제도동향
Gene Therapy and the Concept of Genetic Disease
- 등록일1998-01-01
- 조회수2704
- 분류제도동향 > 종합 > 종합
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자료발간일
1998-01-01
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출처
biozine
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원문링크
Gene Therapy and the Concept of Genetic Disease
I. Background
Scarcely a week goes by without the popular press announcing the discovery of the genetic basis of a new disease or trait. Scientists and the media increasingly stress the importance of the genetic determinants of who we are and how we function. I will refer to the view that the most significant factors for understanding and treating disease are genetic as biomedical reductionism.1 As the tide of biomedical reductionism has risen, the closely linked concept of genetic disease has expanded in several interesting ways.2
In the aftermath of the public rejection of eugenics (after W.W.II), scientists took a fairly restricted view of the concept of genetic disease.3 The simplest, most straightforward definition of a genetic disease (type 1) was a single locus defect, with 1 00% heritability. Diseases like Huntington's, Phenylketonuria (PKU), or Sickle-cell anemia have a very strong basis for the claim genetic disease.
As several commentators have noted, the concept of genetic disease has expanded during the last twenty years.4 It has changed from denoting a simple single locus defect to encompass polygenic traits which have less than 100% heritability. That is, geneti c disease (type 2) came to include any traits which include a genetic component, even if it was less than 100% heritable. So, heart disease, some forms of cancer, and diabetes were added to the list of genetic diseases. Finally, the expanding concept ca me to include complex behavioral traits where the evidence for heritability was less clear (type 3). It has become a widely held view that alcoholism, schizophrenia, and possibly even criminality are also genetic diseases.
Critics of biomedical reductionism have responded in a number of ways, but two different argument strategies have most prominently emerged.
One strategy has been to deny that there is good or sufficient (or even possible) evidence of the alleged heritability of a trait. For example, critics claim that a trait (e.g. alcoholism) is too poorly defined to yield convincing evidence of genetic basi s. Systematic problems have been found with various purported attempts to establish the genetic basis of complex behavioral traits. The methodology of much of the genetics in this area has been criticized.5 This strategy has largely been aimed at blocking the move from the type 2 to the type 3 conception of genetic disease, while occasionally disallowing some type 2 conceptions of genetic disease.
The second anti-reductionist argument strategy has been to emphasize the role of environmental (including social and psychological) factors in the production and therapeutic treatment of genetic disease. Critics have pointed to the importance of environme ntal factors in the production of both type 2 and type 3 traits.6 Interestingly, some critics have focused on the importance of social and psychological factors in understanding and treating even type 1 genetic diseases. Quaid, for example, has argued tha t social and psychological factors play an important role in the symptomology of Huntington's.7 These critics argue that focusing research and therapy at the genetic level may lead to ignoring treatments which are proven to be effective and which involve causally relevant factors.8 PKU is often cited as a genetic disease whose treatment does not involve genetic intervention (though it may require genetic screening).
Recent developments in gene therapy are leading to a new expansion of the concept of genetic disease, one with implications for the strategies of those concerned with combating biomedical reductionism.
II. Gene Therapy
The first successful gene therapy on a human was performed in 1990 by William French Anderson, Michael Blaise, and Ken Culver.9 They developed a protocol for treating Adenosine deaminase (ADA) deficiency, a severe combined immune deficiency, also known as the Boy in the Bubble disease. ADA deficiency is a result of inheriting two copies of the defective ADA gene. (In other words it is a recessive disease). Possession of a normal gene leads to the continuous, regular production of ADA in cells throughout the body. Without at least one properly functioning gene, children have no way of converting deoxyadenosine (a waste product) into inosine. This leads to the rapid build-up of deoxyadenosine in the system, which becomes phosphorlyzed into a toxic triphos phate which kills T-cells. The result is an almost complete failure of the immune system and early death.
