Where Bench and Field Sciences Meet: Molecular Epidemiology at NIEHS
There is a quiet corner in London, not far from the specialty shops and
heavy traffic of Oxford Street, that is the site of the John Snow Pub. Nothing
about this pub would catch the eye of the average passerby. But for epidemiologists
it is a mecca, a memorial to one of their most famous colleagues. John Snow
was a London physician in the mid-1800s who became a legend through one
simple, dramatic act. During a local cholera outbreak, he made a map showing
the geographic distribution of homes with cholera victims. He found that
the affected homes were all in a neighborhood that drew drinking water from
a particular pump on Broad Street. Snow removed the handle from the Broad
Street pump (near where his namesake pub now stands), and the epidemic subsided.
In some ways, this story neatly captures the kind of work epidemiologists
do. Patterns of disease in populations can provide useful clues about causes
of the disease. Snow was able to prevent the spread of cholera while knowing
nothing about the existence of a cholera bacillus. Even though he did not
understand the underlying cause, Snow was able to take effective action
because the link between the polluted water source and the outbreak of diseases
was so direct and unambiguous. Today's public health problems are seldom
so clear.
Gene sleuths. Jack Taylor and Theodora Devereux
hunt for clues to lung tumors in the p53 gene of uranium miners.
Most illness in the United States today is related to chronic diseases
such as cancer, heart disease, diabetes, and diseases of aging. Often there
is a long latency between a dangerous exposure (e.g., to asbestos) and the
actual onset of disease. Also, multiple factors over time contribute to
the risk of disease. Epidemiologists can no longer rely simply on patterns
of disease to lead them to the sources of disease. They must know something
about the biological mechanisms involved. Epidemiologists depend increasingly
on the tools of the laboratory in carrying out their research. This is especially
true for health studies that look for damage caused by low-level environmental
contaminants.
Degenerative Neurologic Diseases
Amyotrophic lateral sclerosis (ALS), also known as Lou Gehrig's disease,
is a devastating, progressive illness that leads to paralysis and death.
Freja Kamel, senior staff fellow, is carrying out a study of ALS as part
of a program to uncover environmental causes of neurologic diseases. One
goal of the ALS study is to determine whether environmental neurotoxins
such as lead might contribute to risk of the disease. This is a plausible
biological hypothesis, but previous studies have been equivocal. A person's
lifetime exposure to lead and other toxins is difficult to determine; previous
studies have relied only on questionnaires.
Kamel's study takes advantage of a newly developed technique, X-ray fluorescence
(XRF), to measure lead exposure. XRF uses extremely low levels of radiation
to measure the lead absorbed in a person's bone tissue over his or her lifetime.
XRF technology was developed partly with a research project grant and small
business innovation research grants from NIEHS to private companies. Although
XRF machines are a useful research tool, there are only a few in the world.
Kamel has collaborated with researchers at Harvard Medical School who operate
an XRF machine. Kamel and her colleagues will measure bone lead of patients
at New England Medical Center newly diagnosed with ALS and of a comparison
group of patients. Higher lead levels in the ALS patients would provide
evidence that lead exposure over a lifetime may play a role in degenerative
diseases of the central nervous system.
In addition, Kamel is storing blood specimens for genetic testing. With
the recent advent of rapid and inexpensive genetic analysis, epidemiologists
can begin to explore the combined effects of genetics and environmental
exposures in large-scale studies. With the DNA specimens Kamel is storing,
she and her colleagues will be able to study genes involved in repair of
neurotoxic damage, protection against free radicals, or metabolism of excitotoxic
neurotransmitters.
Cleft Lip and Palate
There is a rapidly growing list of genes that may play a role in disease
susceptibility. People inherit variant forms of genes that control detoxification
of toxic substances, form hormone receptors, and regulate metabolic pathways.
