Faculty, students, and research staff are trying to discover if the agents in our environment which can cause genetic changes in human cells in the laboratory are also responsible for causing genetic changes leading to human diseases. Genetic diseases are of two kinds. Those arising from mutations in germ cells which are then observed as inherited diseases, or those which arise in the somatic cells of our organs where degenerative diseases or cancers are observed. Inherited genetic changes causing severe physical or mental impairment of our newborns approaches 2% and fills nearly half of the beds in our pediatric hospitals. Human cancers require several genetic changes (mutations) inherited or occurring within the organ from which the tumor arises. We hope to make substantial contributions to understanding basic mutational mechanisms, finding the causes of human mutations and defining the quantitative relationships that govern the lifetime occurrence of diseases which require multiple mutations in humans.
Mutations, cell kinetics and cancer.
COLON CANCER: Death Rate for Persons born in 1880s
Since cancer requires that a particular cell contain several separate genetic changes we undertook the development of a unified field model combining the number of such mutations and the rates of cell division and death in the tissue from which the cancer arises. If such a model were correct it would allow estimation of mutation rates and cell kinetic rates from the observed age-specific cancer mortality data. It would also allow calculation of the fraction of the population at risk of such a cancer. In 1997, we completed two tasks, the completion of the unified theory and ordering of U.S. mortality data and census data so that the cancer mortality rates could be observed for some cancers from 1900 to the present day. An example of an age-specific cancer mortality curve is shown above for colon cancer death .
Using the unified model and observations of cell death and division rates in normal and adenomas of the human colon we have been able to observe the historical increase in the number of Americans at risk of colon cancer and the mutation rates for each of three critical events in this process. Curiously, the estimates of mutation rates and cell kinetic parameters remained almost unchanged throughout the last century and a half while the number of persons at risk increased by about 66%. The estimated mutation rates are very close to those observed for spontaneous mutations in human cells grown in our laboratory, i.e. the rates are the same as seen in human cells that are not exposed to any environmental chemicals. Examination of the kinds and distribution of point mutations in the APC gene which must be mutated to begin the process in most colon cancers reveals that they are of a kind which might be expected to arise by the normal errors of DNA replication. Pursuing this point will be a major activity for the Center.
These data follow on our previous discovery that the number and pattern of point mutations in the mitochondrial DNA in human organs are essentially invariant. These patterns are the same in colon, muscle and bronchial epithelium. A striking finding has been that even cigarette smoking has no effect on the mitochondrial point mutations as demonstrated by our studies in lungs of identical twins discordant for smoking.
The development of technology to directly measure environmental chemicals and genetic change in humans has been our strongest area of contribution in recent years. We now need to invest in studies of cell turnover (the process of cellular renewal in all tissues), errors in the programming of which we believe are important in carcinogenesis. Fortunately, a new faculty appointment in the Division of Toxicology, Dr. James Sherley, addresses this need both in terms of research guidance and teaching. A distinct weakness of the Center, the Division of Toxicology and MIT genetic toxicology continues to be the absence of faculty who would focus on the important disease producing changes which involve rearrangement or losses of whole chromosomes.
We have developed technology which allows us to measure chemical reaction products with proteins and DNA in human tissue (NIEHS Biomarkers Program). We have studied chemicals entering humans from the environment: food in the Biomarkers Program, air in the Mutagenic Effects of Air-borne Toxicants Program, and water in the Superfund Hazardous Substance Basic Research Program. Unfortunately, we have not achieved a synthesis uniting the research which measures the human exposure in terms of DNA reaction products derived from environmental chemicals and the rate and kind of genetic changes. Indeed, the question may well be raised as to whether DNA adducts are precursors of a significant fraction of human genetic changes in either mitochondrial or nuclear DNA.
Yet, we in CEHS have never assumed that environmental chemicals constitute the primary causes of human genetic change however, we are well-positioned to follow up on the present observations. Two major programs, Endogenous Nitrite Carcinogens in Man (NCI) and Genetics and Toxicology (NIEHS), have focused specifically on either one powerful endogenous mutagen, NO, or the endogenous process of DNA replication to determine responsibility for our genetic change rate. We have cast a net to discover if the patterns of spontaneous mutations in bacterial or human cell studies are recapitulated in human tissues.
RESEARCH CORE GROUPS
The Air Quality Core has two components. The first is directed at identifying airborne chemicals found in human lungs, and relating these to their sources and atmospheric transformation processes. The second is to assess the potential human damage associated with the emissions from a variety of thermal processes proposed for remediation of Superfund sites. Professor Jack Howard of Chemical Engineering has become Associate Director for this core group after the retirement of Professor Adel Sarofim. Professor John Vander Sande joined this core group this Fall with the goal of extending his technology of x-ray fluorescence microscopy to identification of the sources of particulate matter in human lungs. A totally redesigned Program (Mutagenic Effects of Airborne Toxicants in Human Lungs) was proposed to the National Institute for Environmental Health Sciences on October 1, 1997 with a five-year budget of approximately 9 million dollars.
