This paper served as the basis for a series of seminars on "Biotechnology, Religion and the Body" given by William Leiss at the Pacific Centre for Technology and Culture. Video archives of these seminars are available online at: http://www.pactac.net/pactacweb/web-content/video15leiss.html
Newspapers around the world picked up a story that came out of a session of the annual meeting of the American Association for the Advancement of Science, held in Seattle in February of 2004. The story reported on the results of a scientific study in which a virus carrying the gene for a growth hormone called IGF-1 was injected into the hind-leg muscles of rats. The rats were then put through an aggressive physical-training program, whereupon the targeted muscles grew between 15-30% in both size and strength, in comparison with a control group of untreated animals. The higher levels of IGF-1 occurred in the muscle tissue, but not in the bloodstream. There is the hope that someday a gene therapy program might be developed for humans suffering from muscle-wasting diseases such as muscular dystrophy.
So why the heavy media coverage of a rat study? The answer is contained in a remark made at the time by Lee Sweeney, the study's lead researcher: "Half of the e-mails I get are from patients, and the other half are from athletes." The prospect of gaining a quick advantage over others in competitive sports using gene therapy is irresistible to some -- especially because current anti-doping tests on athletes could not detect this kind of modification. The fact that this particular therapy has undergone no human safety testing is apparently a trivial point: The dark stories about health damage in later life to the athletes of the former East German communist regime, who were treated by their own government as experimental laboratory animals, appear to hold no terrors for them. The great irony is, of course, that every incremental step in the technological enhancement of performance acts as a spur for the next one. The cycle recurs with increasing rapidity as the rate of innovation grows, as the benefits of newer techniques leapfrog those of their predecessors.
Before too long a great flood of experimental gene therapies will be pouring out of the world's research laboratories. In the not-too-distant future the results of athletic competitions may reflect nothing so much as the differential risk tolerance among individuals for trying out the latest innovations in mixing various therapies. The trophies will recognize those with the courage to live life in the fast lane -- for that day. What comes after is anybody's guess.
Almost two centuries ago a young woman engaged in a parlour game with her traveling companions, including two rather famous English gentlemen by the names of Byron and Shelley. She bore the name of her mother, the famous feminist Mary Wollstonecraft, who died shortly after giving birth to her; but the world knows her by her married name: Mary Shelley. The game -- played while the three of them were vacationing in Switzerland -- was to write a gothic novel, and of the three she was the only one to carry it out. The result was Frankenstein, first published anonymously in 1818; she was all of nineteen years old when she wrote it.
Most people know her achievement only through the equally famous movie, starring Boris Karloff. This is a shame, because although it is a remarkable work of art in its own right, James Whale's 1931 film does not do justice to Mary Shelley's genius. Even her subtitle is important: Frankenstein; or, the Modern Prometheus. Prometheus, in Greek mythology, was the god who stole fire from Heaven and gave it to mankind, and who was punished by Zeus by being chained to a rock, where an eagle fed on his liver, which regenerated daily so that his torment was endless. Even her novel's epigraph -- three lines on the title page from Milton's Paradise Lost, where Adam is addressing God -- is important: Did I request thee, Maker, from my clay / To mould me Man, did I solicit thee / From darkness to promote me?
Mary Shelley's extraordinary far-seeing genius is summed up in the fact that her novel is more "relevant" today than it was when she wrote it. Her main theme is about the responsibility of scientists for their creations. Her narrative tells how Dr. Victor Frankenstein abandoned his creation -- the world's first recombinant entity -- at the moment of his becoming alive. The scientist fled in horror from his laboratory, forcing his creation to go into the world alone. There is immense pathos in Shelley's rendition of the creature's fate, for he thinks of himself as human, and yet every encounter with humans is disastrous, for like Victor they flee from him in fear and disgust. (It is significant that he has no name, of course.)
So he hides out, in proximity to the humans who have spurned him, reading Milton and eavesdropping on the players of classical music. His encounters with humans lead to what are accidental tragedies, but humans regard him as a murderer and hunt him. Meanwhile Victor flees to Scotland, where his creation tracks him down and confronts him with a simple request: You made me, therefore take responsibility for my fate. Humans will not accept me as one of their own. I am dying of loneliness; you must create for me a female mate of my own kind. Victor first agrees, embarks on this task and then reneges, expressing horror at the very thought, whereupon his bitterly-frustrated creation proceeds to wreak terrible revenge upon him.
About two hundred years later the modern science of genetics has turned what was a juvenile literary exercise into a stark reality of the near-term future. Research using genetics focuses on improving human health, the quality of life and life spans, a predicted panacea of treatments for many human diseases in the near future. Every day in the media we read or hear about the next astonishing health or scientific breakthrough that promises to provide revolutionary cures for various diseases derived from the study of our genetic material. This rapid pace of new breakthroughs and promised cures in the near future provides a meaningful context that, as a society, we can feel that we have chosen the correct path exploiting what we know about science, innovation and biotechnology for the greater societal good. However, at the same time, what remains in the shadows, hidden and not discussed, is a fear that we are gaining too much power through the rapid acquisition of knowledge about science and at the same time a reduced choice over random destiny and an imposed alteration of our humanity. While this claim of enslaving ourselves with our own technology may seem fantastical at first it doesn't take long to realize that we have already altered the genetics of other species (hybrid plant varieties) on the planet so profoundly that they have become unable to reproduce successfully without our help.
The limits of genetic technologies are being overcome with great speed, surpassing even the preconceived expectations of the scientists themselves. This was most notable with the achievement of successful mammalian cloning in the late 1990s, since many eminent scientists had been sure that such a breakthrough was still far off in the future. Cloning of animals was first proposed in 1938 by German embryologist, Hans Spemann as a "fantastical experiment" where the nucleus of an egg would be removed and replaced with a nucleus from another cell. The result of such an experiment was to create an exact replica of the original organism, creating life without sexual procreation. Limited by the technical difficulties at the time it wasn't until 1952 that American scientists, Robert Briggs and Thomas King attempted the experiment using frog's eggs due to their large size and ease to manipulate, transferring an adult cell nucleus in place of the egg's nucleus. This initial experiment failed but others continued to refine the technique of somatic cell nuclear transfer.
Partial success was achieved in 1970 when a developmental biologist, John Gurdon, inserted the nuclei from an advanced frog embryo back into the egg rather than previously tried adult cells. The frog eggs developed into tadpoles, but then all died before becoming adults. With the continuation of improved technology in 1984, Steen Willadsen a Danish embryologist succeeded in cloning a sheep using a nucleus from a cell of another early sheep embryo. This result was repeated by researchers using several other animals but seemed limited working only when other early embryo cells were used as donor nuclei. The nuclei from differentiated animal cells could not be used to clone, as they did not seem to be able to "reprogram" themselves to act like an early embryonic cell.
The mystery surrounding reproductive cloning was unveiled from knowledge of the way cells divide, it became apparent that cells don't divide until conditions are appropriate. The reason that all previous attempts at cloning failed was that the egg and the donated nucleus needed to be at the same stage in the cell cycle. In 1995, reproductive biologist Ian Wilmut succeeded in cloning a farm animal from advanced embryos by resynchronizing the host cell and donor nucleus; they cloned an adult mammal for the first time, producing a lamb named "Dolly" from a six-year-old ewe, using tissue taken from the ewe's udder. Out of 277 nuclear transfer attempts, Dolly was the only successful clone. Within two years, the same group from Scotland created Polly, the first transgenic sheep with a human gene in every cell of its body. Since then scientists have successfully cloned a host of animals including cats, cattle, goats, rabbits, mice and pigs.
With the cloning of a higher mammal (Dolly the sheep), public concern immediately jumped to the ability to clone humans. An ominous refrain was the idea, "if we can clone a higher mammal then we can clone a human and we inevitably will" that appeared in several media articles echoing public concern. A few laboratories have already shown their proficiency and ability to clone humans but elected to stop the "experiment" at an early stage. Several countries have adopted the moral position that cloning a human by nuclear transfer (reproductive cloning) is illegal. Such emerging science, when driven by the technological imperative and proprietary business values makes people uneasy because something that can be done in the realm of science is seemingly inevitable and only a question of research time and effort. The example of the history of cloning illustrates that the barriers confronting researchers are usually technical ones and with time these problems are usually overcome; from its inception as a fantastical experiment to actualization took a mere 50 years. This ability to reduce the 'unknown to the known' scientifically because it is technically possible leaves us with an overwhelming sense of a predestined outcome -- one of inescapability; a sense that science is largely unyielding to our concerns and therefore unstoppable. Researchers, for the most part, are unconcerned with the gap between things that "can be done" and "will be done" placing science innovation as a technical exercise apart from any ethical concerns. As a result the ethics of science takes a quiet back seat or even worse it becomes completely irrelevant to the fast pace of innovative research.
The story of Dolly provides an excellent example to show that ethical concerns do have a place alongside the juggernaut of science as it applies to human gene therapeutics. After the birth of Dolly it was determined that there were a number of things wrong with the "successful" clone. At 3 years of age the DNA (Deoxyribonucleic acid or heritable material) in her cells was typical of a much older animal. All chromosomes are capped with telomeres, tiny repeating strands of the DNA that can be related to chronological age. Telomeres shorten each time a cell divides, and continuously erode as an animal ages. The researchers found that Dolly's telomeres were shorter than other 3 year old sheep, suggesting she was genetically much older than her birth date. By 5 years old, she had developed severe arthritis but it was unclear whether the condition was a result of the cloning process. Dolly died at age 6, euthanized after being diagnosed with progressive lung disease; sheep usually live twice this age or longer, arthritis and lung infections are commonly found in older sheep. Human clones even if they don't display monstrous abnormalities in the womb may age prematurely at a severely accelerated rate or show other cloning related diseases; perhaps such technologies should never be applied to humans at all.
We must realize that in time, all of the mysteries of life involving biological processes will be deconstructed by scientific research and become known, however appealing or overwhelming their potential application to the human condition may be. If many of these innovations derived from science are to be realized and actualized as therapeutic treatments we must understand the various kinds of risk that may be associated and ask the question: Should there be limits on what we do even in the name of human health?