In collaboration between NIEHS and the National Institute of Public Health
in Norway, Allen Wilcox, chief of the Epidemiology Branch, is carrying out
a study of genetic susceptibility to birth defects. Wilcox and his colleagues
plan to enroll every baby born in Norway with cleft lip or palate over the
next five years. Norway has an unusually well-organized system of birth
registration and medical care that makes it possible to conduct a population-based
study. When completed, this will be the largest study of facial clefts ever
carried out. Mothers of cases and controls will be interviewed about environmental
and occupational exposures, diet, medications, and other factors during
pregnancy. Blood samples will be obtained from mothers and babies. Questionnaire
information on possible hazardous exposures will be combined with assays
of certain genetic alleles in stored samples to look for evidence that some
mothers or infants may be genetically susceptible to the effects of specific
environmental exposures.
Cancer
There has been more work done on genes that predispose to cancer than
on genes associated with any other group of diseases. Molecular biology
is useful for other areas of cancer research as well. For instance, molecular
markers can improve the quality of epidemiology studies by clarifying disease
subgroups. By identifying homogeneous subgroups of disease, stronger associations
can be found with the underlying risk factors. Dale Sandler, chief of the
Environmental and Molecular Epidemiology Section, has recently completed
a study of acute leukemia that demonstrates this principle. Acute leukemias
are a mixed group of cancers with diverse causes. Sandler interviewed a
large sample of patients and healthy comparison persons about their jobs,
hobbies, and medical history. Leukemia patients were classified not only
according to clinically important pathologic subtypes, but also by chromosome
abnormalities of the blood-forming tissues and by whether or not there was
a mutation of the ras oncogene. (Specific ras gene mutations
have been seen with chemical exposures in animal studies.)
Senior staff. (Left to right) Jack Taylor,
Dale Sandler, Allen Wilcox, and Freja Kamel.
Results on smoking show the usefulness of better classification of patients.
Smoking was found to be associated in older patients with a twofold increase
in risk for acute myeloid leukemia and a threefold risk for acute lymphocytic
leukemia. This relation with smoking was even stronger within certain subtypes
of leukemia, which may offer clues as to how smoking causes the disease.
For example, Sandler has found that smoking is more common among patients
with loss of part or all of chromosome 7. Deletion of this chromosome has
previously been seen in patients with a history of chemotherapy for other
diseases and in patients with occupational exposure to solvents. This suggests
that the leukemogenic effect of smoking may be due to chemicals found in
cigarette smoke (e.g., benzene).
Similarly, Sandler and her colleagues have found that occupational exposure
to solvents is strongly related to mutation of the ras oncogene.
In this case, the occupational exposure had not been associated with the
overall risk of leukemia.
Oncogenes and their relation to environmental exposures are being explored
by Jack Taylor, senior clinical investigator. There are at least two classes
of genes--oncogenes and tumor-suppressor genes--that seem to be critical
targets for environmental agents in cancer initiation and progression. Taylor's
strategy is to collect tumors from people with high exposures to known environmental
carcinogens and then to look for evidence of damage to specific gene sequences.
Taylor has set up collaborations with groups from the United States, Norway,
and Canada to collect tumors from persons with unique exposures. The majority
of his work has been on lung and bladder cancer, both of which have strong
environmental determinants. Taylor has collected bladder tumors from persons
exposed to benzidine, ß-naphthylamine, cyclophosphamide, and
cigarette smoke and is pursuing samples from persons exposed to arsenic,
polycyclic aromatic hydrocarbons, and phenacetin. He has collected lung
tumors from persons exposed to radon, nickel, asbestos, and cigarette smoke,
and is planning projects to collect tumors from people exposed to arsenic
and chromium.
Many of these samples come from blocks of tissue preserved by pathologists
after surgery. Even specimens that are 30 years old or more, retrieved from
remote recesses of hospital basements, can provide ample DNA from a single
microtome slice of tissue. Using the polymerase chain reaction (PCR) technique,
specific genes can be screened and sequenced. By contrasting the pattern
of mutations in tumors from people with different exposures, the critical
chain of events that lead to environmentally induced cancers can begin to
be characterized.
The epidemiologic use of laboratory methods is not new. Today, however,
the range of laboratory tools relevant to epidemiology goes far beyond infectious
diseases. Epidemiologic projects at NIEHS reflect the spectrum of laboratory
methods, from measurement of body burden of toxins to the application of
genetic assays, that clarify and strengthen the study of environmental hazards
and their effects on human health.
