as that treatment merely addresses the symptoms of the disease, not the underlying cause which is autoimmunity); it is a relatively young industry. They can deal with targets in humans that may not be accessible with traditional medicines. A patient typically is dosed with a small molecule via a tablet while a large molecule is typically injected.
Small molecules are manufactured by chemistry but larger molecules are created by living cells such as those found in the human body: for example, bacteria cells, yeast cells, animal or plant cells.
Modern biotechnology is often associated with the use of genetically altered microorganisms such as E. coli or yeast for the production of substances like synthetic insulin or antibiotics. It can also refer to transgenic animals or transgenic plants, such as Bt corn. Genetically altered mammalian cells, such as Chinese Hamster Ovary (CHO) cells, are also used to manufacture certain pharmaceuticals. Another promising new biotechnology application is the development of plant-made pharmaceuticals.
Biotechnology is also commonly associated with landmark breakthroughs in new medical therapies to treat hepatitis B, hepatitis C, cancers, arthritis, haemophilia, bone fractures, multiple sclerosis, and cardiovascular disorders. The biotechnology industry has also been instrumental in developing molecular diagnostic devices than can be used to define the target patient population for a given biopharmaceutical. Herceptin, for example, was the first drug approved for use with a matching diagnostic test and is used to treat breast cancer in women whose cancer cells express the protein HER2.
Modern biotechnology can be used to manufacture existing medicines relatively easily and cheaply. The first genetically engineered products were medicines designed to treat human diseases. To cite one example, in 1978 Genentech developed synthetic humanized insulin by joining its gene with a plasmid vector inserted into the bacterium Escherichia coli. Insulin, widely used for the treatment of diabetes, was previously extracted from the pancreas of abattoir animals (cattle and/or pigs). The resulting genetically engineered bacterium enabled the production of vast quantities of synthetic human insulin at relatively low cost, although the cost savings was used to increase profits for manufacturers, not passed on to consumers or their healthcare providers. According to a 2003 study undertaken by the International Diabetes Federation (IDF) on the access to and availability of insulin in its member countries, synthetic 'human' insulin is considerably more expensive in most countries where both synthetic 'human' and animal insulin are commercially available: e.g. within European countries the average price of synthetic 'human' insulin was twice as high as the price of pork insulin. Yet in its position statement, the IDF writes that "there is no overwhelming evidence to prefer one species of insulin over another" and "[modern, highly-purified] animal insulins remain a perfectly acceptable alternative.
Modern biotechnology has evolved, making it possible to produce more easily and relatively cheaply human growth hormone, clotting factors for hemophiliacs, fertility drugs, erythropoietin and other drugs.[12] Most drugs today are based on about 500 molecular targets. Genomic knowledge of the genes involved in diseases, disease pathways, and drug-response sites are expected to lead to the discovery of thousands more new targets
Genetic testing
Gel electrophoresis
Genetic testing involves the direct examination of the DNA molecule itself. A scientist scans a patient’s DNA sample for mutated sequences.
There are two major types of gene tests. In the first type, a researcher may design short pieces of DNA (“probes”) whose sequences are complementary to the mutated sequences. These probes will seek their complement among the base pairs of an individual’s genome. If the mutated sequence is present in the patient’s genome, the probe will bind to it and flag the mutation. In the second type, a researcher may conduct the gene test by comparing the sequence of DNA bases in a patient’s gene to disease in healthy individuals or their progeny.
Genetic testing is now used for:
Determining sex
Carrier screening, or the identification of unaffected individuals who carry one copy of a gene for a disease that requires two copies for the disease to manifest
Prenatal diagnostic screening
Newborn screening
Presymptomatic testing for predicting adult-onset disorders
Presymptomatic testing for estimating the risk of developing adult-onset cancers
Confirmational diagnosis of symptomatic individuals
Forensic/identity testing
Some genetic tests are already available, although most of them are used in developed countries. The tests currently available can detect mutations associated with rare genetic disorders like cystic fibrosis, sickle cell anemia, and Huntington’s disease. Recently, tests have been developed to detect mutation for a handful of more complex conditions such as breast, ovarian, and colon cancers. However, gene tests may not detect every mutation associated with a particular condition because many are as yet undiscovered, and the ones they do detect may present different risks to different people and populations.
Controversial questions
The bacterium E. coli is routinely genetically engineered.
Several issues have been raised regarding the use of genetic testing:
1. Absence of cure. There is still a lack of effective treatment or preventive measures for many diseases and conditions now being diagnosed or predicted using gene tests. Thus, revealing information about risk of a future disease that has no existing cure presents an ethical dilemma for medical practitioners.
2. Ownership and control of genetic information. Who will own and control genetic information, or information about genes, gene products, or inherited characteristics derived from an individual or a group of people like indigenous communities? At the macro level, there is a possibility of a genetic divide, with developing countries that do not have access to medical applications of biotechnology being deprived of benefits accruing from products derived from genes obtained from their own people. Moreover, genetic information can pose a risk for minority population groups as it can lead to group stigmatization.