The concept of risk provides a suitable canvas on which to array and describe -- in a systematic manner -- the social, ethical, and legal issues raised by the engineering of our heritable genetic material by direct manipulation using either genetics or genomics. The concept of risk has certain intrinsic attributes that make it especially useful for this purpose. In the first place, risk poses the two questions that are of greatest interest to everyone, in terms of outcomes -- of either natural or technological processes -- that cause concern or dread to individuals and societies. These are: (1) How likely is it to happen? (2) If it does happen, what are the expected consequences? In the second place, risk lends itself to both qualitative and quantitative description. In both types, but especially the latter, risks can be compared with each other, across very broad domains, thus facilitating certain critical choices open to us as individuals -- in particular, whether certain risks rise above the threshold of acceptability or tolerability, whereas others do not. Third, the concept of risk asks us to estimate the dimensions of the uncertainties that are attached to particular risky ventures, so that we know whether the risk can be controlled with the strategies that are currently available to us.
Risk is a powerful concept that defines the trajectory of industrial society, intent on the domination of nature for enlarged human benefit, a project envisioned by Francis Bacon in the 17th century. Today we seek to carry out this project in two interconnected ways, (a) by maximizing the spread between benefit and loss and (b) by minimizing the "downside risk," i.e., protecting ourselves from the possible worst-case consequences. To achieve these two interconnected goals we require good risk management that requires us to recognize the pertinent risk factors in a particular endeavour in advance, and failure in this regard can be catastrophic. Recent research into improving human health and the quality of life has led us inexorably to the capacity to engineer our own genomes and to alter the randomness of passing desirable and undesirable traits to future generations. Such knowledge is perhaps the most fateful of all human powers, in that the risks to be managed go beyond specific interventions, and reach into the very foundations of human civilization. Society can manage genomics and genetics risks only if the scientific community becomes actively engaged in this process, assuming its share of responsibility for their potential scope, well in advance of successfully achieving our practical objectives.
We find ourselves at this point in time standing on a precarious slope with the promise of emerging biotechnology that seemingly offers all of society therapeutic benefits to cure diseases beyond anything we could have imagined using conventional medicines a little over a decade ago. The technologies can be divided into two broad categories: "genomics" which is primarily concerned with using genetic information to create tools for human therapeutics that will involve traditional drug treatments and pre-symptomatic disease management; and "genetics" which will use the tools and information derived from genomics and apply this knowledge to other emerging technologies, again for therapeutic disease cures.
"Genomics" is the intersection of bioinformatics (knowledge derived from computer analysis of biological data) and genetics, and is defined as the study of genes and genomes. Genomics now encompasses a broad range of molecular biology technologies ranging from traditional genetics and genetic databases from which new therapeutic areas of study are emerging. Computer databases of genetic information are the culmination of decades of worldwide research.
In 1865 an Augustinian monk named Gregor Mendel mated green pea plants and observed how different traits (colour, appearance) were transmitted to the succeeding generations. He described a gene as a discrete unit of heredity, much later these genes were determined to be made of DNA. The structure of DNA was worked out in 1953 by James Watson and Francis Crick, its basic unit being a nucleotide base that consists of a sugar and phosphate group to which one of four nitrogen bases are attached. The nucleotide bases are joined together, to form a long, linear strand of DNA; for stability DNA exists as a double stranded helix or twisted ladder. Physically characterized, a gene is a string of nucleotide bases located somewhere along the DNA strand, and the average size of a human gene is 3,000 nucleotide bases. A single gene encodes for the trait or directions to make a single protein that is needed inside the cell.
The genome consists of all DNA inside our cells that encodes all our genes for making and expressing all the proteins. The technique of DNA sequencing was discovered independently in two different labs at around the same time, Walter Gilbert (with graduate student Allan Maxam) in the United States and Frederick Sanger in England, each developed new techniques for rapid DNA sequencing. Within a decade, the technique for sequencing had been automated along other innovations allowing for high throughput data collection. The first genome from a bacterium was completed in 1995 and the complete genetic sequence of other model organisms (fruit fly, mouse) quickly followed. The human genome project began in 1990 as a collaborative, public domain effort; the completed draft of the entire human genome was published in April, 2001. The human genome sequence revealed that there are 3 billion nucleotide base pairs in our genome that encode 30,000 different genes; all of the genes that we consider the important parts comprise less than 2% of the entire DNA molecule.
Currently, the amount of information contained in the largest DNA database called "Genbank" is truly astounding -- some ~30 billion base pairs. In addition to the complete human genome data there are genes and DNA sequences from other species genomes. Collectively, the amount of sequence data is doubling every 12-14 months. However, large repositories of DNA sequences by themselves, while impressive for sheer volume, have little impact on improving human health; they are a fundamental tool for genomic medicine acting as a road map to locate disease gene loci.
Emerging from static databases of genetic information are a number of important areas of genomics including pharmacogenomics, which focuses on analyzing single nucleotide polymorphism databases, and transcriptomics and proteomics, which will help in pre-symptomatic medical treatment, individualized disease detection, and individualized therapeutic treatments.
The idea of "biochemical individuality" was first proposed by Roger Williams in 1956 to explain variability in disease susceptibility, nutrient needs, and drug responsiveness among otherwise seemingly healthy people. It is only now with the ongoing genomic revolution, that the number of gene targets identified has increased, and with genetic testing will allow medical doctors to assess true biochemical individuality. The combination of pharmacology with diagnostic genomics is called "pharmacogenomics," and this emerging research branch holds the promise that drugs might one day be tailor-made for individuals and adapted to each person's own genetic makeup. Environment, diet, age, lifestyle, and state of health all can influence a person's response to medicines, but understanding an individual's genetic makeup is thought to be the key to creating personalized drugs with greater efficacy and safety. Pharmacogenomics combines traditional pharmaceutical sciences such as biochemistry with annotated knowledge of genes, proteins, and single nucleotide polymorphisms that have been derived from catalogued database sources.
Single nucleotide polymorphisms (SNPs, pronounced "snips") are sites in the human genome where individual DNA sequence differs usually by a single base. Single base-pair variations are the most common and can determine whether or not we develop a certain disease. The magnitude of deleterious effects from infectious microbes, toxins, and drug treatments are also moderated by SNPs. Analysis using SNPs is an important diagnostic tool since they are widespread and easy to detect. One database has catalogued over 1.4 million human SNPs. Some well-characterized examples of genetic polymorphisms include a mutation that causes sickle cell anemia with reduced susceptibility to malaria; polymorphism in the cytochrome P450 CYP2D6 gene that affects adverse drug responses; and alcohol intolerance influenced by aldehyde dehydrogenase gene polymorphisms.
Medical research is just now beginning to correlate DNA polymorphisms with individual responses to medical treatments. Patients determined by their DNA variation will have drug treatments customized for their subgroup. During medical treatments 0.1 million people die from unexpected, adverse side effects while another 2.2 million experience serious reactions, still others fail to respond at all. Enzymes involved in drug metabolism, like cytochrome P450, are responsible for metabolizing most drugs used today, including many for treating psychiatric, neurological, and cardiovascular diseases. Characterization of DNA variants in such genes will virtually eliminate adverse reactions. Tens of thousands of people are hospitalized each year as a result of toxic responses to medications that are beneficial to others. Some cancers respond dramatically to current therapeutic regimens while the same treatment has no effect on disease progression in others. Scientists in major pharmaceutical companies are trying to sort out the specific regions of DNA associated with drug responses, identify particular subgroups of patients, and develop drugs customized for those populations. These capabilities are expected to make drug development faster, cheaper, and more effective while drastically reducing the number of adverse reactions.
The central dogma of molecular biology states that the heredity information flows from DNA to RNA (ribonucleic acid) to protein. It is a concept that explains how the genes in our genome made of DNA encode the amino acids of the proteins; RNA acts as an intermediate between DNA and the proteins it encodes. Such a set up allows the DNA to stay protected in its own separate compartment called the nucleus away from the caustic chemistry of the cytoplasm and provides an easy way to regulate the amount of a certain protein needed in the cell by making more or less of the intermediate message.
RNA has the same structure as DNA, consisting of a sugar phosphate polymer backbone; but due to slightly different chemistry RNA is too bulky to form a stable double helix like DNA so it exists as a single-stranded molecule. There are several kinds of RNA inside the cell but only one type, called messenger RNA (mRNA), acts like the cellular photocopier for genes. It carries the information from the DNA in the nucleus out to the cellular machinery in the cytoplasm where it is used to make the protein.
Not all genes are turned on in all cells. The subset of DNA genes that are turned on represented by these intermediate mRNA forms in a given cell is called the transcriptosome. Transcriptomics describes the levels or amounts of the mRNAs present in the cell under a given set of conditions and reflects the link between the genome, the proteins being expressed and the cells physical state and appearance. If a cell is healthy and functioning normally it will express a number of mRNAs as it should, but if sick or malfunctioning the amounts of the mRNA expressed could be significantly altered for a number of genes; for example a cell that becomes cancerous and dividing rapidly has many genes for cell growth turned on and this is easily detected when tested for. The regulation of highly variable gene expression of mRNA within the cell can be tested and monitored by using a technique called DNA microarray analysis.
A microarray slide consists of a set of known DNA genes, derived from the human genome sequencing project stuck onto the surface in individual, discrete spots usually laid out in a grid-like pattern. The technology of spotting the DNA onto the slide to create the microarray has been miniaturized with genes representing the entire human genome (all 33,000 genes) now available on two microarray slides each no bigger than a few centimeters in size. In order to see what genes are turned on or off the mRNAs are isolated from the cell or tissue and a reverse copy linked to a fluorescent dye is made as a way to detect the amount that binds to its corresponding gene on the microarray slide, computer enhanced laser detection quantifies the signal. Microarray technology uses the sequence data from genome projects to determine which genes are differentially expressed in a particular cell type of an organism, at a particular time, under particular treatment conditions. While only recently created the microarray databases already contain significant amounts of experimentally generated data. Transcript profiling has already been used to identify possible drug targets and biological markers that allow for the prediction of a patient's response to chemotherapy drugs.
The largest sequence repositories (NCBI, PIR, Swiss-Prot, TrEMBL and Uniprot) contain all known protein sequences, mostly derived from conceptual translation of DNA gene coding regions. Most entries do not contain any information about individual protein function or activity. There is a subset of protein databases that deal with distinct protein families and these are well annotated usually maintained by interested researchers wishing to share research results. A more functional subset of databases for pharmacogenomics are proteomic databases that use analytical techniques (2D gel analysis) to separate and catalogue all of the proteins of a cell under particular growth conditions. Much like transcriptomics and microarrays the proteome information can determine which genes are expressed in a particular cell type of an organism, at a particular time, under particular treatment conditions.