Previous treatment options included bone marrow transplants which worked well with matched donors. But, that did not help all of the small number of children who are afflicted with this disease. A major breakthrough occurred with the development of polyet hylene glycol coated ADA (PEG-ADA). This treatment introduces coated ADA into the blood stream, although not into the cells. It requires expensive, painful shots on a weekly basis, but it succeeded in giving children with ADA deficiency a new lease on lif e. While their immune systems were far from normal, PEG-ADA got kids out of the bubble and allowed some semblance of a normal life and a much increased life span.
The gene therapy treatment was attempted in 1990. Initial attempts at altering stem cells had failed. Instead, the NIH team focused on T-lymphocytes. Using a genetically altered mouse retro-virus as a vector, a properly functioning ADA gene was spliced in to the nucleic material (RNA). The vector delivered its genetic payload to the T-lymphocytes, as the protein shell of the retrovirus binds to the cells' receptors. During cell replication, when the cell is actually synthesizing DNA, the RNA from the ret rovirus is converted into DNA and incorporated into the DNA of the cell. The genetically altered cell now has a functioning ADA gene which produces ADA within the cell. Cultured T-lymphocytes are then reintroduced into the children. The results of the gen e therapy were quite impressive. The first children to have the gene therapy (in combination with PEG-ADA) had tremendous increases in their immune functions. The children even grew tonsils. Because T-lymphocytes have shorter life spans than stem cells, t he treatment needs to be repeated every six months. Nonetheless, the success of the therapy resulted in tremendous publicity for gene therapy and for its founding fathers.
As a result of this success, gene therapies are being worked on by an increasingly large number of workers and protocol approval seems to be coming faster for experimentation on humans.10 Most experts anticipate several new therapies on the market in the coming years, but one of the most significant involves the work of Ken Culver, one of the three pioneers of ADA deficiency.
Culver was thinking about ways of applying gene therapy to cancer. A number of other people were working on this problem, but Culver was especially interested in trying to find a therapy that would be inexpensive, possibly requiring a simple series of inj ections. His ingenious idea was the following. Using essentially the same techniques as in the ADA deficiency treatment, researchers could splice a gene from the Herpes-Simplex virus into the vector, in particular the gene which expresses the enzyme thymi dine kinase (HS-tk). HS-tk had been used as a marker in the past, so it was promising as a tool. Culver reasoned that once a cell had been transduced to express HS-tk it would become vulnerable to the anti-herpes treatment, ganciclovir (GCV). Basically, t he HS-tk phosphorlyzes the GCV, initially into a monphosphate, then into a triphosphate. This triphosphate is toxic to cells during cell replication. Culver and a team of researchers introduced brain tumors into mice. Brain tumors were a particularly like ly cancer to focus on because this involves a relatively immuno-isolated area, has a high mortality rate, and the tumor is the only significant source of cells which are actively synthesizing DNA. When tumors which did not express HS-tk were introduced in to the mice, all 15 had palpable tumors within 5 weeks. When 100% of the introduced tumors expressed HS-tk, the GCV treatments were extremely effective. After 2 weeks there were no palpable tumors and after 5 weeks only 2 mice out of 15 had tumors.
In addition to this evidence of success, the initial studies in mice turned up something rather surprising when a combination of genetically altered (Hs-tk expressing) tumor cells and unaltered tumor cells were introduced. If 50% of the tumor cells expres sed HS-tk, the GCV treatment were just as effective as if 100% of the cells had been transduced. After 5 weeks only 1 mouse out of 15 had a tumor. If only 10% of the tumor cells expressed HS-tk only 6 out 15 mice had tumors after 5 weeks. This unexpected killing of unaltered cells was termed the bystander effect by Culver and Blaise and it made this a promising cancer treatment. It is unlikely that all of a tumor's cells could be transduced by any current methods. But the bystander effect means that onl y a fraction of the cells need to be altered for a therapy to be effective. While there has been much research into the causes of the bystander effect, to date, the precise mechanism is unresolved.11
Encouraged by these results, Culver and his colleagues initiated a study in rats in which they introduced tumors, and then tried to genetically alter the tumors in situ. Murine fibroblasts which continually produce the vectors were introduced to se e if the retroviruses could transduce enough of the cancer cells for the GCV to be effective. Once more the results were promising. 11 out of 14 rats showed tumor regression in the initial study, compared to 0 in the control.
