AOH :: DIAGNO1.TXT|
(From "Biotechnology at Work" by Industrial Biotechnology
Association, Washington, DC 20006, Tel. 202/857-0244)
After five days of suffering a miserable sore throat, you
find yourself in your doctor's office. Your doctor thinks
you may have strep throat, a serious bacterial infection
that, if left untreated. can lead to kidney and heart
The doctor swabs your throat, sends the specimen to a labo-
ratory for analysis, and three days later you know if you
have strep throat. Meanwhile, the doctor is unsure whether
or not to prescribe an antibiotic to fight the infection.
But if the doctor could detect strep throat while you are
still in the office, appropriate treatment could begin imme-
Now, because of the diagnostic applications of biotechnolo-
gy, doctors can identify strep throat, right in their of-
fices, in a matter of minutes.
The first step in treating or curing any disease or infec-
tion is diagnosis, and the diagnostic applications of
biotechnology extend far beyond strep throat. Heart
disease, cancer, AIDS, cystic fibrosis, kidney disease and
sickle-cell anemia are just some of the areas for which the
biotechnology industry has been developing new diagnostic
This article discusses the latest advances in diagnostics
and looks at where applications of biotechnology are headed.
DISCOVERY OF DNA AND CELL FUSION TECHNOLOGIES
The origin of DNA technology can be traced to the mid-1800s
and the work of Gregor Mendel, an Austrian monk and
botanist. His work with pea plants uncovered the first
evidence that genetic traits were passed from generation to
In the early 1900s, biologists discovered that humans obeyed
the same basic laws of heredity expressed in Mendel's work.
THey found that conditions such as hemophilia, color
blindness and baldness were passed from parent to child
through chromosomes, the components of every living cell
that contain genetic information.
By the early 1950s, scientists developed an understanding of
the workings of DNA, or deoxyribonucleic acid, the molecule
that carries the genetic information for all living systems.
In the early 1970s, genetic engineering entered a new
frontier. Scientists created new genetic instructions by
combining segments of DNA from different organisms. This
process is called gene splicing, or recombinant DNA.
At the same time, other scientists focused their attention
on monoclonal antibodies. Antibodies are produced in the
body by white blood cells. They locate (and assist the body
in attacking) bacteria, viruses, cancer cells and other
foreign substances. Monoclonals are highly specific
versions of the antibodies.
But it wasn't until the mid-1970s, when two scientists
discovered how to mass produce monoclonals, that their use
as diagnostic (and also therapeutic) tools began to take
shape. By fusing, in a laboratory petri dish, an antibody-
producing white blood cell with a cancer cell that produces
unlimited generations of cells, the scientists developed a
method to produce increased and consistent quantities of a
particular monoclonal antibody. This manipulation is called
Using monoclonals in diagnostic tests requires scientists to
produce the purest quality of these specific antibodies
possible. At the same time, scientists also need mass
quantities of the monoclonals. Hybridoma technology meets
both of these needs.
The 1970s gave us yet another major contribution from the
scientific world: DNA probes. Scientists developed the
ability to extract single, small strands of DNA that could
be used to seek their complementary matching strand.
These DNA probes can locate specific genetic material,
information that is useful for both the detection and the
treatment of various diseases.
IMPACT OF ADVANCES IN DIAGNOSTICS
The primary targets of research in the diagnostics field
have been genetic and infectious diseases. Genetic diseases
are those in which heredity plays either an exclusive or
significant role. Infectious diseases are spread from
person to person through exposure to a virus or bacterium.
Many Americans suffer from these conditions: Adult
polycystic kidney disease - 300,000 to 400,000; Sickle-cell
anemia - 50,000; Cystic fibrosis - 30,000; Huntington's
disease - 25,000; Duchenne muscular dystrophy - 20,000 to
30,000; Hemophilia - 20,000; Alzheimer's disease - 2 to 4
million; and Manic depression 1 to 2 million. These data
are reflective of the number of lives that are touched by
To a large extent, the discovery of the genetic basis for
these diseases has occurred in the last decade. Currently,
there are more than 3,000 known genetic diseases. The
development of biotechnology-based diagnostics will allow
physicians to identify many of these illnesses more
accurately and quickly.
Meanwhile, infectious diseases are among the most prevalent
and dangerous threats to the health of the American public.
Federal officials estimate that more than 1.5 million people
have already been exposed to human immunodeficiency virus
(HIV), which can lead to the acquired immune deficiency
syndrome (AIDS). AIDS had already claimed the lives of more
than 30,000 Americans by early 1988.
