MIT
Reports to the President 1994-95
Faculty, students and research staff are focused on discovery of the agents in
our environment responsible for genetic changes in humans. Our focus is based
on our perception of public health needs. Genetic disease 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.
We have developed technology which allows us to measure chemical reaction
products with proteins and DNA in human tissue (NIEHS Biomarkers Program). We
have developed means to measure the point mutational spectra arising in the
human mitochondrial genome (NIEHS Superfund Program, DOE Human Cell Mutagenesis
Grant). 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 Program have all received our attention.
Yet we have never assumed that environmental chemicals are the primary causes
of human genetic change. 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 are responsible 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. Recent data suggests that for
human mitrochondrial DNA, errors in DNA replication, not exogenous chemicals,
are the primary causes of point mutation.
CEHS research is Organized as three Programs:
The Air Quality Program has two components. The first is directed at
identifying airborne chemicals which are mutagens for human lung cells and to
relate 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.
The Water Quality Program 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.
Our Toxicology and Epidemiology Program focuses on discovering the causes of
genetic change 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.
Our study of air samples from major US cities has confirmed that they contain
chemicals which are potent mutagens in human cell assays. We have identified
the specific chemicals accounting for 1/3 of this activity in the form of 4
polycyclic aromatic hydrocarbons. We should soon know the identities of most
of the remaining mutagenic compounds which appear to be semipolar derivatives
of the polycyclic aromatic hydrocarbons.
These mutagenic air pollutants are among the larger, less volatile air
pollutants. We find that these are disproportionately represented on the
smallest air-borne particles which are most likely to reach and reside in the
human lung.
Our effort to use electron microscopy to characterize particles from various
sources has brought gratifying results. It appears that the approach should
allow accurate identification of environmental sources of the particles found
in human lungs.
In attempting to find a cause for the 1970-1986 Woburn, Mass childhood leukemia
cluster, we used hydrogeologic methods to show that municipal wells would have
drawn some 60% of their volume from the nearby Aberjona River. Sediment core
analysis showed that at or about the time of the wells' use, substantial
quantities of arsenic and chromium were suspended or dissolved in the river.
To discover if these or other metals reached the users of the municipal water
supply, we collected 109 hair samples cut from children from 1938 to 1994.
Testing for metals in hair allowed us to demonstrate that the suspected
municipal wells could not be associated with metals in children's hair.
Another may help clean up arsenic Professor Hemond has announced the
discovery of two forms of bacteria; one which takes up arsenic and oxidize it
to an insoluable form, while another turns arsenic into an insoluble glop
called "orpiment." Having identified the kinds and sources of chemicals now
moving down the Aberjona River, we are working to devise means of preventing
this continuing process. We will investigate how these new bugs can be used to
clean up arsenic as it seeps from groundwater into surface waters.
One key observation arising from the use of neutron activation analysis of hair
and sediments was the discovery of a recent increase in the lanthanide
elements. These highly reactive elements are being used in a wide and growing
number of manufacturing processes and automobile catalytic converters. Their
properties as strong redox catalysts would seem to make them potent persistent
irritants. We will follow this lead in 1995 both in the Air and Water Quality
Programs.
We have at long last observed point mutations as they occur in human tissues
and compared them to those arising in human cells in culture. Curiously, the
mutations observed, some dozen hotspots in a 100bp mitochondrial sequence,
appear to be the same in human cell culture, human colon, human lung and human
muscle samples. This may mean that such mutations in humans arise from
endogenous chemical reactions or DNA replication error. It may also be that
the first sequence studied is not representative of other mitochondrial or
nuclear sequences. Reconstruction experiments seem to exclude the possibility
of analytical artifact, but at the mutation fractions of about 2 X
10-5 and 2 X 10-6 respectively, caution in interpretation
of these observations is justified.
Our ability to measure DNA adducts with the methionine 35S post labeling
approach coupled to HPLC has given increased sensitivity as well as a
separation and isolation procedure which integrates with mass spectrometry.
This, with continuing advances in the technology to measure certain polycyclic
aromatic hydrocarbons adducted to proteins, has greatly advanced our ability to
measure the actual amounts of many environmental chemicals which react with
the chromatin (DNA and histones) of all human organs. The combination of
analytical chemistry and analytical genetics in studying human populations
opens new vistas for students and faculty alike.
We may now imagine studies of humans in which both exogenous and endogenous
causes of genetic change are considered and analyzed. For instance, the
finding that mismatch DNA repair defects were important in the early appearance
of colon cancer in certain families followed our earlier discovery that human
cell mutants existed with high spontaneous mutation rates which were deficient
in this repair pathway. These "mutator" human cells mutate on their own so
fast that the low levels of environmental chemicals in the human body are
unlikely to contribute to mutations arising in such individuals.
CEHS faculty recognized that there was no formal way for these students to gain
a working understanding of environmental chemical problems. Thus, we created a
series of four courses collectively called Chemicals in the Environment. CEHS
faculty teach the first three: Sources and Controls (Sarofim), Fate and
Transport (Hemond), and Toxicology (Thilly). Professor L. Susskind in the
Department of Urban Planning teaches the fourth: Policy and Regulation. These
courses have been a hit with students and we find both undergraduates and
graduates enrolled. In 1991 we received the Sizer Award for Outstanding
Contribution to Graduate Teaching at MIT for the series.
