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THIRD WORLD NETWORK BIOSAFETY INFORMATION SERVICE 17 February 2003 Dear Friends and colleagues, RE: US SUSPENDS GENE THERAPY TRIALS Following the discovery that a second child treated in a French gene therapy trial for severe combined immunodeficiency disease (SCID) has developed a leukemia-like condition, the US Food and Drug Administration (FDA), in a precautionary measure, placed on “clinical hold” all active gene therapy trials similar to those of the French. FDA’s action comes on the back of a temporary hold on the enrollment of new patients into gene therapy trials that came into effect last year when a 3-year old French boy, undergoing the gene therapy trials under Dr Alain Fischer of the Necker Hospital in Paris, succumbed to cancer. This also prompted other European authorities to halt similar new gene therapy trials in their own countries until the problem was better understood. However, now that a second child (whose details are not disclosed) had come under the same leukemia-like side effect, the FDA has decided to take greater precaution by temporarily stopping about 27 US experiments that use retroviral vectors to insert genes into blood stem cells, similar to those in France, to cures illnesses such as SCID. Both the children are reported to be responding to chemotherapy and in stable condition but their long-term conditions remain uncertain. But FDA said it would consider allowing trials to proceed if retrovirus experiments happen to be the only option to people with life-threatening illnesses and this would be on a case-by-case basis with appropriate warnings given to the subjects. According to FDA gene therapy chief Dr Phil Noguchi, the action is prudent as “there are things going on here that we really don’t understand.” This is the third case in four years which exhibit the risk of gene therapy that scientists had long warned about. In September 1999, an American teenager died in a gene therapy experiment which was later criticized by the FDA for having violated multiple safety rules. As pointed out in the scientific article below, the hazards of gene therapy are many. Although regulations have tightened, the technical and scientific problems remain unsolved. Diseases are not understood, animal models are misleading, vectors for delivering genes are ineffective and unsafe and the effects of genes delivered cannot be predicted. As such, a comprehensive review of gene therapy is urgently needed. Below are three reports for your information: 1. FDA Places Temporary Halt on Gene Therapy Trials Using Retroviral Vectors in Blood Stem Cells, US FDA, FDA Talk Paper, Jan 14, 2003 2. Second Boy Receiving Gene Therapy Develops Cancer, By Rick Weiss, The Washington Post, Jan 15, 2003. 3. Genetically Modified Humans: For What and for Whom? By Dr. Mae-Wan Ho and Prof. Joe Cummins, ISIS Feature With best wishes, Lim
Li Lin and Chee Yoke Heong Email: twnet@po.jaring.my ----------------- REF: Doc.TWN/Biosafety/2003/J Item 1 FDA Places Temporary Halt On Gene Therapy Trials Using Retroviral Vectors In Blood Stem Cells Source: U.S. Food and Drug Administration, FDA Talk Paper, Jan 14, 2003 http://www.fda.gov/bbs/topics/ANSWERS/2003/ANS01190.html FDA Talk Papers are prepared by the Press Office to guide FDA personnel in responding with consistency and accuracy to questions from the public on subjects of current interest. Talk Papers are subject to change as more information becomes available. January 14, 2003 Media Inquiries: +1-301-827-6242 Consumer Inquiries: +1-888-INFO-FDA FDA PLACES TEMPORARY HALT ON GENE THERAPY TRIALS USING RETROVIRAL VECTORS IN BLOOD STEM CELLS Agency Action Provides Way for Patients to Continue Therapy Under Certain Circumstances if Additional Measures Taken In a precautionary measure, the Food and Drug Administration (FDA) today placed on “clinical hold” all active gene therapy trials using retroviral vectors to insert genes into blood stem cells. FDA took this action after it learned that a second child treated in a French gene therapy trial has developed a leukemia-like condition. Both this child, and another who had developed a similar condition last August, had been successfully treated by gene therapy for X-linked severe combined immunodeficiency disease (X-SCID), also known as “bubble baby syndrome.” Infants with X-SCID have a gene defect that leads to a complete lack of white blood cells that can fight infection. Without treatment, they die from complications of infectious diseases during the first year of life. The only treatment for this condition is a bone marrow transplant. In early results of the French study in which a normal gene is inserted into blood stem cells of patients with X-SCID, nine of the 11 children had promising results and could leave the hospital and lead relatively normal lives. After notification of the first case last year, FDA identified the three