Vision for the Future Sets NIEHS Priorities
"At a time when expanding research opportunities are at odds with
tighter budgets, priority setting is a must," says Kenneth Olden, NIEHS
director. Two documents will play a key role in priority setting for NIEHS:
a recently completed document, NIEHS's Vision for the Future, and
its companion report which provides the basis for the Vision document,
the 1992 Report of the Fourth Task Force for Research Planning in Environmental
Health Sciences, Human Health and the Environment: Some Research Needs.
The National Advisory Environmental Health Sciences Council, a key NIEHS
advisory body of scientists and other professionals from outside government,
oversaw the development and review of both reports. The task force report
was mandated by Congress and prepared by 19 internationally recognized science
and public health professionals, co-chaired by Morton Lippmann and Arthur
Upton, the deputy director and former director of the Institute of Environmental
Medicine, New York University Medical Center, respectively.
The NIEHS'sVision for the Future built on the task force report
and on input over the past two years from university-based centers and scientists
in the field of environmental health sciences, relevant scientific societies,
colleagues at NIH and at other federal agencies, industry, and the public.
Vision for the Future describes the NIEHS mission this way:
Human health and human disease result from three interactive elements:
environmental exposures, individual susceptibility and time. The mission
of the National Institute of Environmental Health Sciences (NIEHS) is to
reduce the burden of human illness and dysfunction from environmental exposures
by understanding each of these elements and how they interrelate. NIEHS
achieves its mission through multidisciplinary biomedical research programs,
prevention and intervention efforts, and communication strategies that encompass
training, education, technology transfer, and community outreach.
One major theme in the document is good science for good decisions. "Environmental
health policy is only as good as the scientific foundation upon which it
rests," states the report. NIEHS must maximize the effectiveness of
public policy decisions by providing the most complete information on the
environmental components of human disease and the biological mechanisms
of these diseases. The institute is interested in promoting clinical research
programs that can more readily translate laboratory findings into practical
human therapies.
More than identifying environmental causes of diseases, NIEHS seeks to
understand the molecular and genetic basis of environmentally related disorders,
relying on recent advances in molecular biological techniques that enable
scientists to understand the interaction of environmental agents and basic
cellular functions. Promising areas for such advances include environmental
effects on cell proliferation and apoptosis, events controlling differentiation
and development, receptor-mediated pathobiology, and genetic susceptibility
and predisposition to environmentally related diseases.
A different environment. Studies show that
minorities and the poor suffer more than their share from pollution. |
Vision for the Future sets out the institute's approach to prevention
of and intervention in environmentally related disease and dysfunction.
In hazard identification and characterization, NIEHS proposes to use approaches
including mechanistic data, biomarkers, noncancer endpoints, development
of animal model systems, and sentinel animals.
The report acknowledges the institute's role in providing a science base
for social policy, especially in the areas of environmental justice, global
climate change, and bioethics related to emerging science and technology.
Vision for the Future also describes the institute's considerable
role as an educational institution, promoting the education of science professionals
in the multidisciplinary studies that are vital to environmental health
sciences.
Communication is central to NIEHS's mission. Community outreach is vital
to addressing environmental concerns that frequently occur in localized
areas. The institute actively seeks to transfer technology developed in
its laboratories to clinical and other applied use. Workshops, symposia,
and conferences supported and hosted by NIEHS, often in collaboration with
other organizations, are another major forum for communication.
To obtain a copy of Vision for the Future or the task force report,
Human Health and the Environment: Some Research Needs, write, phone,
or FAX the NIEHS Office of Communications, MD B2-05, PO Box 12233, Research
Triangle Park, NC 27709; telephone (919) 541-3345, FAX (919) 541-0462.
Applications for Grants on EMF Effects Requested
People from all walks of life and of all ages are exposed to power frequency
(60 Hz) electric and magnetic fields. Increasingly, scientists, regulators,
and the public are asking whether human exposure to these fields involves
risks to human health. NIEHS proposes to respond to these concerns by issuing
two requests for grant applications (RFAs) on biological effects of electromagnetic
fields (EMF).
