MIT Reports to the President 1997-98
For the last twenty years the Center for Environmental Health Sciences has tried to discover if the chemicals or radiation in our environment are responsible for causing the genetic changes which cause human diseases. This report formally acknowledges that the preponderance of the available evidence now favors an interpretation that human genetic changes are not caused by reactions with environmental agents but may arise primarily from errors in DNA replication.
It must also be acknowledged that only a small fraction of professional scientists and a minority of toxicology faculty at MIT are of this opinion.
Toxicology at MIT has developed as a distinct faculty using the hypothesis of environmentally induced mutations in humans as a Central Premise. Research and education have used a common paradigm of human exposure, metabolism of environmental compounds to reactive intermediates, reaction with cellular macromolecules especially DNA and, failing repair of this damage, genetic change. CEHS coupled this toxicological paradigm with environmental engineering studies aiming at understanding sources of chemicals and their chemical changes as they are transported through the environment in air, water or food to humans.
The available evidence, which requires us to rethink our scientific positions, has two parts. The first is that the mutations inherited via germ cells in humans are chiefly G->A transitions (>70%) and small deletions at locally repetitive sequences( 20%). A similar pattern is observed in mutations in cells in tissues as human's age or within tumors. These kinds of changes are associated with patterns of mutations caused by DNA polymerases and not with induction by any known exogenous chemical in bacteria, yeast, rodent or human cells. A single exception to this finding is that the mutations reported in human skin are consistent with mutations induced in human cells by ultraviolet light. The second is that the rate of mutation as observed by determining mutant fractions in white blood cells in humans from youth to old age indicate a constant rate of mutation at a rate per stem cell division equal to or somewhat less than observed for mutations in human cells grown in the absence of added chemicals in the laboratory.
There is, however, only one published direct test of the Central Premise in humans and that is in the mitochondrial DNA, not the nuclear DNA which carries tumor suppressor genes in which mutations required for human cancer occur. In this case, careful examination of a 100 base pair sequence revealed that the mutations were >90% G->A or A->G transitions distributed over some 17 base pairs as hotspots. It is now known that this distribution of transition mutations is found among humans in the mitochondrial DNA inherited in maternal lineage indicating that our studies have revealed a pattern of mutation common to the entire mitochondrial genome. In direct studies of the lung epithelium of twins discordant for cigarette smoking it was found that cigarette smoking had no effect on the number or kind of mitochondrial mutations. A study in progress with human mitochondrial DNA polymerase has shown that the same quantitative pattern of G->A transitions observed in the organs of humans are produced when the mitochondrial sequence is copied by the polymerase in the laboratory.
However, after dissection of lungs from smokers and nonsmokers and assay of two different point mutations in the K-ras and P53 nuclear genes, we find that the number of mutant colonies in smokers and nonsmokers are identical. While more lungs and assays are required prior to offering for publication it seems that cigarette smoking probably does not induce point mutations in human lung cells.
These findings may be considered in terms of the natural progress of science inexorably discovering former error but they have also created a great deal of discomfort among MIT toxicology faculty and among scientific reviewers of CEHS proposals.
One reason is that when some scientists hear the arguments for a spontaneous source of human mutations and they interpret them to be arguments against a role for environmental chemicals in human disease, especially cancer. This is not logically implied by CEHS proposals in which it is argued that the historical record of rising fractions of Americans at risk for lung cancer, leukemia, lymphoma, and cancers of the central nervous system and kidneys is prima facie evidence of the importance of environmental factors. What is logically inferred is that in addition to press for direct testing of the Central Premise in human nuclear genes, CEHS must invest in basic research, which examines biological phenomena in addition to mutations, which could be affected by environmental factors?
To this end CEHS has created a network of collaborating physicians interested in the pathology of lung and colon and in its new Building 16 facilities established core laboratories to receive, dissect and study tissues, organs and blood samples as autopsy or surgical discards. These samples may be studied for indications of exposure to environmental and endogenous chemicals, genetic changes at the DNA sequence or chromosome structural level, changes in gene expression or local morphology. Younger faculty in toxicology such as Professors David Schauer, Bevin Engelward and James Sherley are paying close attention to the role of cell kinetics, death and division rates, in human tissues as factors, which could be affected by the presence of environmental pollutants.
In the area of human exposure to chemicals, chaos reigns. Our senior faculty laboratory leaders are expressing strong reservations about the accuracy of results from their own and othersí laboratories which indicated that cells in the human body carried thousands of DNA adducts derived from food, air and water.
Since March 1998, the Center has undergone three NIH site visits and one more is scheduled for 15 October. For the program grants, Mutagenic Effects of Airborne Toxicants (W.G. Thilly, P.I.), Nitrite Carcinogenesis (S.R. Tannenbaum, P.I.) and the Center for Environmental Health Sciences center grant we have been informed of high ratings and funding over the next five years of some 19 million dollars. New initiatives abound in the areas of human genomics, exposures to radiation emanating from DOE sites, and the health effects of materials used or created in computer chip manufacture.
Key to the success of the CEHS renewal for five years of additional core funding was the MIT investment in the new facilities and the fact that eleven junior faculty joined the Center in the past seven years and three have already been awarded tenure through their Departments and Schools. The Center received a rating of Outstanding with enthusiasm, despite a recognition by the reviewers that observations were discordant with generally held beliefs. This is the highest rating the Center has received since its founding in 1978.
The Center Director, W.G. Thilly, was elected in the past year to the presidency of two organizations representing university environmental health and engineering researchers across the U.S.: Association of University Environmental Health Science Centers and the Superfund Basic Research Universitiesí Association. In these positions he continues 12 years work organizing some two hundred annual explanatory sessions in states and congressional districts regarding progress and limits of knowledge in the environmental health field as well as the research needs and opportunities.
William G. Thilly