U.S. gene therapy studies that most closely resembled the French trial and stopped enrollment of human subjects in those trials. They remain on clinical hold, a condition which FDA can impose when adverse events or other safety questions arise during a clinical study. FDA’s continuing review of adverse event reports from all U.S. studies involving retroviral vectors has to date found no evidence of leukemia caused by the gene therapy. Moreover, the agency has to consider the potential risks of any experimental therapy within the context of the disease it may treat - in this case a devastating disease in children. FDA’s action includes a temporary hold on the enrollment of new patients in a subset of gene therapy trials that involve the use of retroviruses to insert new genes in blood stem cells, irrespective of the disease condition. The temporary hold reflects FDA’s appreciation that some of these trials involve patient populations and gene therapy products that may be appropriate to continue after they are updated to reflect this new risk information. FDA will consider and evaluate specific requests for clinical indications for fatal or life-threatening disorders for which there are no viable alternative treatments. In all cases, sponsors will need to inform treated and new subjects of the two adverse events, and will need to have a plan to actively monitor subjects for leukemia like events. FDA continues to review the data from the adverse event in France, as well as the risks and potential benefits of all ongoing gene therapy trials, and will continue to work closely with the National Institute of Health’s Office of Biotechnology Activities to oversee gene therapy studies in the U.S. The agency expects to hold an advisory committee meeting late next month to discuss the new adverse event in particular and retroviral gene therapy in general. Item 2 Second Boy Receiving Gene Therapy Develops Cancer FDA Responds to Event in France by Suspending 27 U.S. Studies Involving Similar Techniques By Rick Weiss, The Washington Post, USA, Jan 15, 2003 http://www.washingtonpost.com/ac2/wp-dyn/A56894-2003Jan14?language For the second time in four months, a child treated with an experimental gene therapy in France has developed a form of leukemia apparently caused by the treatment. The new cancer case, in a boy who was given new genes to cure a severe immune system deficiency, undercuts scientists’ initial hopes that the first case was a fluke, and calls into question the value of the radical treatment, which had been promoted as the first successful use of DNA to cure a disease. In response, the Food and Drug Administration yesterday suspended as “a precautionary measure” more than two dozen U.S. gene therapy studies that involve techniques similar to those in the French experiment. Three U.S. gene therapy studies that even more closely resemble the French experiment had already been on hold since the first leukemia case came to light in September. The new cancer case is a serious blow for an experimental field that has struggled for a dozen years to produce its first cure and which suffered a terrible setback in 1999 with the death of an American patient, Arizona teenager Jesse Gelsinger. The approach involves the delivery of new genes to take over for missing or broken ones. Gelsinger died in a gene therapy experiment at the University of Pennsylvania that was later heavily criticized by the FDA for violating basic safety rules. But until the recent leukemia cases, gene therapy had at least seemed safe when used in accordance with approved protocols. Now, scientists said, that sense of safety has been undermined. “When the first leukemia showed up, we as a community were certainly upset and concerned about the patient,” said Joe Glorioso, president of the American Society of Gene Therapy and chairman of molecular genetics and biochemistry at the University of Pittsburgh Medical Center. “But when the second event happened, that really is a red flag.” Nonetheless, Glorioso and others noted, no cases of leukemia have been documented in any of the thousands of other people who have received some form of gene therapy, which suggests that the risk may be specific to this particular disease or treatment plan. Researchers said they held out hope that they will learn how to modify the treatment so it can still be used in children born with the boys’ life-threatening disorder—severe combined immunodeficiency, or SCID. Affected children can die from even minor infections, and the only cure—a bone marrow transplant from a well-matched donor—is unavailable for many. “We continue to see gene therapy as a promising therapy for all those who have not benefited from current technologies,” said Philip Noguchi, acting director of the FDA’s office of cellular, tissue and gene therapies, which regulates gene therapy experiments in this country. Noguchi praised the leader of the French