Examples of research areas of interest under one RFA are the in vivo
effects of EMF on melatonin; effects on reproduction and development;
effects on the neuroendocrine system; effects on behavior, and effects on
tumor promotion or other aspects of cancer development. Investigators are
encouraged to study these or other topics that have been reported in the
peer-reviewed literature.
In addition, the RFA notes that the effects of EMF on the behavior of
cells exposed to electric and/or magnetic fields in vitro have often
been cited. For example, there have been reports of EMF effects on cell
membranes, RNA transcription, ornithine decarboxylase activity, calcium-ion
efflux, and cellular response to hormones. Examples of research interests
under this RFA include effects on calcium and calcium-mediated processes;
effects on gene expression, particularly genes that may be involved in cancer;
effects on signal transduction; effects on proto-oncogenes such as c-myc,
c-jun, and c-fos in human cells; and effects on activity of
protein kinase. Applications may be in any area previously reported in peer
reviewed literature.
To ask questions or to receive a copy of the RFA, contact NIEHS either
by FAX at 919-541-2843 or voice mail at 919-541-3319 or write to Michael
J. Galvin, Jr., program administrator, Environmental Health Resources Branch,
Division of Extramural Research and Training.
Environment-Breast Cancer Link and Community Outreach Targeted
The National Advisory Environmental Health Sciences Council, a key advisory
body of NIEHS made up of outside science and public health professionals,
has given approval for the institute to request research grant applications
in two high priority areas: the determination of a possible link between
environmental agents and breast cancer and the role that socioeconomic disadvantage
might play in environmentally related disease and dysfunction (environmental
justice). Requests for applications (RFAs) will be published in the Federal
Register, the NIH Guide to Grants and Contracts, and the Commerce
Business Daily.
The RFA on environmental agents and breast cancer will focus on the critical
timing of environmental exposures and their relationship to changes in the
growth and development of the mammary gland. Critical periods of time include
the fetal period, birth to puberty, puberty, puberty to first pregnancy,
pregancy, lactation, surgical and natural menopause, and postmenopause.
Other critical periods of time may also be identified and should be studied
in relation to cancer development and latency.
Exposures to chemicals or other agents that may act as environmental
estrogens and influence the endogenous levels of all relevant steroid hormones
are of interest. Research that explores the biologic mechanism of these
environmental effects on cell growth and development and hormone synthesis
and regulation will help researchers to better understand the role of these
agents. Cellular processes that may be involved include cell proliferation,
apoptosis, ovarian and pituitary steriod metabolism and bioavailability,
growth factor regulation, ductal morphogenesis, and mammary gland cell differentiation.
Research is encouraged using animal model systems, human cell lines, and
tumor and normal breast tissue samples from animals or humans. For further
information contact Gwen W. Collman, program administrator, NIEHS, (919)
541-4980, FAX (919) 541-2843.
NIEHS seeks to support research to fill gaps in knowledge about the area
known as environmental justice or equity through grants to universities
and other research institutions.
There are few data available regarding levels of exposure and ranges
of exposure to which socioeconomically disadvantaged groups are exposed
or on exposures of particularly sensitive subgroups such as children, pregnant
women, the elderly, the chronically ill, or the undernourished. The role
of occupational exposures needs to be better studied, as well as the role
of geographical location. The role of inadequate medical care also needs
to be researched; the lack of resources for early identification of the
effects of toxic agents may lead to an increased disease burden in people
economically least able to cope with it.
NIEHS will address these questions through the Community Outreach and
Prevention Education Program (COPE), which focuses on direct interaction
with underserved populations, to directly involve these populations in determining
their future with respect to environmental public health. The main objective
of the COPE Program is to establish a new research paradigm linking members
of the community who are affected by environmental conditions with researchers.
These preliminary investigations will gather descriptive data so that further
research hypotheses can be formed and protocols developed for testing.
Examples of research and related activities that may be appropriate under
COPE are collecting and analyzing data by income and race to assess the
impact of the environment on human health; developing efficacious methods
for risk communication in minority and low-income communities; carrying
out community-based training to increase environmental health literacy;
and creating partnerships between research institutions, health care providers,
and low-income communities.
