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Why This Brochure?
A 1983 Harris poll found that 82 percent of those
surveyed believe that "even if it brings no immediate
benefits, scientific research is an endeavor worth
supporting." This public enthusiasm is matched by tremendous
excitement in the research community. Scientists are
amassing new information about life processes and developing
sophisticated tools and technologies at an increasingly
rapid rate. The research horizon is expanding, as are the
benefits and applications of research results.
This brochure describes the goals, nature, and some of
the advances made possible by basic biomedical research.
While it is intended primarily for high-school and college
students and their teachers, we hope that it will be of
interest to many others as well.
Why Do Basic Research?
Why make bigger mice? After all, as a clever editorial on
gene transfer experiments with mice pointed out, we already
have rats. Why change the color of a fruit fly's eyes? Why
train sea slugs to react to certain stimuli? Why would
anyone devote a lifetime to the study of specialized
chemical reactions in one-celled animals?
In short, why do basic biomedical research? Why not just
concentrate on treating sick people? How can experiments
with animals so different from people or experiments with
extracts in test tubes possibly have relevance to us?
The answer lies in what we don't know. With some
diseases, we don't even know enough to begin a treatment
that might be successful. Often there aren't adequate models
for the study of a disease, or we know so little that the
design of experiments is impossible.
Smallpox, polio, pneumonia, and many other diseases are
no longer the terrible cripplers and killers they once were.
Science has made great strides in finding ways to prevent or
cure some illnesses.
Modern medicine has also made a quantum leap
technologically. Hundreds of incredibly complex machines and
surgical procedures stand ready to help the physician
diagnose and treat patients--once they become sick, and
often at great cost. If we knew more, if we could prevent a
disease entirely or cure it in its early stages, there would
be tremendous savings of both money and misery.
This, in fact, is what basic biomedical research is all
about. In order to attack such major diseases of today as
cancer, heart disease, AIDS, arthritis, and diabetes, we
need a broader base of knowledge. We need to know more about
the specific cellular and molecular changes involved in the
development of these conditions. By providing this
knowledge, basic biomedical research such as that supported
by the National Institutes of Health forms the foundation
for advances in the diagnosis, treatment, and prevention of
such diseases.
Untargeted Research
Untargeted basic biomedical research is usually seen to
differ from other types of basic and applied or clinical
research by its lack of a direct connection to a specific
disease. The latter forms of research are easier to
understand. Very simply put, an investigator sets out to
develop a means of treating or preventing a particular
disease. Extensive laboratory studies often lead to tests in
animals to assure the safety and usefulness of the therapy.
If it appears to be safe and to work, tests are then
performed on humans in a carefully controlled clinical
trial.
The researcher doing basic, untargeted studies is looking
for answers to more general questions. He or she is seeking
to add to the store of knowledge about how living things
work. These basic researchers' experiments add pieces to the
immensely complex puzzles of life. It may take time to see
significant advances; "miracle cures" are not the goal of
this work. Sometimes, of course, the pieces come together
and a real clinical breakthrough occurs. But the scientists'
main purpose is to keep following the leads that appear most
likely to yield missing pieces of information, even if the
exact applications of the new knowledge are not immediately
evident. The National Institute of General Medical Sciences
(NIGMS) encourages and supports just such untargeted
studies.
From the body of knowledge and understanding amassed by
basic researchers, clinical investigators can construct more
rational and systematic ways to approach the problems
presented by the diseases plaguing us today. Untargeted
basic research thus provides the fundamental theories and
concepts for more disease-oriented investigations.
Research Models
Human beings are very complicated creatures, but our
cells contain the same fundamental materials as those of all
living things. Researchers can therefore learn much about
the way our cells work by studying simpler organisms. Since
cells vary in size, shape, and function, scientists can
select cells with special characteristics that make it
easier to examine a given problem or process. The goal of
using such models is always to gain a general understanding
of biological events that occur in or affect humans.