DNA-based tests are among the first commercial applications arising from genomics. Genetic testing for known disease loci can be used to diagnose disease, confirm the existence of a disease in asymptomatic individuals and help predict the risk of disease in healthy individuals or their progeny. Individuals who are asymptomatic can take preventative treatments in advance to delay the onset or reduce the severity of symptoms. The diagnostic tests reveal a disease condition or estimate the likelihood for developing one. Gene tests involve looking at the DNA sequence obtained from any tissue scanning it for specific mutations or changes that have been linked to a known disorder. Although there are several hundred DNA-based tests for different disease conditions, most are still offered as informative research tools only. Fewer than 100 gene tests are available commercially, and most are for mutations associated with rare diseases in which just a single gene is involved. Common diseases that involve the interaction of several genes do not have, at this time, accurate predictive tests.
Databases and profiling of diseases by pharmacogenomics, transcriptomics and proteomics will allow for individualized drug treatment plans and pre-symptomatic disease treatments. The therapeutic treatments will consist of drug regimes prescribed by medical doctors that will use approved pharmaceuticals that are well regulated under Canadian law. However, the use of genetic sequences derived from databases and the classification of an individual's SNPs, transcriptosome and proteome data for personalized therapeutics faces complex social, moral and legal issues.
There are several areas of intrinsic risk that relate to the protection of individuals, the privacy of genetic information and the possibility of using data in a discriminatory manner. The result of genetic testing may lead to social stratification, with expensive pre-symptomatic drug treatments being available only for those who can afford them. Employers, insurance companies and even potential mates could also discriminate against individuals who are tested and found to carry certain disease loci. The emotional trauma of knowing that you carry and will get a number of serious diseases predetermined by your genetics is a burden of knowledge that some individuals may not want to carry and the personal right "not to know" if close relatives are tested. Moreover, many diseases that can be currently tested for have no known cure or treatment and as rare diseases many pharmaceutical companies will not see any profit in spending research and development money to deliver orphan drugs. Finally, there are issues surrounding confidentiality and privacy concerns of who should have access to personal information derived from personal genetic profiling.
Extrinsic risks also exist with genomics technologies and the large scale database collection of information of entire populations could have transformative social effects. Like individuals entire ethnic communities could face widespread stigmatization and be considered pariahs if it is found they are carriers for a high number of deleterious gene polymorphisms. There is also a bigger problem of the expansion of and linkage of to other databases that will transform the data for individuals, cohorts or communities far beyond their original intention. Police and police states will find the collective and personal polymorphism databases an easy way to perform racial profiling, when linked to other personal information. Companies will exploit personal pharmacogenomic data to market and target specific segment groups and communities for a variety of consumer products based on their level of risk for specific future diseases.
The biology of genetically engineering ourselves falls into three major categories: first, making chimeras by creating quasi-human animal hybrids through the mixing genetic materials between species; second, eugenics/gene therapy, which alters the existing genetic material to fix or replace undesired diseases and improve desirable qualities of beauty, health, intelligence or longevity; andthird, xenotransplants, which mix human and animal genetic material to harvest animal organs for human use without fear of immunologic rejection.
The most promising of these three is gene therapy for a number of reasons. Genomics is already providing the working gene targets for gene enhancement and gene therapy. Gene therapy techniques are being refined in laboratories with the promise a virtuous benefit -- to repair gene defects and cure diseases in adults and in unborn children. It is a far less contentious prospect, morally, than creating new chimeric life forms or human-animal entities. Moreover, gene therapy using therapeutic cloning and stem cell techniques will avoid the problems of any immune rejection that complicates work on xenotransplants. Researchers who are commercializing this work have chosen, out of practicality, the least perilous system to champion first.
All of these new genetic techniques rely on genetic engineering, which can be defined as the process of manipulating the pattern of proteins in an organism by altering its existing genes. Either new genes are added, or existing genes are changed so that they are made by the body's DNA at different times or in different amounts. Because the genetic code is similar in all species, genes taken from one person or animal can function in another human. In addition, the promoters or "on-off switches" from one coding sequence can be removed and placed in front of another coding sequence to change when or where the protein is made. The various types of "omics" research will provide the tools and a broadened array of identified gene targets that will be available to be manipulated.
Research has been perfecting the ability to manipulate genes in lower life forms, and favourable characteristics from a wide range of organisms have been introduced into recipient plant species creating genetically modified crops. These new characteristics can be introduced using a number of techniques including: injection into the nucleus of the cell with a tiny needle; by an electrical shock to the cells, which briefly depolarizes the membrane allowing for DNA uptake; by attaching the DNA to small metal particles and using a "gene gun" to shoot the particles into the cells; or by using viruses and bacteria engineered to infect cells with the foreign DNA. The newly introduced DNA must find its way into the nucleus and then become incorporated into the recipient's own genetic material. Once incorporated into the host at the DNA level, the introduced gene functions like all other genes of the host. This process of transplanting desired traits from one organism to another is called "transformation," or more commonly "gene splicing." The resulting products from recombinant manipulations are termed "transgenics" or "genetically modified organisms" (GMOs). Repair and replacement of defective human genes requires slightly more sophisticated technologies and are currently being developed using delivery systems (viral, liposome mediated, naked DNA) similar to those already worked out in plant systems. Humans receiving gene therapy treatments will be rightly considered to be GMOs or, in the case of therapeutic cloning that use stem cells maintained on a layer of mouse feeder cells during growth, they will be considered to be xenotransplants.
Genetic enhancement refers to technologies that transfer genetic material to modify non-pathological human traits. Unlike gene therapy that treats disease conditions gene enhancements are used to treat non-disease characteristics and mainly provide cosmetic alterations. Enhancements will be used to make someone who is already in good health even better by optimizing what society deems to be "desirable" attributes. Physical traits that could be altered include appearance such as hair or eye colour, height, physical build, increased muscle mass, decreased body fat, improved strength and increased endurance; behavioral traits could be changed as well to improve intelligence, temperament and altering basic personality traits to make individuals outgoing.
Athletes have been well aware of the importance of single nucleotide gene polymorphisms and how they influence sports performance for many years. At the 1964 Winter Olympics in Innsbruck, Austria, a cross-country skier from Finland who won two gold medals was later found to have a genetic mutation that increased the number of red blood cells in his body because he could not switch off erythropoetin (Epo) production; this mutation increased his capacity for aerobic exercise. Synthetic Epo is currently used to treat anemia, but it has also been abused by athletes as a way to improve their stamina. During the 1998 Tour de France professional bicycle race, an entire team was disqualified and two top cyclists admitted taking the drug. Recent efforts to deliver the Epo gene into patients' cells would eliminate the need for regular injections, but this could also be abused by athletes.
As mentioned in the Prologue, experiments at the University of Pennsylvania have revealed that when normal mice are injected with a modified virus that adds an essential growth gene (insulin-like growth factor, IGF-1) to their cells, they develop into heavily muscled, super-strong animals (nicknamed "mighty mice" by the scientists who created them). The effects were doubled when the gene therapy is coupled with a weight-training regime that forced the mice to climb ladders. The added IGF-1 gene also stopped the ageing process in older mice: none suffered from typical old age muscle wasting. Now being developed to treat patients with muscular dystrophy and other muscle wasting diseases, this gene therapy could be used as a gene enhancement given to athletes to deliver vast improvements in speed, power and strength. Gene enhancements have the potential to boost sport performance more radically than any combination of existing drugs, such as anabolic steroids and Epo.
Dr. Leo Sweeney, the lead scientist, has already been approached by coaches and athletes, mainly bodybuilders, seeking to try this gene therapy, even though the technique is barely ready for patient trials. He lamented: "This is but one example of a number of potential gene therapies that are being developed with disease treatment as the goal, but if given to a healthy individual would provide genetic enhancement of some trait." It is highly likely that gene enhancements will be used by professional and amateur athletes alike for performance enhancement, just as many drugs are used and abused today. The chairman of the World Anti-Doping Agency said he was concerned that gene doping would become a major problem for Olympic sport with gene enhanced athletes "certainly realistic" by the 2012 games and beyond.
The genes for enhancement are already being well characterized from genomics research and will be used to supplement the functioning of normal genes or may be engineered to produce a desired enhancement. Gene insertion into adults for enhancement purposes will be intended to affect only the single individual through somatic cell modification. Trying to identify just what conditions are considered therapeutic or enhancements can lead to confusion. For example, enhancements for anticipatory resistance to disease in already-healthy individuals, or for resistance to environmental or workplace toxins, or for improving "normal" eyesight are all enhancements that do not correct an actual disease state but do have some potential individual benefit. The real prize of gene enhancement will be treatments to increase intelligence, memory, logical thought, and critical reasoning. There is at present widespread agreement that germline engineering (see following section) should be banned for both therapeutic and enhancement applications, but how effective this will be in practice remains anyone's guess.
Human gene therapy is the introduction of DNA into humans or human cells with the purpose of treating or curing diseases. In order to perform gene therapy the defective gene must be identified and genetic engineering techniques will create copies of the normal, functioning gene and transfer this correct copy into the target cells. There are several ways in which gene therapy can correct a gene defect: a normal gene may be inserted into a nonspecific location within the genome to replace a nonfunctional gene(this is the most common approach); the abnormal gene could be swapped for the normal gene using site specific homologous recombination; or the abnormal gene could be repaired inside the cell nucleus by selective reverse mutation changing the single base pair; or, finally, the regulation (how much gene product is made) could be altered.
There are two kinds of gene therapy. "Somatic gene therapy" refers to treatments in which DNA is introduced into cells or tissues other than germ cells (sperm and egg). The second type is "germline gene therapy," in which DNA is introduced only into male or female germ cells. The germline (or sex) cells are responsible for making our gametes (sperm or egg) for reproduction so changes to genes in these cells would affect all subsequent generations. The transformative ability of germline gene therapy is already a known ethical issue; in 1983 the U.S. President's Commission endorsed somatic, but not germline, gene therapy treatments. Many other countries including Canada have adopted this distinction as part of the legislation surrounding gene therapy. Gene therapy has much potential for treating and curing genetic and acquired diseases including various cancers by using normal genes to supplement or replace defective genes. There are various classes of diseases that gene therapy will cure in the future: inherited single-gene diseases (Cystic fibrosis, Parkinson's disease, familial hypercholesterolemia, Fanconi anemia, to name a few); infectious chronic diseases (HIV); acquired disorders (peripheral artery disease and rheumatoid arthritis); and multi-gene diseases (cancers).