For further information contact Donald I. McRee, Environmental Health
Resources Branch, NIEHS, (919) 541-7508, FAX (919) 541-2843.
Environmental Factors and Breast Cancer
NIEHS and the National Cancer Institute have jointly funded six epidemiologic
studies to better understand the causation of breast cancer in high risk
areas including Connecticut, Delaware, Maryland, Massachusetts, New Hamshire,
New Jersey, Rhode Island, Vermont, and Washington, DC. The studies are designed
to take known risk factors into consideration and focus on markers or indicators
of environmental exposure that may influence geographic differences in rates
and changes over time in incidence and mortality. Grants awarded were as
follows:
* Tongzhang Zheng, Yale University, "Organochlorine Compounds and
Risk of Breast Cancer";
* Mary S. Wolff, Mount Sinai School of Medicine, "Environmental
and Genetic Determinants in Breast Cancer";
* David Hunter, Brigham and Womens Hospital, Inc., "Environmental
Risk Factors and Breast Cancer in the NHS";
* Jo L. Freudenheim, State University of Buffalo, "Environmental
and Genetic Determinants of Breast Cancer";
* Lee S. Caplan, Research Foundation of SUNY, "EMF, OCPS and Breast
Cancer on Long Island, New York"; and
* Kathy J. Helzlsouer, Johns Hopkins University, "Environmental
Factors and Breast Cancer Risk in Maryland."
NIEHS Needs Assistance in Clearinghouse
By mid-year 1994, NIEHS is planning to establish and begin operation
of an environmental health clearinghouse available via a toll-free telephone
line and/or by mail to the general public, patients, physicians, and industrial
hygienists. In preparation for this clearinghouse, NIEHS is currently developing
a directory of information systems available to the general public, that
provide information needed to better understand the contribution of environmental
factors to the burden of human disease and disabilities.
Digging up information. The Gopher system
logo is derived from the
University
of Minnesota mascot, the "Golden Gophers."
All systems or services that provide information to respond to environmental
and medical emergencies or that provide general information to understand
and evaluate health and environmental risks in the home, ambient, and work
environments will be included. If you know of a resource accessible by telephone
(e.g., clearinghouse operations, hot-line and health information service
desk operations, and on-line systems accessed via modems), contact Barbara
Jaffe, Information Ventures, Inc., 10,000 Newhall Road, Potomac, MD 20854;
telephone (301) 983-5418, FAX (301) 983-5426.
Coming Soon to a VDT Near You--Gopher
The National Institute of Environmental Health Sciences now has available
selected NIEHS and National Toxicology Program information in electronic
format worldwide, through access to the Internet and Gopher client software.
The Internet is a large network of networks in which regional nets are
all interconnected, communicating at amazing speeds. Many of the world's
scientific, academic, and industrial communities now use computers linked
through electronic networks to share and move vast amounts of information.
Through Gopher, NIEHS will offer information to users of Internet, which
is estimated to have as many as 25 million users worldwide. As a server,
NIEHS will accept simple inquiries and respond by sending the user a document.
Through Gopher, NIEHS will offer the following information:
* The NIEHS directory--gives an overview and mission statement of NIEHS,
a list of current events, press releases, newsletters, phone/fax directories,
organizational structure, and maps and background material on NIEHS campuses
and Research Triangle Park.
* The EHP directory--contains an overview of EHP, information for perspective
authors, subscription information, and text from selected issues.
* The NTP directory--contains abstracts of the more than 400 NTP reports
and related information.
* The Research Grants and Contracts (DERT) directory--contains information
of interest to grant applicants and lists grants awarded, by year.
* The Intramural Research (DIR) directory--contains information on DNA
sequences and protocols.
* The NIEHS Library directory--contains an overview of the NIEHS library,
the library's card catalog, reprint/loan requests, lists of in-circulation
newsletters, Current Contents, CD-ROM searching, and links to other
research libraries.
* The Administrative Information and Applications (OM) directory--contains
information and applications of interest to personnel within NIEHS.
* The NIEHS Network Facilities and Support directory--contains on-line
versions of "Connections," the NIEHS newsletter focusing on computer
technology at NIEHS.
Last Update: August 18, 1998