The Greek philosopher Aristotle (384–322 B.C.) speculated on the function of the human body, but another ancient Greek, Erasistratus (304–250? B.C.), is considered the father of physiology because he attempted to apply physical laws to the study of human function. Galen (A.D. 130–201) wrote widely on the subject and was considered the supreme authority until the advent of the Renaissance. Physiology became a fully experimental science with the revolutionary work of the English physician William Harvey (1578–1657), who demonstrated that the heart pumps blood through a closed system of vessels.
However, the father of modern physiology is the French physiologist Claude Bernard (1813–1878), who observed that the milieu interieur (“internal environment”) remains remarkably constant despite changing conditions in the external environment. In a book entitled The Wisdom of the Body, published in 1932, the American physiologist Walter Cannon (1871–1945) coined the term homeostasis to describe this internal constancy. Cannon further suggested that the many mechanisms of physiological regulation have but one purpose—the maintenance of internal constancy.
Most of our present knowledge of human physiology has been gained in the twentieth century. Further, new knowledge is being added at an ever more rapid pace, fueled in more recent decades by the revolutionary growth of molecular genetics and its associated biotechnology, and by the availability of ever more powerful computers and other equipment. A very brief history of twentieth-century physiology, limited by space to only two citations per decade.
вторник, 28 сентября 2010 г.
суббота, 25 сентября 2010 г.
Development of Pharmaceutical Drugs
The development of new pharmaceutical drugs can serve as an example of how the scientific method is used in physiology and its health applications. The process usually starts with basic physiological research, often at cellular and molecular levels. Perhaps a new family of drugs is developed using cells in tissue culture (in vitro, or outside the body). For example, cell physiologists, studying membrane transport, may discover that a particular family of compounds blocks membrane channels for calcium ions (Ca2+). Because of their knowledge of physiology, other scientists may predict that a drug of this nature might be useful in the treatment of hypertension (high blood pressure). This drug may then be tried in experimental animals.
If a drug is effective at extremely low concentrations in vitro, (in cells cultured outside of the body), there is a chance that it may work in vivo (in the body) at concentrations low enough not to be toxic (poisonous). This possibility must be thoroughly tested utilizing experimental animals, primarily rats and mice. More than 90% of drugs tested in experimental animals are too toxic for further development.
Only in those rare cases when the toxicity is low enough may development progress to human/clinical trials.
Biomedical research is often aided by animal models of particular diseases. These are strains of laboratory rats and mice that are genetically susceptible to particular diseases that resemble human diseases. Research utilizing laboratory animals typically takes several years and always precedes human (clinical) trials of promising drugs. It should be noted that this length of time does not include all of the years of “basic” physiological research (involving laboratory animals) that provided the scientific foundation for the specific medical application.
In phase I clinical trials, the drug is tested on healthy human volunteers. This is done to test its toxicity in humans and to study how the drug is “handled” by the body: how it is metabolized, how rapidly it is removed from the blood by the liver and kidneys, how it can be most effectively administered, and so on. If no toxic effects are observed, the drug can proceed to the next stage. In phase II clinical trials, the drug is tested on the target human population (for example, those with hypertension). Only in those exceptional cases where the drug seems to be effective but has minimal toxicity does testing move to the next phase. Phase III trials occur in many research centers across the country to maximize the number of test participants. At this point, the test population must include a sufficient number of subjects of both sexes, as well as people of different ethnic groups. In addition,
people are tested who have other health problems besides the one that the drug is intended to benefit. For example, those who have diabetes in addition to hypertension would be included in this phase. If the drug passes phase III trials, it goes to the Food and Drug Administration (FDA) for approval. Phase IV trials test other potential uses of the drug.
The percentage of drugs that make it all the way through these trials to eventually become approved and marketed is very low. Notice the crucial role of basic research, using experimental animals, in this process. Virtually every prescription drug on the market owes its existence to such research.
If a drug is effective at extremely low concentrations in vitro, (in cells cultured outside of the body), there is a chance that it may work in vivo (in the body) at concentrations low enough not to be toxic (poisonous). This possibility must be thoroughly tested utilizing experimental animals, primarily rats and mice. More than 90% of drugs tested in experimental animals are too toxic for further development.
Only in those rare cases when the toxicity is low enough may development progress to human/clinical trials.
Biomedical research is often aided by animal models of particular diseases. These are strains of laboratory rats and mice that are genetically susceptible to particular diseases that resemble human diseases. Research utilizing laboratory animals typically takes several years and always precedes human (clinical) trials of promising drugs. It should be noted that this length of time does not include all of the years of “basic” physiological research (involving laboratory animals) that provided the scientific foundation for the specific medical application.
