Gene Therapy

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Gene Therapy "Gene Therapy -- Status, Prospects for the Future, and Government Policy Implications"

Dr. M.R.C. Greenwood
Associate Director for Science

Office of Science and Technology Policy

Testimony before the Committee on Science, Space, and Technology
U.S. House of Representatives

September 28, 1994

Good afternoon, Mr. Chairman, members of the committee. I would like to thank you for giving me the opportunity to participate in this hearing on Gene Therapy -- Status, Prospects for the Future, and Government Policy Implications.

Introduction

We can all appreciate that specific technologies have transformed societies. For example, the industrial revolution transformed this country from an agrarian-based society into one more dependent on and rooted in industry. Many scientists and contemporary observers of science believe that we are in the midst of a biological revolution. Many of the ideas emerging from the field of biology are transforming our society -- how we view our relationship with Nature; how we evaluate quality of life; how we understand, diagnose and treat disease; even how we define life and death. The subject of today's hearing, gene therapy, is both a derivative of our past and present scientific prowess and an indicator of a whole new set of future issues.

For decades we have known that height, hair and eye color are all traits that people inherit from their forebears. We also know that some dreadful diseases come about as a consequence of having inherited a gene from one or both parents. Some of the worst of these devastate the lives of young children and their families and cost hundreds of thousands of dollars, if not more, simply to relieve the pain and suffering in less than satisfactory ways. For the families of those afflicted, any approach that could prevent or cure such conditions would be worth any cost and many would welcome information that would predict whether they or a child would be affected by a genetic disease.

However, in addition to these traumatic and still rather rare inherited conditions affecting only a small group of patients, we now know that a huge proportion of the population carries not a certain commitment, but a predisposition to chronic disabling conditions which take a lifetime to develop such as diabetes and some forms of cancer and heart disease. When put together, then, the impact of genes and our ability to modulate or change their function is relevant to virtually everybody in this country.

Before I go on and talk about gene therapy specifically, I want to point out that "fixing" genes and improving health and quality of life is completely consistent with our long term goals of providing preventative and corrective medicine targeted to the known individual needs of our citizens. In the past, we have had to focus only on relieving the symptoms of genetically determined disease. The future offers the opportunity to diagnose, cure and alter the course of disease.

There is a degree of public interest in the nature and philosophy of gene therapy, and its potential problems. This is not a new response to the advent of innovative therapeutic agents. For example, in 1802 when Edward Jenner proposed injecting humans with material from cows to vaccinate against smallpox, there was a great outcry illustrated by cartoons depicting people sprouting horns and tails. It is overwhelmingly important for Congress to help the American people to understand the scientists and also to help the scientists understand the public's concerns. We believe the Nation cannot afford to lose this opportunity to improve the lives of patients and cure these diseases. It also cannot afford to ignore the misunderstandings or mistakes that could develop and which thoughtful debate can prevent.

As a life sciences researcher, I spent 25 years before coming to Washington trying to understand the genes that predispose or cause diabetes and obesity; two diseases which, if you look around this room, are of great personal interest to at least some of us. Today, we know on which chromosomes the genes that cause these diseases reside in some animals, and have learned in the past month that insulin dependent diabetes mellitus, the form that so often and tragically afflicts young people, is regulated in part by genes on chromosomes 6 and 11, but that as many as 18 other chromosome regions may also be associated. So, to be sure, these issues are not simple. In other words, some genetic diseases can be traced to a single simple problem in one individual gene, while numerous other familial conditions are linked to a highly complex set of coding faults. We have to understand that the situations our biomedical investigators face today are as complex as they are heartbreaking.

Although there has been a resurgence of antibiotic-resistant strains, e.g., tuberculosis, antibiotics are largely adequate to manage many previously fatal bacterial infections and great strides have been made in curbing certain viral diseases. Vaccines are our most powerful weapon against the common infectious diseases of childhood--measles, mumps, rubella, and now Haemophilus influenza, as well as others such as hepatitis B. I characterize vaccines in this way because they actually prevent the occurrence of infection which is the most cost-effective approach to illness.

