Recent developments in gene transfer: risk and ethics
BMJ 2005; 330 doi: https://doi.org/10.1136/bmj.330.7482.79 (Published 06 January 2005) Cite this as: BMJ 2005;330:79
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EDITOR – We congratulate Jonathan Kimmelman on providing a comprehensive discussion about the risks and ethics of gene therapy.1 It is certainly true that we cannot predict the future, but it is also important to point out that the risks should be weighed against the complete lack of alternative options for many of the diseases discussed.
The two cases of T-cell leukaemia in the X-linked severe combined immunodeficiency gene therapy trial are presented as typical examples of malignant transformation. However that treatment involved the modification of immature stem cells, which may present additional risks.2 Much work is ongoing in vector design to lessen these risks. Relative risks and toxicities are also likely to be linked to the disease type and target cell. For non-lethal disorders such as the inherited retinal dystrophies, minimising risk is of even more importance. However, gene transfer to a post-mitotic cell such as a photoreceptor using a vector with limited genomic integration, such as recombinant adeno-associated virus, is much less likely to be mutagenic.
Finally the risks of gene therapy must be weighed carefully against the risks and efficacy of existing treatment. One should not forget the significant morbidity and mortality associated with conventional therapies such as organ transplantation, which are no longer considered experimental.3 The difficult balance is to steer a path between the ethical application of new untested strategies with the potential to improve healthcare, and a position of caution. As with conventional medicines, the risks and ethics of gene therapy should probably be reflected in this light.
1. Kimmelman J. Recent developments in gene transfer: risks and ethics. BMJ 2005; 330: 79-82.
2. McCormack MP, Rabbitts TH. Activation of the T-Cell oncogene LMO2 after gene therapy for X-Linked severe combined immunodeficiency. N Engl J Med 2004; 350: 913-22.
3. Newstead CG. Assessment of risk of cancer after renal transplantation. Lancet 1998; 351:623-8.
Robert E MacLaren, MRC Research Fellow, Division of Molecular Therapy, Institute of Ophthalmology, UCL, London EC1V 9EL
Robin R Ali, Professor of Human Molecular Genetics, Division of Molecular Therapy, Institute of Ophthalmology, UCL, London EC1V 9EL
Adrian J Thrasher, Professor of Paediatric Immunology, Molecular Immunology Unit, Institute of Child Health, UCL, London WC1N 1EH
Competing interests: None declared
Competing interests: No competing interests
Jonathan Kimmelman presents a good overview of the present concerns in gene therapy and gene transfer. There are two key points that I think he misses.
One relates to the gap between the actual capabilities of present scientific knowledge within present legislative frameworks and the public's perceptions and hence expectations and fears. For instance, designer babies are not possible within either the science or lawful allowances. But that does not prevent media speculation about them.
The second point relates to the role of a patient signing up for phase 1/ safety trials. I think, to say "many severely ill patients construe trials as 'therapy'" insults both their awareness and altruism in participating in these trials as well as undermines the work of the regulatory agencies spending considerable time and effort to prevent miscommunication or setting of wrong expectations.
Perhaps better and responsible scientific communication aimed at the general public will help, with the choice of media being as important as the tone and themes of the message.
Competing interests: None declared
Competing interests: No competing interests
Dear Sir,
Just as people believe that there is a pill for every ill, we have been hoping that with the unraveling of the genome most of our knotty problems would vanish into the thin air. The truth is otherwise. I do not think that the genome would make life any easier for either the doctor or the patient in this field, at least in the foreseeable future. The present paper is a good example of this.
The first surprise has been that instead of the projected 100,000- 150,000 genes, the final picture gives us just about double the number of genes compared to a round worm-around 30,000-40,000 genes. Obviously, there are not enough genes to go round giving a gene for every human ill! On the contrary, prior knowledge of the genome would certainly make life miserable for the unfortunate person who might inherit some of the killer genes. While the gene's absence reasonably rules out the future occurrence of that disease, its presence, in no way, ensures that the disease would manifest for certain. The penetrance of the gene depends, to a great extent, on the environment. However, the child who knows its genome has to live with the Damocles' sword on its head all its life! Our dreams in this filed have never been realized. The reality is otherwise. My predictions in this field have come true!1
Time evolution in any dynamic system, like the human body, does not depend on partial knowledge of the organism, like the genome. Instead, it depends on the total initial knowledge of the organism. In case of man the total knowledge should include the phenotype (body characters like height, weight, BMI, BP, Cholesterol etc), the genome, and, most importantly, his consciousness. Mind, body and the genotype together make a man and all predictions of the future would be wrong if not based on all these three. We have been all along predicting the unpredictable in medicine.2
In the early 50s, there was a real war of words between two giants in the field of hypertension, Sir George Pickering and Lord Platt, regarding the genetic basis of hypertension. While Sir George was emphatic that hypertension could only be a polygenetic trait, Lord Platt argued that a single gene must be the cause of hypertension. This led to both writing extensively in The Lancet that at one stage, a serious reader had to ask the editor for a moratorium on their views! Time has proved both to be partially right! While there are single gene defect rare congenital hypertensive disease states like the Liddle's syndrome, the common variety of hypertension, the primary hypertension, is definitely polygenetic in nature.
Little known work of the Nobel laureate, Baraba McClintock, shows that genetic code of an organism "is not a static blueprint that can be read off like a book, but flexible, dynamic code responding to the surrounding environment". Her notion of the dynamic genome, expressed as the "jumping genes" has revolutionized genetics!3 Interestingly, Barbara has said that she came to this conclusion by "listening" to her corn plants and trying to see the world from their perspective.
