FREQUENTLY ASKED QUESTIONS
General Questions
3. WHAT ARE BIOMEDICAL RESEARCH METHODS?
(Taken from Unit I, Chapter 3, of the
Rx for Science Literacy teacher manual.)
"An integrated approach using chemical, mathematical and computer simulations, in vitro tests, whole animal models, and human epidemiological studies and clinical trials is currently the best approach to advance science, develop new products and drugs, and treat, cure and prevent disease."
Alan M. Goldberg, Ph.D., Director
Johns Hopkins Center for Alternatives to Animal Testing
In nature, the living, biological world is connected with the nonliving, physical world. In science, there is a similar link between biology and chemistry — both of which are essential to understanding the world around us. While we look to biology to describe life processes and living organisms, we rely on chemistry to explain these processes in terms of ions and atoms. All biological processes, including photosynthesis and digestion, are chemical reactions involving changes in molecules made up of atoms. As chemistry has revealed, all things are composed of atoms from less than 110 different elements.
Just as the sciences must be linked to understand the world, biomedical research techniques must be linked to understand truly the life process. Therefore, as scientists look for clues and cures to human and animal disease, they use a combination of highly interdependent, state-of-the-art methods such as:
- Chemical, mechanical, mathematical and computer simulations prove most useful in the preliminary stages of research where they can stimulate ideas about new research directions.
- In vitro tests are experiments performed in laboratory containers using tissues or cells. These tests are most useful during the early and intermediate research stages to study a single effect of a substance in isolation.
- Nonhuman animal models provide the most reliable and complete data on the functioning of a living system, and they offer the best indicator of how humans will react to a new drug or medical procedure.
- Human studies involve taking laboratory data on the safety and effectiveness of new vaccines or medicines and evaluating them in carefully staged clinical trials using informed human volunteers.
- Epidemiological studies are another type of human study. These studies look at occurrence and distribution of disease in a population.
Chemical, Computer and Mathematical Models
Introduction to the Models: Biomedical research is increasingly incorporating chemical, mathematical, computer and mechanical methods to understand and simulate living systems. These approaches are being applied in studies at all levels of biological organization, from interactions among molecules to interactions among major organ systems. While these models represent a simplified version of reality, they are nonetheless helpful in understanding complicated biological principles and dynamics, particularly in the preliminary research stages when scientists are sorting out fundamental questions. In addition, they often provide ideas about new research directions to pursue.
Examples of chemical, computer and mathematical models include:
Chemical models: Analytical chemistry tests detect a substance or measure its potency and are useful in developing vaccines, prescription drugs and vitamins. Some of these methods are based on the selective binding that occurs between a particular substance and its antibodies. For example, in an assay for botulism toxin, which traditionally required up to 200 mice, antibodies obtained from rabbits are modified so the binding of the toxin can be easily detected. In four weeks, one rabbit can produce enough antibody, with little discomfort, to perform tests that would otherwise require thousands of mice.
Mathematical and computer models: Advances in computer technology have led to sophisticated mathematical models that can predict biological responses on the basis of a chemical’s structure and “activity” in an organism. Using this approach, the biological effects of chemicals can be quantified and correlated with a chemical’s biochemical properties, composition and structure. When a new and somewhat similar compound is developed, it can be compared to the database of characteristics for known compounds. This allows researchers to predict a new chemical’s likely biological properties.
Researchers are applying this approach to the human immunodeficiency virus (HIV), the virus that causes AIDS. Powerful computer programs and structural information about HIV’s key proteins are being used to design highly specific anti-HIV compounds. Investigators announced that they have clarified the structure of a key protein manufactured by the simian immunodeficiency virus (SIV), which causes an AIDS-like illness in monkeys.
Structural information on this SIV protein has been generated as three-dimensional, computer-generated portraits showing the exact locations of its constituent atoms.
Strengths of Models: Models increase the speed and efficiency with which data can be studied and processed. Using pattern recognition programs enables scientists to compare characteristics of one compound with another.
The simpler the system being modeled, the more accurate the results.
Models also provide scientists with the capability of extrapolating data from high-dose experimental exposures to low-dose exposures. They can also extrapolate data from animals to humans.
As a result, models may reduce the number of animals required for research.
Limitations of Model: While computers are valuable research tools, they cannot replace laboratory testing. Computers do not “generate” data, they only “process” what has been entered.
Computer models rely on existing data. Therefore, their reliability is a function of how well the organism or system being simulated is defined. When a computer model is applied to a new area of research, the results must be validated by extensive testing in complex living systems. Computer models can replace living systems only after they are found to simulate real life.
In addition, sophisticated computer equipment and software are sometimes prohibitively expensive.
In Vitro Studies
The term in vitro literally means “in glass.” Biomedical research scientists use the term when referring to any biological process or reaction that takes place in an artificial environment.
The cells or tissues studied originally come from a living organism such as a plant, a person or another animal. These studies may include an assortment of living systems-bacteria, cultured animal cells, fertilized chicken eggs or frog embryos, to name a few.
Scientists use cell cultures, isolated tissues and organs extensively in the early and intermediate stages of biomedical research. Many potential remedies are first tested in vitro to discover how they interact with cells and tissues. In vitro studies are an essential part of medical research.
Examples of in vitro studies:
- Ames test for mutagenicity: A compound is tested first in bacteria for its ability to cause mutations, which signal that a compound could cause cancer. However, not all cancer-causing substances cause mutations, and not all mutagens cause cancer. This means more extensive testing is necessary.
- Pregnancy tests: At one time, rabbits were injected with the urine from pregnant women and then put to sleep in order to examine their ovaries, which would determine if the woman was pregnant. That practice led to the common expression, “the rabbit died,” which meant the woman was pregnant. Now, in vitro pregnancy tests offer the convenience and privacy of at-home testing without the use of a rabbit.
Strengths: In vitro tests allow scientists to study a single effect of a substance in isolation, without the interference from other biological phenomena such as hormones, enzymes and immune responses.
They can also be significantly less expensive, less time-consuming, more accurate and more readily controlled than in vivo (whole animal) systems. By enabling complete control of temperature, acidity, oxygen levels and environmental conditions of cultured cells, in vitro studies yield more precise results.
Cell cultures often, although not always, contain cells that can replicate themselves in a liquid medium in a laboratory container. New techniques have been refined that allow individual cells or pieces of tissue to grow for long periods, in fact decades.
In vitro tests are critical to the study of viruses, which grow only in living cells. These viruses are grown and attenuated, or weakened, to provide the killed or weakened viruses needed to produce vaccines.
Limitations: The biochemical process leading from chemical exposure to toxic effect is so complex that it cannot be duplicated in vitro. In the study of cancer, for instance, which we now know is a multistep process, the steps cannot be put together in vitro in a way that accurately duplicates the process in the whole
organism.
Cells grown in a culture are not exposed to other functions taking place in a living organism; for example, there is no regular pumping of blood and interstitial fluid, and there is no nervous system or endocrine gland adjusting the metabolism of cells.
In addition, cells do not metabolize toxins in culture the same way they do in the whole body. The variety of cells, tissues and organs just cannot be represented as they exist in the body. (More than 200 different cell types exist in the human body.)
It is also difficult to maintain differentiated cells in a culture since the cells tend to become unspecialized after a short time, losing the characteristics of the organ or tissue from which they were taken.
As a result, cell cultures cannot generate sufficiently reliable data about how a substance affects a complex interactive system made up of millions of cells, thousands of enzymes, hundreds of biological messengers and dozens of organs. For example, blood pressure medications cannot be tested without the presence of blood pressure.
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