Medicine and Society

Anticipating Molecular Medicine: Smooth Transition from Biomedical Science to Clinical Practice?
NORBERT W. PAUL, PH.D., Heinrich-Heine-University Medical School, Duesseldorf, Germany

See related "Medicine and Society" on page 1707.

The past decades have seen a spectacular burgeoning of a new cognitive field--molecular genetics--beginning with Watson and Crick's^1,2 description of the structure of DNA. However, translating new biomedical knowledge into clinical applications has been difficult. Effective therapy through molecular medicine will require: (1) new biomedical knowledge to allow the description, classification and explanation of disease entities on a molecular level; (2) new tools to diagnose molecular findings in patients; and (3) new therapies to intervene on the same molecular level on which disease entities were defined and diagnosed.

Scientific theories must be translated into diagnostic and therapeutic applications in order to effectuate the transition from biomedical explanatory models to molecular medical practice.³ It is often assumed that new technologies are the hinges on which the doors of molecular medicine may finally begin to swing. At first glance, this view seems to be correct. In a remarkably short period of time, laboratory technologies of molecular biology designed to identify and locate genes were developed for in vitro use in the clinical laboratory. Since then, they have become the diagnostic backbone of predictive testing and genetic counseling. The problem has been in translating molecular and recombinant technologies into therapeutic procedures for in vivo application to patients. The difficulties associated with the development of therapeutic applications are not just technologic in nature. To understand the problems that have prevented a smooth transition to molecular practice, we must discuss the three levels of medical innovation that were previously mentioned.

First, models in molecular genetics are still inadequate for defining clear-cut molecular disease entities. In the case of cancer, despite tremendous research efforts in the scientific field, molecular genetics still has not shown a strong correlation between genotype and disease.⁴ Second, on the level of diagnosis, tests for susceptibility-conferring genotypes share this problem of limited causal correlation. Low positive predictive values of tests do not usually justify tailoring treatments to genotypes (except perhaps for monogenic disorders with unusually high penetration like Huntington's disease).⁵ Third, it is still uncertain if treatments can be reliably tailored to genetic conditions. On May 25, 2000, only 3,476 patients worldwide were registered in clinical studies of somatic gene therapy.⁶ Despite the latest reports on single successful therapeutic trials,⁷ controlled gene delivery, reliable gene expression and potentially lethal reactions to therapy--the last resulting in the highly publicized death of Jesse Gelsinger^8-11--remain major obstacles in the vast majority of experimental approaches to somatic gene therapy.¹²

Notwithstanding the fundamental problems that have plagued molecular medical practice for decades, enthusiasm for molecular medicine as such does not wane. Taking into account all we know thus far about the functions of genes, some practical hope for molecular medicine appears to be justified, especially with respect to diseases clearly rooted in molecular genetics. Nevertheless, we should be aware that the discourse on molecular medicine--even the apparently scientific discourse--is, in its current form, driven by politics.¹³ Thus, it is sometimes difficult to distinguish wish from reality.

We can identify two distinct approaches to innovation: utility- and evidence-based. Utility-based approaches are more characteristic of the public domain, while evidence-based modes occur within the context of science and technology. The utility-based mode refers simultaneously to an independent market and professional practice, and the legal regulations, ethical considerations and consumer forces used to determine utilization of new procedures (e.g., BRCA1 or 2 testing, or somatic gene therapy), given its uncertain practical significance. In contrast, the evidence-based mode refers simultaneously to scientific and biomedical knowledge, the definition and feasibility of particular pragmatic goals of applications, and the prioritization of these goals by relating them to the socially defined tasks of science, technology and medicine.¹⁴

At this point, the evidence-based approach is not ready to provide definite answers with regard to the molecular vision of health and disease. In other words, science is lagging behind molecular genetics' promise of public benefit. For now, advances in the implementation of molecular genetics must rely on the utility-based mode, with the main purpose being to establish consensus about possible benefits of innovative procedures. The main goal is to balance uncertainty and keep the momentum of research projects going.

A focus on the public interest is a legitimate purpose, a legitimate goal and a necessary part of medical innovation. At the same time, it is important to remember that utility-based and evidence-based arguments are not the same thing. In the current discussion about molecular medicine, we must distinguish between issues we address in our role as members of the community and issues we have to be concerned with as professional health care providers. Professional decision making requires evidence-based discourse.

Research for this paper has been generously supported by the Alexander von Humboldt Foundation, Bonn, Germany, the Stanford University Program in History and Philosophy of Science and the Stanford Program in Genomics, Ethics, and Society.