We need more such thinking scientists in the field human genetics to lessen the sorrow of the prior knowledge of the genome in the future generations. "Happiness is living dangerously" is a thought-provoking adage in an English Primary School. Man is happy in this world only because man does not know his future. Now that the genome is threatening to become a reality, many would be miserable indeed!
. From the "thrifty" genes that we have inherited because of the thousands of years of scarce food, we have, in the last one hundred odd years, put ourselves in the food plenty atmosphere. This gene-food mismatch has been responsible for many a human illness. Genotype-phenotype interaction could be more important than the role of the gene alone. 4 To give an example it is almost impossible to assign a role to individual genes in a mosaic like hypertension. Even our attempts to assess gene therapy in modulating and controlling blood pressure have come to naught so far. Although it would be an ideal situation if gene therapy could control diseases on a long term basis, avoiding the risk of drug side effects on life long therapy as also to avoid the problems of non- compliance. But this utopia still remains a mirage in 2004 as shown in this article. Man lives on hope and we hope that one day we will be able to crack the nut. The pace of gene research is mind boggling, to say the least. 5, 6
Conclusions:
We are back to the square one. As stated earlier, our modern medical research is linear and reductionist. The whole need not be the sum total of the bits. The whole remains a whole and works like a whole. Genotype, phenotype, and the human mind must be assessed in Toto to solve any problem of mankind. No short cuts would help. In the distant horizon is the new science of chaos and fractals that would integrate all these in the non-linear holistic future research. Already some progress has been made in this direction.7, 8.
BIBLIOGRAPHY.
1. Hegde BM. Genes, dreams, and realities. Postgraduate Medicine (book) ed. Munjal YP. API Books 1999.
2. Firth WJ. Chaos-Predicting the unpredictable. BMJ 1991; 303: 1565-1568.
3. Wertheim M. Feature. S.G.I.Quarterly 2001; 26: 2-8.
4. Tiago AD, Nkeh B, Candy GP et. al. Association study of eight candidate genes with rennin status in mild-moderate hypertension in Africans. Cardiovasc.J.S. Afri. 2001; 12: 75-80
5. 6. Warnock DG. Genetic forms of human hypertension. Curr. Opin. Nephrol. Hypertens 2001; 10: 493-499.
6. Smithies O. Quantitative genetic variations in essential hypertension. Harvey Lectures 1999-2000; 95: 1-20
7. Hegde BM. Chaos- a new concept in science. Jr.Assoc. Physi. India. 1996; 44: 167-168.
8. Hegde BM. Heart Rate Variability (HRV) - a non-linear measure.Kuwait. Med. J 2003;35:208 Yours ever, bmhegde
Competing interests: None declared
Competing interests: No competing interests
Gene doping: besides risks and ethics of gene therapy.
Dear Editor,
Recent advances in biotechnology have disclosed new and revolutionary therapeutic perspectives for the treatment of inherited pathologies and single gene disorders (1). Since the early '90s, biotechnology companies have developed and tested innovative gene therapies, originally intended to treat patients with severe congenital pathologies, which could also embrace sport to boost athletic performances. Gene doping is a sinister option on the theme of doping (2). Gene therapies stimulating erythropoiesis and improving the aerobic performances, along with transfection of genes supposed to be used in patients with degenerative muscle diseases and capable to enhance the muscular output are supposed to be attractive alternatives for traditional performance-enhancing drugs, like human recombinant erythropoietin and anabolic agents. There are several reasons that predict easy success for this new form of cheating. Transfection of genes virtually identical to those naturally represented in the human genome should outweigh the problem of positivity to antidoping testing, making gene doping almost undetectable by traditional laboratory techniques. Then, as gene doping is expected to exhibit long- lasting or perpetual effects, abolishing the need for repeated administrations of exogenous pharmacological agents, athletes might consider it a more attractive option to traditional doping.
Although there are as yet no conclusive evidences of genetic manipulation of athletes, gene doping might become a serious concern for the scientific community and for the public health, as already highlighted by the World Anti-Doping Agency (2). Gene therapy is not safe from side effects, most of which are hardly predictable and potentially deleterious. The onset of severe complications might be ethically justified in patients with serious, life-threatening disorders; however, such a risk is unacceptable in otherwise healthy individuals, who only seek to enhance athletic performance or fitness. Then, such treatments are currently considered almost impossible to reverse; early athletic benefits might later turn into serious and unpredictable complications. The report of two developed case of leukemia after retrovirus-mediated gene transfer to treat X linked severe combined immunodeficiency, recently appeared on this Journal, further reinforces this concern (3), as risks and ethics of gene doping outweigh largely those of the gene therapy.
As we proceed in comprehending the molecular mechanisms that regulate the expression of human genoma, innovative therapeutic resources will emerge, which rebound-effect is easily predictable. The accurate analysis of the history of doping teaches us how eagerly people will reach for premature technology, with little fear of side effects or complications and the medical community should be at odds of healthy athletes using gene therapy.
References
1. Lusky M. Good manufacturing practice production of adenoviral vectors for clinical trials. Hum Gene Ther 2005;16:281-91.
2. Lippi G, Guidi G. New scenarios in antidoping research. Clin Chem 2003;49:2106-7.
3. Kimmelman J. Recent developments in gene transfer: risk and ethics. BMJ 2005;330:79-82.
Competing interests: None declared
Competing interests: No competing interests