Other infectious diseases do not share the headlines with
AIDS, but their dangers persist. For example, hepatitis B
is diagnosed in 300,000 patients every year. Influenza
causes up to 50,000 death per year.
Advances in biotechnology-based diagnostics will afford
improved and earlier detection of infectious and genetic
diseases. Currently, some diseases are extraordinarily
difficult to diagnose properly. What will these new
advances mean for the patient? Early diagnosis of diseases
can have a significant impact in three areas:
HIGHER SURVIVAL RATE. Breast cancer is one of the
leading causes of death in women, and most Americans are
aware of the value of monthly breast self-examinations.
Finding a lump in a breast before it spreads to other parts
of the body can save a woman's life. The theory is the same
for biotechnology-based diagnostics. In fact, some of these
diagnostics will be able to identify illnesses (cancer,
alcoholism and others) before the appearance of any
symptoms. Although early detection is not a guarantee of
survival against all diseases, many patients will live
longer if appropriate therapy begins as soon as possible.
IMPROVED QUALITY OF LIFE FOR THE PATIENT. By
identifying a disease at its earliest stages, doctors can
often prescribe treatments with the fewest side effects.
For heart disease, it may mean a change in diet and
increased exercise instead of surgery. For cancer, early
diagnosis may mean surgical alternatives to chemotherapy are
REDUCED HEALTH CARE COSTS. Again, by diagnosing a
disease at its earliest stages, patients can often avoid
surgery and hospitalization by undergoing less expensive
treatments. Not only does this benefit the patient
afflicted with the disease, but it can have an impact on
health care and insurance costs throughout society.
APPLICATIONS OF BIOTECHNOLOGY-BASED DIAGNOSTICS
MONOCLONAL ANTIBODIES. As discussed earlier,
monoclonal antibodies are highly specific. They are cloned,
or duplicated, from a single white blood cell that produces
a specific type of antibody. Because of their specificity,
monoclonals can be used to diagnose infectious diseases and
In order for a monoclonal antibody to be used in health care
application, it must be linked to some sort of substance,
such as a drug or an imaging agent. The monoclonal acts as
a guided missile programmed to reach an exact location. When
it hits its target, an imaging agent, such as a tiny
radioactive particle, transmits information back to the
Many people are already using monoclonal technology in their
homes to detect blood in the stool (an early warning sign of
rectal cancer and other illnesses), to identify the time of
ovulation, or to test for pregnancy. Diagnostic uses of
monoclonal antibodies in laboratories include testing for
sexually transmitted diseases (syphilis, gonorrhea,
chlamydia), hepatitis B and cystic fibrosis.
Monoclonals are also used in the battle against AIDS.
Current technology allows doctors to identify the existence
of antibodies produced by the body when it is exposed to
HIV. But scientists are trying to develop a monoclonal
antibody-based diagnostic that will confirm when a patient
has actually been infected with AIDS. They are also trying
to find a way to treat AIDS using monoclonal antibodies.
Although not yet available for widespread use, clinical
testing of monoclonal antibody-based technology for heart
disease is underway. It is hoped these tests will locate
dangerous blood clots, determine the severity of
atherosclerosis (the hardening or narrowing of arteries,
which is the underlying cause of most deaths from
cardiovascular disease), and the extent of damage to a
patient's heart following a heart attack.
Other diagnostic applications of monoclonal antibodies focus
on cancer. One currently available diagnostic test
identifies the continued presence of ovarian cancer in women
who have already undergone initial treatment. This test
helps doctors determine the necessity of follow-up
exploratory surgery, and assists them in deciding to alter
or discontinue therapy following this second look. Some
12,000 women die from ovarian cancer each year.
Clinical trials are underway for another monoclonal-based
diagnostic, designed to help diagnose six cancer types
(lung, colorectal, breast, pancreatic, stomach and ovarian).
Together these cancers account for over 60 percent of the
annual cancer deaths in the United States.
In this procedure, a radioactive substance is linked to a
monoclonal antibody that can identify the presence of any
one of these six types of cancer. The monoclonal transports
the radioisotope to tumor sites, making their location
visible through the use of an X-ray machine.
The test also confirms the malignancy of the tumors, and
helps physicians determine which tumors can be successfully
removed before surgery ever takes place. These distinctions
were not possible with previous diagnostic methods.