One of the earlier, tragic attempts at gene therapy that failed involved the death of 18-year-old Jesse Gelsinger, who suffered from a genetic disease called ornithine transcarboxylase deficiency (OTCD), a rare liver disease that fails to properly control ammonia metabolism. His death was triggered by a severe immune response to the modified adenovirus vector that was being used to carry the healthy copy of the transcarboxylase gene. Adenovirus is a class of viruses with double-stranded DNA genomes that cause respiratory, intestinal, and eye infections in humans -- it is the same virus that causes the common cold. The goal of the gene therapy treatment was to deliver and express the transcarboxylase gene, but there is low transfer efficiency in this procedure (only 1% of all injected adenovirus with the good gene gets delivered to the cells and recombined into the human genome). The doctors sought to overcome this limitation by using an extremely high infection dose of 38 million viral particles, which was calculated from animal testing and it was believed to be accurate. But less than 24 hours after they injected Jesse with this amount of virus, his entire body began reacting adversely. He went into a coma and died two days after from multiple organ failures, just four days after starting the treatment, his death a direct result of the gene therapy experiment.
In January 2003 the U.S. Food and Drug Administration, which oversees gene therap,y placed a temporary halt on all gene therapy trials using retroviral vectors in blood stem cells after learning that a second child treated in a French gene therapy trial had developed similar leukemia-like conditions after being treated for X-linked severe combined immunodeficiency disease (X-SCID), also known as "bubble baby syndrome."
Despite the tragedies, over 600 clinical gene-therapy trials occurred worldwide in 2002, with most trials focusing on various cancer types, infectious diseases and vascular diseases. Worldwide, the majority (~75%) of all gene therapy protocols, trials and patient treatments occur in the United States. Canada has relatively few gene therapy trials and gene therapy patients (~3% worldwide). Current protocols in the formative stages are focused on establishing the safety of gene-delivery procedures rather than effectiveness. The technology itself still faces many obstacles before it can become a practical approach for treating disease. In Canada, gene therapy is regulated by Health Canada (The Biologics and Genetic Therapies Directorate, BGTD) with responsibility for biologics and biotechnology products used for gene therapy. Prior to gene therapy product approval, BGTD requires data for safety and efficacy with provisions to monitor products after approval. Due to the ethical considerations that surround gene therap,y granting agencies for research in Canada including the Natural Sciences and Engineering Research Council (NSERC), the Social Sciences and Humanities Research Council (SSHRC), and the Canadian Institutes of Health Research (CIHR) have ethical conduct and policy requirements for research involving human subjects.
Often overlooked in discussions of SNPs for use in gene therapy or enhancements is the acknowledgement of the complexity of human gene expression, involving both epistatic interactions and pleiotropic expression. These terms refer to the fact that many traits such as height, body-type, weight, and metabolic rate are governed by the cumulative effects of many genes. Polygenic traits, or those traits involving multiple genes, are not expressed as absolute or discrete characters but are expressed as a continuous variation or gradation of small differences. Not only is gene expression temporal (some genes are turned off or on at various stages of development), but it is also tissue specific: inappropriate expression of a particular gene product or a knockout of another unrelated gene product, when the new gene from gene therapy is recombined into the genome at random in a non-target tissues, could have serious detrimental effects.
One of the major problems with current disease treatments is the body's immune response system. When foreign cells from donated organs, tissues or blood are transplanted, transfused, or xenografted, the recipient mounts a rejection response, attacking and destroying these cells. People using donated organs and tissues who are a close match must endure a lifetime of immuno-suppressive drugs. Using a patient's own cells as a source for the treatment would circumvent this problem of rejection and scarcity of compatible donor organs. Special undifferentiated cells, called stem cells, if somehow harvested and used from the patient would avoid the immunological rejection as the cells and tissues would genetically be a match. Therapeutic cloning is a way to obtain these needed stem cells by using somatic cell nuclear transplantation.
"Adult DNA cloning" like the method to clone Dolly, on the one hand, and "therapeutic cloning" to produce cells and tissues for transplant, on the other, are quite different procedures, but they both begin by transplanting a nucleus into a donor egg and both terms contain the word "cloning." This causes a great deal of confusion among those who wish to understand what exactly therapeutic cloning is. Cloning, as in the production of Dolly the sheep, means making an identical genetic copy of an individual by nuclear transfer from a somatic donor cell to an enucleated host egg; this is called "somatic cell nuclear transplantation" or "adult DNA cloning." The multi-cell embryo at the blastocyst stage is implanted back into the uterus of a surrogate host and pregnancy is allowed to proceed normally.
With therapeutic cloning the somatic cell nuclear transplant also creates a blastocyst, but there is never any intention of implanting to create a living being. At day 5-6 the blastocyst is a ball of cells organized into an outer layer that will become the placenta and an inner layer called the inner cell mass containing the stem cells which are harvested for use. The inner cell mass will form the tissues of the developing body and can differentiate into any other cell types; this ability of the stem cells is called "pluripotentcy."
The great potential of pluripotent stem cells for therapeutic purposes is that they can create any required cell type needed. This plasticity of cell fate has resulted in an exponential growth in stem cell research; however, due to the demand compared to the small numbers of starter cells, very slow growth and problems of bacterial contamination of tissue culture, the supplies of stem cells are very limited for research. Embryonic stem cells can be derived from several sources but there remains a central, contentious ethical issue of the use of a human embryo as the initial source of stem cells. Stem cell research has potential for use in regenerative medicine to supply replacement cells for degenerative diseases and traumatic injuries. Stem cells can be used as a supply of nerve cells for the treatment of Parkinson's disease, spinal cord injuries, pancreatic islet cells to treat diabetes, and blood cells to treat anemia and muscle cells to treat muscular wasting diseases. Transplantation can be done with unmodified or genetically modified stem cells or subsequently differentiated cells. The potential individual medical benefits of using stem cells in therapeutics are enormous.
An orientation to the world where systematic risk-taking is the norm rests upon a more fundamental notion, namely, that the world of nature is essentially a field in which human ingenuity can be exercised without restriction. The phrase "without restriction" is crucial: It means that there are no other interests subsisting there, no other entities possessing a will and consciousness -- no gods or spirits or demons -- that can oppose us with an alternative plan as we proceed to manipulate nature to our benefit. This world is simply full of latent "power" (what we now call matter -- energy) that can be appropriated and turned to human benefit. The traditional competitions among people within society are zero-sum games, where gains are won only at the expense of others. But the contest with nature is different, because there are no competing interests.
Yet all powers are two-edged swords. As the scope of the good they can do for us expands, so does that of the harm they might do, either inadvertently or by someone's deliberate choice. Two examples must suffice. Unlocking the power of the atom yields a new energy source and a fearsome new weapon of mass destruction at the same time. The technique of "DNA shuffling" and the creation of "daughter genes" makes possible the creation of new biological traits -- as well as the possibility of so-called "synthetic pathogens" and the prospect of confronting novel infectious diseases against which no immunity exists.
A simple lesson flows from this perspective. The challenge of managing effectively the risks we create -- to ourselves, other creatures, and ecosystems -- in the search for human benefits grows in proportion to our technological prowess. Managing risks means adopting a precautionary mode of behavior, trying to identify and limit potential trouble before it hits us in the face. We have a collective responsibility -- an ethical duty, if you will -- to act in this way. Yet, quite obviously, discharging this responsibility is easier said than done and gets harder with each passing day. This is so because the global reach of innovation demands effective international collaboration in managing risks, a capacity which presently exists at a primitive stage of development.
The purpose of risk management, as first developed in the financial sector and later extended into the health and environmental zones, is to bring a systematic perspective to bear on the propositions already enunciated. Another way of saying this is to recognize that through risk management we seek to introduce a foundation of precaution beneath our risk-taking activities. This occurred first in the domains of public health and of occupational health and safety: The introduction of sanitary measures to control the spread of infectious disease is an attempt to head off the adverse consequences, or at least a certain proportion of them, before they arise. Establishing allowable limits of exposure to hazardous substances in the workplace is an alternative to ignoring the casualties and just replacing sick workers with others not yet sick, without bothering to ask whether it was the workplace that sickened them.
The management of health and environmental risks, considered as a precautionary exercise, developed as a step-wise procedure for controlling risk:
Advances in methodologies for toxicology, epidemiology, and statistical analysis have been one of the primary drivers of progress in this area. In this respect risk assessment resembles detective work, where the "culprit" sought is the significant association between risk factor and adverse outcome than can be deeply hidden, especially in epidemiological data. To be sure, these "technical" aspects of the risk management approach are only one side of the whole story, for there are important social interests that can be affected by it.
Risk is unequally distributed in many ways -- in occupations, socio-economic levels, neighborhoods, race, and other ways ?, bringing matters of justice, equity, and equality to the fore. Risk is also unequally distributed as a result of idiosyncratic variations in personal proclivity (degree of risk aversion) and preferences or choices. This means that very important dimensions of health risk can be, at least in principle, under substantial personal control -- affected by personal choices in patterns of diet, exercise, intake of alcohol and other drugs, recreation, driving behavior, tobacco smoking, and many other domains. In addition, people can perceive the nature and significance of many hazards, especially those which they believe are being imposed on them without their consent, in terms that are radically opposed to those who are using formal methodologies to perform quantitative risk assessments.
So bitter battles over risks can erupt and have done so regularly. These battles began a century ago with respect to occupational risks. Firms routinely denied that there was sufficient cause-and-effect proof (using a legal standard of proof) to justify lowering allowable exposures, since expenses were incurred in doing so. Evidence often was hard to come by, and in many cases was concealed when it surfaced. Few cases are as notorious and long-lasting, or as fraught with catastrophic health consequences, as that of occupational exposure to asbestos, which goes on to this day. The history of occupational risk is important for showing us that social and economic interests come into play whenever changes are sought to the prevailing community standards for acceptable levels of risk.
In public health no battle has been as bitter as that with the tobacco industry, which fronted the longest-running battle against epidemiological science that has ever been waged. At its height in the 1980s and 1990s, before the industry finally capitulated, specialists were recruited with secret payments to cast doubt on epidemiological studies. More recently, the perceived economic costs of complying with greenhouse-gas emissions reductions targets, to control the risks associated with climate change, resulted in attacks on the credibility of the scientists who support the reports of the Intergovernmental Panel on Climate Change. Science itself, as represented by toxicology and epidemiology, is drawn into fray when controversies erupt among social interests about risk assessment and management. Risks associated with the engineering of genomes, especially the human genome, will without a doubt be intensely controversial, and the scientists working in those areas will be drawn into those controversies, along with the rest of us.
Considered simply as an area of scientific investigation having practical applications for human benefit, molecular biology and genetics is an immensely important field of inquiry. In particular, the sequencing of complete genomes and (ultimately) what will follow -- full knowledge of individual gene functions, gene expression mechanisms, and the pleiotropic effects of gene alteration -- will have nothing less than revolutionary consequences for us as the data will be applied to gene therapy. And these steps will introduce us to a range of risks which we have never before confronted. At present, we do not know even where to start in confronting them.
