INTRODUCTION
Madame Chairman and members of the Committee, we are pleased
to appear before you today to discuss our programs at the
National Institutes of Health. Revolutionary advances in our
understanding of human genetics have opened a window on the
chemical quirks in our genes that make us susceptible to many
devastasting diseases including cancer. Over the past two
decades, using the tools of recombinant DNA technology,
researchers identified a number of "single gene" diseases, in
which an alteration in just one gene may cause disease. Most
human disease, however, is thought to arise from the complex
interplay between inherited genetic alterations and the
environment. Analyzing these complexities and teasing apart the
genetic and environmental components involved represents both a
daunting challenge and an important scientific opportunity. This
challenging research is done using -a wide range of approaches,
including basic research in the laboratory, clinical
applications, translation to community practitioners, and
research into behavioral and lifestyle factors, and is supported
across the National Institutes of Health (NIH) and the many
institutions across the country that receive funding from NIH
through a rigorous competitive process.
Recently, there have been many spectacular and far-reaching
discoveries of genes associated with cancer. After years of
intensive research, we have learned that first and foremost
cancer is a genetic disease. Mutations in our own genes drive
the development of this disease, which strikes more than a
million Americans each year. Determining which mutations render
us vulnerable to cancer is at the heart of genetic research
today. Although we still have a long way to go, a cautious
optimism is beginning to ripple through the scientific community,
as a result of an enormous increase in our understanding of just
what happens to transform a normal cell into a cancer cell.
Changes in DNA are responsible for the progression toward and
development of cancer, and these changes accumulate over a
lifetime of exposures and are the result of multiple events.
However, the single most important carcinogen, responsible for
over 30 percent of all cancer deaths, is smoking. A vast amount
of research conducted on tobacco use over the past 40 years
conclusively demonstrates its harmful effects. Children,
especially teenagers, are highly vulnerable to the addictive
nicotine-delivery systems marketed as cigarettes. Unfortunately,
they will carry into their futures the increased risk of disease
and premature death caused by tobacco use. Research supported
primarily by NIH is attempting to develop effective interventions
to reduce tobacco use, particularly among our youth, and
investigates other effective methods to reduce the terrible
public health burden of tobacco use on our country.
Our new understanding of cancer has evolved in part from the
observation that cancer runs in certain families. Through
studying these families, researchers have learned that a single
genetic event is associated with an increased risk for cancer.
The development of a cancer is the result of gradual and
sequential changes in perhaps half a dozen genes in a single cell
over the lifetime of that cell. While scientists have identified
a few genes associated with several cancers in high risk
families, genes associated with cancers in the general population
are not yet known. Discovering both the candidate genes for
sporadic cancers and the mix of non-genetic factors, such as the
environment and diet, which may contribute to the disease, is
part of the research challenge that lies ahead.
An immediate spin-off of these advances in cancer gene
discovery is the potential for genetic testing, which predicts an
individual's risk for developing the disease. In the short term,
this may transform the practice of preventive medicine by
encouraging individuals who carry these genetic errors to alter
their life styles or participate in increased screening. This is
particularly effective for cancer, where early detection is often
the best chance for cure.
Yet not all individuals will want to know their genetic
script. The ability to read our genetic blueprints raises
troubling societal and personal issues that must be addressed.
Of particular concern is the fear that we will lose our jobs or
health insurance because we are shown to be at high risk for
cancer. And what are the personal ramifications of knowing our
own cancer risks Will available treatments keep pace with new
genetic tests? How will physicians and health care workers relay
sensitive information and stay on top of rapidly evolving gene
discoveries?
The National Cancer Institute, the National Center for Human
Genome Research and the National Institute of Environmental
Health Sciences are all working to take advantage of the promise
that human genetics offers to alleviate human suffering. As
leaders in genetics research, each institute has a dual
responsibility to advance promising scientific findings and to
ensure the appropriate use of this new information.