DNA PROBES. In the 1970s, scientists found ways to cut
DNA into fragments at predictable points, using a kind of
chemical scissors called restriction enzymes. After
studying large groups of family members and their genetic
makeup, they identified variations in the size of the DNA
segments, called polymorphisms, that appeared along with
Using this knowledge, scientists devised DNA probes, short
portions of DNA that are able to attach themselves to the
polymorphism associated with a specific disease. The probes
are labeled with a radioactive substance. They can be
easily visualized by exposure on film.
DNA probes are used to diagnose a variety of genetic
diseases, including Huntington's disease, Duchenne muscular
dystrophy, and cystic fibrosis. Because they can often
detect and identify diseases and infections in a matter of
hours, DNA probe-based tests could replace current tests
that take days to complete.
Dentists are also using DNA probes to diagnose periodontal
(gum) disease, perhaps the most prevalent of all infectious
diseases other than the common cold. According to the
National Institute of Dental Research, more than 90 million
Americans have periodontal disease. At least 23 million of
them have severe cases. Gum disease accounts for 70 percent
of all adult tooth loss.
Although this infection can be extremely painful, it often
begins and progresses unnoticed. A test using DNA probe
technology can now detect the various bacteria that cause
the disease. This test establishes progression of the
condition, helps dentists select appropriate therapy, and
monitors treatment results.
Another important application of DNA probes is found in the
food industry. DNA probe-based diagnostic tests can rapidly
detect disease-causing microorganisms such as Salmonella, a
bacterium that is a common cause of food poisoning.
The standard culture method for the detection of Salmonella
in food requires a minimum of four days to identify negative
samples. If the culture is positive, indicating the
presence of the bacteria, an additional two to three days
are required for confirmation,
This slow process causes a considerable expense to food
processors, whose food must remain in quarantine during
these diagnostic tests. Rapid detection of Salmonella in
food products benefits the food industry by reducing
inventory costs and response time in the event of a
A new DNA probe-based assay provides much quicker diagnosis
of Salmonella contamination. When the probe is labeled with
an identifiable "tag," it can determine the presence or
absence of the bacteria. Nearly 100 samples can be analyzed
in four to five hours following the growth of a culture in
the laboratory. The test also provides confirmation of
GENE MAPPING. Human genetics is in the midst of a
revolution. In the mid-1970s, about all that could be done
was study inherited diseases and track their frequency. Not
it is possible to locate and identify those genes that cause
hereditary diseases. As scientists learn more about
defective genes, the role they play in disease, and their
locations relative to each other, they are able to create a
type of map. This process is called gene mapping.
Just as the explorers Lewis and Clark pieced together
information into maps that guided settlers of the new
American frontier, scientists are creating maps that will
help lead medical researchers into the 21st century, and
Genetic mapping allows for the development of tests to
diagnose diseases. Further study of the gene may provide
new directions for treatment.
The complete genetic code of a human being is contained in
50,000 to 100,000 genes comprised of DNA. As discussed
earlier, these genes are located in the 23 pairs of
chromosomes that each of us possess.
Scientists are able to break the chromosomes into pieces
called RFLPs, or restriction fragment length polymorphisms.
RFLPs are also called genetic markers because they mark the
location of a defective gene. Imagine you are looking for
the public library, and someone tells you that it is next to
a certain landmark, such as city hall. Now every time you
try to find the library, you may look for the landmark and
know that you will find it.
An RFLP is like city hall, a marker that helps scientists
find the approximate location of a defective gene.
Currently, genetic markers are useful for diagnosis in
families in which specific inherited diseases are prevalent,
such as cystic fibrosis.
Scientists have pinpointed the gene that causes cystic
fibrosis, a disease that affects the digestive and
respiratory systems so severely that, if not diagnosed
early, premature death is often the result. With the
discovery of the defective gene, the fetus of a woman who
already has one child afflicted with cystic fibrosis can now
be screened and diagnosed early in her pregnancy with 99
While there is no known cure for cystic fibrosis, early
diagnosis can lead to therapy that can improve both the
quality of life and the life expectancy of the patient.
Defective genes have been linked to other diseases as well,
including Duchenne muscular dystrophy, adult polycystic
kidney disease, a familial form Alzheimer's disease, a
familial form of colon cancer, and a form of manic
depression found among the Pennsylvania Amish.