At the individual level, the absence of privacy and anti-discrimination legal protections in most countries can lead to discrimination in employment or insurance or other misuse of personal genetic information. This raises questions such as whether genetic privacy is different from medical privacy.
3. Reproductive issues. These include the use of genetic information in reproductive decision-making and the possibility of genetically altering reproductive cells that may be passed on to future generations. For example, germline therapy forever changes the genetic make-up of an individual’s descendants. Thus, any error in technology or judgment may have far-reaching consequences. Ethical issues like designer babies and human cloning have also given rise to controversies between and among scientists and bioethicists, especially in the light of past abuses with eugenics.
4. Clinical issues. These center on the capabilities and limitations of doctors and other health-service providers, people identified with genetic conditions, and the general public in dealing with genetic information.
5. Effects on social institutions. Genetic tests reveal information about individuals and their families. Thus, test results can affect the dynamics within social institutions, particularly the family.
6. Conceptual and philosophical implications regarding human responsibility, free will vis-à-vis genetic determinism, and the concepts of health and disease.
Gene therapy
Main article: Gene therapy
Gene therapy using an Adenovirus vector. A new gene is inserted into an adenovirus vector, which is used to introduce the modified DNA into a human cell. If the treatment is successful, the new gene will make a functional protein.
Gene therapy may be used for treating, or even curing, genetic and acquired diseases like cancer and AIDS by using normal genes to supplement or replace defective genes or to bolster a normal function such as immunity. It can be used to target somatic (i.e., body) or germ (i.e., egg and sperm) cells. In somatic gene therapy, the genome of the recipient is changed, but this change is not passed along to the next generation. In contrast, in germline gene therapy, the egg and sperm cells of the parents are changed for the purpose of passing on the changes to their offspring.
There are basically two ways of implementing a gene therapy treatment:
1. Ex vivo, which means “outside the body” – Cells from the patient’s blood or bone marrow are removed and grown in the laboratory. They are then exposed to a virus carrying the desired gene. The virus enters the cells, and the desired gene becomes part of the DNA of the cells. The cells are allowed to grow in the laboratory before being returned to the patient by injection into a vein.
2. In vivo, which means “inside the body” – No cells are removed from the patient’s body. Instead, vectors are used to deliver the desired gene to cells in the patient’s body.
Currently, the use of gene therapy is limited. Somatic gene therapy is primarily at the experimental stage. Germline therapy is the subject of much discussion but it is not being actively investigated in larger animals and human beings.
As of June 2001, more than 500 clinical gene-therapy trials involving about 3,500 patients have been identified worldwide. Around 78% of these are in the United States, with Europe having 18%. These trials focus on various types of cancer, although other multigenic diseases are being studied as well. Recently, two children born with severe combined immunodeficiency disorder (“SCID”) were reported to have been cured after being given genetically engineered cells.
Gene therapy faces many obstacles before it can become a practical approach for treating disease. At least four of these obstacles are as follows:
1. Gene delivery tools. Genes are inserted into the body using gene carriers called vectors. The most common vectors now are viruses, which have evolved a way of encapsulating and delivering their genes to human cells in a pathogenic manner. Scientists manipulate the genome of the virus by removing the disease-causing genes and inserting the therapeutic genes. However, while viruses are effective, they can introduce problems like toxicity, immune and inflammatory responses, and gene control and targeting issues.
2. Limited knowledge of the functions of genes. Scientists currently know the functions of only a few genes. Hence, gene therapy can address only some genes that cause a particular disease. Worse, it is not known exactly whether genes have more than one function, which creates uncertainty as to whether replacing such genes is indeed desirable.
3. Multigene disorders and effect of environment. Most genetic disorders involve more than one gene. Moreover, most diseases involve the interaction of several genes and the environment. For example, many people with cancer not only inherit the disease gene for the disorder, but may have also failed to inherit specific tumor suppressor genes. Diet, exercise, smoking and other environmental factors may have also contributed to their disease.
4. High costs. Since gene therapy is relatively new and at an experimental stage, it is an expensive treatment to undertake. This explains why current studies are focused on illnesses commonly found in developed countries, where more people can afford to pay for treatment. It may take decades before developing countries can take advantage of this technology.
Human Genome Project
DNA Replication image from the Human Genome Project (HGP)
The Human Genome Project is an initiative of the U.S. Department of Energy (“DOE”) that aims to generate a high-quality reference sequence for the entire human genome and identify all the human genes.
The DOE and its predecessor agencies were assigned by the U.S. Congress to develop new energy resources and technologies and to pursue a deeper understanding of potential health and environmental risks posed by their production and use. In 1986, the DOE announced its Human Genome Initiative. Shortly thereafter, the DOE and National Institutes of Health developed a plan for a joint Human Genome Project (“HGP”), which officially began in 1990.
The HGP was originally planned to last 15 years. However, rapid technological advances and worldwide participation accelerated the completion date to 2003 (making it a 13 year project). Already it has enabled gene hunters to pinpoint genes associated with more than 30 disorders
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