However, the medical armamentarium is still limited with respect to the prevention or treatment of many common chronic or long- term disabling diseases including arthritis, diabetes, heart disease, cancer, and mental illness. The most highly desired goal, from the perspective of the patient and the country's health care system, is to prevent the occurrence of disease. The bulk of our treatment strategies for such conditions rely on ameliorating symptoms but fall short of actually curing patients. For those situations in which genetic elements are the causative agents, it stands to reason that the route to prevention and cure is through molecular biology and gene therapy. I think the promise is real, but we have a long way to go before genetic medicine is a common practice.

Questions Raised by the Committee

The charter describing the objectives of this hearing emphasizes the goal of using gene therapy to correct inborn genetic defects that occur in humans. Although truly Herculean, this is a worthy goal. The entire human genome is comprised of between 50- and 100,000 genes. Mendelian Inheritance in Man, the catalogue of genes associated with human disease now cites roughly 4,200 known single gene defects, of which only 300 to 400 have actually been cloned. Many of these genetic defects are responsible for known rare metabolic diseases such as Tay-Sachs and Gaucher, or other pathological conditions including sickle cell anemia, cystic fibrosis and familial hypercholesterolemia. The Human Genome Project has played a significant role in developing the research tools that have accelerated the pace of gene discovery. As noted before, many more human disorders are the result of the interaction of several genes, thereby compounding the difficulties in getting to the root causes. When the role of genetic susceptibility to environmental influences is added to this already complex equation, the true magnitude of the long term task becomes apparent.

Current State of Gene Therapy

Gene therapy encompasses both the replacement of missing or defective genes and augmenting existing biological processes for fighting disease. Although it was expected that the first applications of gene therapy would be directed toward correction of genetic defects, in fact, that has not been the case. The first actual gene transfer protocol involved patients with cancer. The purpose of this trial was not therapy, per se, but to see if genetically "marked" cells from a small group of patients would behave as predicted upon reintroduction into the patients' bloodstream. I know that my colleague Dr. Wivel will describe these examples in more detail later. The point I want to emphasize is that we are at a very early stage in the development of this technology. The first targets for gene therapy trials will be determined by the available scientific capabilities. Some of the thousands of diseases caused by just the tiniest change in a patient's genetic code may not be treatable using these methods for quite some time. The reasons for such limitations are varied but I will describe just a few.

Almost all inherited metabolic disorders are the result of improperly functioning proteins, especially enzymes. Enzymes are the catalysts that permit us to extract nutrients from the food we eat, to transfer energy enabling us to perform tasks, to send signals from one cell to another, and to detoxify and excrete the endproducts of these life processes. Enzymes are essential to life and a defect in the gene coding for these compounds would be lethal to the developing fetus. Every living organism relies on the appropriate enzymes being present at the right time and in the right amounts. Therefore, the simple replacement of a defective gene may not be sufficient to improve the condition of the patient. Exquisitely fine regulation of production of the enzyme at the molecular level is also crucial in some cases.

Another example of how complicated genetic intervention can be is the fact that we may need to reach the genes in a specific organ like the islets of Langerhans in the case of patients with diabetes. It may not be feasible or practical to rely on surgically removing the target cells, altering them in a petri dish in the laboratory and returning them to the patient. Other options include creating methods that will enable the replacement genetic material to home in on the target cells or tissues, such as using viral delivery systems that are already accustomed to reaching the desired cells, or selecting for treatment those conditions that can be remedied without need for such specificity. Both of these options are under study.