In phase I clinical trials, the drug is tested on healthy human volunteers. This is done to test its toxicity in humans and to study how the drug is “handled” by the body: how it is metabolized, how rapidly it is removed from the blood by the liver and kidneys, how it can be most effectively administered, and so on. If no toxic effects are observed, the drug can proceed to the next stage. In phase II clinical trials, the drug is tested on the target human population (for example, those with hypertension). Only in those exceptional cases where the drug seems to be effective but has minimal toxicity does testing move to the next phase. Phase III trials occur in many research centers across the country to maximize the number of test participants. At this point, the test population must include a sufficient number of subjects of both sexes, as well as people of different ethnic groups. In addition,
people are tested who have other health problems besides the one that the drug is intended to benefit. For example, those who have diabetes in addition to hypertension would be included in this phase. If the drug passes phase III trials, it goes to the Food and Drug Administration (FDA) for approval. Phase IV trials test other potential uses of the drug.
The percentage of drugs that make it all the way through these trials to eventually become approved and marketed is very low. Notice the crucial role of basic research, using experimental animals, in this process. Virtually every prescription drug on the market owes its existence to such research.
среда, 22 сентября 2010 г.
Use of Measurements, Controls, and Statistics
Suppose you wanted to test the hypothesis that a regular exercise program causes people to have a lower resting heart rate. First, you would have to decide on the nature of the exercise program. Then, you would have to decide how the heart rate (or pulse rate) would be measured. This is a typical problem in physiology research, because the testing of most physiological hypotheses requires quantitative measurements.
The group that is subject to the testing condition—in this case, exercise—is called the experimental group. A measurement of the heart rate for this group would only be meaningful if it is compared to that of another group, known as the control group. How shall this control group be chosen? Perhaps the subjects could serve as their own controls—that is, a person’s resting heart rate could be measured before and after the exercise regimen. If this isn’t possible, a control group could be other people who do not follow the exercise program. The choice of control groups is often a controversial aspect of physiology studies. In this example, did the people in the control group really refrain from any exercise? Were they comparable to the people in the experimental group with regard to age, sex, ethnicity, body weight, health status, and so on? You can see how difficult it could be in practice to get a control group that could satisfy any potential criticism.
Another potential criticism could be bias in the way that the scientists perform the measurements. This bias could be completely unintentional; scientists are human, after all, and they may have invested months or years in this project! Thus, the person doing the measurements often does not know if a subject is part of the experimental or the control group. This is known as a blind measurement.
Now suppose the data are in, and it looks like the experimental group indeed has a lower average resting heart rate than the control group. But there is overlap—some people in the control group have measurements that are lower than some people in the experimental group. Now, is the difference in the average measurements of the groups due to a real, physiological difference, or is it due to chance variations in the measurements? Scientists attempt to test the null hypothesis (the hypothesis that the difference is due to chance) by employing the mathematical tools of statistics. If the statistical results so warrant, the null hypothesis can be rejected and the experimental hypothesis can be deemed to be supported by this study.
The statistical test chosen will depend upon the design of the experiment, and it can also be a source of contention among scientists in evaluating the validity of the results. Because of the nature of the scientific method, “proof” in science is always provisional. Some other researchers, employing the scientific method in a different way (with different measuring techniques, experimental procedures, choice of control groups, statistical tests, and so on) may later obtain different results. The scientific method is thus an ongoing enterprise.
The results of the scientific enterprise are written up as research articles, and these must be reviewed by other scientists who work in the same field before they can be published in peer-reviewed journals. More often than not, the reviewers will suggest that certain changes be made in the articles before they can be accepted for publication.
The group that is subject to the testing condition—in this case, exercise—is called the experimental group. A measurement of the heart rate for this group would only be meaningful if it is compared to that of another group, known as the control group. How shall this control group be chosen? Perhaps the subjects could serve as their own controls—that is, a person’s resting heart rate could be measured before and after the exercise regimen. If this isn’t possible, a control group could be other people who do not follow the exercise program. The choice of control groups is often a controversial aspect of physiology studies. In this example, did the people in the control group really refrain from any exercise? Were they comparable to the people in the experimental group with regard to age, sex, ethnicity, body weight, health status, and so on? You can see how difficult it could be in practice to get a control group that could satisfy any potential criticism.
Another potential criticism could be bias in the way that the scientists perform the measurements. This bias could be completely unintentional; scientists are human, after all, and they may have invested months or years in this project! Thus, the person doing the measurements often does not know if a subject is part of the experimental or the control group. This is known as a blind measurement.