study, Alain Fischer of the Necker Hospital in Paris, for promptly informing the FDA about the new leukemia case last month. The setback became public yesterday when the FDA placed a “clinical hold” on all U.S. gene therapy experiments that, like the French experiment, use retroviruses to deliver new genes into blood stem cells. The FDA hold demands that studies already underway be stopped and enrollment of new patients be suspended. Noguchi estimated that 27 such trials have been approved in this country and are at various stages of patient enrollment or testing. The agency will assess the latest data at a Feb. 28 meeting, he said, but it may lift the hold on some studies before then if it believes patients are more likely to be harmed by the shutdown of a study. Few details about the new case were available yesterday. The boy was one of about 11 children treated by Fischer in the past several years, nine of whom Fischer has said appear to be cured of their immune system disease. The treatment uses retroviruses to deliver a crucial immune system gene to blood cells. Glorioso said yesterday he had been told that the latest leukemia case involved a boy who was admitted to a hospital in Louisiana, suggesting he may be an American who was treated in Paris. In both leukemia cases, tests showed that the cancer was apparently triggered when the newly delivered gene disrupted a nearby gene whose job is to help prevent cancer. Both boys have been treated for their leukemia and are “stable,” Noguchi said. Staff researcher Lucy Shackelford contributed to this report.
Genetically Modified Humans: For What and for Whom? By Dr. Mae-Wan Ho and Prof. Joe Cummins, ISIS Feature A longer, referenced version of this article is available on ISIS members’ website (http://www.i-sis.org.uk) Promises and perils Gene therapy involves introducing genes into human cells in order to cure diseases. Billions have been invested, and hundreds of clinical trials carried out since 1990, mostly in the United States, but there has not been a single documented case of the miracle cure that was promised. It took the death of a healthy teenager Gelsinger in an early phase clinical trial in September 1999 to alert the public to the hazards of gene therapy. The US Food and Drug Administration (FDA) and the National Institutes of Health (NIH) responded to widespread concern. Clinical trials were suspended. A public enquiry turned up 652 cases of serious adverse events that went unreported, along with seven other deaths. David Baltimore, Nobel laureate and president of the biotech company Caltech with interests in gene therapy, declared, “ I disagree we’ve had any benefit from gene therapy trials so far, many of us are now asking, what the hell are we doing putting these things into people?” Administrative changes were put in place amid calls for more research, and clinical trials resumed with further promises. Although more stringent regulation can tighten up the protocols and ensure quality control, the inherent technical and scientific problems remain unsolved. Some of the necessary research that should have been done long ago is only now being carried out, revealing findings that confirm our worst fears. These problems are not new. The NIH’s 1995 report documents a plethora of scientific and clinical risks associated with gene therapy research, many highlighted independently in an ISIS report. The NIH expert panel found that all gene transfer vectors were ineffective and little is understood on how they interact with the host. Basic studies on disease pathology and physiology have not been done. It was not possible to extrapolate from animal experiments. In cystic fibrosis, cancer and AIDS, animal models do not have the major manifestation of the human disease. Gene transfer frequency is extremely low. There were no controls, and biochemical or disease endpoints were not defined. The panel concludes, “only a minority of clinical studies... have been designed to yield useful basic information”. It expressed “concern at the overselling of results of laboratory and clinical studies by investigators and their sponsors, either academic, federal, or industrial, leading to the widespread perception that gene therapy is further developed and more successful than it actually is”. Gene therapy, genetic determinism and eugenics Gene therapy is currently directed towards changing the genetic makeup of the cells in the body of an individual only (somatic gene therapy). Most countries outlaw gene therapy on germ cells (germline gene therapy) - which would change the genetic makeup of the next generation - on account of the its obvious eugenics implications. But there have nevertheless been calls for gene therapy on the unborn and on human embryos, all on the back of the publicity generated by the human genome project. Among the promises of the human genome project and genomics research are the possibilities of