The early candidates for gene therapy therefore, are those defects that may be remedied in a fairly simple fashion by introducing a gene that codes for a product that does not require careful regulation but can be functional and useful in any amount while present in the general circulation. Other candidates fall in the second category that I mentioned, as treatments for diseases such as cancer and AIDS that work by boosting the patient's internal defense systems. For now, the selection of disease targets is limited by the available science and technology. As we learn more and more about regulation of gene expression in the normal organism, we will be able to apply this to our understanding of disease processes.

I think it is fair to say that today's biomedical investigator has , for the first time, the scientific knowledge and technological tools to begin addressing questions that have eluded us in the past. The answers open doors to additional avenues of investigation, bringing us closer to understanding the fundamental biological processes underlying normal and disease states. This knowledge, in turn, points toward means to diagnose, treat and, ultimately, cure or prevent disease.

Breast Cancer Susceptibility Gene

The recent identification of a breast cancer susceptibility gene is a good illustration of this process. Although the existence of a gene associated with inherited forms of breast and ovarian cancer was postulated in 1990, it was just two weeks ago that the precise chromosomal location of the gene was announced, prior to publication in SCIENCE, the journal of the American Association for the Advancement of Science. Mutations in this gene are thought to account for one-half of the 5 percent of cases of hereditary breast cancer, which often strikes women at a relatively early age. Breast cancer is diagnosed in approximately 180,000 American women each year and the race to find this gene was intense, involving several groups of researchers. The team that made this finding was headed by scientists from the University of Utah Medical Center and Myriad Genetics, Inc., in Salt Lake City; and the National Institute of Environmental Health Sciences, North Carolina-based component of the National Institutes of Health.

I think it is worth paraphrasing a statement made by one of the scientists that locating the BRCA-1 gene creates more questions than it answers. With this key gene in hand, we can begin to examine the entire cascade of events that lead up to the development of breast cancer, including, perhaps, the 95 percent of cases that are not hereditary. We also expect that this discovery may be extended to helping to understand the normal forces that regulate cell growth and cell division and how disruption of this function leads to cancer. Of course there is immediate interest in using the gene to develop a screening test to identify women at increased risk of inherited breast cancer and ovarian cancer. This will take some time -- time we will need to identify and establish procedures under which such tests would be helpful.

I will return to the issue of ethics and genetic information in a moment. The point I want to underscore is that a great deal of fundamental scientific research must be done in order to put the results of genetic studies to use in the diagnosis and treatment of disease. Continued support for the science that offers such tremendous promise will result ultimately in better quality, more cost-effective health care than we can provide today with our still rudimentary understanding of the genetic basis of disease. Research in molecular biology and genetics is supported not only through the Human Genome Project, but also by virtually all NIH components, the National Science Foundation and many other agencies. I believe you will hear more about this work from Dr. Wivel. We must not lose sight of the long-term value of this commitment.

The discovery of the breast cancer susceptibility gene and the attention it generated in the press offers a useful opportunity to educate the public about the power and limitations of biomedical science. Dr. Varmus and the NIH scientists deserve the credit for explaining what this discovery means for women at risk of breast cancer and for the public at large. When this announcement was made, we were gratified to see that the press showed great sensitivity in explaining that a screening test would not be forthcoming immediately. But questions about who should be screened and under what conditions have been raised and should be fully aired, even before such a test becomes available.

Issues to be Discussed

Similar questions have surfaced to accompany other medical achievements. One concern that has been raised is that therapeutic regimens usually lag behind the technology used to diagnose illness. For example, prenatal genetic screening now is available for a number of conditions, including Tay-Sachs, which is fatal to affected children between the ages of 2 to 4. Other diagnostic tests may be easier to consider if the condition, such as colon cancer, is treatable with early detection. Nonetheless, the vexing question of how to utilize information on genetic disease or predilection in the absence of a cure will remain of intense interest to our citizens.