THE HUMAN GENOME PROJECT
Last Fall we celebrated the fifth anniversary of the Human
Genome Project with a record of excellent progress toward our
goals. Co- funded with the Department of Energy, the Human
Genome Project is an historic 15-year research endeavor with the
goal of producing detailed maps of the 23 pairs of human
chromosomes and sequencing the 3 billion nucleotide bases that
make up the human genome. The primary mission of the project is
to develop research tools-genetic and physical maps, DNA sequence
information, and new technology--to allow researchers to find and
analyze quickly and efficiently the 50-100,000 genes present in
our cells. The project thus far has been successful in meeting
or exceeding the goals outlined in its original plan. The human
genetic map has been completed and is much more detailed than was
originally contemplated. Recently, a team of scientists published
a physical map of the human genome composed of over 15,000
well-ordered markers, and covering approximately 94% of the
genome. This a major milestone on the way to completing a
comprehensive physical map of the human genome. Though original
projections were that this map would not be completed until the
end of 1998, completion is now expected by early 1997.
The most challenging goal of the Human Genome Project is to
sequence the entire 3 billion nucleotides that comprise the human
genome. This year we are embarking on this ambitious and
exciting phase of the Human Genome Project. Improvements in DNA
sequencing technology and strategy have dramatically reduced the
cost of sequencing and increased the efficiency. To further
stimulate development of high-capacity DNA sequencing capability,
pilot projects for large-scale human sequencing and for further
improvements in DNA sequencing will get underway in April. As a
result, a number of laboratories are now positioned to sequence
over 10 million basepairs a year by 1997.
Though we look forward to the first complete DNA sequence of
the human genome with great anticipation, we do not have to wait
until the end of the project to reap its benefits. Already this
information is changing the way biomedical research and the
practice of medicine are being conducted. The information, tools
and resources generated by the Human Genome Project are quickly
disseminated to and utilized by researchers across the United
States and throughout the world. All of the information from the
Human Genome Project is placed in public electronic databases
which are accessed by researchers over 150,000 times each week.
The tools and technology created by the Human Genome Project
are being used by scientists to help in their discovery of the
genes associated with disease. Already the maps generated by the
Project have greatly facilitated gene discovery. For example,
more than 10 years of research were required to isolate the gene
for cystic fibrosis in 1989, while the recent isolation of the
second breast cancer gene, BRCA2, took about 2 years. When the
Human Genome Project is complete, isolating a disease gene of
interest will take just a couple of months. In addition to the
reductions in time required to find disease genes, there will be
significant reductions in cost.
Most of the disease genes isolated so far are so called
"single gene" diseases where a misspelling in a single gene is
sufficient to cause disease. Many common diseases including
diabetes, Alzheimer's, alcoholism and cancer are much more
complex and may involve the interactions of many genes as well as
environmental factors.
CANCER GENETICS
Years of intensive research have established how tumors develop.
and foremost, mutations in our own genes drive the development of
cancer. These mutations alter the normal processes that help a
cell regulate its fate. When they go wrong, control is lost and
tumor development is promoted. Second, we now understand that a
cancer will arise only after several mutations occur in the same
cell. One mutation is never sufficient, and in some adult
cancers ten or more mutations may be needed to generate the full
set of changes that make tumors aggressive. we have learned that
the number of different genes that can be mutated and contribute
to all types of cancer is large, but the number may be no more
than ten altered genes for a specific cancer. Certainly the
number of genes involved in cancer overall will be in the
hundreds; our current guess would suggest that it will not reach
one thousand. These numbers are large, daunting perhaps, but not
impossible to handle.
Cancer is a disease caused by mutations in key target genes
that give a selective advantage to the growth of the tumor cell.
The accumulated mutations allow the cells to grow out of control.
They divide, obstruct, invade, and destroy normal tissue
architecture. Through the accumulation of genetic changes, these
cells acquire properties that allow them to escape the normal
biological defenses and controls and. in turn, pose a
life-threatening problem to the affected individual.
While cancer is a disease of genetic changes, it is generally
not an inherited disease like cystic fibrosis or sickle cell
anemia. Rather, most cancers arise within a cell of the body
that, through its lifetime, accumulates the genetic changes
peculiar to each cancer. For some cancers, we now know that the
gradual and sequential change in perhaps half a dozen genes
signals the transformation from a normal, well-behaved cell to a
growing and spreading cancer. In about ten percent of cancers,
an individual has inherited an alteration in one gene which
predisposes them to the subsequent genetic changes that will
result in cancer. These individuals may have a ninety percent
chance of developing cancer over the course of their lifetime.
The identification of these cancer predisposition genes and
the determination of how these genes function normally, and of
how the loss of function of these genes predisposes to cancer,
are vitally important research questions. Discoveries in this
area are profoundly and fundamentally changing our knowledge, not
only of inherited cancers, but of their much more common sporadic
counterparts.
