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Ann Thorac Surg 2002;73:704-706
© 2002 The Society of Thoracic Surgeons
a Section of Thoracic Molecular Oncology, Department of Thoracic and Cardiovascular Surgery, The University of Texas M.D. Anderson Cancer Center, Houston, Texas, USA
* Address reprint requests to Dr Smythe, Department of Thoracic and Cardiovascular Surgery, The University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Blvd, Box 445, Houston, TX 77030, USA
e-mail: rsmythe{at}mdanderson.org
The physician without physiology and chemistry flounders along in an aimless fashion, never able to gain any accurate conception of disease, practicing a sort of popgun pharmacy, hitting now the malady and again the patient, he himself not knowing which. William Osler
In this issue, Kurdow and associates [1] demonstrate improved effectiveness of one of the oldest paradigms in gene therapy ("prodrug" gene therapy utilizing transfer of the herpes simplex thymidine kinase gene followed by ganciclovir administration) for experimental non-small cell carcinoma. Improvements in both the vector (gene therapy transfer vehicle) and transgene (new gene transferred to somatic cell) of this therapeutic system are described [1]. By efforts at the bench, the authors have modified a technique that has thus far not been as clinically useful as anticipated into a paradigm that may have a greater chance of patient benefit. This article is a good example of current progress in experimental practice in gene therapy and reminds us of the future promise of the field. However, the article also illustrates why we should be pragmatic about the work that still needs to be done.
Approximately 7 years ago, a thoracic surgical laboratory published one of the first descriptions of successful adenoviral gene transfer in an orthotopic human model of neoplastic disease (mesothelioma) here in The Annals [2]. An accompanying editorial suggested that, "Thoracic surgeons, thanks to studies like that published in this month’s Annals, are no longer silent witnesses in these exciting developments." [3]. What are the obstacles that we still face for widespread clinical application of gene therapy, how have we fared since this time in regard to the treatment of thoracic diseases utilizing these techniques, and to what degree have the members of our specialty been involved?
The basic problems that we face in the translation of gene therapy from bench to effective bedside therapy have not changed dramatically since our report in 1994. However, all represent areas of active investigation, recent progress, and exciting opportunity as follows.
Vectorology
The goals of systemic delivery of gene therapy vectors with efficient uptake in targeted areas, and prolonged therapeutic gene expression are still basically unmet. The majority (approximately 63%) of the near 600 gene therapy clinical trials completed, ongoing, or approved/pending around the world have relied upon use of a recombinant retrovirus or adenovirus delivery system [4].
The retroviral system utilized by Kurdow and associates in this issue is able to achieve long-term gene expression in certain cells after infection and incorporation into the host genome (integration), but continues to suffer from a relatively inefficient rate of gene transfer in vivo (cells must be actively mitotic with nuclear membrane disruption), and a cumbersome delivery system. These factors currently limit the utility of in vivo application of retroviral vectors, largely relegating this technology, as is demonstrated in the paper discussed here, to ex vivo approaches. However, many recent advances such as changing the retroviral envelope proteins to make the virus more likely to infect mammalian cells ("pseudotyping"), have been made with potential for clinical application [5].
Adenovirus, although much more efficient in transferring genes to cells, suffers from short-term gene expression and engenders an immune response due to the necessity for retention of some viral protein coding sequences. There has been steady progress, however, in the use of "targeted" adenoviral vectors. These modifications (viral protein fiber alterations, tissue specific promoter sequences) may allow for systemic administration of viral vector, but with limitation of cellular infection to a particular cell type or organ [6]. Many new viral gene therapy vector paradigms are now being evaluated, each with particular appeal. Notable among these new candidates are the adeno-associated virus (AAV), the lentivirus, and the herpes simplex virus (HSV) [7]. Finally, nonviral systems continue to be evaluated by many investigators, and recent advances in lipid biochemistry (liposomes) and cellular transfer techniques promise to make these approaches more clinically applicable as well [8].