For there are some types of downside consequences associated with genomics which, if they come to pass, will have one of two results: Either they will produce catastrophic harms or they will so frighten the population that there will be a demand for an end to research and development in this area. Or both.
The term "risk factor" connotes a probable cause of an adverse effect, taking into account not only varying degrees of uncertainty, but also the fact that risk is by definition probabilistic. When one says, for example, that tobacco smoking is a risk factor for cancer (lung, mouth, pharynx, larynx, esophagus, pancreas, uterine, cervix, kidney, and bladder) and dozens of other diseases, it means (a) that the existence of an association between the two is highly plausible, (b) that a scale of harmful dose is known, and (c) that a certain percentage of smokers will fall victim to these diseases. About 10% of regular smokers will get lung cancer, on average, but the distribution of the risk is also very important: Women have double men's risk of lung cancer, and are at risk for more serious type of this disease, at an equivalent dose. This terminology is very widely used and is relatively easy to communicate, despite the fact that there are some residual difficulties in understanding.
The term "risk factor," then, has to do with adverse consequences only and thus begs the question as to what benefits accrue as a result of the risk-taking behavior. As a general rule we can assume that risks in this sense are encountered as a result of the search for benefits, even with something like smoking. A fair description of a risk domain, therefore, requires a sketch of both benefits and costs (where costs are the probabilities of harm, or risk factors), and both sides of these equations may be phrased in either monetary or non-monetary terms.
Risk factors for technologies can be sorted into two categories; for want of better terms they are divided into "intrinsic" and "extrinsic." In the former are those hazards which are inherent in either the nature of the technology itself or in its normal applications. To give an example from the world of chemicals: trihalomethanes and their cancer risk are created as byproducts of using chlorine to disinfect water. The occupational hazards associated with producing chlorine, or the risk of accidental releases to those who live in proximity to the plant boundary, are other examples of intrinsic risk factors. "Extrinsic" refers to the impacts that specific technologies can have on a wide range of institutional subsystems in society -- law, ethics, religion, and politics. As a society, we need to have as accurate an idea as possible about the nature and scope of the hazards we face in this domain. Equipped with this idea as well as with the precautionary approach, we would then be in a position to engage a wider public in a discussion on how to manage the associated risks, proactively, and not wait to be confronted with the actually existing harms.
A general description of the two distinct classes of risk factors associated with genomics and genetics might be as follows: Intrinsic risks arise inevitably out of achieving the ability to undertake genetic alterations in existing genomes, or to construct entirely new genomes, with predictable and reliable results in achieving the expression of desired traits. Intrinsic risks of genetics include many of the same problems of intrinsic risk associated with genomics: Concerns of privacy, safety and efficacy, for example, apply to all branches of genetics as medical information is compiled into large databases. Unintended effects due to gene therapy include altered metabolism, altered brain functions or unforeseen gene actions, insertions and recombination events that would occur to individuals as a result of the technology. Some technologies have special intrinsic concerns like stem cell research and therapeutic cloning with ethical uncertainty of creating life solely for the purpose of therapeutics and the underlying valuation of one life over another. Likewise, xenotransplantation could have psychological ramifications with individuals who have become part animal and are treated differently or unforeseen problems of zoonotic diseases from retroviral sequences that will infect the tissue recipient with a life long non-transmissable infection.
Extrinsic risks are the impacts that this almost certainly will have on a wide range of institutional subsystems outside the bounds of scientific discovery itself -- law, ethics, religion, and politics, including such things as the concept of the person and the family. A provisional list of extrinsic risks associated with gene therapy and its convergence with other technologies is outlined as follows:
First, we must be clear about what is the scope of the "power over nature" that genomics science seeks. Altering smaller or larger sections of the genomes of existing entities (plants, animals, humans), in order to achieve human benefits otherwise unattainable, is what most people would think of right away. But there is a much larger prize lurking in the background: creating de novo the biological "platform of life" onto which any desired set of traits whatsoever could be grafted. This is known as the "minimally necessary genome" and it is now a prize being sought, by -- among others -- the irrepressible Dr. Craig Ventner of the Human Genome Project fame:
"Scientists in the United States plan to build a tiny new germ from scratch, promising it will be harmless to people and could someday be used to produce new forms of energy. The scientists ... want to keep portions of their work secret to prevent terrorists or hostile nations from using the new organism to make biological weapons. If the experiment works, the synthetic germ would begin to reproduce on its own."
A Stanford University bioethicist was quoted as saying that she wasn't too worried by this project "partly because I have a sense that the scientists are aware of the possible risks of what they're doing." We would certainly hope so, but a second example shows that researchers are already delving into using humans as a "platform of life" to introduce desired traits. The absolute transformative nature of genetics and gene therapy has the ability to change what we are as a species, quite possibly including the creation of various isolated (non-breeding) sub-species of humans. Ongoing research into gene therapy is currently struggling to overcome the technical barrier of introducing good genes, but one avenue of research is trying to leapfrog this problem by introducing a new, artificial chromosome:
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.
The words "not affecting their workings or causing mutations" presumes that those researchers already have some understanding of the long-term implications of their proposed molecular tinkering. Considering that evolution is a slow process occurring over tens of millions of years, introducing an entirely new chromosome, engineered by humans, moves us into the zone of unfathomable risks, for example, the potential of giving rise to post-zygotic isolating mechanisms that could create a number of reproductive problems in the human species. Those with extra chromosomes could experience one of the following conditions:
Exchanging health for procreation in the name of therapeutics, or worse, the potential creation of a sub-species of humans are hardly risk-benefit choices we should even be considering at this point in time. At the very least, scientists -- when presenting such miraculous upside benefits of gene therapy's future -- should make note of potential risks and problems.
The amount of money spent each year on weight-reduction products and services, including diet foods, products and programs in North America is close to $33 billion; to combat baldness more than $1 billion is spent each year, and consumers spent roughly $800 million on herbal remedy products to boost their immune systems and to treat illnesses. Without a doubt, gene enhancement technology to correct non-disease conditions will be readily accepted and likely widely used by consumers seeking a "quick fix." W. Gardener argues that the technology of gene enhancement used for cosmetic reasons in the future may be so dispersed and so easy to apply as "junk medicine" that it will be virtually impossible to contain it from widespread use:
There are some controls over the proliferation of nuclear weapons, but only because H-bombs require distinctive tools and materials that can be tracked. The knowledge required to build a bomb is everywhere. Generations from now, the human biology required for enhancement may be everywhere. But whereas bombs require esoteric tools and materials, genetic enhancement is likely to require the tools and materials of gene therapy, which may be distributed throughout medicine.
The ultimate biological result of widespread, indiscriminate use of gene enhancements will be a skewing of gene allele frequencies for certain traits within a large population and a reduction in genetic biodiversity. There are single gene alterations for enhancing weight loss or improving stamina that would affect a number of other interrelated metabolic pathway genes; many enzyme pathways are interconnected both up and down-regulating other genes by feedback loops. Treatments for one cosmetic condition may create an entire population of enhanced individuals that may be at higher risk for other diseases as a result. It is already known that allele frequencies in a population can both fortuitously protect or selectively predispose them from different disease states.
"This is the neutron bomb of agriculture."
-- Camila Montecinos, agronomist, Chilean-based Center for Education and Technology
Not all of the examples for extrinsic risk involve human therapeutics derived from genetics and genomics by the manipulation of human genetic material. One ongoing example of a technology that has extrinsic risk and the power to subvert entire societies, culture and their way's of life not only to affluent countries but developing countries is the technology of genetically modified (GM) food crops that produce sterile seeds, termed "terminator genes."
In 1997, the Canadian-based Rural Advancement Foundation International (RAFI, now called ETC group) called upon the U. S. Government to deny the patent pending on the terminator gene, submitted by the Monsanto corporation (now owned by Pharmacia), on the grounds that it is contrary to public and social morality. ETC group contacted government officials and civil society organizations in the 87 countries where the Terminator patent was pending to ask them to reject the patent by invoking the legal mechanism of "ordre public." When patent offices invoke this mechanism, they not only reject the specific claim; they also reject the whole technology and its use by anyone within their borders. ETC group also wanted international regulatory agencies to rule that the Terminator can't be sold as "seed," since it is the opposite of what a seed is -- something that can reproduce itself from generation to generation. The ETC group failed in their attempt to stop commercialization of the first terminator gene plant technology. The Delta and Pine Land Company, a seed company owned by Monsanto Inc., in collaboration with the United States Department of Agriculture, was awarded U.S. Patent Number 5,723,765, entitled "Control of Plant Gene Expression," in March 1998. The patent covers several applications, but the main invention is to engineer crops that produce seeds that are reproductively sterile in the second generation. This would make it impossible for farmers to save and replant seeds making them dependent on the seed suppliers.
Modern agriculture relies on hybrid varieties to produce food crops that are genetically uniform; that is all plants look identical in size, height and possess desirable traits not present in either parent alone. When these hybrids make seeds, however, the second generation is quite variable due to the natural shuffling of genes that occurs during sexual reproduction. Large-scale industrial agriculture requires uniformity, because the plants must mesh with harvesting combines. Farmers in North America who grow hybrid corn varieties usually buy over 80% new seed every year to avoid harvesting losses and loss of the characteristics found in the hybrid strain.
Non-hybrid variety food crops include several major food crops: wheat, rice, soybeans, and cotton. Farmers in some of the most populated parts of the world (India, Asia) often save the seeds from these crops, and may not go back to the seed company for up to a decade or more before purchasing more seeds or a new crop variety. The genetic engineering mechanism of sterile seeds is a complicated process involving the expression of three genes (repressor gene, recombinase gene and a toxin gene) and a reshuffling of the plant DNA after treatment with an inducer chemical. Sterility in the second generation is ensured if the seeds are treated with the inducer, usually an antibiotic like tetracycline before they are planted.
Since 1997 the first terminator strategy has been refined by researchers and there are now two different kinds of technologies developed as a way for large corporation to maintain control over their GM technologies. Both are "Genetic Use Restriction Technologies" or GURTs. The terminator gene technology is an example of a V-GURT and results in genetically engineered crops that produce sterile seeds when grown.
The second type is called T-GURTs, dubbed "traitor technology" by opponents. These engineered plants require chemical triggers to switch on or off important traits during growth. The crop's basic functions germination, flowering, ripening and immune deficiency rely on hormone chemicals and the plants have been genetically engineered to respond only to a specific corporation's agrochemical applied externally, failure to treat the seeds results in the seeds not growing at all.