The revolution in human molecular genetics is making these
gene identifications possible. Over the past two years alone,
scientists have identified genes responsible for inherited forms
of breast and ovarian cancers, colon cancer, melanoma, and kidney
cancer, to name but a few. One of the major goals of cancer
research is to predict who will get a particular cancer. With
the ability to identify individuals within cancer prone families
who do and who do not carry the mutated gene, we can predict who
in those families carries the particularly high predisposition to
cancer and who does not.
While these inherited cancer syndromes explain a minority of
cancers, the number of affected individuals is large--perhaps one
million Americans carry a breast cancer predisposition gene
mutation and another one to two million Americans carry mutations
in colon cancer predisposition genes. In these inherited cancer
syndromes, the mutated or defective gene, which results in the
cancer predisposition, is present in the DNA carried in each and
every of the trillions of cells of the individual. It is present
in the DNA of blood cells and it is present from birth, long
before cancer develops. It is this fact that allows the
possibility of genetic testing to identify those individuals who
carry the mutation. We are funding projects at multiple centers
aimed at identifying new cancer predisposition genes involved in
prostate, gastrointestinal, skin, brain, lung, and other cancers.
This, however, is easier said than done. While the past few
years have seen the rapid discovery of some cancer susceptibility
genes responsible for inherited cancer syndromes, more await
discovery. Each gene is made up of hundreds to many thousands of
letters of the genetic code. A defect in spelling anywhere in
these enormous genetic words can, theoretically, be the culprit.
Even when the cancer gene is discovered', such as the first
breast cancer predisposition gene, BRCA-1, which accounts for
about 50 percent of inherited breast cancer and greater than 75
percent of inherited breast plus ovarian cancer, nearly every
affected family has its own misspelling. The result of this
genetic heterogeneity stretches the technical and financial
feasibility of screening for mutations outside of families in
which the painstaking work of mutation identification has already
been done using currently available technology. Because the
mutation found in each family is, by and large different, it is
not yet feasible to screen the general population.
The remarkable discovery of a single misspelling in the
BRCA-1 gene that is found in as many as 1 percent of Ashkenazi
Jews, or Jews of Central or Eastern European origin was announced
last September. This group represents 90 percent of the 6-7
million Jews in the United States. For the first time, the
technical ability to actually screen a population for a cancer
predisposition gene is feasible. This discovery signals a
fundamental change in the many issues we must come to grips with
and, because of the pace of scientific discovery, we must be
prepared for the challenge of this changing landscape of
medicine.
The recent discovery of the gene for ataxia-telangiectasia
will also contribute to our understanding of the relationship
between genetic alterations and cancer risk. You may have seen
Brad Margus and his family recently on the television news
program Turning Point. Two of Brad's four sons have
ataxia-telangiectasia (A-T). A-T is a rare but fatal childhood
neurological disorder. The discovery of this gene paves the way
for more accurate diagnosis in the short term and the potential
for effective treatments in the long term for children suffering
from A-T. One of the interesting aspects of the A-T gene is the
indication that it may play a role in predisposition to certain
cancers. Although the disease itself is rare, an estimated one
percent of the U.S. population are carriers of the altered gene
and appear to have an four to five fold increased risk for
various cancers, including breast, lung, stomach, and skin
cancer.
Significant progress is also being made to identify the
genetic contributions to all cancers. Prostate cancer is the
most common form of cancer diagnosed in men in the United States,
yet little is known about the molecular basis for this disease.
Not only does it account for one in every four cancers diagnosed
in American men, but it can spread (metastasize) beyond the
prostate, killing 40,000 men annually. Although only 25 percent
of these cancers are the lethal variety, physicians have no way
of determining which prostate cancers can be ignored and which
must be surgically removed. this dilemma is further complicated
by the fact that prostate cancer surgery is difficult, requiring
a lengthy recovery time and frequently rendering a man
incontinent or impotent. By characterizing the genetic
fingerprint of prostate cancer, we will be able to develop
screening procedures to identify patients requiring surgery, and
we will enhance our ability to develop therapeutic strategies to
more effectively treat this devastating disease. Ultimately,
studies may lead to the identification of environmental agents
involved in the development of prostate cancer.