Basic science
Equally important to technical advances in vector development is a true understanding of the diseases we seek to treat with gene therapy. Without thorough comprehension of the cellular and molecular biology of a disease, our efforts to treat it with gene therapy techniques are going to continue to be a gamble. As an example, the only unequivocal gene therapy success to date for treatment of a genetic deficiency, a particular type of severe combined immune deficiency, should be considered [9]. The investigators worked on the basic science and preclinical model for gene therapy for this disease for more than 6 years! During this time, they thoughtfully picked a disease with a replaceable enzyme that would confer a survival advantage to transduced cells, carefully chose a viral vector and packaging cell line, refined the target cell delivery system, and finally created a knockout mouse model to perform proof of principle experiments before embarking on a clinical trial. Using this model as an example, we should consider hesitating to spend a great deal of time, money, or precious effort for gene therapy research and clinical application without solid background basic science to support the hypotheses set forth in our experiments. This being said, however, it is certain that the fruits of the recent effort to sequence the human genome and the proteomic information that is forthcoming will provide us with a wealth of useful information and many key therapeutic "targets" in the coming years with which to work.
Public education
A past editor of the journal Molecular Therapy stated that, "Pure science moves fast and is driven by facts, whereas society moves slowly, encumbered by opinion, prejudice, faith and social constraints" [10]. This discrepancy between truth and understanding can lead to mistrust, especially when things do not go well, or when progress does not live up to hype. Media exposure can be helpful, as it can bring to the attention of the public important issues and indirectly increase support for scientific endeavors. However, when inappropriate claims or promises are made by investigators that cannot be currently fulfilled, or when disproportionate attention is paid to rare bad outcomes, the results can be counterproductive. This has had an impact on funding for gene therapy research as well as our ability to accrue subjects for clinical trials, and could continue to do so in the future. We must assure the lay public that the applied science of gene therapy does indeed hold real promise, but that realization of true benefit awaits additional progress in the areas enumerated.
Molecular medicine and thoracic surgery
Although we are still anticipating a cure for a thoracic disease utilizing gene therapy techniques, have members of our specialty contributed to the ongoing effort to do so? The answer is a resounding yes, as thoracic surgical investigators have published laboratory and clinical trial findings regarding the use of gene therapy to treat ischemic heart disease, carcinoma of the lung, mesothelioma, as well as disorders related to transplantation of thoracic organs [11–20]. There are indeed many aspects of thoracic diseases that only a thoracic surgeon may completely comprehend, such as anatomical nuances and the physiology of the postsurgical state. An incomplete understanding of these practical concerns may lead to unfounded applications, or premature dismissal of promising gene therapy paradigms due to something as simple as inappropriate delivery techniques. It is also likely that the gene therapy approaches will be most useful in multimodality settings that include surgical therapy. Thoracic surgeons facile in both clinical and basic/translational sciences such as gene therapy will be needed so that our patients might receive the greatest and most expeditious benefit from the new biology emerging now from laboratories all over the world. These individuals will be able to either directly participate in the development of new advances, or simply serve as the important "bridgetender" between basic scientists and clinicians by virtue of an understanding of the concepts involved on both sides. In addition, even those without interest in translational research should consider becoming familiar with the terminology and mechanisms behind new therapies, or run the risk of assuming the role of technician rather than physician. In this scenario, thoracic surgeons of the future function much like factory workers that have no knowledge of the inner workings of the machines they operate: simply pushing buttons and pulling levers.
Although the era of anatomic and physiologic research in surgery is certainly not dead, it is not likely to be where the major battles in the war against our persistently daunting and common thoracic diseases, such as carcinoma of the lung and coronary vascular disease, will be won. There is no doubt that current treatments based on these types of research have improved patient care, but far from a point at which we should feel complacent. Osler’s chemistry and physiology at the turn of the last century are the cellular and molecular biology at the turn of this one. Although we may be more pragmatic about the timeline, the promise for genetic-based therapy to have a major impact on the diseases we treat is unchanged. We should continue to expand thoracic surgical leadership in the development of the new clinical science that is certain to develop and not allow the opportunity to slip away to interventional medical specialists that we have seen usurp many other aspects of general thoracic and cardiac surgical practice over the last 20 years. As thoracic surgeons, we should strive to be participants in these exciting times to come rather than "silent witnesses."
References
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