To help inform the public discussion, we will have to continuously explain the scientific and ethical issues. That is one of the reasons that in its position paper on research, Science in the National Interest, the Administration has pushed for more programs to enhance public scientific literacy. Enhancing our scientific literacy empowers our populace, providing the means for informed decisionmaking. Providing a forum for airing tough issues and exposing them to the scrutiny of experts and interested individuals is also important. This hearing makes an important contribution to increasing awareness of issues related to gene therapy. I think the early public interest in human gene therapy protocols, before the technology was in hand, also played a role in resolving some reservations and permitting approval of this work.

National Bioethics Advisory Commission

The Administration believes that the time has come for the Federal government to assume a more proactive role in creating an atmosphere that fosters open discussion of thorny issues related to biomedical and behavioral research and the applications of that research. That is why Dr. Gibbons and the Office of Science and Technology Policy have proposed establishing a National Bioethics Advisory Commission. The goal is to establish a panel of non-government experts in the relevant scientific disciplines, law, and ethics, as well as community representatives, to provide advice and recommendations to the Federal government. In order to engage broader public participation in the discussion of such a group's role and composition, a draft charter for a National Bioethics Advisory Commission was published on August 12 in the Federal Register for comment. The Commission would report to the President's National Science and Technology Council and would operate under the provisions of the Federal Advisory Committee Act.

OSTP began developing this proposal at the request of the Departments of Energy and Health and Human Services, in October 1993. These agencies had been considering establishment of a joint advisory panel to examine issues related to maintaining the confidentiality of genetic information resulting from the Human Genome Project. It became clear that there were a number of other bioethical issues that would benefit from consideration by an expert, standing advisory body. Thus, the informal interagency working group was expanded to include representatives of DOD, NASA, VA, NSF and Justice. Discussions also took place with members of Congress including Representative Markey and Senators Kennedy, Glenn and Hatfield. With their interest and encouragement, several improvements were made in early drafts. The products of these discussions are the draft charter and preamble which have been recently published in the Federal Register.

The key points of the charter are:

The immediate charge to the Commission will be to consider issues in the protection of the rights and welfare of human research subjects and management and use of genetic information.
The general charge to the Commission will be to consider current and prospective issues pertinent to the conduct of research on human biology and behavior and to identify broad, overarching principles to govern the ethical conduct of such research. The Commission would have broad authority to establish its own priorities and agenda, in accordance with the following four criteria:
1. Public health or policy urgency of the bioethical issue;
2. Relation of the issue to the goals for Federal investment in science and technology;
3. Absence of another body able to fruitfully deliberate on the issue; and
4. Extent of interest in the issue across the government.
The Commission would accept input on potential issues for consideration from the National Science and Technology Council, Congress and the public at large.
The Commission would be composed of experts in the fields of bioethics and theology, social and behavioral science, law, medicine and
biological research, in addition to representatives of the general public. Its members would be appointed by the President.

You may recall the groundbreaking work of the National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research and the President's Commission for the Study of Ethical Problems in Medicine and Biomedical and Behavioral Research; reports such as Defining Death, Splicing Life and Research Involving Children. It is our hope that this new group would build upon the impressive body of collective wisdom generated by earlier commissions. We believe that the Commission would be useful in considering some of the difficult issues that will be discussed today.

Summary

As we move forward in our search to prevent and cure human disease, it is critical that we support the fundamental science from which this new field is emerging and that we encourage the development of ethical guidelines for its applications. There is still a long way to go before the significant potential of gene therapy can be realized and put into general practice. As the research continues, we must also support efforts to communicate an awareness of its promise and limitations and get the public engaged in the dialogue. Finally, we must look forward to training a new cadre of scientists, physicians and health professionals who are able to use this technology and its outgrowths in the future for the prevention of some diseases and the amelioration of others and whose practices are in the finest ethical traditions.

I thank you for your attention and offer to answer any questions you might have.

1994 OSTP Speeches

Statement - Dr. Robert T. Watson

Statement - Dr. Mark Schaefer

Gene Therapy

Remarks at the 25th Anniversary of Apollo 11

Testimony - Dr. Greenwood

PNGV-Remarks by the President

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