The Water Quality Core focuses on the behavior of toxic chemicals in the natural environment with particular emphasis on processes that lead to human exposure. The studies also work to determine the effectiveness of remediation technologies to attain high waste destruction efficiencies without the formation of mutagenic by-products from deposits such as found on Superfund sites. Professor Harold Hemond is Associate Director for this core group as well as head of the Parsons Laboratory, Department of Civil and Environmental Engineering.
Our Toxicology and Epidemiology Core focuses on discovering the causes of genetic change or other physiological conditions leading to human disease. We have developed technology which allows us to measure chemical reaction products with proteins and DNA in human tissue, and have also developed means to measure the point mutational spectra arising in the human mitochondrial genome. These twin technologies are now being used in parallel to try to discover the causes of mutations in people. The retirement of Professor Gerald Wogan and his replacement by Professor Steven Tannenbaum as head of the Division of Toxicology vacated the Associate Director's position long held by Professor Tannenbaum. He has now been replaced by Professor Peter Dedon, Associate Professor of Toxicology, who is already active in our nascent effort with microchip manufacturing faculty in several engineering departments.
We expect to compete for a specialized center in human genomics when announced as a joint effort of the National Institute of Environmental Health Sciences and the National Cancer Institute. This proposal will stand on the legs of our advances in analyzing public mortality records to identify populations depleted of inherited disease causing genes and our technology for recognizing DNA sequence changes which may be applied for scanning 1,000 persons' blood samples simultaneously.
We have been invited to join the new Microsystems Technology Lab to create a major program to assess the materials used and created within the semiconductor manufacturing industry. It is clear from initial discussions that the CEHS' approach to complex mixtures analysis for chemical identity and biological activity are a natural "fit" to the needs of faculty groups involved in the manufacturing process design.
The Core Laboratory is a central resource in analytical chemistry for CEHS project participants, providing them with analytical expertise, training, and access to analytical instrumentation. A major goal of the CEHS is to foster collaborative research among combustion engineers, genetic toxicologists, analytical chemists, civil engineers and other investigators in order to solve important problems in human health effects research. The Core Lab is a centrally important resource in making this research collaboration come to fruition. It is headed by Dr. Arthur Lafleur who succeeded the retiring Professor Klaus Biemann as Associate Director for analytical chemistry. Dr. Lafleur is organizing a Boston area consortium of university laboratories with special interests and abilities in analyses of sources, environmental samples and human tissue samples. The goal is to increase our several universities efforts in environmental health and engineering to be more competitive in grant proposals and to offer a wider spectrum of analytical chemistry experiences for our MIT students necessitated by the abandonment of analytical chemistry as an academic area at MIT.
To promote broader public understanding of our methods and goals, CEHS has teamed up with the Massachusetts Corporation for Educational Telecommunications (MCET). MCET is a not-for-profit, distance-learning organization serving the needs of the K-12 community. It reaches an audience located in 47 states or approximately 1.3 million participants and every school district in Massachusetts. MCET has an annual budget of approximately $9 million funded from various U.S. federal agencies, state agencies and corporations.
In 1996 we aired a highly successful pilot program for a six program series for middle school teachers and students that would increase understanding of how hypothesized connections between the environment and health are explored. The program highlighted the scientific processes used by researchers to prove or disprove hypothetical connections between the environment and disease. Afterwards, we prepared a proposal for a series of programs and submitted it along with the pilot video to the National Institute of Environmental Health Sciences. As a result, CEHS obtained full funding for the series. On 10 October 1997 we presented our first full length segment to some 45 Massachusetts high schools. Credit is given to Dr. Heidi Nepf, Assistant Professor in Civil and Environmental Engineering, for her leadership in this project. As second session is already "in the can" and a third will be completed by Thanksgiving.
HIRING AND RECRUITMENT PRACTICES
The CEHS supports the affirmative action goals of the Massachusetts Institute of Technology while maintaining our commitment to hiring solely on qualification of the candidate for the position. This year two of our feasibility studies by female junior faculty members went on to receive direct support as projects in our program grants. The majority of our staff, including research specialists and graduate students are women. Additionally, as has been the case in CEHS, we receive a Minority Supplement from NIEHS for support of a Research Assistant.
In 1996-97 the director identified and worked for the appointment of Dr. James Sherley, M.D, Ph.D (Harvard, Johns Hopkins) of the Fox Chase Cancer Center as an Assistant Professor in Toxicology. Dr. Sherley is an African-American and will occupy newly renovated CEHS office and laboratory space (bldg 16) ceded by CEHS.
William G. Thilly
MIT Reports to the President 1996-97