Studies of this technique on mice, rats, and primates revealed the treatment to be safe. There was no indication that loose vector particles were altering healthy tissues which would then become vulnerable to GCV. Because the vector binds to many sites on the cancer cells, few particles escape. Even more importantly, because the vector binds to nearly any tissue in the body, and most cells are not replicating, the treatment has turned out to exceed safety expectation. Vectors intoduced randomly into the b ody will harmlessly attach themselves to non-replicating cells (and will not therefore be incorporated into the nucleus).
Experiments on humans with brain tumors have begun. Patients were chosen who had severe tumors (often as a result of cancer elsewhere in the body) and were viewed as terminal with weeks left to live. 5 of the first 8 patients showed tumor regression. Expe rimentation on humans with brain tumors continues, and this powerful new therapy should be on the market within as little as two years.12 The HS-tk/GCV treatment (thanks to the bystander effect) is so powerful and promises so little in side effects, that a number of groups are working on it for several different kinds of cancer. Animal studies have all been promising, and protocol approval has been fairly quick. Recent approval has been granted for using the HS-tk/GCV system for ovarian cancer and leptome ningeal carcinomtosis, and there are several protocols awaiting approval, including one for liver cancer.13 The results of this research have received a great deal of attention, and a powerful new treatment for several kinds of cancer seems to be just aro und the corner.
III. The new concept of genetic disease
One of the most conceptually interesting aspects of the development of gene therapy treatments like the HS-tk/GCV system (and there are a number of other therapies being pursued which share this feature) is the way they are changing the concept of genetic disease. Culver has claimed that this work shows that cancer is a genetic disease. In other words, any disease or trait which can be altered by gene therapy is a genetic disease. This is the current usage of gene therapists and molecular geneticists. N ote that this therapy does not assume that the trait is at all heritable. In fact, recent usage by both clinicians and geneticists suggests the disentangling of the concepts of 'genetic' and 'heritable.'
On the surface, it seems as if gene therapists and geneticists, perhaps caught in the grip of biomedical reductionism, have simply committed a category mistake. Surely any reasonable concept of genetic disease will necessitate its heritability. What w ould motivate the expansion of the concept in this apparently unreasonable way?
First, it is important to recognize that the actual techniques involved are essentially the same, whether the disease being attacked is inherited or not. The ADA deficiency treatment and the HS-tk/GCV treatment are extremely similar. They use the same vec tor, and both involve genetically altering specific tissues (as do most gene therapies). This technical similarity is particularly important for a field as technologically driven as molecular genetics.14 Second, from the molecular point of view, it does n ot really matter where in the body genes occur. In some diseases, the genes involved occur in all cells, and are a result of transmission through the sex cells. Some diseases involve genes which occur in only some cells. The difference is not that signifi cant from a molecular point of view. [quote from gene wars?] Neither is it significant from a therapeutic point of view. If manipulation of some of the body's genes can provide effective therapy, what difference does it make whether a trait is inherited? The therapy is still the same.