Researchers study a bacterium called Escherichia coli
(E. coli) because it is well-suited for research: A
bacterium consists of only one cell which is simpler than
the cells of higher organisms. As a result, much is already
known about E. coli, and since all genetic material
is similar, findings in bacteria have relevance to humans
and other higher organisms.
Scientists study the fruit fly, Drosophila
melanogaster, because it is more complex than E.
coli but can still be easily maintained in the
laboratory. Fruit flies have easily studied chromosomes and
reproduce rapidly, so the effects of genetic changes can be
determined relatively quickly. Equally important is the fact
that like E. coli, these flies have been studied
for many years and a great deal is known about their
genetics, biochemistry, and behavior.
Mice are valuable research animals that are genetically
much more complicated than flies. Many mutant strains of
mice that have been specially bred for research are
available today. Breeders provide investigators using the
mice with information on the animals' genetic background,
diet, and other characteristics so that variables which
might confuse the research results are minimized. Scientists
can also select animals that are particularly prone to
developing certain tumors, metabolic disorders, or other
conditions.
Researchers who modify the genes of test animals to
produce, for example, especially large mice or red-eyed
flies are attempting to learn vital facts about gene
expression and control. Knowing how genetic processes are
regulated may someday have relevance to a host of human
diseases which develop when normal function goes awry.
What Makes Good Research?
We are all familiar with that favorite science fiction
scenario: The scientist knocks over a test tube or
accidentally puts two solutions together and suddenly
discovers the secret of eternal life...or possibly produces
a huge cucumber that tears out of the laboratory and starts
eating the neighborhood. In fact, the history of science is
sprinkled with anecdotes of accidental discoveries that do
turn out to have a dramatic impact.
For example, major efforts are made searching for new
anticancer drugs, but sometimes beneficial drugs are
discovered by researchers working on other problems.
Cisplatin is a case in point: This drug was discovered by
chance by an NIGMS grantee who was studying the effect of
electrical fields on bacteria. He noticed that in some
situations the bacteria did not divide as usual, and traced
the cause of this phenomenon to the platinum electrodes he
was using. Further investigation revealed that the platinum
compounds also prevented certain normal cellular functions
and had specific antitumor effects in animals and humans.
Today, cisplatin is a key drug in the treatment of
testicular, ovarian, and bladder cancers.
A number of other important advances have come about
almost by accident, and even achievements that occur based
on a specific plan, after years and years of hard work,
still seem a little miraculous when they finally happen.
But of course, most scientific advances are not
accidental. Most findings are not made by one lone scientist
either. They are products of years of intensive labor by
teams of researchers that include many graduate students and
postdoctoral fellows. These teams, in laboratories all over
the world, are often working in the same or related areas,
each contributing a little bit to the eventual "discovery"
or answer to a problem.
"Chance favors the prepared mind," said Louis Pasteur.
Basic researchers are seeking to prepare minds, to provide
the knowledge necessary to make and use important
discoveries. For every accidental discovery that was
immediately recognized as important, there are many whose
significance was not fully realized for years. Today,
frequent scientific meetings, computer listings of published
articles arranged by subject, and generally improved
communications help convey the results of experiments to a
large number of interested scientists.
Some of the ingredients that make good research happen
are lucky combinations of stimulating personal interaction,
adequate funds to buy instruments and pay personnel, and
other factors that add up to the right scientists being in
the right place at the right time. Not all of these
ingredients can be planned for or predicted.
However, one thing seems increasingly clear: Too many
efforts to direct untargeted research toward specific goals
may reduce the chance that something really interesting will
emerge. As Lewis Thomas, the biologist and writer,
observed,"It is hard to predict how science is going to turn
out, and if it is really good science it is impossible to
predict." Scientists benefit from working in a relatively
unfettered environment in which they can shift the direction
of their research to follow promising leads.
Basic Research Pays Off
It is not really possible to document the many "payoffs"
of basic biomedical research. Often new facts and theories
become generally known and accepted quickly. The influence
they have is far- reaching and not immediately traceable to
the source.