The Author

NORBERT W. PAUL, PH.D.,
is assistant professor of history, philosophy and ethics of medicine and related sciences at the Institute of Medical History, Heinrich-Heine-University Medical School, Duesseldorf, Germany. Dr. Paul is also an affiliated assistant professor in the Program in History and Philosophy of Science at Stanford University, Stanford, Calif.

Address correspondence to Norbert W. Paul, Ph.D.,Heinrich-Heine-University Medical School, Institute of Medical History, PF 10 10 07, D-40001 Duesseldorf, Germany (e-mail: npaul@stanford.edu). Reprints are not available from the author.

REFERENCES

1. Watson JD, Crick FH. Molecular structure of nucleic acids. A structure for deoxyribonucleic acid. Nature 1953;171:737-8.
2. Watson JD. The double helix: a personal account of the discovery of the structure of DNA. 1st Scribner ed. 1968. New York: Scribner, 1998.
3. Paul N. Incurably suffering from the 'hiatus theoreticus'? Some epistemological problems in modern medicine and the clinical relevance of philosophy in medicine. Theor Med Bioeth 1998;19:229-51.
4. Lichtenstein P, Holm NV, Verkasalo PK, Iliadou A, Laprio J, Koskenvuo M, et al. Environmental and heritable factors in the causation of cancer--analyses of cohorts of twins from Sweden, Denmark, and Finland. N Engl J Med 2000;343:78-85.
5. Holtzmann NA, Marteau TM. Will genetics revolutionize medicine? N Engl J Med 2000;343:141-4.
6. Wiley Gene Medicine. Clinical trial database. Retrieved May 2000 from: http://www.wiley.co.uk/wileychi/genmed.
7. Kolata G. Scientists report the first success of gene therapy. The New York Times, April 28, 2000:A,1.
8. Marshall E. Gene therapy death prompts review of adenovirus vector. Science 1999;286:2244-5.
9. Nelson D, Weiss R. Earlier gene tests deaths not reported. The Washington Post, January 31, 2000.
10. Vogel G. Gene therapy: FDA moves against Penn scientist. Science 2000;290:2049-51.
11. Geisinger v The Trustees of the University of Pennsylvania, Wilson, Genovo Inc., Raper, Batshaw, Kelley, Children's Hospital of Phildelphia, Childrens National Medical Center and Caplan (still in litigation). Retrieved January 2001 from: http://www.sskrplaw.com/links/healthcare2.html.
12. Capecchi MR. Human germline therapy: how and why. In: Stock G, Campell J, eds. Engineering the human germline: an exploration of the science and ethics of alerting the genes we pass to our children. Oxford: Oxford University Press, 2000:31-42.
13. Collins FS. Shattuck lecture--medical and societal consequences of the Human Genome Project. N Engl J Med 1999;341:28-37.
14. Wilfond BS, Nolan K. National policy development for the clinical application of genetic diagnostic technologies. Lessons from cystic fibrosis. JAMA 1993;270:2948-54.

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Gene Therapy: If At First You Don't Succeed . . .
DAVID A. DEAN, PH.D., Northwestern University Medical School, Chicago, Illinois
R. ALLEN PERKIN, M.D., M.P.H., University of South Alabama College of Medicine, Mobile, Alabama

"Study Details Success of First Gene Therapy"
Headline, Los Angeles Times, October 20, 1995

"Scientists Report the First Success of Gene Therapy"
Headline, New York Times, April 28, 2000

"Teen Dies Undergoing Gene Therapy"
Headline, Washington Post, September 29, 1999

See related "Medicine and Society" on page 1704.

Gene therapy represents the culmination of medical research and its application to human health. Less than 60 years ago, Linus Pauling and others¹ described at the molecular and genetic level what was to be the first of many molecular diseases. In the most simple form, a mutation of just one base pair in a gene can alter the production or function of a protein that is vital to health and life. A "rough draft" of the human genome sequence has been completed and, with this, the sequence of every human gene is now theoretically available to scientists, physicians and the general public. Subsequently, the mapping of diseases to individual genes will be only a matter of time and effort. Over the past 50 years, investigators have teased out the mechanisms of many diseases at the physiologic and genetic levels and have made great progress in developing pharmacologic drugs to alleviate these maladies. The next step, already in progress, is to use genes themselves as the drugs--replacing or altering the expression of defective or misregulated genes--to treat patients at the molecular level.