Regardless of the potential confusions, the concept of genetic disease is expanding. It is already common among researchers to adopt the expanded usage, and now it has entered more popular usage. Jeff Lyon and Peter Gorner, two Pulitzer prize winning jour nalists for the Chicago Tribune write,
One's chances of developing a life threatening cardiovascular problem are dictated to a large extent by genetic endowment... Similarly, our prospect of acquiring cancer appears to hinge on the environmental assaults visited upon certain growth-regu lating genes we all harbor within our cells. Though it is not, primarily, an inherited affliction, cancer is in the truest sense a disease of the genes.15
A forthcoming book on biotechnology includes a chapter on cancer as a genetic disease, and increasingly the concept of an environmentally induced genetic disease has gained currency.16
There are three implications of gene therapies like Culver cancer treatment and the expanding concept of genetic disease. First, the concept has now expanded to be virtually all encompassing. As Lyon and Gorner report, Researchers have concluded that vir tually all human illness, even infectious disease, has some relationship to genetic endowment.17 In the words of Noble-laureate Paul Berg, I start with the premise that all human disease is genetic. Even aging and death are seen as genetic diseases.18 Second, because the expanded concept of genetic disease in no way requires that a trait be inherited to be genetic, the first strategy adopted by critics of biomedical reductionism is rendered moot. The powerful arguments and strategies that so many crit ics have devised are no longer sufficient against this newest expansion of the concept. Again, the decoupling of the concepts of 'heredity' and 'genetic' undermine many of the methodological criticisms of reductionism (though these attacks will still be valuable as criticisms of hereditarianism or the view that many or most significant traits are the result of heredity). Third, the dramatic success of the therapy and its promise of changing the face of medicine makes a strong prima facie case ag ainst the second strategy. If diseases can be effectively treated by gene therapy, who cares about environmental aspects of disease? Gene therapy is now seen by many as having the potential to change the way medicine is practiced. Its uses are tremendousl y varied and publicity and public reception suggest that gene therapy will soon join the ranks of antibiotics, vaccinations, and organ transplants as the great scientific triumphs of Western (allopathic) medicine.
IV. A lesson from history
While gene therapy shows a great deal of potential, opponents of biomedical reductionism will undoubtedly have several responses. The way a person experiences a disease involves many social and psychological elements (such as the emotional impact of the d isease, the stigmatism attached to it, the cost and employment implications, etc.). These important aspects of disease are neglected by therapeutic approaches aimed strictly at the genetic level.
Although this version of strategy 2 has some validity, the enormous prestige attached to high-tech success renders it less than overwhelming. I will offer a lesson from medical history which places the current issues in a different context. Then I will tr y to show why these historical considerations are relevant to assessing the likely impact of the triumph of the biomedical reductionism. This will allow a different approach to salvaging strategy 2.
Champions of gene therapy and genetic approaches to disease hail recent developments as comparable to the development of vaccines and antibiotics. These earlier successes of scientific medicine are widely claimed to be the chief causes of the decline in mortality in the U.S. in the past century. Indeed, the mastery of infectious disease and the particular medical measures associated with various diseases are often seen as the primary illustration of the power and success of medicine.
It is true that mos t of the decline in mortality in the U.S. this century is due to the decline of fatalities due to infectious disease. However, empirical studies of the effect of medical measures on the health of populations is rather surprising.19 Studies of the decline of mortality due to infectious diseases, for example, show that while there has been a large decline in mortality, little of the decline can be attributed to the effects of the introduction of medical measures. For most of the major infectious diseases f or which there is good data, the typical pattern over time is a large decline in mortality prior to the introduction of the major medical measures (e.g. vaccines or antibiotics).
Typically, the mortality rate has neared the end of its decline at th e time of the widespread introduction of the medical measure. For example, the two leading contributors to the drop in the sex and age adjusted death rates in the U.S. in the 20th century are tuberculosis and pneumonia. Yet 91.64% of the decline in the (a ge and sex adjusted) death rate in tuberculosis in the U.S. occurred prior to the introduction of Izoniazid and streptomycin treatments.20 Similarly, for Pneumonia, 82.81% of the decline in the death rate occurred prior to the introduction of widespread treatment of sulphonamide in 1935. Other infectious diseases reveal the same pattern. 98.62% of the decline in mortality due to measles occurred prior to the use of the vaccine.