TOX 104J required of Civil Engineering IE students is being revised to account
for the greater understanding of molecular biology resulting from the Institute
biology requirement.
We have been studying the chemical sources, fate and transport, and human
exposure in the Aberjona River Watershed here in Massachusetts for seven years.
When we began this work we knew we had a special obligation to the people in
the several towns included in our work to communicate our aims, our findings
and our limitations in interpreting these findings in terms of public health.
To do this we hold two annual public meetings to discuss our progress and try
to answer questions. Faculty and students present their work and hear what the
public thinks soon thereafter.
Of course, since we have found that a local Superfund Site is "leaking" fair
quantities of chemicals like arsenic into the Aberjona, our presence is
regarded as a problem to those who wish to inexpensively develop the site for
municipal and commercial use. In order that our observations are available to
all in a timely manner, we have agreed with Congressman Edward Markey's staff
to meet some weeks before our public presentations to discuss technical
progress with representations of the U.S. EPA, Massachusetts Department of
Public Health, Massachusetts Department of Environmental Protection, the
custodial and remedial trusts responsible for the particular Superfund Site as
well as elected public officials or their representatives. In our first
meeting of this group an assertion was made that the public could not
understand our work as we present it and it was causing undue stress when it
was discussed in newspaper articles. My answer was, and is, that our
interactions with the public have impressed all of us with their basic
understanding, interest and support for a policy of openness as expressed
through our public meetings. Let any one attend one of these open forums and
hear the intelligent and informed questions from the audience before positing
that the public cannot comprehend the essential elements of our research tasks
or fail to differentiate between the testing of hypotheses and findings of
fact.
Tangible assistance from the community has taken many forms, including site
access, contribution of sample material (including human hair), recollections
of historical events not otherwise recorded in the literature, and the
identification of potential sources of contamination (repositories of tannery
waste, etc.). In the long run, we believe such outreach is both a
responsibility of scientists who work in a community, and a policy that is in
the long-term best interests of the research itself.
Each spring graduate students from the Center teach a toxicology course for
nearby Aquinas College's program to train area adults to enter the
environmental technology field. The program, designed last year, to allow
motivated, older students with little or no technical skills to take positions
as environmental technicians after one year of class work and internships, was
the initiative of three graduate students, Hilary Coller, Paula Lee and Aoy
Tomita. This spring Rony Gal taught the course entitled Applied Toxicology and
Environmental Health. The course covers fate and transport of chemicals in the
environment and within the body, metabolism, DNA structure and function,
mutagenesis and case studies on the toxicity of several different chemicals.
Laboratory work includes bacterial mutagenesis and molecular biology
experiments. Several of the students in the class have secured internships and
even permanent positions in the environmental field as a result of their
experience. Next year, students from the Center are expected to teach not only
toxicology but also related classes including biochemistry and microbiology.
As we look into the future we see a real need to provide our elected
representatives with knowledge about public health and hazardous waste issues
as well as our need for basic research support. We know that in a real sense
"all pollution is local" but who among us has the means to go into a community
and discover the primary causes of mutations leading to cancer, birth defects
or other diseases requiring genetic change? To this end, we have coordinated
an endeavor involving 23 Superfund Research Centers and 24 NIEHS centers
nation-wide. Faculty from these research centers made presentations to members
of Congress or their appropriate aides both in their home districts and in
Washington, D.C.
In fiscal year 1995 our research volume exceeded 8 million dollars, a first in
our history. This has been due to our successful renewal of the grants that
have become the base of the CEHS support. These grants include a NIEHS Center
Grant (funded to 1999) as well as the NIEHS Superfund Basic Research Program
(funded to 2000), our program studying mutation induced in human lungs by air
pollutants, NIEHS Mutagenic Effects of Air-Borne Toxicants in Human Lungs
(funded to 1997), and our program studying the role of nitric oxide as an
internal toxicant, NCI Endogenous Nitrite Carcinogenesis in Man (funded to
1999). Additionally two renewal proposals are currently under review; our
program in genetics and toxicology (NIEHS Genetics and Toxicology and our
program using mutational spectra to measure point mutations in humans (DOE
Comparative Mutagenesis of Human Cells In Vivo and In Vitro). Unfortunately,
one of our Programs: NIEHS Molecular Biomarkers did not fare well as reviewers
reacted negatively to the news that our new technology raised doubts about the
role of environmental chemicals in causing human mutations.
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 we were pleased to
fund four feasibility studies submitted by female junior faculty members. The
majority of all members of our staff, including research specialists, students
and support staff are women.
The Center has continued to actively recruit graduate students from minority
institutions. We, with NIEHS, support undergraduates in summer research
internships which have yielded multiple top-notch recruits. This past year we
hosted more than a dozen potential applicants from Cheyney College near
Philadelphia; one of their number then served a summer internship and has
recently entered our graduate program in toxicology. Our Director, Bill Thilly
along with Dean Ike Colbert coauthored a grant request to the Sloan Foundation
which now provides funds for entering minority graduate students to take the
time to fill in their backgrounds if necessary before beginning the graduate
curriculum.
William G. Thilly
MIT
Reports to the President 1994-95