NEEDS AND CHALLENGES
The recent breakthroughs in cancer genetics have focused on
cancer predisposition genes that geneticists refer to as simple
traits, in which the inheritance of one specifically altered gene
is alone responsible for the increased cancer susceptibility and
where the chance of getting cancer, given an alteration in the
culprit gene, is very high. Such simple genetic predispositions
already provide us with enormous scientific and technical
challenges. However, it is fair to say that these simple genetic
predispositions are likely to only be the tip of the iceberg of
the influence of heredity on cancer predisposition. We will need
to develop the ability to identify genetic predisposition in
families where it results from inheritance of more than one
genetic locus. We need also to be able to identify modifier
genes that affect what we call the penetrance of a cancer
predisposition gene--in other words, genes that modify the risk
of getting cancer in individuals with the inherited
predisposition. Finally, we need to establish the non-genetic
factors, such as environmental and dietary exposures, behavior
and lifestyle, infectious agents, and others that will
undoubtedly influence whether the presence of an altered cancer
susceptibility gene actually results in cancer and when.
Successfully dealing with these challenges will involve
generating and analyzing enormous amounts of data about dozens of
genes and hundreds of alterations in each gene plus correlating
each of these alterations with clinical outcomes. Therefore, an
informatics system is needed to collect, store, analyze and
integrate molecular data with epidemiologic and clinical data.
For example, as new families that suffer a predisposition to
cancer are identified, the properties of their disease need to be
passed to the researchers who will map the gene. Basic
researchers' discoveries about how a tumor develops must be
available to the physicians who treat cancer- prone families.
The latest developments in genetic mapping need to be converted
into useful genetic tests. These critical information needs
demand a new level of exchange that can only be achieved
through coordinated efforts. The NIH has recently established a
variety of databases, tissue and DNA repositories, tumor
registries, and registries of high risk cancer families in order
to address all of these issues throughout the country and in
multiple populations within our diverse society. One example is
the Cooperative Family Registry for Breast Cancer Research. which
will provide a registry resource for interdisciplinary studies on
the etiology of breast cancer, encourage translational research,
and identify a population at high risk that could benefit from
new preventive and therapeutic strategies. Another is the
NCI/NIEHS Long Island Breast Cancer Study Project which will in
part correlate genetic predisposition to breast cancer with
environmental exposures, hormone levels, and behavior in this
region of the country known to have higher than average rates of
breast cancer incidence and mortality.
ENVIRONMENTAL INFLUENCES
Nearly all diseases are thought to arise from the interplay
between inherited genetic alterations and the environment.
Exciting, opportunities now exist to advance our understanding of
the environmental and genetic basis of many common illnesses and
design effective prevention and intervention strategies to combat
their development.
Humans are exposed to a multitude of environmental agents from
conception to death. These agents include foods and nutrients,
synthetic and naturally-occurring chemicals, and physical agents
such as heat and ionizing radiation. The extent of exposure to
environmental agents with carcinogenic or toxic potential and
their possible consequences may be influenced by age, the time of
exposure, socioeconomic status, and behavior. Thus, the scope of
what comprises the environment has been extended beyond the
historical preoccupation with industrial products and byproducts.
Environmental health risk assessment research originated
because of the need to determine whether technologic and
industrial advances might also impair human health.
Environmental health and safety regulations, based on this
research, have safeguarded public health and led to dramatic
improvements in the environment. Regrettably, however, these
regulations may have been more costly and less effective than
they might have been because of uncertainties or gaps in the
science used in the risk assessment process. Over the past five
years, NIEHS has involved industry, the public. and academia
together have worked to identify gaps in scientific knowledge
required for more rational risk assessment decisions. As
uncertainties are reduced, the scientific basis for sound risk
management decisions is strengthened and better public health
prevention practices can be introduced, often at less cost to
industry and consumers.
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. 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. In
addition, as many environmental exposure issues are transnational
in scope, international research collaboration has an important
role in developing the science base relevant to the global
environment.
Environmental health research is at a critical and exciting
juncture. New refinements in molecular biology techniques
provide unprecedented opportunities for understanding the
molecular and cellular basis of environmentally-associated
diseases. These opportunities build upon the foundation of
almost 30 years of research.
PRE-CLINICAL MODELS
Technical advances have always played a key role in improving
our ability to manage and treat disease. This link between new
technical advances and rapid progress is equally true for the
discovery process in cancer research. The lack of animal models
for human cancer and cancer development has been a major
roadblock in cancer research. This roadblock has now been
overcome by recent advances in mouse genetics. Recently
developed methods in animal genetics allow the study of cancer in
ways that were impossible even a few 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. Using techniques developed through NIH support,
investigators can now place any mutation they choose into a
mouse.