However, in an effort to examine the process by which
medical advances are made, in the mid-1970's Julius H.
Comroe, Jr., formerly of the Cardiovascular Research
Institute at the University of California, San Francisco,
and R.D. Dripps, then professor of anesthesia and vice
president for health affairs at the University of
Pennsylvania (both are now deceased), asked 90 physicians to
list the top 10 developments in cardiovascular-pulmonary
medicine. Such improvements as open-heart surgery, blood
vessel surgery, and drug treatment of hypertension headed
the list.
Comroe and Dripps then traced the roots of these medical
breakthroughs. They found that 42 percent of the conceptual
steps in the development of the 10 most important medical
treatments in this field came from the work of biochemists,
endocrinologists, physiologists, and other basic scientists
who were not working specifically on that disease area.
Clinical progress was reaped from their work because they
boosted understanding of the heart, lungs, muscles, and
other components of the human body, as well as of hormones
and drug receptors.
When scientists were unraveling the mysteries of heart
and lung cells, they may not have realized how their
discoveries would apply to the use of surgical implants for
coronary artery disease or to treatments to reduce high
blood pressure. They may simply have wanted to understand
how cells contract or how hormones enter cells and change
cellular activity.
Based on their findings, Comroe and Dripps recommended
that a generous portion of the Nation's biomedical research
dollars be targeted to identify and provide long-term
support for creative scientists whose main goal is to learn
how living organisms work, without regard to the immediate
relation of their research to specific human diseases.
Some Early Returns
Basic research in genetics has led us to the beginning of
a new era in medicine. More than 40 years ago, James D.
Watson and Francis H.C. Crick determined and published the
structure of the hereditary material, deoxyribonucleic acid
(DNA). Since then, scientists have decoded many of the gene
segments contained in DNA molecules. They can now remove a
gene from one cell and manipulate it so that it can be
inserted into another cell.
This work, called recombinant DNA technology, grew out of
years of research--much of it supported by NIGMS--on the
genetics of simple creatures such as viruses and bacteria.
Gene-splicing techniques now make it possible to produce
previously scarce biological or chemical agents such as
human insulin, growth hormone, and interferon by placing
genes that direct their formation into the cellular
machinery of fast-growing bacteria and yeast. Scientists are
working on ways to manufacture many more biological
compounds that are difficult, impossible, or prohibitively
expensive to produce by other methods.
Scientists are also using the new technology to follow
the inheritance pattern of specific DNA sequence differences
in families with genetic diseases for which neither the gene
nor the biochemical defect is known. If linkage between the
occurrence of an inherited illness and a specific DNA
sequence (called a marker) is observed, then the general
location of the gene causing the illness can be identified.
Eventually, this could enable researchers to isolate the
specific gene, determine its protein product, and learn more
about how it causes disease. Isolation of a marker can also
lead to a test that will predict which individuals are
likely to get the disease.
Recombinant DNA technology opens new vistas. Scientists
hope to use it to find the causes of and cures for many
diseases that cannot be prevented or treated satisfactorily
today. Although no one can predict the future, it seems
likely that the basic research now in progress will
eventually have major clinical applications.
Recombinant DNA technology is also an important
laboratory tool that has allowed scientists to study the
genes of higher plants and animals directly, whereas in the
past they were generally limited to studying the genes of
bacteria and viruses. Researchers can now isolate specific
genes, determine their structures, compare them to the
structures of other genes, and relate gene structure to
function.
Another tool coming directly from basic science
laboratories, the nuclear magnetic resonance (NMR)
instrument, promises to improve diagnostic exploration of
the body. Before x-ray machines, physicians had to use
external signs and symptoms described by patients to try to
determine what was happening inside the body. X rays were a
great advance, but they posed a radiation risk and were
limited to measuring the density of bones and tissues,
making fine distinctions difficult. More elaborate scanners
combining computers with x rays (computed tomography or CT
scans) or radioactively tagged compounds (positron emission
tomography or PET scans) are now being used to "see" soft
tissues, tumors, and even brain metabolism. But NMR is
improving doctors' diagnostic capabilities even further.