replacing ‘bad’ genes in gene therapy, including germline gene therapy, of ‘genetic enhancement’ and ‘designer babies’ to create superior human beings. In reality, the only concrete offering from the human genome sequence is hundreds of patented gene tests. The high costs of the tests have prevented them from being used in cases where it might benefit patients in providing diagnosis. At the same time, healthy subjects who testing positive are likely to suffer from genetic discrimination and risk losing employment and health insurance. The value of diagnosis for conditions for which there is no cure is highly questionable. The claim to identify putative ‘bad’ and ‘good’ genes is also fuelling the return of eugenics, which has blighted the history of much of the 20th century. This is exacerbated by the dominant genetic determinist mindset that makes even the most pernicious applications of gene technology seem compelling. A prominent band of scientists and ‘bioethicists’ are advocating human genetic engineering, not just in ‘gene therapy’ for genetic disease, but in positively enhancing and improving the genetic makeup of children whose parents can pay for the privilege, and have no qualms about human reproductive cloning either (see “Why clone humans?”, this series). The United States Food and Drugs Administration suspended an experiment in gene therapy because of concerns that it might alter the germ line, a possibility many have pointed out previously. The recombinant DNA Advisory Committee (RAC) of the National Institutes of Health met to consider the implications, regarded the risks to be ‘extremely low’ and germ-line modification acceptable as one of the ‘side-effects’. Meanwhile, researchers isolated male germ-line stem cells from the testis of mice and genetically modified them in vitro. The modified stem cells were then injected into the testes of genetically infertile mice, which the cells successfully colonised, and matured into sperms. This is so easily done that it may become the method of choice for all genetic engineered animals in future, including human beings. The testis of genetically infertile mice is so readily colonised by the male germ-line stem cells that it is an open door to corporate control of male reproduction. It has already been suggested that human males undergoing irradiation and chemotherapy treatments for cancer that destroy stem cells could have their male germ-line stem cells removed and frozen, to be re-transplanted after the cancer is eradicated. This is a short step from genetic manipulation of the male stem cells in vitro. In vitro fertilisation, human nuclear transfer cloning, surrogate motherhood, have all passed with relatively little comment from the establishment, as these were all aimed at manipulating reproduction in women. Adding male reproduction certainly increases the possible routes for germ-line gene therapy (see Box 1). Germ-line gene therapy has enormous impacts on the social fabric of human societies, and should not be allowed in the name of ‘scientific progress’, particularly as it is based on a discredited, outmoded paradigm that has largely ignored both physical risks and ethical implications. Box 1 Routes for Germline Gene Therapy Via female germ cells and embryos · Injecting naked DNA into egg or embryo · Transducing eggs by retroviral vector · Transducing embryonic stem cells by retroviral vector and injecting transgenic stem cells into blastocyst embryos · Transducing adult stem cells and injecting transgenic stem cells into blastocyst embryos · Transducing adult cells by retroviral vector and transferring transgenic nuclei into ‘empty’ eggs Via male germ cells · Transducing sperms by retroviral vector and fertilizing eggs in vitro · Transducing male germline stem cells with retroviral vector and injecting transgenic stem cells into testis to develop into sperms Gene therapy, how and for what? In gene therapy, an artificial construct - consisting in the minimum, of a promoter driving the expression of a gene, and the gene itself - is delivered, either by viral vectors, or as naked DNA into cells. There are two main ways to carry out gene therapy, ex vivo and in vivo. In the ex vivo procedure, the constructs are transfected (or transduced) into cells outside the body, and the resulting transgenic cells are reintroduced into the body. In the in vivo procedure, the constructs are introduced into the body by numerous routes depending on the locating of target cells, emphasizing the ease with which cells take up foreign DNA. These include rubbing on the skin, applying in drops to the eyes, inhalation, swallowing, injection or perfusion into the bloodstream or directly into the tissues such muscle or solid tumours. The only limited success stories so far have been associated with the ex vivo procedure, which avoids most, if not all the risks of in vivo procedures. In April 2002, a team in London’s Great