For example, researchers 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 development of
endometriosis, uterine fibroids, and cancers of the breast,
uterus, and ovaries. In men, these compounds might explain the
increase in testicular cancer, decline in sperm count and other
reproductive tract anomalies.
This strategy will ultimately allow us to study in laboratory
animals the mutations that are likely to drive the development of
human cancer. These mice will provide a natural setting to study
carcinogenesis and all stages of tumor development. They will
allow us to test in animals early detection, prevention and
treatment strategies, and to develop the targeted cancer
therapies of the 21st century.
IMPROVED RISK ASSESSMENT THROUGH THE USE OF NEW MODELS AND
METHODOLOGIES
The dilemma facing environmental and regulatory scientists is
lack of animal models that completely duplicate the toxic or
carcinogenic response of humans. Most of the scientific data used
in determination of the toxic or carcinogenic properties of
environmental agents is derived from experimental animals.
typically rodents. Such studies have resulted in a great deal of
dissatisfaction. mostly due to unresolved uncertainties and the
time and costs required for the conduct of the conventional
two-year rodent bioassay.
Assessment of dose-response relationships and relevance of
the experimental model are often the most difficult and
controversial issues in risk assessment. Data in experimental
animals is usually obtained with relatively high doses of
exposure because of limited resources and the need to minimize
the numbers of animals used. This requires use of methods to
extrapolate health effects to exposure levels much lower than
those for which experimental data are available. Depending on the
methods used, risk estimates may vary by several orders of
magnitude.
To address this important issue, greater emphasis has been
placed on (1) developing a mechanistic understanding of disease
etiology for use in extrapolating from rodents to humans, and (2)
developing quicker and cheaper alternatives to the current
two-year rodent bioassay to enable more efficient use of
resources. Mechanistic data is now routinely generated during
the performance and evaluation of the results of the rodent
bioassay. Also, new transgenic mice are being evaluated for
their effectiveness in producing reliable, relevant carcinogenic
information in a shorter time frame (six months versus two years)
using fewer animals. Preliminary results with the transgenic
mice have been very promising in that of the approximately 40
chemicals screened to date, test outcomes are comparable to those
reported for the rodent bioassay. Partnerships have been
developed involving industry, Environmental Protection Agency
(EPA), and Food and Drug Administration (FDA) so that the
screening required for validation can be completed within two to
three years. If validated, the new transgenic models could
reduce our dependency on the costly and time-consuming two-year
rodent bioassay and would allow for screening of dozens of
chemicals annually. Further, the results would be more relevant
for the assessment of risk to human health because the tests can
be performed with low dose exposures. We estimate that four
chemicals can be screened in the new system for the price of a
single chemical in the two-year rodent bioassay. Additionally,
representatives of the pharmaceutical industry have indicated
that shortening the carcinogenicity test from 24 months to six
months may result in a net benefit (combination of reduced cost
for development and increased sales revenue during patent
protection) of up to one half billion dollars per so-called
typical drug introduced into the marketplace. Thus, the
potential impact of these new models on carcinogenicity testing,
human risk assessment, and on the Nation's economy is
substantial.
Understanding the environmental components and basic biology
of disorders can lead to prevention and intervention strategies
that circumvent many adverse health effects. Traditionally,
these strategies have focused on eliminating or reducing
environmental exposures. These approaches will continue to be
important parts of the Nation's environmental health programs.
NIEHS is working to improve risk assessment methodology so that
regulation is not needlessly restrictive, but rather protects
both public health and economic vitality.
As we gain a better understanding of the molecular and cellular
basis of environmentally associated diseases, we may be able to
develop prevention and intervention techniques to treat people
following an adverse environmental exposure. These molecular
interventions would rely on manipulations of the biological
mechanisms underlying environmentally induced diseases. such as
activating and inactivating enzymes, receptors, and other
molecular components. They would be particularly useful in
dealing with environmental exposures that are ubiquitous or
difficult to eliminate. Further. they would have important
implications in the pharmaceutical and pesticide industries,
which could in the future develop products with maximal
effectiveness and minimal adverse effects.