Until recently, NMR was used only in research
laboratories to study chemicals in test tubes. Now, NMR
machines are being used in conjunction with computers to
provide detailed pictures of the body's interior. When it is
used for diagnostic purposes in patients, the technique is
called magnetic resonance imaging (MRI), to remove the
ambiguity of the word "nuclear," which has nothing to do
with nuclear power in this case. MRI is truly noninvasive:
In contrast to x rays and CT scans, it uses no ionizing
radiation. Unlike PET scans, it does not require the
injection of radioactive material. Rather, MRI uses magnetic
and radio frequency energy to reveal new information about
the chemistry of the living body.
Because MRI can provide more information about the
biochemical state of tissues and organs, it may help
diagnose some types of stroke earlier and better, reveal
disease buried in dense bone, expose tumors and determine if
they are malignant or benign, and indicate whether a heart
attack has occurred and how much damage it has caused.
Cost
Basic research is an investment in the future, but it is
a relatively inexpensive investment compared to the cost of
health care. In 1990, all health-related research and
development, including drug development by the
pharmaceutical industry, amounted to 3.7 percent of the
total U.S. health care costs. It has been estimated that the
basic research cost was less than 1 percent of total health
care costs.
The cost of treating diseases is high. Contemporary
medicine is reeling under the economic burden of expensive,
halfway technological fixes that do not cure. The use of
kidney transplants and dialysis machines for patients whose
kidneys have failed and heart transplants or bypass surgery
for those with coronary artery disease illustrates the
costly and unsatisfactory methods that result from
insufficient biological knowledge.
Such halfway technologies contrast with methods that
prevent or cure diseases. Basic biomedical research can
provide such methods, as happened with the polio vaccine,
whose development depended on basic knowledge of the cause
of the disease and the three types of poliovirus.
When such fundamental applications are developed, they
show that the investment in basic biomedical research pays
off with savings, benefits, and even profits. Selma J.
Mushkin, author of Biomedical Research: Costs and Benefits,
did an economic analysis of biomedical research conducted
between 1900 and 1975. She found that every dollar invested
returned $10 to $16, measured in increased productivity due
to longer life and less illness.
Basic biomedical research also benefits the economy in
more direct ways. Many nonbiomedical industries have been
either created or enhanced by biomedical discoveries. An
example in the food processing industry is freeze-drying, a
method developed by basic biomedical research to concentrate
and preserve samples. Similarly, knowledge of the
biochemistry of enzymes has enhanced production in the beer
and laundry detergent industries. In fact, Mushkin lists 10
industries based primarily on developments transferred from
basic biomedical research that boosted the U.S. gross
national product by $37 billion in a single year in the
1970's.
Unfinished Agenda
Biomedical science has conquered many bacterial, viral,
and parasitic diseases that plagued people for centuries. We
now live longer and are healthier. Children do not have to
die of polio, diphtheria, smallpox, or pneumonia.
But humankind is still confronted by another type of
disease, called intrinsic, which results from failures of
basic molecular mechanisms within cells and tissues.
Intrinsic diseases, including heart disease, cancer,
arthritis, kidney disease, and some forms of diabetes, were
once thought to be the "natural" consequences of aging. We
now know that these disorders are neither natural nor
inevitable. They may be prevented or cured if scientists
understand their basic mechanisms and learn to intervene at
the initial stages.
Lewis Thomas believed that "the major diseases of human
beings have become approachable biological puzzles,
ultimately solvable," and that "it is now possible to begin
thinking about a human society relatively free of
disease"--a notion unthinkable half a century ago.
Humankind awaits the conclusion of an unfinished medical
drama that depends largely on the progress of basic
biomedical research.
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