Now suppose the data are in, and it looks like the experimental group indeed has a lower average resting heart rate than the control group. But there is overlap—some people in the control group have measurements that are lower than some people in the experimental group. Now, is the difference in the average measurements of the groups due to a real, physiological difference, or is it due to chance variations in the measurements? Scientists attempt to test the null hypothesis (the hypothesis that the difference is due to chance) by employing the mathematical tools of statistics. If the statistical results so warrant, the null hypothesis can be rejected and the experimental hypothesis can be deemed to be supported by this study.
The statistical test chosen will depend upon the design of the experiment, and it can also be a source of contention among scientists in evaluating the validity of the results. Because of the nature of the scientific method, “proof” in science is always provisional. Some other researchers, employing the scientific method in a different way (with different measuring techniques, experimental procedures, choice of control groups, statistical tests, and so on) may later obtain different results. The scientific method is thus an ongoing enterprise.
The results of the scientific enterprise are written up as research articles, and these must be reviewed by other scientists who work in the same field before they can be published in peer-reviewed journals. More often than not, the reviewers will suggest that certain changes be made in the articles before they can be accepted for publication.
воскресенье, 19 сентября 2010 г.
Scientific Method
All of the information in this text has been gained by application of the scientific method. Although many different techniques are involved in the scientific method, all share three attributes:
(1) confidence that the natural world, including ourselves, is ultimately explainable in terms we can understand;
(2) descriptions and explanations of the natural world that are honestly based on observations and that could be modified or refuted by other observations;
(3) humility, or the willingness to accept the fact that we could be wrong. If further study should yield conclusions that refuted all or part of an idea, the idea would have to be modified accordingly. In short, the scientific method is based on a confidence in our rational ability, honesty, and humility. Practicing scientists may not always display these attributes, but the validity of the large body of scientific knowledge that has been accumulated—as shown by the technological applications and the predictive value of scientific hypotheses—are ample testimony to the fact that the scientific method works.
The scientific method involves specific steps. After making certain observations regarding the natural world, a hypothesis is formulated. In order for this hypothesis to be scientific, it must be capable of being refuted by experiments or other observations of the natural world. For example, one might hypothesize that people who exercise regularly have a lower resting pulse rate than other people. Experiments are conducted, or other observations are made, and the results are analyzed. Conclusions are then drawn as to whether the new data either refute or support the hypothesis. If the hypothesis survives such testing, it might be incorporated into a more general theory. Scientific theories are statements about the natural world that incorporate a number of proven hypotheses. They serve as a logical framework by which these hypotheses can be interrelated and provide the basis for predictions that may as yet be untested.
The hypothesis in the preceding example is scientific because it is testable; the pulse rates of 100 athletes and 100 sedentary people could be measured, for example, to see if there were statistically significant differences. If there were, the statement that athletes, on the average, have lower resting pulse rates than other people would be justified based on these data. One must still be open to the fact that this conclusion could be wrong. Before the discovery could become generally accepted as fact, other scientists would have to consistently replicate the results. Scientific theories are based on reproducible data.
It is quite possible that when others attempt to replicate the experiment their results will be slightly different. They may then construct scientific hypotheses that the differences in resting pulse rate also depend on other factors—for example, the nature of the exercise performed. When scientists attempt to test these hypotheses, they will likely encounter new problems, requiring new explanatory hypotheses, which then must be tested by additional experiments.
In this way, a large body of highly specialized information is gradually accumulated, and a more generalized explanation (a scientific theory) can be formulated. This explanation will almost always be different from preconceived notions. People who follow the scientific method will then appropriately modify their concepts, realizing that their new ideas will probably have to be changed again in the future as additional experiments are performed.
(1) confidence that the natural world, including ourselves, is ultimately explainable in terms we can understand;
(2) descriptions and explanations of the natural world that are honestly based on observations and that could be modified or refuted by other observations;
(3) humility, or the willingness to accept the fact that we could be wrong. If further study should yield conclusions that refuted all or part of an idea, the idea would have to be modified accordingly. In short, the scientific method is based on a confidence in our rational ability, honesty, and humility. Practicing scientists may not always display these attributes, but the validity of the large body of scientific knowledge that has been accumulated—as shown by the technological applications and the predictive value of scientific hypotheses—are ample testimony to the fact that the scientific method works.