There are serious ecological and health questions that need to be addressed with sterile seed technologies. V-GURTs are activated by treating large quantities of seeds by soaking them in kilogram quantities of tetracycline an antibiotic still used widely in medicine, this will rapidly increase tetracycline resistance in bacteria. It seems unscrupulous that the large life science companies would knowingly do this given the medical warnings against increasing antibiotic resistance worldwide. T-GURTs require using large-scale amounts of an inducer chemical (chemical hormone mimic) that will definitely impact other plants in the environment in unforeseen ways. Moreover, the presence of high amounts of toxin products (expressed ribosomal inhibitor protein) in seeds left accidentally in the fields year after year will have unknown long term affects on the ecosystem.
It is doubtful that farmers or consumers will still have a choice between sterile or non-sterile (hybridized or open-pollinated varieties) in the near future since a handful of other big Life-Pharma companies have been aggressively purchasing all seed producing companies since 1997 in an attempt to monopolize the market. By the end of the year 2000 the biotech-seed market was already dominated by less than a handful of large corporations. By 2001, the main six corporations (Syngenta, Bayer Aventis, Monsanto, DuPont, BASF and Dow) based in the U.S. and Europe controlled 98% of the market for GM crops and over 70% of the world's pesticide market.
The proposed use Terminator sterile seeds has infuriated critics who believe the technology will force farmers in developing countries to buy seed each year. The large companies producing sterile seed argue that the genetic manipulation is designed solely to protect their unique varieties not to subvert entire societies "way of life." The U.S., Canada, Argentina, and China grew 99% of the world's GM crops in 2002 with South Africa and Australia accounting for most of the remaining 1%. Another 12 countries grew under 50,000 hectares. Genetically engineered plant technology and associated agrochemicals are definitely aimed at the biggest and richest food producers and are not being created intentionally to subvert third world countries.
But unintentionally there are reasons to worry, crop geneticists who have studied the Terminator seed genetic modifications believe it is almost certain that pollen from crops with the Terminator trait will infect neighbouring fields of farmers who either refuse or can't afford the technology. Their crop won't be affected initially but when the farmers sow seed the following season they could find that a portion of their seed stock is sterile, the result of sterile pollen blown onto their crops from nearby Terminator fields. The resulting seed loss, crop yield loss, food security loss and potential increased human suffering may be quite astounding, all affecting the poorest farm communities. It has been estimated that 50% of the world's farmers are too poor to purchase commercial seed every year. Half the world's farmers feed 20 percent of the world's population or 1.4 billion people in Africa, Asia and Latin America. The potential risk, human cost and dire effects to entire societies make the Terminator gene technology unacceptable.
The public backlash associated with GURT technologies has been nothing less than incredible. Intense hostility and attempts to block the patents have occurred in several countries and even farmers from North America who are the most accepting of GM plants condemn this developing technology. The GM plant offers no advantageous characteristics to the consumer and farmer while threatening the survival of non-hybridized crops, it appears that the GURT technologies are being pursued in the face of huge opposition for purely economic control.
Syngenta was formed from the agrochemical merger of AstraZeneca (formerly Zeneca) and Novartis on November 13th, 2000. The next day the company won a Terminator patent approval, US Patent 6,147,282, "Method of controlling the fertility of a plant." With 1999 sales of $7 billion U.S., Syngenta is the world's largest agrochemical multinational, the third largest seed corporation. In a letter from the Zeneca Research and Development director, dated February 24th 1999, the company stated: "Zeneca is not developing any system that would stop farmers growing second-generation seed, nor do we have any intention of doing so." Moreover corporate competitors like Monsanto also bowed to public pressure in late 1999 vowing "never to commercialize sterile seed technology," Syngenta now controls at least six Terminator plant type patents and a host of new patents on genetically modified plants with defective immune systems. It seems that Syngenta is intent on creating plants which will not survive to a second generation, or even grow successfully during a first generation without the application of the company's own chemicals.
Other companies also have GURT technologies under development that could easily be turned into sterile seed Terminators, given the global market value for GM seeds alone in 2002 was estimated to be $4.25 billion, it is not surprising that each of the large biotechnology companies is racing at breakneck speeds to develop their own version of suicide seed. Seed sterility is a profitable goal for the multinationals with large investments in seed companies because close to 75% of the world's farmers routinely save seed from their harvest for re-planting.
The issue of terminator genes must be put into the larger context of genetically-engineered food crops. Use of genetically-engineered food crops to resist insects like Bt corn, on a large scale, places severe selection pressure on insect and pest populations making them super-resistant within a relatively short time period. The result is an increased risk that reduced yield and potential food shortages will occur more frequently. However, Bt corn with Terminator technology could be used exclusively until resistance appears; then it could be removed entirely from the world market place and replaced with another different resistant GM corn species until insect and weed resistance becomes widespread again, and so on. As long as the seed companies can develop transgenic plants with safe, novel resistance mechanisms quickly enough, they will maximize food yields. The use of the terminator technology ensures that outbreeding to wild relatives will not occur and that insect and pest resistance will never arise. Hypothetically, all farmers (globally or by continent) could switch over synchronously to the new pest resistance GM food crop in the same year. While many may be uncomfortable with a large food biotech company oligopoly, this would be one of the best ways to implement a global insect/weed resistance control strategy.
The best example of extrinsic risks in genetics (driven in this case by international politics) is the bioengineering of virulent bacteria and viruses for warfare. Research on chemical weapons and viral pathogens for biowarfare has continued since the end of World War II -- although it is useful to remember that biological weapons have been in existence since medieval times, when invading soldiers catapulted plague-ridden corpses over city walls to infect and destroy the besieged population.
However, so far biological terrorism has been rare in and the use of biological weapons during warfare has been limited. Japan first used biological weapons during the 1930s against China, and from 1980 to 1988 biological weapons were used during the Iran -- Iraq war by both countries. In 1942 British officials allowed the military to conduct anthrax tests on sheep just off the Scottish coast on Gruinard Island; today the island is still uninhabited and still infected with deadly anthrax spores. During the 1950's and 1960's the United States expanded its offensive biological warfare program initially started during World War II. In 1992 Dr. Kanatjan Alibekov, former first deputy directory of Biopreparat (the civilian arm of the Soviet Union's biological warfare program), defected to the United States. He revealed what some had already suspected, that Russia had an extensive offensive biological program, including its use of smallpox stock to make new deadlier bioweapons. This was the first indication that genetic engineering was being used to make deadlier "designer" viruses.
Twenty years ago only two countries -- the former Soviet Union and the United States -- actively developed biological weapons programs. Now at least 18 countries are reportedly known or suspect for biological weapons development. Countries with active bioweapons programs include Iran, Syria, Libya, North Korea, Taiwan, Israel, Egypt, Vietnam, Laos, Cuba, Bulgaria, India, South Korea, South Africa, China, Russia and the United States. In an increasingly global world connected by transcontinental travel it is likely biological weapons engineered for virulence would easily spread beyond the target country. That the indiscriminate use of biological weapons has not yet occurred is due largely to the inability to target bio-engineered weapons accurately.
The extrinsic risk involved here is that genomics will reveal the sequence of human and many viral pathogens, providing any group with the sufficient knowledge of genetics to begin designing bioweapon agents (bacteria or viruses) that target specific gene alleles in a given ethnic populations. Populations are known to have skewed gene allele frequencies for many cell proteins. The cell surface proteins to which viruses bind could be singled out as targets, cross referenced to human populations and engineered to a specific gene polymorphism with the ultimate goal of targeting virulence to specific populations.
The 1925 Geneva Protocol, appealing to "the conscience and the practice of nations," forbade the use of chemical and bacterial agents as offensive weapons that were "justly condemned by the general opinion of the civilized world." The 1972 biological weapons international convention describes biological germ warfare agents as "repugnant to the conscience of mankind." Dr. Joshua Lederberg, who received the Nobel Prize in 1946 for the discovery of gene swapping in bacteria, is a member of a working group of scientists who advise the American government on biological weapons and are actively trying to maintain an open dialogue with Russian biologists. He has stated: "There is no technical solution to the problem of biological weapons. It needs an ethical, human, and moral solution if it's going to happen at all." It would be naïve to think that the horror and ability to infect many countries along with the intended target would prevent the use of genetically modified biological weapons.
Extrinsic risks can also occur from genetic engineering of organisms during routine government funded research. Australian researchers recently demonstrated extrinsic risk when designing a contraceptive for mice for use in pest control when they accidentally created a genetically engineered mousepox virus with 100% lethality. Mousepox virus does not affect humans, but it was speculated that a similar genetically engineered virus with human genes would likely be both extremely virulent and lethal.
Preimplantation genetic diagnostics (PGD) are tests that screen for genetic flaws among embryos created by in vitro (in-glass) fertilization. Embryos from in vitro fertilization (IVF) can be tested for a variety of abnormalities (abnormal number of chromosomes, Down's Syndrome), sex determination and gene defects (cystic fibrosis, Duchenne muscular dystrophy, fragile X syndrome, hemophilia, retinitis pigmentosa, Tay-Sachs disease and others). The technique involves extracting one cell from the eight-cell embryo, then testing and freezing the embryo until the results of genetic testing are known. Fertility specialists can use the results of this analysis to select only mutation-free embryos for implantation into the mother's uterus; the technique is designed to avoid termination of affected gestations later in a pregnancy.
Before PGD couples at higher risks for conceiving a child with a particular disorder would have to initiate the pregnancy and then undergo chorionic villus sampling in the first trimester, or amniocentesis in the second trimester, to test the fetus for the presence of disease. If the fetus tested positive for the disorder, the couple would be faced with the dilemma of whether or not to terminate the pregnancy. With PGD couples are much more likely to have healthy babies. Although PGD has been practiced for years, only a few specialized centers worldwide offer this procedure.
In the future PGD could be coupled with gene therapy to correct the early embryo's defective genes. Treatment by gene therapy at this stage is enticing, since repair of 4-8 cells is much more easy to deal with than is the prospect of doing gene therapy on adults, who have on average about 100 trillion cells. Given that this is currently only a technical problem, it is likely that once gene therapy delivery systems are perfected, correcting diseases of IVF embryos, as well as early embryos in utero, will be feasible. Individual couples wanting "the best" for their children may be seduced with the prospect of correcting both disease and non-disease traits (enhancement of intelligence, height and body symmetry) in their offspring. The extrinsic risk is two-fold: First, the impact on society will be profound with a skewing of social ideas of what exactly "normal" intelligence, height, physical strength and beauty are; second, there will be a stratification of those who are enhanced and those who are not.