Unfortunately, while gene therapy may be to the 21st century what antibiotics were to the last, we have a long way to go before success is at hand. As can be seen in the headlines above, gene therapy has had multiple "first" successes followed by the realization that much of the enthusiasm for each success has been perhaps premature or overstated. Further, much of the early excitement about this approach has been dampened following the recent death of a young male involved in one clinical trial, as noted in the third headline above. However, as with all discoveries and new fields, problems do exist, and they need to be identified, studied and overcome. Indeed, these are exciting times to practice medicine, but much of the initial unbridled enthusiasm for gene therapy has worn off, and now the real work has begun.

Gene therapy began in the mid-1970s when it was discovered that DNA could be manipulated in the test tube. Forward-thinking investigators quickly realized that the possibility of expressing normal or foreign genes in human cells (and ultimately in humans themselves) could usher in a new era of medicine. Theoretically, mutant genes, in patients with such diseases as sickle cell disease and cystic fibrosis, could be replaced and the diseases corrected by transferring the wild type, or normal, genes into these patients.² Other diseases (e.g., cancer) might be treated with genetic therapy by adding genes to increase antitumor immune responses or by inhibiting angiogenesis and cutting off the tumor's blood supply.³ Furthermore, infectious diseases might be combated by altering the body's immune response.⁴

As more and more of the human genome was discovered, new associations between genes and diseases were identified, and the possibilities for genetic medicines became apparent. All of these treatments require moving desired genes into the appropriate cells in both animals and people--and this is where problems have been encountered over the past 10 years.^5,6

Two major approaches have been taken to deliver genes to cells: viral and nonviral. In the case of viral delivery, the vectors (delivery agents) are modified viruses that have had their genomes largely replaced with therapeutic genes.⁵ This allows the desired genes to be packaged into virus particles that are effective at entering cells within the body. By removing most of the viral genes, the chance for viral replication and aberrant infection in the host is, hopefully, removed. Thus far, adenoviruses and retroviruses are the two families of viruses that have been used in the majority of clinical trials.

Adenoviruses are good at infecting the non-dividing or very slowly dividing cells that make up most of our tissues. Conversely, the application of retroviruses is limited because they can infect only dividing cells; however, this application results in life-long expression of the carried gene because it actually incorporates itself into the host's chromosome.⁷ Unfortunately, such effective gene delivery comes at a price: viral vectors, especially adenovirus, can induce significant localized and systemic inflammation, and a sustained immune response. While each person will vary in inflammatory response to viral administration, the response can range from unnoticeable to severe.

Indeed, in the recent case at the University of Pennsylvania, administration of recombinant adenovirus carrying a gene to alleviate ornithine transcarbamylase (OTC) deficiency in a 17-year-old male resulted in activation of his innate immune system and fever, and ultimately led to his death.^8,9 Although the preceding 17 patients in the same study had received the same viral vector, they did not exhibit anywhere near these levels of inflammation or response, thus revealing no indication predictive of the patient's death. This case only exemplifies the variations that are possible.⁹

Another result of an immune response to viral vectors is that the response limits the number of times the virus can be administered. Once antibody and T-cell responses are developed, and as soon as a second dose of the viral vector is given, the virus and the cells it infects will be targeted for destruction when a second dose of the viral vector is administered, thereby greatly limiting the expression of the transferred therapeutic gene. Although these drawbacks may seem daunting, investigators are actively engaged in moderating these responses and finding ways to circumvent the problems. To this end, novel and modified viruses are being tested and show great promise in terms of significantly reduced inflammatory responses and the ability to administer repeated doses for multiple gene therapies.

The second approach for gene delivery and therapy is to use nonviral systems. The latter include plasmid DNA that is either delivered directly (termed "naked DNA") or complexed with carriers such as liposomes that encase the DNA, add stability and increase cellular delivery and entry.¹⁰ Based on design, plasmids have the ability to express in dividing and nondividing cells, thus making them appropriate for administration to all cells in the body. Further, the lack of viral proteins and genes that the body sees as foreign and worthy of reaction means that little inflammation is induced; thus, no immune response is mounted against the DNA, which, in turn, makes multiple effective treatments possible. Unfortunately, the level of expression obtained with nonviral methods is usually much lower than that occurring with viral methods.

Other potential delivery vehicles that produce increased gene expression are in development. They include delivery to the skin by Star-Trek­like pneumatic guns and the use of electric fields and sound waves to drive DNA into cells.

Although the levels of nonviral DNA delivery and gene expression are much lower than those obtained using viruses, the lack of an immune response may lead the field to favor these systems over the potential hazards associated with viral methods. As time goes on, it will most likely be found that each system has its unique applications and both may ultimately find their way to the physician's office.