Ormond Street Hospital in Britain used gene therapy to cure a child with X-linked severe combined immunodeficiency disease (SCID). They followed the approach taken earlier by the team at the Hospital Necker-Enfants Malades in Paris, which involved ex vivo manipulation of bone marrow stem cells. The identification and successful isolation of stem cells (both adult and embryonic) may make ex vivo gene therapy the preferred procedure for some diseases. Four main types of disease are targeted for gene therapy: rare single-gene inherited disorders such as cystic fibrosis and sickle-cell anaemia, multi-factorial disorders such as cardiovascular disease and diabetes, cancers and infectious diseases. Among the first candidates for gene therapy was cystic fibrosis, a mutation in the gene, cystic fibrosis transmembrane conductance regulator (CFTR). But 12 years on, there has been no success. It is difficult to deliver the vector to the cells, there’s lack of persistent gene expression, while immune responses developed to viral gene products, transgenes, or the cells targeted by the vectors. Furthermore, mice with deletion of the CFTR gene or the common human CFTR mutations do not develop lung diseases like people. Multi-factorial disorders, like coronary heart disease or diabetes, involve many genes and are strongly influenced by environmental factors. Studies from Finland, US to China have all documented the overwhelming influence of diet and exercise in reducing type 2 diabetes as well as heart disease. In 2000, the American Heart Association (AHA) expert panel on clinical trials of gene therapy in coronary angiogenesis found gene therapy unsatisfactory, especially in comparison to conventional treatments, and expressed serious concerns over safety. Hazards of gene therapy One of the major technical hurdles for delivering foreign genes is the form in which the constructs are delivered. Although naked DNA is widely used for modifying germ cells, this does not work as well for somatic cells therapy, for which viral vectors are routinely used. The ideal vector would possess the characteristics listed in Box 2. Unfortunately, such an ideal vector has not yet been developed. Plasmid vectors are easy to produce and manipulate and capable of stably transducing cells. But they are inefficient in delivering transgenes to non-proliferating cells - which constitute most of the cells in the body - and can cause immune responses directed against CpG repeat sequences that are plentiful in plasmids of bacterial origin. All the problems of gene delivery are the same as those involved in creating other GMOs (see “GMOs 25 years on”, this series). Box 2 The Ideal Vector · Is easily produced in pure forms at high titres (yields) · Targets genes to specific site in the genome · Tranduces non-proliferating cells in vivo efficiently and stably · Enables long term expression of transgenes without toxic effects, inflammation or immune responses · Capable of tissue-specific targeting and transgene expression · Allows regulated transgene expression There are several kinds of viral vectors, all of which carry risks of generating new viruses by recombination, or by activating endogenous viruses. As they insert into the genome at random, they can cause genetic disturbances (position effects) including cancer. In addition, some are immunogenic, and can trigger acute fatal reactions. The main vectors used are as follows. Retroviral vectors such as murine leukaemia virus-derived vectors, were among the first used, but are no longer regarded as first choice because of several drawbacks. Low titres, inability of virus to infect non-dividing cells, lack of stable expression and recombination within cells are feared to cause activation of pre-existing, dormant retroviruses. Adenoviral vectors were used for epithelial cells specifically, and was the first choice for cystic fibrosis. They can infect non-dividing cells, but not stem cells, so treatment has to be repeated at intervals. The vector is immunogenic and even the first application can cause inflammatory events. After repeated applications, the cells will no longer become infected. The teenager Gelsinger died from a high dose of adenovirus, leading to liver failure followed by multi-organ failure. Post-mortem revealed that many organs were infected with high concentrations of adenovirus, contrary to the anticipated cell-specificity of adenovirus infection. As with retroviral vectors, gene delivered with adenoviral vectors are frequently shut down. Adeno-associated viral vectors (AAV) are not pathogenic, and are thought to integrate at a defined position in chromosome 19. However, this site-specific integration is linked to the viral rep gene involved in viral replication. Immune responses occur also against AAVs. Moreover, a helper virus (usually herpes simplex or adenovirus) is required for AAV production, with danger of contamination as well as