This month, the National Institute of Environmental Health Sciences marks 30 years--the anniversary of a reorganization that led to the creation of the National Institute of Environmental Health Sciences within the National Institutes of Health. We celebrate our progress from a time, as one Governor of North Carolina remarked, when there were more possums on our Research Triangle campus than Ph.D.s.
The environmental health sciences have made great progress. There is a long list of hazards that have been identified and thus made less hazardous. There is a long list of illnesses that can now be avoided or reduced. The NIEHS has contributed to the understanding of the causes and development of an impressive list of diseases. Because the environmental factors leading to these diseases can be avoided and changed more easily and cheaply than can our genes, we are in the disease prevention business, and we have been building the basic science to help us do more of that.
Yet, while anniversaries are celebrations of the past, they can also serve as pep rallies for the future. We are in a time of great change and no little uncertainty. As we move toward the year 2000, we hear pronouncements of impending doom, even a prediction of human sterility, and we also hear forecasts of wondrous progress.
Health care expenditures approach a trillion dollars a year, or about 14% of the Nation's gross national product, and the annual costs of regulatory compliance have increased to hundreds of billions of dollars. Thus, the prevention-oriented or public health-oriented research agenda of the environmental health sciences gains support. Our stock is up. Or, to paraphrase former President Ronald Reagan, environmental health research is standing tall and looking to the year 2000 with courage, confidence, and hope.
In the biosciences and, specifically, in the environmental health sciences, we have a historic opportunity to develop and apply knowledge to improve the human condition. My hope is that the Nation will exploit the opportunities in biomedical research that present themselves.
We have entered an era in which scientific opportunities have converged with public health and regulatory needs and in which remarkable advances in our understanding of human genetics present the opportunity to determine the causes and prevention of devastating diseases.
Over the past 20 years using the tools of recombinant DNA technology, researchers have identified a number of genes involved in the development of specific diseases such as cystic fibrosis and sickle cell anemia. These discoveries have been of the single gene variety (an alteration in just one gene causes a disease). Today we seek the causes and prevention of more common diseases such as cancer, Alzheimer's, Parkinson's, and osteoporosis that appear to arise from a complex interplay between inherited genetic alterations and the environment, rather than from a single gene.
Challenge: Teasing apart the causes of disease. Before we can prevent or improve the treatment of most diseases, we need a better understanding of individual function of critical genes involved in the growth and development of humans and the ability of environmental agents to interact with and damage these genes. Analyzing these complexities and teasing apart the genetic and environmental components involved represents a daunting challenge and an important scientific opportunity. The tools and technology developed by molecular geneticists are being used by environmental health scientists to help in the discovery of genes modulated by the environment.
The identification of disease predisposition genes, the determination of how these genes function normally, and how loss of function of these genes predisposes to disease are vitally important research issues. Their discovery will pave the way for development of novel strategies for prevention, early detection, and treatment; however, bigger challenges are presented by attempts to identify genetic predisposition resulting from inheritance of a complex of several genes. Also, identification of the nongenetic factors--environmental and dietary exposures, behavior, lifestyle, and infectious agents that influence whether the presence of altered susceptibility genes actually lead to disease--offers great potential to improve human health.
Challenge: Understanding carcinogenesis. Outstanding opportunity also exists to develop a mechanistic understanding of the carcinogenic and toxic action of environmental agents. Insights into molecular mechanisms involved in carcinogenesis or other disease processes are important in several ways: 1) they can provide a more rational basis for assessing human risk based on data obtained in animals; 2) knowledge of mechanisms can suggest new laboratory procedures for use in epidemiologic studies to more precisely identify the causes of human illnesses; 3) insights into the mechanism of disease initiation can increase understanding of the wide person-to-person variation in risk to disease; and 4) information on mechanisms of action of environmental agents is crucial for development of molecular medicine strategies to prevent, detect, and treat various diseases.
The axiom in carcinogenesis is that chemical agents initiate the carcinogenic process by damaging cellular DNA. While such alterations in genetic material may represent the major mechanism of cancer development, it is now clear that chemical agents can cause cancer and other human illnesses by other modes of action. Once the different modes of action have been deciphered, appropriate risk assessment methodologies can be developed to replace the current approach, which is based on the faulty assumption of a single mechanism of action.