Nanotechnology is an emerging field using technologies and processes, materials, devices and structures that occur on the scale of nanometers (a nanometer is one billionth of a meter). The use of DNA derived tools in the fields of molecular and medical nanotechnology promises a plethora of medical benefits with potential applications to gene therapy.
Even in nanotechnology's infancy early stage products for medical treatment are being constructed. A "nanodevice" composed of a titanium oxide nanocrystals attached to short DNA fragments is being developed to target defective genes. After binding the nanodevice with DNA to its defective, homologous gene in the cell, the nanodevice is exposed to light; titanium oxide is photocatalytic and therefore can cut out the defective gene. Researchers developing this technology state that the titanium oxide DNA scaffolding also is amenable to attaching other molecules for repair (enzymes that would rearrange, copy or join DNA pieces) as a way to introduce a good gene copy.
This type of DNA-repair device does create a form of "active nanotechnology" with the potential to perform unwanted DNA manipulations if it were to enter an organism. Due to their extremely small size (under 70 nanometers in diameter), such devices would not trigger an immune response from the body, and the particles could disperse eventually from the tissues being treated and enter all cells, including germline cells. Since there is no way to turn off the repair enzymes, they could continue to rearrange and join DNA segments causing other serious genetic damage to sex cells (sperm or eggs).
The DNA used in gene therapy will likely consist of either short fragments or segments carried on viruses or other carriers (liposomes, synthetic polymers) that will be rapidly degraded inside our cells to short fragments. Research has shown that DNA injected intravenously into pregnant mice was detected in fetuses, suggesting that if used to deliver gene therapy treatments that the DNA fragments would dissipate and persist internally, affecting somatic and germline cells (sex cells). It is also known that short double-stranded DNA oligonucleotides are internalized into cells by endocytosis (pinching in of the outer cellular membrane) and easily crosses membranes before the majority is degraded. A small fraction does escape degradation. Gene modification by homologous recombination is one of the techniques that may eventually be used for gene replacement therapy. There is evidence to show that small, synthetic, single-stranded DNA fragments are capable of participating in homologous recombination in human cells and are incorporated into the genome. Gene therapy for treatments using millions of injected fragments undoubtedly has the potential to induce unwanted recombination events in germline cells.
There are extrinsic risks that at first may not be obvious with genetics but their use, development and widespread availability could easily lead to the exploitation of derived technologies with the application used in ways that are morally corrupt to the point of extreme abhorrence.
One of the advantages of genetics is the improvement in forensic methods to match criminals to violent crimes, rapes and murders or exonerate innocent individuals by DNA testing of crime scene evidence. Those committing crimes wishing to avoid being found guilty simply have to undergo gene therapy to alter a number of polymorphic sites known to be used in diagnostic DNA testing. The change of specific DNA markers would alter their diagnostic DNA profile when tested, introducing a level of doubt as a defense. Gene therapy could also be used to change the physical ridge pattern found on our fingers and thumbs or blood type cell antigens making crime scene fingerprint and blood matching useless. This presumes that 'underground' gene therapy treatments would be available.
Humans have used opiate drugs such as morphine and heroin for thousands of years to lessen pain and produce euphoria. The discovery of proteins called opiate receptors in the brain showed how drugs like morphine and heroin affect the brain and led to characterization of opiate-like chemicals produced in the body to control pain, immune responses, and other body functions. Research on opiate drugs has given rise to many discoveries that could revolutionize not only pain relief but also the understanding of addiction, reproduction, and the immune system. The opiate receptor is a protein located on the surface of nerve cells or neurons, which communicate with each other by releasing signaling chemicals called neurotransmitters. These chemicals attach to receptors on nearby neurons in the same way a key fits a lock.
With gene therapy it would be possible to alter the protein receptor genes expressed in specific regions of the brain for several different kinds of hallucinogenic drugs, changing them so that they would bind to simpler molecules, for example sugars or other small, inert, organic molecules that are cheap and abundant. Such gene therapy would result in substances that would cause neurotransmitter release in the same way that psychoactive drugs do. The ability to become euphoric on an ever-changing number of readily available, cheap, innocuous substances would make drug enforcement impossible. Other brain receptors could also be altered in this way as well.
Cannabinoid receptors in the brain respond to marijuana and do not require mind-altering substance or any other chemicals to activate. The cannabinoid receptor (CB1) is one of the brain's most plentiful, with multiple simultaneous activities of controlling mood, learning, perception of pain, memory, the immune system, stimulating the appetite and controlling nausea all at the same time. Unlike opiate receptors that are turned on by specific chemicals, cannabinoid receptors are already stimulated, signaling about 30-40% of the time. Cannaboid receptors often dominate other receptors in the cell by holding onto important activating proteins (G proteins) that regulate calcium ion channels. The CB1 receptor binds to the G protein and shuts down the calcium channel, keeping neurotransmitters inactive. In certain parts of the brain gene therapy could be used to alter the CB1 receptors to prevent its binding or introduce a protein agonist to bind the CB1, thus leaving the calcium channel open, with the effects of reducing pain, decreasing memory, and inducing a permanent marijuana-like high.
A second example is research into severe obesity, where brain scans have revealed that, like drug addicts, severely obese people have fewer receptors for dopamine, a neurotransmitter that helps produce feelings of satisfaction and pleasure. Scientists speculate that people overeat to stimulate the dopamine "pleasure" circuits in the brain, just as addicts do by taking drugs: "This is the first scientific contribution that the addictive pathways are deficient in the obese and it may explain their cravings," said Dr. George Blackburn, an associate professor of nutrition at Harvard Medical School. In animal studies exercise has been found to increase dopamine levels and to raise the number of dopamine receptors. Gene therapy could be used to increase the number of dopamine receptors by adding multiple gene copies. The treatment would be exploited by those who are only slightly overweight seeking a quick diet fix for their poor eating habits or as a way to avoid exercising. There are a number of brain functions for mood and personality that could be significantly altered in specific segments of society. Young adults may "experiment" with cannabinoid receptor alteration and young women worried about body image may find alterations to dopamine receptors an easily acceptable alternative. Widespread usage will have transformative social impacts on ideas of normalcy.
There are currently 6 billion people on the earth, with population predictions of over 9 billion by the year 2050. Control of population growth is a serious sustainability concern for some over-populated countries. Governments may consider using mass gene therapy to alter reproduction by linking it to a specific drug or inducing chemical. Much like the sterile seeds T-GURT technology developed in plants, similar gene therapy could be used to prevent functional gametes from developing, for example by altering key genes for egg maturation or sperm motility. Given as a mass public inoculation to adults or newborns, gene therapy targeting sex cells would ensure sterility and a zero population growth. Couples wishing to procreate would apply to the government for permission to conceive a child and be given the inducer chemical, or would otherwise remain reproductively sterile. This technology given the correct gene delivery vehicle (virus delivery in genetically modified plants or nanoparticles in water) could be turned into a clandestine weapon for genocide or ethnic cleansing.
Given the magnitude of the extrinsic risks it is clear that genomics and genetics can intersect with a number of other technologies with potentially destructive outcomes. The use of genetics applied to other areas creates a synergy and resulting applications that can have far reaching consequences when used in ways we may not be able to control. A full list of risk factors within these two categories should be compiled, to make it as accurate and complete -- from a scientific standpoint -- as possible. We must also make an effort to describe the risk factors in terms that are understandable to the public. Once this is done, undertaking three important tasks will become feasible: First, engaging the public in an informed and sustained dialogue about risk management options. Second, identifying the areas where proactive, precautionary risk control measures should be instituted by researchers and research sponsors, such as funding agencies. Third, identifying the areas where changes in law and regulations are needed.
A simple and familiar example of this typology is provided by the case of genetic screening. Here the benefits include taking precautionary health measures, adjusting one's lifestyle with the knowledge of special risk factors, and making informed choices about mating and reproduction. The intrinsic risk is the psychological damage that could be done to an individual by the gaining the knowledge that he or she is carrying certain types of defects, which carry the "sentence" of premature death, or debilitating disease, or social stigma. The extrinsic risk is the possibility that adverse effects will follow from others gaining access to this knowledge: effects on private health or life insurance coverage, employment prospects, and on judgments made by others about one's suitability as a mate.
Types of intrinsic risks inherent in any technological intervention -- using products of industrial chemistry, say, or DNA manipulations -- are, by definition, closely tied to the benefits we seek in making that intervention in the first place. For example:
From this we can derive an illustrative list of intrinsic risk factors associated with the above set of manipulations:
Extrinsic risks are the impacts that this ability almost certainly will have on a wide range of institutional subsystems outside the science itself -- law, ethics, religion, and politics. An illustrative list of extrinsic risk factors associated with the above set of manipulations is:
A further provisional accounting of intrinsic and extrinsic risks associated with genomics and genetics using the framework outlined above is given in Tables 1 and 2.
|Genomics Technology||Anticipated Benefits||Intrinsic Risks||Extrinsic Risks|
|Identifying medical responders||
|Genetic screening (karyotype, PND, microarray chips)||
|Assisted Reproduction / Prenatal diagnostics||
|Genetics Technology||Anticipated Benefits||Intrinsic Risks||Extrinsic Risks|
|DNA medical nanotechnology (active nanotech)||
|Gene modification of behaviour||
|Stem cell research||
|Pronuclear / Nuclear transplantation (cloning)||
|Convergence of technologies||
|Genetic engineering (non-human)||
Using the concept of risk helps us greatly to array systematically the risk factors involved in genomics and genetics. But of course it does not, and cannot, yield a simple decision rule to resolve difficult matters of judgment in this area. With each of these genomics techniques there are known competing risks and benefits and determining the level of the likely risks to benefits outcome is not an easy task open to a great deal of interpretation and speculation.
A good illustration of these difficulties is supplied by the matter of therapeutic cloning. Two opposing interpretations of the risk and benefit trade-offs here have been given by members of the academic community in Canada. Tim Caulfield made the case for permitting this form of cloning in the context of Bill C-13, arguing in effect that the future health benefits are substantial and that the downside risk could be controlled by effective regulation. FranÁoise Baylis and Jocelyn Downie have argued the opposite case, saying that the health benefits may be achievable in other ways and that the downside risk is too great. The difference between the two views is largely in the conception of the nature and the scope of the downside risk.