recombination to generate infectious viruses. Recently, researchers in the Department of Medicine, University of Washington Seattle, reported that the AAV does not integrate at specific sites. The AAV integrated into at least six different chromosomes. Although it was most frequently found in chromosome 19, the insertion was not at the specific intended site. Furthermore, insertions were “associated with chromosomal deletions and other rearrangements”, or genome scrambling. In another experiment, newborn transgenic mice with the mucopolysaccharide storage disease MPSVII were treated with recombinant AAVs carrying the enzyme that breaks down the mucopolysaccharide. A high proportion of the mice were found to develop liver and other cancers. The cancers were found to be specific to rAAV, as they were absent in mice with bone marrow transplant and in transgenic mice carrying the same enzyme cassette but without the rAAV. Lentiviral vectors, a subgroup of retroviruses, are capable of infecting non-dividing, but not truly quiescent cells. The AIDS associated virus HIV-1 is currently the candidate, after disarming the genes that cause disease. However, cell lines used for packaging may contain the disarmed genes, and give them back to the vector to generate pathogenic viruses. Like other retroviruses, these might activate endogenous retroviruses within recipient cells. Apart from these main classes of viral vectors, others have been developed, including herpes simplex virus and baculovirus, an insect virus that’s being modified to control insect pests in agriculture, and has been found to infect all kinds of mammalian cells. Even bacterial pathogens that can gain access into mammalian cells are being exploited as vectors, including Agrobacterium, widely used in genetic modification of plants, that was also found to transfer genes into mammalian cells. There is no limit to the dangerous agents that are being developed for gene therapy. Researchers in Heinrich-Pette-Institute, Hamburg, and Hannover Medical School, and their colleagues found that a retroviral vector carrying a marker gene, thought to be ‘biologically inactive’, actually induced leukemia in all the mice. The disease appeared to have resulted from a combination of the vector inserting in a position that activates a cancer gene and the transgene product interfering with cancer suppression. Although cancer itself is a risk of gene therapy, it is also the major target for gene therapy, for economic, if not good medical reasons. Gene therapy for cancer Cancer gene therapy has indeed taken over as the more active research area. A recent review states, “Although no cures can consistently be expected from today’s cancer gene therapy, the rapid progress may imply that such cures are a few short years away.” Cancer gene therapy targets cancer cells, cancer blood supply, the immune system and the bone marrow. One of the main candidate genes is the tumour suppressor gene p53, which induces cell death if DNA damage is extensive. Viral-mediated p53 gene therapy is in clinical trials with certain lung cancer and head and neck cancers. Another candidate is the ‘suicide gene’. This gene kills cells as it codes for an enzyme that converts a precursor drug to a toxic compound. The suicide gene is delivered to the target cells in a viral vector by injection before the precursor is given. The Herpes Simplex Virus (HSV) thymidine kinase is an example, it adds a phosphate group to the drug ganciclovir, 1000 times more efficiently than the mammalian enzyme. This blocks DNA synthesis, leading to cell death. Clinical trials are already taking place. Anti-angiogenic gene therapy uses inhibitors of blood vessel formation in tumours. Another approach is through genetic enhancement of anti-tumour immune responses by modifying immune cells. Cytokine-based therapy aims also to enhance the immune response to tumours. The genes used include those encoding the interleukins, IL -1b, IL-2, IL-4, IL-12, as well as GM-CSF and IFN-g. In clinical trials, a partial clinical response has been recorded in some of the patients. Simplistic approaches to complex reality The profusion of cancer gene therapy reflects the desperate attempts of the simplistic gene-centred science to cope with the complex reality of the organism. Decades of cancer research focusing on molecular genetics have brought us no closer to understanding the causes of cancer while many cancers have been increasing at alarming rates. The stepwise development of human cancer is clinically well-recognised: initiation, promotion and progression, but trying to establish causal links between genetic alterations to different disease manifestations is something else. One of the hallmarks of cancer cells is genetic instability, both at the level of single nucleotides and the chromosomes. Thousands of point mutations and small deletions are typically present in cancer cells, as well as