EARLY DETECTION
We are now faced with the new ability to determine the
molecular and genetic "fingerprint" of a cancer, whether it
results from an inherited predisposition or not. The first
identification of a human cancer gene was reported approximately
20 years ago, and progress in this field has been rapidly
expanding since then. This explosive increase in our knowledge
of the mechanisms that drive tumor development is one of the
success stories of modem biology. We now understand the
molecular basis for many of the changes that drive tumor
development. This explosion in our knowledge needs to be applied
to the diagnosis of cancers. Molecular diagnostics provides one
of the most obvious, and what promises to be one of the first,
links between the molecular characterization of cancer cells and
patient care. In its simplest terms, this new phase of cancer
diagnostics will provide a snapshot of the properties of a tumor,
which will detail the key differences between a normal and cancer
cell and will provide a molecular scorecard of the properties of
a tumor cell. Molecular diagnostics will transform the practice
of clinical oncology. It will allow us to predict the behavior
of each cancer - will it grow fast? Will it spread or
metastasize? Will it respond to therapy? Ultimately the molecular
description of each cancer will guide us to choose new and
effective therapies and will be the basis on which we plan
patient care.
New opportunities to make major advances in early detection
methodology now exist. They include the detection of solid
tumors through screening for proteins secreted by them and not by
their normal cell counterparts. Tumor cells also harbor certain
mutant genes which can be detected in body fluids with which they
come into contact, signaling the presence of a nearby cancer.
Cancer cells regularly influence the behavior of neighboring and
distant tissues, alike. Blood vessels, the kidney, the brain,
endocrine glands and other organs are all susceptible to changes
in structure and function as tumors grow. The proteins secreted
by tumors which account for these changes are being rapidly
discovered, making sensitive methods for their detection
feasible. Detecting such tumor products in a blood sample early
in the course of one's disease could signal the presence of small
numbers of tumor cells. Diagnostic imaging technology is rapidly
becoming more sensitive and specific, enabling the detection of
ever smaller numbers of tumor cell collections than ever before.
New methods of sensing tumor cell-specific signatures should
provide opportunities to detect tumors at their earliest stages
when even the most potentially aggressive tumors are most likely
to be curable. These technology-based approaches to early
detection are the direct result of our Nation's investment in
untargeted basic research. The Radiation Diagnostic Oncology
Group provides one national mechanism for multi-institutional
clinical trials in imaging. Promising new initiatives in breast,
prostate, and aerodigestive imaging, including the coordinated
development and application of military and space technology
relevant to imaging, has brought together successful consortia
that will allow us to learn to detect cancer before it is beyond
the possibility of current curative therapy.
PATIENT-ORIENTED RESEARCH
Our knowledge will continue to grow about the function of
these genes as researchers analyze at the molecular level the
genetic causes of disease, and associate specific gene
alterations with an individual's risk for disease. Eventually,
researchers will be able to develop new treatments for many of
the diseases that result from malfunctions in our genes.
Detailed knowledge of the specific genetic alterations underlying
disease and an understanding of their role in cellular processes
will allow the design and development of rational drug and
gene-based therapies. However, there will often be a substantial
lag between our ability to offer a genetic test and the ability
of researchers to understand the disease sufficiently well to
develop new treatments and therapies.
The ability to identify cancer predisposition genes raises a
new set of pressing questions that will only be answered by a
greatly expanded effort in clinical research. These efforts must
be aimed at being able to know what we can do with the
information that an individual is at risk of developing cancer.
How can we detect such cancers as early as possible? Are there
ways to prevent cancer development? What is the optimum treatment
if cancer arises? The responsibility of the biomedical community
at this point must be aimed at providing information that
addresses these issues so that individuals can make informed
decisions about whether or not to seek such genetic testing.
It is important to point out that testing negative for a
particular cancer susceptibility gene defect tells an individual
that they do not carry the risks of a particular cancer or
cancers associated with that specific gene defect but does not
change the significant risk that this individual, like any
individual, has of getting cancer due to causes other than that
particular predisposition gene.
On the other hand, what do we have to offer people who do test
positive? Here is the central problem. It is attempting to
answer this question that takes us to the limits of our current
knowledge and tells us what types of information we will need to
gather for a particular mutation in a particular cancer
susceptibility gene: - What is the risk of developing cancer and
when? These are cancer susceptibility genes and even when they
confer an 80 to 90 percent lifetime risk of developing cancer, we
need to know what other environmental, behavioral, and genetic
factors determine when, and if, an individual who carries a
particular mutation develops cancer. - How should "at-risk"
individuals be followed to monitor for the development of cancer?