Challenge: Using animal models to understand human disease. Technical advances have always played a key role in improving our ability to prevent and treat disease and are equally important in the discovery process in environmental health research. Technical advances in mouse genetics have now overcome an important impediment in biomedical research: the lack of animal models in which to study the development of human diseases. Recently developed methods in animal genetics allow the study of diseases in a way that was impossible when this Institute was created 30 years ago. These new techniques provide the remarkable ability to introduce mutations into the genetic material of mice that can be passed to their offspring. Investigators can now insert any mutation they choose into the mouse genome. They can also transfer genes from one animal species to another, and they can express genes at a different time and in different tissue than normal. Researchers are on the verge of creating the three most important animal models needed to determine the role of the environment in the development of breast and ovarian cancers.
For example, researchers at NIEHS have developed a "knock-out" mouse that lacks the estrogen receptor. The female hormone estrogen directs and controls cell growth and differentiation by binding to the estrogen receptor located in tissues throughout the body. Many environmental compounds bind to these same receptors, thus, potentially acting as environmental estrogens. These environmental compounds may play a role in a wide range of diseases. In women, they may be implicated in the development of endometriosis, uterine fibroids, and cancers of the breast, uterus, and ovaries. In men, these compounds might explain the increase in testicular cancer, the decline in sperm count, and other reproductive tract anomalies. Also, with the recent isolation of the human breast cancer susceptibility genes BRCA1 and BRCA2 (with major contributions by NIEHS scientists), efforts are under way to create "knock-out" and transgenic mouse models for these genes.
Challenge: Developing new animal models for testing. We also have the opportunity to develop new models for use in carcinogenicity and toxicity testing. Existing measures of carcinogenicity are based largely on rodent bioassays in which mice are fed large amounts of a single chemical. Human diets, in contrast, consist of small amounts of several natural and synthetic chemicals. These differences in exposures raise considerable uncertainties about whether the data derived from animal tests can be applied directly to humans. Uncertainties also result from variations among species and among individuals due to differences in age, gender, socioeconomic status, and genetic predisposition. Moreover, the current rodent bioassay for assessing carcinogenicity is too costly ($2-6 million per chemical, depending on the route of exposure) and too time consuming (taking up to five years to plan, conduct, interpret, and certify).
I am pleased to report that genetically engineered mice and in vitro assays have been developed that could become the new standard for carcinogenicity testing. The genetic alterations were designed to provide results faster, with fewer animals and less expense, than the current cancer bioassay. While it is still uncertain as to what extent these models can be used in lieu of the two-year rodent bioassay, the best guess is that they will greatly reduce our dependency on this assay, with considerable savings in both time and cost. Also, the new models may be more relevant to human risk assessment in terms of dosimetry, mechanism, and genetic background. While there are reasons for excitement concerning the potential impact that these genetically engineered models can have on environmental health research, it is important to emphasize that they represent only the first generation; better models will be developed!
Though the scientific challenges are daunting, rapid advances in a number of fields offer great promise. As more becomes known, it will be possible to develop regulatory policies based on a better understanding of how environmental agents affect human health. Continued research will eventually provide answers for many of the difficult questions about the link between environment and human health.
To summarize, environmental health research is at the crossroads of tremendous change. With the advent of sophisticated tools of cell and molecular biology, researchers can now obtain more rigorous data about the environmental effects on human health. It is no longer adequate to assume exposures; it is time that the putative exposures be quantified and their health effects documented. This information will be invaluable to physicians and public health officials in preventing, diagnosing, and treating disease. It will also assist policy makers in decisions about risk and regulatory responses, and the research may help clarify the influence that behavior and socioeconomic status have on human susceptibility to environmental agents with carcinogenic or toxic potential.
Thanks to the vision and hard work of many, including particularly Institute directors Paul Kotin and David P. Rall and Nobel Laureate Martin Rodbell, the foundation built during NIEHS' first 30 years is broad, solid, and distinguished. Since 1991, as the third director of NIEHS, I have seen the creativity and dedication of Institute personnel. I have been proud of their prizes and discoveries and of the benefits that flow from these discoveries for the diagnosis, treatment, and, especially, the prevention of disease. I believe these extraordinary achievements will not only continue but will quickly overshadow what has gone before.
The problems are enormous, the questions exciting--and the solution will require enthusiasm, creativity, and hard work. But the answers will come.
Kenneth Olden
National Institute of Environmental Health Sciences and the
National Toxicology Program of the National Institutes of Health
Last Update: August 4, 1997