For Baylis and Downie permitting therapeutic cloning will make human cloning more likely, because it will generate technological advances in the art of mammalian -- and thus human -- cloning generally. This is an excellent beginning for an informed debate, which must be pushed further. Between these two cases Baylis and Downie, it seems to us, have the more persuasive argument, largely because the regulation proposed by Caulfield would hold sway only in Canada, whereas the techniques perfected by Canadian researchers would become the property of the global community, where no regulation is even imaginable at this point in time.
The risks posed by the internationalization of science are illustrated in the following report:
"A respected Chinese scientist ... Lu Guangxiu, 61, who heads a team of 60 scientists at a high-tech laboratory in Changsha, south central China, said last week she had created more than 80 embryos containing the genetic blueprint of an existing adult.... Lu also disclosed that she had created cultures of human cells capable of proving 'spare parts' for a variety of fatal human diseases.... In four cases, the embryos have been kept alive to the stage where they are clusters of hundreds of cells and would normally be transferred to the wombs of mothers if they were being used to create babies."
Unless and until effective international regulation of molecular biology applications is a reality, the precautionary approach suggests that therapeutic cloning should be prohibited by law in Canada, and that Canada should press the international community to establish appropriate and enforceable safeguards against human cloning.
We know that emerging branches of genomics and genetics holds significant promise for generating therapeutic treatments, pre-symptomatic disease treatment, replacement or regenerative tissue treatments and cures for a number of diseases. Emerging technology such as human cloning -- force us to examine the very essence of what it means to be human; stem cell research coupled with nuclear transplantation with the ability to reprogram cells into gametes to create new embryos from somatic cells confronts us with the morality of the value of life and what legal rights do all human somatic cells have.
Convergence of emerging technologies may give rise to extrinsic risks that are far beyond the capacity of our social and regulatory institutions to control or manage. The far reach of these issues demands that we enter into some form of informed dialogue to understand the implications and impact of these emerging technologies. With each new emerging technology the ability to ultimately exert control over every aspect of our humanity comes ever closer. While the intrinsic and extrinsic risks discussed here dealt mainly with individual choices, there should be consideration of the role and responsibility of society in seeking to minimize harm. Thus we have two competing value sets, the reduction in suffering and harm to individuals from adopting new emerging genomics technologies versus ensuring societal safety by a stringent precautionary approach that would delay or ultimately deny the benefits to those who require them the most.
The emergence of new technologies like pharmacogenomics, cloning or stem cell research should not automatically translate into availability, absence of regulation and commercialization of the technology without regard for public safety and well being. Genomics technologies have and are continuing to outpace the development of appropriate forward thinking policies in many of the areas outlined (the lack of regulation for genetic testing, medical privacy and genetic discrimination for example). The recent cloning of humans creating a number of embryos and the ensuing media frenzy reveals our current societal sensitivity that surrounds technologies that have the power to create, control, alter and manipulate life. Given the current status of mammalian cloning, we already know that there are tremendous potential risks for both the mother and child. Mammalian cloning has revealed that there are medical risks, severe problems of developmental delays, heart defects, lung problems, malfunctioning immune systems and accelerated aging. In one animal example that seems like science fiction come true, some cloned mice that were normal as young adults suddenly grew grotesquely fat. The current cloning techniques are not adequate to abolish the downside risks and provide a minimum level of safety and efficacy.
A precautionary approach is needed for emerging genetics technologies with applications providing cures, treatments and a means to alleviate human disease and suffering, the benefits of therapeutic treatments for adults should not be obstructed and allowed. Some technologies like pharmacogenomics, DNA testing and PGD may require only slight caution, while other areas of research such as gene therapy, therapeutic cloning research, and convergent genetic technologies should have a more rigorous precautionary approach applied to them in order to minimize the downside risks, as well as the extrinsic risks we may not yet be aware of. There is a need for an open, informed debate that must guide public policy about rapidly advancing genomics and genetics technologies.
Genomics gives rise to types of both intrinsic and extrinsic risks that are unique as well as exceptionally "potent" for individuals and societies. Some of the reasons are as follows. Both the potential benefits and the risks touch upon aspects of life that are at once intensely personal and private and, at the same time, crucial to social interactions. These include most of the factors that are thought to be important for individual happiness and social acceptance: appearance, pleasing personality, health, sociability, intelligence, attractiveness to mates, fecundity, livelihood, and on and on. As individuals, we each should have the choice of deciding whether or not we will pursue purely cosmetic alterations based on our notions and values.
However, the risks associated with genomics touch upon aspects of life that are fundamental to social organization: the concept of personal responsibility in law and religion, an individual's autonomy with respect to their parentage (the "accidental" character of genetic mixing in animal reproduction), the character of political freedom (the development of the "free" individual unconstrained by genetic heritage), and the great values of democracy: justice, equity, and equality. The level of genetics and genomic science does not give rise to any of these extrinsic risk factors today but there is a fear that generations from now, the human biology required for enhancement may be everywhere with the capability to transform society.
What is important -- given the sensitivity of these types of risks -- is that we look ahead to the capabilities that are undoubtedly sought-after now, and almost certain to be achieved in the future. The types of possible impacts in this domain are not those for which remediation after the fact is appropriate. On the contrary, the potential consequences inherent in these types are such that we must resolve to deliberate and act in a precautionary way, so as to prevent certain types of consequences from ever arising in the first place. Such deliberation must start within the academic community, where issues are clarified and posed in an appropriate way. Then, of course, it must move out to the public domain, where credible information resources should be provided to the public well in advance of engaging citizens in prolonged dialogue.
Society can manage genomics risks appropriately only if the scientific community becomes actively engaged in this process, by assuming its share of responsibility for their potential scope, well in advance of successfully achieving the practical objectives stemming from research. Under a system of innovation and research that separates the communities of experts in the usual way -- where media reports about scientific discovery elicit passing comments from a few "ethicists" ?, the results are utterly unsatisfactory, because the two rarely or never engage each other in public dialogue.
At the end of Mary Shelley's novel is a moving scene in which the creature delivers a eulogy while standing over his creator's lifeless body:
Fear not that I shall be the instrument of future mischief. My work is nearly complete. Neither yours nor any man's death is needed to consummate the series of my being, and accomplish that which must be done; but it requires my own.
Perhaps this may serve as an appropriate forewarning, at the beginning of our journey into genomics and genetics research, that will move us inexorably towards the fateful endgame of widespread genetic manipulation. Our capacity to engineer genomes is perhaps the most fateful of all human powers, in that the risks to be managed go beyond specific interventions, and reach into the very foundations of human civilization. Therefore we must be proactive in managing these risks, acting in a precautionary mode, rather than waiting for consequences to emerge before doing so.
from: Leiss, William and Powell, Douglas. Mad Cows and Mother's Milk: The Perils of Poor Risk Communication,
Second Edition. Montreal: McGill-Queen's University Press, 2004. pp.296-340.
 There is an excellent commentary by Harold Bloom in the Signet Classic edition and a full contextual analysis in Susan J. Wolfson's more recent edition.
 The Guardian. Philip Angell, US director of corporate communications of agro-chemical corporation Monsanto: "This technology might prove attractive." He added that it was "not very different from 'hybrid' crops", which do not reproduce." Online: http://users.westnet.gr/~cgian/guardian.htm (accessed March 16, 2004).
 Nobel Prize-winning scientist James Watson, who co-discovered the structure of DNA, admitted that his reaction to the cloning of Dolly was surprise that she had been cloned from an adult cell. The science show, Online: http://www.abc.net.au/rn/science/ss/stories/s10969.htm (accessed March 11, 2004); and John Carey, "Cloning's strange past-and stranger future." Online: http://www.businessweek.com/1998/05/b3563047.htm (accessed March 16, 2004).
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 Cloning of various animals as reviewed in: T. Shin et al., "A cat cloned by nuclear transplantation."
 K. H. Campbell et al., "Sheep cloned by nuclear transfer from a cultured cell line."
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 The Human Genome U133 (HG-U133) set consists of two gene chip arrays representing more than 39,000 transcripts derived from approximately 33,000 well-substantiated human genes. This set design uses sequences selected from large DNA databases (GenBank, dbEST, and RefSeq). Affymetrix Gene Chip Arrays. online: http://www.affymetrix.com/products/arrays/specific/hgu133.affx (accessed March 15, 2004)
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 The National Center for Biotechnology (NCBI) was established in 1988 as a national resource for molecular biology information, NCBI maintains public genome databases, http://www.ncbi.nlm.nih.gov/ ; TrEMBL and Swiss-Prot have been incorporated into the Universal Protein Resource or UniProt database maintained by the European Bioinformatics institute, http://www.ebi.ac.uk/swissprot/ (accessed March 12, 2004)
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 Supra note 23.
 CDC. Laura M. Beskow, Marta Gwinn, and Mark A. Rothstein, "Integrating Genomics into Public Health Policy and Practice." Online: http://www.cdc.gov/genomics/oldWeb01_16_04/info/books/beskow.htm (accessed March 11, 2004)
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 Pleiotropic gene: A gene that has multiple, apparently unrelated, phenotypic manifestations. An example is the "frizzle-trait" in chickens. The primary effect of this gene is the production of defective feathers, secondary effects include increased metabolic rate, decreased egg-laying, changes in organs (heart, kidney and spleen). Pleiotropic gene is synonymous with polyphenic gene. Ibid.
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 This is Francis Bacon's idea. See W. Leiss, The Domination of Nature, ch. 3.
 Carina Dennis, "The Bugs of War."
 The best example is the fate of the International Convention on Biological and Toxic Weapons, which came into force in 1974 but remains a "dead letter" because it has no inspection and verification protocol. Full information is available at: http://www.bradford.ac.uk/acad/sbtwc/ (accessed March 16, 2004).
 This ugly episode is related and documented in Stanton A. Glantz et al., The Cigarette Papers, ch. 8.
 For an overview see Leiss, In the Chamber of Risks.
 BBC News, "Women at higher risk of lung cancer." Online: http://news.bbc.co.uk/1/hi/health/2542725.stm (accessed March 17, 2004) ; WomenOf.com, "Women at higher risk of lung cancer." Online: http://www.womenof.com/Articles/hc0117002.asp (accessed March 17, 2004)
 Saying "smoking is a risk factor for lung cancer" can be confusing to some people because it is not the only risk factor for this disease, although it happens to be overwhelmingly the predominant one. The statements (1) "smoking accounts for 30% of cancer deaths," (2) "10% of regular smokers will get lung cancer," and (3) "smoking causes 75-85% of lung cancers," are all accurate.
 Brad Evenson, "U.S. scientists aim to build new life in a test tube," National Post, 22 November 2002, A3.
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