Finally, how should "at-risk" individuals be counseled in terms
of treatment and prevention options? - To answer all these
questions requires carefully designed and conducted clinical
studies. Patients and health care providers must have knowledge
about and access to studies aimed at answering questions about
risks. surveillance, screening, prevention, and treatment.
The identification of genetically high risk individuals provides
an extraordinary opportunity to more rapidly and effectively
accomplish clinical trials in cancer prevention through dietary,
drug, immunologic, or other interventions. It also provides the
opportunity to establish trials aimed at developing and
evaluating early detection using genetic or other biomarkers as
well as imaging technologies.
The extensive clinical research and clinical trials
infrastructure of NCI, including 55 cancer centers and
cooperative groups involving over 9000 physicians at more than
1500 hospitals, is now being used to incorporate molecular
diagnostics into clinical research. New funding initiatives have
been developed to allow these groups and centers to expand their
activities in cancer genetics. informatics, and in clinical
trials that correlate molecular properties of tumors with their
natural history, prognosis, and predicted response to and
selection of therapy. Recently, NCI entered into an agreement
with the Department of Defense (CHAMPUS) that may serve as a
model for allowing cancer patients access to NCI-sponsored
clinical trials as a routine part of their health plan benefits.
It has long been observed that cancer runs in families. Today,
all of us are participants in a revolution in medicine, in
science, and indeed a revolution in our very conceptualization of
individual identity and of predicting the type of future an
individual may face in terms of his or her health. These
discoveries, as with all discoveries, raise opportunities and
very serious challenges. We must address ourselves to both the
new opportunities raised by these discoveries, opportunities for
the early detection, for the possibility of prevention and
ultimately for the development of new therapies for cancer.
Equally, we must be aware of the challenges. We are ready to
address the scientific, technical, and human resource challenges,
but the challenges do not end there. The potential power of
reading ones own genetic script raises societal and personal
issues about insurance, employability, privacy, and personal
choice that we cannot ignore.
Genetics is changing the landscape of biomedical research and
it will change the landscape of clinical practice. To be
prepared for these changes will require attention to human
resource development. Foremost is the need for genetic
counseling in oncology. There is a real need to train genetic
counselors and for physicians, other health care providers,
patients and communities to have access to effective educational
materials and guidelines for all the issues surrounding the use
and interpretation of tests aimed at addressing genetic
susceptibility to cancer. We must include training in genetics,
risk assessment, and the ethical, legal, social, and behavioral
aspects of genetics for health care providers. A
recently-initiated comprehensive cancer genetics program will
address these issues through the nationwide cancer centers
program.
THE ETHICAL, LEGAL, AND SOCIAL IMPLICATIONS PROGRAM
As an integral part of the Human Genome Project, the NCHGR and
the Department of Energy (DOE) have each set aside a portion
of their funding to anticipate, analyze, and address the ethical,
legal, and social implications (ELSI) of the new advances in
human genetics that human genome research has made possible. The
goals of the ELSI program are to improve the understanding of
these issues through research and education, to stimulate
informed public discussion, and to develop policy options
intended to ensure that genetic information is used for the
benefit of individuals and society. The NCHGR ELSI program has
focused on several high-priority areas raised by the most
immediate potential applications of genome research:
- privacy and fair use of genetic information;
- responsible clinical integration of new genetic
technologies;
- ethical issues surrounding the conduct of genetics
research; and,
- professional and public education.
The NCHGR has taken two approaches to address the ELSI goals:
1) a research grant program on which NCHGR spends five percent of
its annual budget and 2) an interagency working group, the
NIH-DOE Joint Working Group on the Ethical, Legal, and Social
Implications of Human Genome Research (ELSI Working Group).
Testing and Counseling Initiatives
There are two key initiatives underway at NIH to address some
of the crucial questions surrounding genetic testing, especially
for cancer susceptibility. To examine issues surrounding the
safe integration of genetic testing and counseling for cancer
risk into clinical practice, several institutes are supporting
clinical research studies on testing and counseling for heritable
breast, ovarian, and colon cancer risks. These investigators are
studying the psychological and social impact of cancer testing on
individuals and their family members and are developing
recommendations for approaches to genetic testing and counseling
for cancer risk.