large-scale chromosomal disturbances. A cancerous cell does not stop dividing. Cell division is a complex process, involving not just precise copying of the genes but also their exact distribution to the two daughter cells so that each has two copies of every chromosome. Anything that disturbs this process can result in genomic imbalance. Damage to the genes that monitor the intricate copy and delivery process, the so-called guardians of the genome, can result in an altered chromosome balance in the daughter cells. Mutations in those key genes can initiate chromosome imbalance, so there may be a role for gene mutation in cancer. However, many other disturbances can start the process going wrong, such as chemicals from the environment, radiation or any form of stress, or indeed, stray foreign DNA jumping into the genome, as in gene therapy. It doesn’t have to be a gene mutation. Once genomic imbalance starts, it will tend to get worse: further disturbances to cell division will result from a positive feedback effect. However, this is counteracted by the reduced survival of disturbed cells and the body will tend to get rid of them, until some eventually escape the immune system and grow out of control. There does seem to be a positive correlation between the number of chromosomal alterations within a tumour and the malignant potential of the cancer. As every cancer is genetically different, it will be very difficult to target cancer cells with specific drugs, let alone specific genes. So the key is prevention. Recognition of the diverse factors that can disturb cell division means that the multitude of chemicals that pollute our environment must be screened for their capacity to induce chromosomal imbalance. Most of these don’t cause mutation, but may well disturb chromosome separation. Finally, the phenomenon of cancer remission needs to be much more thoroughly investigated. Remissions can occur after various types of stimulus to the whole body, such as change of diet or life-style, and many other non-specific influences. Cancer is primarily a systemic disease of the whole organism, and only secondarily a disease of particular cells or of genes in those cells. The same kind of simplistic approach characterises other forms of gene therapy. The expression of the introduced gene is not the only, nor the main problem, its regulated expression within the body is the key to normal functioning. Unfortunately, most foreign genes are introduced with aggressive viral promoters that simply make them over-express in an unregulated way. The underlying assumption is that the single gene product is necessary and sufficient to provide a cure. But this does not even work for so-called single gene disorders. Helge Grosshans of Heidelberg University, Germany, has said it well: “Gene therapy follows a simple principle: causal therapy instead of symptomatic treatment. Accordingly, expectations were high....By now, however, it has become evident that particularly in those cases where the idea of “causal therapy” appears most appropriate, i.e., monogenic diseases, success is minimal. This is due, among other factors, to the cell being a very complex and dynamic system. A change in the genetic make-up that causes a cellular defect also brings about a number of compensating mechanisms. Mere addition of the “health” gene does not automatically re-create the original situation, because the compensatory mechanisms will not necessarily be turned off again.” Also, “A newly synthesised normal protein will appear abnormal to an immune system that has never been exposed to it”. In other words, the cell, and ultimately the entire organism functions as a whole, so practically every part of it will have changed when even a single gene is mutated. Consequently, restoring that gene is unlikely to put things right, and may even result in the gene product being targeted by the body’s immune defence. Most of all, the procedure of gene therapy is itself hazardous: “The additional steps of gene therapy, such as integration and expression, would present additional problems and safety risks. A therapeutic chemical can be broken down and will be eliminated from the body within a certain period of time. Foreign DNA, on the other hand might stay in the body until death and even be transferred into additional cells or passed on to future generations.” The simplistic gene-centred approach has failed because it is fundamentally at odds with the complex reality of the organic whole. By contrast, many indigenous cultures all over the world never lost touch with the organic reality that encompasses an entire way of life. Contemporary western science is beginning to rediscover this sense of the whole across the disciplines. It is a challenge for western and indigenous scientists to work in equal partnership towards restoring sustainable, healthy ways of life to all.
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