The scientific method involves specific steps. After making certain observations regarding the natural world, a hypothesis is formulated. In order for this hypothesis to be scientific, it must be capable of being refuted by experiments or other observations of the natural world. For example, one might hypothesize that people who exercise regularly have a lower resting pulse rate than other people. Experiments are conducted, or other observations are made, and the results are analyzed. Conclusions are then drawn as to whether the new data either refute or support the hypothesis. If the hypothesis survives such testing, it might be incorporated into a more general theory. Scientific theories are statements about the natural world that incorporate a number of proven hypotheses. They serve as a logical framework by which these hypotheses can be interrelated and provide the basis for predictions that may as yet be untested.
The hypothesis in the preceding example is scientific because it is testable; the pulse rates of 100 athletes and 100 sedentary people could be measured, for example, to see if there were statistically significant differences. If there were, the statement that athletes, on the average, have lower resting pulse rates than other people would be justified based on these data. One must still be open to the fact that this conclusion could be wrong. Before the discovery could become generally accepted as fact, other scientists would have to consistently replicate the results. Scientific theories are based on reproducible data.
It is quite possible that when others attempt to replicate the experiment their results will be slightly different. They may then construct scientific hypotheses that the differences in resting pulse rate also depend on other factors—for example, the nature of the exercise performed. When scientists attempt to test these hypotheses, they will likely encounter new problems, requiring new explanatory hypotheses, which then must be tested by additional experiments.
In this way, a large body of highly specialized information is gradually accumulated, and a more generalized explanation (a scientific theory) can be formulated. This explanation will almost always be different from preconceived notions. People who follow the scientific method will then appropriately modify their concepts, realizing that their new ideas will probably have to be changed again in the future as additional experiments are performed.
четверг, 16 сентября 2010 г.
Introduction to Physiology
Physiology (from the Greek physis = nature; logos = study) is the study of biological function—of how the body works, from cell to tissue, tissue to organ, organ to system, and of how the organism as a whole accomplishes particular tasks essential for life. In the study of physiology, the emphasis is on mechanisms—with questions that begin with the word how and answers that involve cause-and-effect sequences. These sequences can be woven into larger and larger stories that include descriptions of the structures involved (anatomy) and that overlap with the sciences of chemistry and physics.
The separate facts and relationships of these cause-andeffect sequences are derived empirically from experimental evidence. Explanations that seem logical are not necessarily true; they are only as valid as the data on which they are based, and they can change as new techniques are developed and further experiments are performed. The ultimate objective of physiological research is to understand the normal functioning of cells, organs, and systems. A related science—pathophysiology—is concerned with how physiological processes are altered in disease or injury.
Pathophysiology and the study of normal physiology complement one another. For example, a standard technique for investigating the functioning of an organ is to observe what happens when it is surgically removed from an experimental animal or when its function is altered in a specific way. This study is often aided by “experiments of nature”—diseases—that involve specific damage to the functioning of an organ. The study of disease processes has thus aided our understanding of normal functioning, and the study of normal physiology has provided much of the scientific basis of modern medicine. This relationship is recognized by the Nobel Prize committee, whose members award prizes in the category “Physiology or Medicine.”
The physiology of invertebrates and of different vertebrate groups is studied in the science of comparative physiology. Much of the knowledge gained from comparative physiology has benefited the study of human physiology. This is because animals, including humans, are more alike than they are different. This is especially true when comparing humans with other mammals. The small differences in physiology between humans and other mammals can be of crucial importance in the development of pharmaceutical drugs (discussed later in this section), but these differences are relatively slight in the overall study of physiology.
The separate facts and relationships of these cause-andeffect sequences are derived empirically from experimental evidence. Explanations that seem logical are not necessarily true; they are only as valid as the data on which they are based, and they can change as new techniques are developed and further experiments are performed. The ultimate objective of physiological research is to understand the normal functioning of cells, organs, and systems. A related science—pathophysiology—is concerned with how physiological processes are altered in disease or injury.
Pathophysiology and the study of normal physiology complement one another. For example, a standard technique for investigating the functioning of an organ is to observe what happens when it is surgically removed from an experimental animal or when its function is altered in a specific way. This study is often aided by “experiments of nature”—diseases—that involve specific damage to the functioning of an organ. The study of disease processes has thus aided our understanding of normal functioning, and the study of normal physiology has provided much of the scientific basis of modern medicine. This relationship is recognized by the Nobel Prize committee, whose members award prizes in the category “Physiology or Medicine.”
The physiology of invertebrates and of different vertebrate groups is studied in the science of comparative physiology. Much of the knowledge gained from comparative physiology has benefited the study of human physiology. This is because animals, including humans, are more alike than they are different. This is especially true when comparing humans with other mammals. The small differences in physiology between humans and other mammals can be of crucial importance in the development of pharmaceutical drugs (discussed later in this section), but these differences are relatively slight in the overall study of physiology.
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