99.71% of the decline in Typhoid came before the widespread use of chloraphen icol. Polio was one of the few diseases which seemed to indicate that the medical intervention was somewhat effective, but even here 74.13% of the decline in polio deaths occurred before the widespread use of the salk vaccine. In terms of the rate of decl ine after the introduction of medical measures, only in the case of polio does there seem to be much evidence of an impact from the treatments. Mckinley and Mckinley conclude from their data that only between 1 and 3.5% of the decline in mortality in the U.S. between 1900 and 1973 can be attributed to medical measures. In general, medical measures (both chemotherapeutic and prophylactic) appear to have contributed little to the overall decline in mortality in the United States since about 1900.21
Studies of the effect of medical measures on the decline of mortality in a number of European countries in the 18th, 19th, and 20th centuries have yielded similar results. It is important to note that none of these studies show that these medical measures are not effective on an individual basis. What they show is that in terms of the health of populations, they are not very powerful forces. Whatever effect medical measures have is swamped by much more powerful forces: public health measures, large scale social changes, and changes in diet and sanitation.22
How is this relevant to biomedical reductionism? Biomedical reductionism leads us to focus research and therapeutic efforts on the genetic basis of disease and on gene therapies, to the exclusion of efforts aimed at other levels. Claims that all factors, genetic and environmental, are important ring hollow given the reality of an emphasis on genetic factors and fixes. As Keller puts it,
Most responsible advocates are of course careful to acknowledge the role of both nature and nurture, but rhetorically, as well as in scientific practice, it is 'nature' that emerges as the decisive victor. Like others, Koshland [editor of Science] takes his object of advocacy to be research-- not on environmental influences, but on genetic determinants; similarly, he does not cite the importance of social, psychological, or political training, but only scientific training.23
This exclusionary tendency is well illustrated by the development of the ADA therapy. PEG-ADA was a very successful and promising treatment. Yet excitement over the prospect of gene therapy resulted in its neglect by the scientific and popular press, even before there was an actual gene therapy.
In the excitement over the possibility of gene therapy, PEG-ADA kept getting short shrift in the press. In fact, the drug had just that week received final approval as the first medicine that could be used to treat an inherited metabolic disease by replac ing the missing enzyme, yet this triumph inexplicably continued to be down played in reports about gene therapy. For instance, stories in Science magazine, and the New York Times ignored or discounted the life saving new drug treatment. It w as as if the reporters had not been aware of its efficacy or even its existence...24
Clearly there is public excitement about the prospects of genetic medicine. At the same time, there are financial forces promoting these approaches, from private biotech firms, to government funding (including the Human Genome Project). The result of the increasing focus on reductionist measures is the neglect of the social factors which studies show are the key determinants of the health of populations. Consideration of the main causes of death, including cancer, leave open the possibility that emphasis on gene therapies may not be the best allocation of resources. The Hs-tk/GCV system and other gene therapies are very promising, but most of the causes of cancer and other causes of death are preventable. Indeed, an estimated 50% of all deaths in the U.S. in 1990 were due to preventable causes.25 The leading cause of cancer (an estimated one third of all cases) and of death in the U.S. (19%) is tobacco. An estimated 400,000 people die each year as a result of tobacco. Diet, alcohol, and activity levels ar e also powerful causal forces in the health of the U.S. population. Tobacco use is increasing globally at a rapid rate. Internationally, the major health problems are largely issues which require public health measures. If tobacco is the main health probl em in the U.S.
(and a fast rising one globally) the leading health problems in most developing countries are largely products of overpopulation and limited resources. The problems facing health professionals who deal with AIDS are also largely public heal th issues. Ken Culver has said that one of his main motivations for developing the HS-tk/GCV system is to make a reasonably inexpensive cancer treatment available to developing nations. He and many other scientists and clinicians are struggling to bring the fruits of the molecular revolution to all parts of the globe. The history of medicine, and a knowledge of the primary determinants of health calls into question the biomedical reductionist assumptions of this project.