The investigators in these projects have formed a consortium
to pool resources, reduce duplication of effort, and increase
coordination of some aspects of the studies. Some of the key
aspects the investigators agreed to coordinate include: the use
of a core set of evaluation tools to assist in the comparison of
results from the studies; the identification of the key elements
to be included in all consent forms used in the consortia
studies; and a plan to develop specific recommendations for
individuals who test positive for BRCA1 mutations. The studies
are well underway, and the investigators have developed draft
recommendations for how to counsel patients and families who
carry a BRCA1 mutation.
A second highly relevant initiative funded by the NIH is the
Task Force on Genetic Testing (TFGT). The mission of the Task
Force is to examine the strengths and weaknesses of current
practices and policies relating to the development and delivery
of safe and effective genetic tests and the quality of the
laboratories providing the tests. The membership of the Task
Force includes representatives from the biotechnology industry,
the professional medical and genetics societies, the insurance
industry, consumers, and the relevant federal agencies involved
in the diffusion of new genetic tests. The TFGT was established
in April 1995 and is expected to complete its work in early 1997.
The Task Force is concentrating on three areas:
- scientific validation--developing validation criteria for
the sensitivity, specificity, and predictive value of the tests;
- laboratory quality--addressing the gaps in monitoring the
quality of genetic tests; and
- education, counseling, and delivery--providing ways to
educate practitioners and consumers about the limitations and
capabilities of current test technologies, including their
predictive and interpretative value.
The rapid pace with which genes are being discovered and genetic
tests are being developed indicates that the findings of the TFGT
are urgently needed and will be crucial to the development of
sound policies and practices for the introduction of new genetic
tests.
Fair Use of Genetic Information
As our knowledge grows about the genetic basis of disease, so
too does the potential for discrimination and abuse. One
particular concern is that individuals will be denied health
insurance or employment based on genetic information.
Furthermore, we are all at risk for certain diseases, and as gene
discoveries and genetic testing advance, we will have the
opportunity to learn more about our individual susceptibilities.
A health insurance system that uses this information to deny
individuals coverage will be unworkable in the long term.
However, there are no Federal laws now in place to prevent health
insurance companies from using genetic information to deny
coverage. Several states are concerned about the use of genetic
information and have passed legislation that protects individuals
from being denied health insurance based on their genetic status.
These state laws prohibit insurers from denying coverage based on
genetic test results, and/or prohibit using this information to
establish premiums, charge differential rates, or limit benefits.
A few of these states, including California, Florida, and Oregon
integrate protection against discrimination in insurance
practices with privacy protections that prohibit insurers from
requesting genetic information and from disclosing genetic
information without authorization. The federal Employee
Retirement Security Act (ERISA) exempts self-funded plans from
state insurance laws. Thus, state laws do not provide protection
for the many Americans who obtain their health insurance coverage
through employer based plans.
The ELSI Working Group has long been involved in discussions
about the fair use of genetic information, particularly as it
relates to health insurance. In 1993, the ELSI Working Group's
Task Force on Genetic Information and Insurance concluded that,
"Information about past, present, or future health status,
including genetic information, should not be used to deny health
insurance coverage. " Another important group recently formed is
the National Action Plan on Breast Cancer (NAPBC), a
public-private partnership established to address the research,
education, and policy issues in breast cancer. The NAPBC has
identified the issue of genetic discrimination and health
insurance as a high priority.
Building on their shared concerns, the ELSI Working Group and
the NAPBC co-sponsored a workshop on July 11, 1995, to address
the issue of genetic discrimination and health insurance.
Consumers, researchers, federal and state government
representatives, and insurance industry representatives came
together with the members of these two groups to participate in
the one day session. Based on the information presented at the
workshop, the ELSI Working Group and the NAPBC developed and
published recommendations for state and federal policy makers to
protect against genetic discrimination.
The new advances in human genetics offer the promise that we
will find new ways to fight some of the most devastating diseases
that Americans suffer from today. We must ensure that our health
care policies and practices relating to the introduction of new
genetic tests and the subsequent use of genetic infon-nation keep
pace with these significant new advances.
This concludes our remarks. We would be pleased to answer
any questions you may have.
** Attached is 1 chart "Human Genome Project Progress"
Shows: The percentage of completion of Genetic Maps, Physical
Maps, and DNA Sequencing between years 1990 - 2005.