So, has gene therapy succeeded? In the realm of theory and laboratory experimentation, the answer is a resounding yes. Results from experiments have demonstrated that genes can be transferred to animals and humans and can exert therapeutic effects. In animal models, diseases can be corrected transiently and, in some cases, even on a long-term basis. In the earliest "first success" of gene therapy, Blaese and colleagues¹¹ transferred the gene for adenosine deaminase (ADA) using a retrovirus to T cells isolated from two young females with severe combined immunodeficiency as a result of ADA deficiency. When it was transfused back into the patients, small increases in their ADA levels were detected, as were minor increases in T cells and immune responses. However, the benefit was incomplete and did not fully "cure" the patients.¹¹

In a more recent "first success," researchers in France took a similar approach to this earlier work to treat a different form of severe combined immunodeficiency but, rather than target T cells, they targeted stem cells isolated from the bone marrow of three different infants, also using retrovirus.¹² When transfused back into the infants, the successfully transduced stem cells propagated and expanded, outgrowing and replacing the endogenous defective cells. Indeed, success may be at hand, but only time will tell. Thus far, more than 390 other clinical trials involving gene therapy have been conducted over the past 10 years.

In conclusion, how close are we to using gene therapy in the family practice setting? When will an injection of recombinant virus or a plasmid infusion be used to control hypertension, sickle cell disease or cancer instead of using the traditional approaches? When will the first success of clinical importance occur? Hopefully soon, but to be realistic, definitely not before you have to take the Boards again.

The authors are supported in part by grants HL59956, EY12962, and AI44567 (DAD) from the National Institutes of Health and by grant 2-D15-PE-10242-04 from the Health Resources and Services Administration (RAP).

The Authors

DAVID A. DEAN, PH.D.,
is associate professor in the Division of Pulmonary and Critical Care Medicine at Northwestern University Medical School, Chicago, Ill. He received a doctorate from the University of California, Berkeley, and completed a fellowship in molecular virology at the University of California, Los Angeles. Dr. Dean previously held the position of associate professor in the Department of Microbiology and Immunology at the University of South Alabama College of Medicine, Mobile. His research focuses on developing nonviral methods of gene delivery and unraveling the mechanisms of gene transfer.

R. ALLEN PERKINS, M.D., M.P.H.,
is associate professor, vice-chair and residency director in the Department of Family Practice and Community Medicine at the University of South Alabama College of Medicine, Mobile. He received a medical degree from Tulane University, New Orleans. Dr. Perkins served a residency in family practice at the University of South Alabama College of Medicine.

Address correspondence to: David Dean, Ph.D., Division of Pulmonary and Critical Care Medicine, Northwestern University, Tarry 14-707, 303 E. Chicago Ave., Chicago, IL 60611 (e-mail: dean@northwestern.edu). Reprints are not available from the author.

REFERENCES

1. Pauling L, Itano HA, Singer SJ, Wells IC. Sickle cell anemia: a molecular disease. Science 1949;110: 543-8.
2. Mulligan RC. The basic science of gene therapy. Science 1993;260:926-32.
3. Blaese RM. Gene therapy for cancer. Sci Am 1997; 276:111-5.
4. Weiner DB, Kennedy RC. Genetic vaccines. Sci Am 1999;281:50-7.
5. Verma IM, Somia N. Gene therapy--promises, problems and prospects. Nature 1997;389:239-42.
6. Friedman T. Overcoming the obstacles to gene therapy. Sci Am 1997;276:96-101.
7. Wilson JM. Adenoviruses as gene-delivery vehicles. N Engl J Med 1996;334:1185-7.
8. Fox JL. Gene therapy safety issues come to fore. Nat Biotechnol 1999;17:1153.
9. Preliminary findings reported on the death of Jesse Gelsinger. IHGT, University of Pennsylvania. 1999. Retrieved February 2001 from: http://www.med.upenn.edu/ihgt/findings.html.
10. Felgner PL. Nonviral strategies for gene therapy. Sci Am 1997;276:102-6.
11. Blaese RM, Culver KW, Miller AD, Carter CS, Fleisher T, Clerici M, et al. T lymphocyte-directed gene therapy for ADA-SCID: initial trial results after 4 years. Science 1995;270:475-80.
12. Cavazzana-Calvo M, Hacein-Bey S, de Saint Basile G, Gross F, Yvon E, Nusbaum P, et al. Gene therapy of human severe combined immunodeficiency (SCID) - XI disease. Science 2000;288:669-72.

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