USES IN AGRICULTURE. Have you ever noticed a house
plant that has sagging leaves? Or maybe they have turned
yellow, or have fallen off their stems. When it comes to
their health, plants are a little like people. Infectious
diseases can make them sick. The same is true with farm
animals. That's why biotechnology-based diagnostics will
play an important role in agriculture.
Some of the most promising aspects of new diagnostics are
their potential to reduce the use of certain chemicals, and
to better target the application of some necessary chemicals
in the fields. By quickly identifying a crop disease, a
farmer can use a more specific type of herbicide or
fungicide in a smaller dose. This can help a farmer
increase the yield and reduce the cost of raising crops. To
the consumer, it might mean lower food prices. It can also
mean a cleaner environment, including fewer chemicals in
Diagnostics for conditions that cause rotting in stored
vegetables can also prevent tremendous losses, as can tests
for diseases common among expensive fruit trees.
Monoclonal antibody-based diagnostics can identify fungal
diseases affecting many plants. An example of a test
already in use involves turf grass. It is being marketed to
golf courses and will soon be available to home gardeners.
The turf grass diagnostic kit detects three highly
destructive fungal diseases (pythium blight, dollar spot and
brown patch) before visible symptoms appear. As with early
diagnosis of diseases in humans, early identification of
turf grass problems means appropriate treatment can begin at
a time when it can be the most beneficial.
The disease can be diagnosed by using a dipstick. A plastic
stick is coated with the diagnostic material. The stick is
dipped into the soil, and if a disease is present, the tip
of the dipstick is turns purple. The severity of the
disease is determined by the depth of the color.
Monoclonals will also provide quick and definitive diagnoses
of animal diseases. Now, when an animal gets sick, the
farmer or veterinarian often can only treat the symptoms.
But many diseases can produce similar symptoms, so without a
quick and accurate diagnosis, the farm animal -- or the
domestic companion animal -- may not receive proper
As the advances in diagnostics expand our knowledge of the
human genetic code, society must ensure that this
information is used properly. The biotechnology industry
must be careful to protect the rights and safety of people;
it does not take this responsibility lightly. This is one
of the roles of government regulation, and various federal
agencies are working with the scientific community to ensure
that our health and the environment are protected.
While biotechnology-based diagnostics may confirm the
presence of some diseases for which there are no life saving
treatments at this time, the ability to use the tests to
study these diseases enables scientists to develop new
approaches for prevention and cure.
THE FUTURE OF DIAGNOSTICS
Have you ever wondered why some people smoke two packs of
cigarettes a day and live to be 90 years old, while others
develop lung cancer at the age of 45? Or why an apparently
healthy person dies of a heart attack at 40, while someone
who is overweight and has bad eating habits seems to be
immune to heart disease?
The answer may lie in their genes. It appears some people
are more likely than others to develop high blood pressure,
heart disease, cancer, diabetes, arthritis, alcoholism and
other conditions. These people are said to have a genetic
predisposition to certain diseases.
Scientists hope that gene mapping will lead us into a new
era of diagnostics. Much of the scientific community is
concentrating its efforts on mapping the genome, the entire
genetic material of humans. The project, which is being
worked on by government and private scientists, is expected
to take years to complete. It will probably cost hundreds
of millions of dollars to pay for this research.
Through the mapping of defective genes and their markers,
many diseases could be diagnosed just a few weeks after
conception. In some instances, gene mapping may lead to
effective treatments where currently there is no cure.
In late 1987, several judges around the country allowed the
results of biotechnology-based tests to be used as evidence
in criminal cases. A Florida court convicted a man of rape
and assault on the basis of a DNA test.
Some scientists and law enforcement officials believe that
DNA probes and monoclonal antibody-based tests will be used
more extensively in the future. The tests, which can
analyze blood and other body fluids, may provide more
accurate identification of both suspects and victims. As
the use of these tests becomes more widespread, prosecutors
and defense attorneys may turn to biotechnology to support
Biotechnology-based diagnostics that have been approved by
federal regulatory agencies involve in vitro (in the
laboratory) techniques. But researchers are developing
diagnostics that are used in vivo, or in the body. In vivo
diagnostics will allow doctors to "see" diseases as they
appear within our bodies. This will provide doctors with
greater insight into diseases that have confounded us for
centuries, leading to improved treatment for all of us.
But the most promising potential result of advances in
diagnostics goes beyond merely treating the diseases that
affect our lives. The understanding that biotechnology-
based diagnostics will provide may help scientists find the
true causes of these diseases and provide them with the
information necessary to prevent and cure them.
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