Instrumentation Applied to the Biological Sciences - Advances in

Instrumentation Applied to the Biological Sciences MICHAEL

KNIAZUK

Downloaded by EAST CAROLINA UNIV on January 3, 2018 | http://pubs.acs.org Publication Date: January 1, 1956 | doi: 10.1021/ba-1956-0016.ch021

Merck Institute for Therapeutic Research, Rahway, N. J. Techniques of indirect measurement, made possible by the vacuum tube, have led to many refinements and innovations in methods of measuring physiological responses in the living or ganism. These improvements have resulted not from the in vention of new instruments, but through their application to measurement of biological phenomena. The older direct meth ods of measurement, which required relatively simple equip ment, not infrequently produced disturbing influences on the organ systems involved, and were slow in response and limited in sensitivity. The newer procedures overcome many of these limitations, but with a sacrifice of simplicity. Development of newer techniques has required close cooperation between the biologist and the instrumentation specialist. The tying together of two widely separated fields of activity is a further complication in the problem of exchange of scientific informa tion.

Scientific progress i n practically every field of investigation is directly traceable to the development and use of a wide variety of measuring instruments. The field of biology is no exception, yet the need for cooperation and better exchange of informa tion is probably most acute between the sciences of instrumentation and biology. Biology and instrumentation represent two highly skilled but seemingly unre lated fields. Biology, as defined, means the science of life or l i v i n g organisms. In strumentation, as used here, means the development and application of measuring devices which respond quantitatively to some physical property of a situation and give an output which depends on this property. Although one field deals w i t h the animate, the other w i t h the inanimate, their dependence is evident i f we analyze one of the simplest measurements that can be performed—counting a total number. In this instance, the object whose property is being measured is treated as a discrete entity, as when the hematologist counts red or white cells. The microscope and the graduated slide are instruments that per mit him to make this measurement. More recently, a television eye and a high speed counter have replaced the technician, performing the operation i n a matter of seconds. Sometimes the physical property is continuous, like changes i n body temperature, blood flow, and blood pressure, bioelectric potentials produced by the brain, heart, and many other organs. When man first started to examine the mechanism of life, he had to school him self along the lines of phénoménologie inductive approach, as he did not know what factors were involved or how to measure them. L o r d Kelvin's famous words aptly describe the situation at that time: One's knowledge of a subject is of a poor kind indeed, unless one knows how to measure quantitatively the factors involved. The consequence of this now famous statement is evident when we examine the rapid progress that was made i n biology immediately following the introduction of biochemistry with its science of quantitative measurements. Today more is known about complicated chemical structures and chemical reactions w i t h i n the body than about relatively simple physical processes. On the first consideration it would appear that simple physical processes as sociated with animate matter would lend themselves readily to measurement. In204

A Key to PHARMACEUTICAL AND MEDICINAL CHEMISTRY LITERATURE Advances in Chemistry; American Chemical Society: Washington, DC, 1956.

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deed, as f a r back as 1600, Harvey, the father of circulatory physiology, started mak i n g systematic measurements i n an attempt to correlate biological phenomena w i t h physical laws. H e was the first to demonstrate the circulation of blood, yet today, 300 years later, there is still no completely satisfactory method for measuring the blood flow in the intact l i v i n g system. This research has lagged because i n some instances it has been difficult to define the exact physical magnitudes involved, while i n others the available principles or methods of measurement could not be applied without seriously influencing the system or the phenomenon itself.


Instrumentation as a Science

F o r a long time it was the responsibility of the scientist to develop and construct his own equipment, relying usually on the skill and ingenuity of a glassblower or a machinist. Today the ever-increasing emphasis on greater speed and sensitivity calls for more advanced physical methods of measurement, and the investigator, a l though a specialist i n the phenomenon he wishes to measure, frequently cannot hope to attain the same degree of proficiency i n building his measuring equipment, and even i f he were proficient i n the mechanical, electrical, and optical principles that enter into the design of an efficient instrument, he could not take the time from his research to devote to instrumentation. Condon drew attention to this point i n a speech before the Instrument Society of A m e r i c a when he said, " P r i o r to this century an analysis of the experimentalist's activity might have shown that the bulk of his time was spent i n getting ideas and in analyzing the data of his subsequent experiments, while a minimum of time was spent i n the construction of instruments. In the present period, too often the scientific situation is such that the bulk of his time has to be spent i n devising and constructing his instruments." If the investigator of today devotes any appreciable amount of time to instru ments, he quickly realizes that he is actually dividing his efforts between two sciences, his own and instrumentation. This growing appreciation of instrumentation as a distinct science has taken place only w i t h i n the last decade, and has come through the realization that the problems met i n designing various kinds of instruments have a great deal i n common. Recognition of this fact is exemplified by the forma tion of the Instrument Society of America, and the establishment at the N a t i o n a l Bureau of Standards of a division of basic instrumentation devoted to the study of the basic problems of instrumentation (including mechanical, optical, electrical, and electronic) i n a l l the physical sciences. To the uninitiated i t would seem that the instruments used are so various as not to have much i n common. I f this were so, there would be no general basis to the science of instrumentation. That i t is not so is evident from the fact that two i n struments, designed, built, and used for entirely unrelated purposes, w i l l operate on exactly the same basic principle. F o r example, both the biologist and the engineer make use of the thermocouple for the measurement of temperature : one to measure body temperature, the other to measure furnace temperature. The instruments used are different i n appearance but the principle employed is the same—namely, that two dissimilar metals, suitably joined, w i l l generate a voltage that can be re lated to temperature. Although the principle may be the same, the application w i l l dictate how i t shall be used. If the problem called for temperature measurements of venous blood, i t would be necessary to make the sensing element very small, perhaps mount i t inside a fine hypodermic needle. On the other hand, the engineer's concern may not be so much w i t h the shape and size of the element, but rather w i t h whether the metàls withstand the temperature they may encounter. To develop either element re quires a knowledge of both the principles of temperature measurement and the man ner i n which they are to be used. This example also serves to illustrate a logical approach to analyzing many of our complex instruments. U s u a l l y only one part of the instrument has any bear ing on the phenomena being measured and that is the sensing element, such as the thermocouple i n the above example. The design of the intermediate and usually the greater and more complex part of the instrument, such as the amplifier, voltage stabilizers, and îeference potentials, depends solely on the output of the sensing ele ment, not at a l l on the physical quantity to be measured, and w i l l be the same no A Key to PHARMACEUTICAL AND MEDICINAL CHEMISTRY LITERATURE Advances in Chemistry; American Chemical Society: Washington, DC, 1956.

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matter i n what branch of science i t is to be applied. The last part of the instrument depends only on the use to be made of the data the instrument provides, such as i n indicating, recording, or controlling. The sensing element, or transducer, usually determines the usefulness of the instrument, and performs the function of translating one physical property into a n other. In measurements, the attempt is made to effect the translation so that i t is evident to the sense of sight, which has the greatest sensitivity and resolving power. F o r example, although we can sense heat or cold, we can detect small difference i n temperature only by observing the change i n length of a mercury column i n a ther mometer. In the case of the thermocouple we perform an indirect measurement ; the temperature change is first translated into a voltage, then magnified, and finally transformed into a suitable form for observation.


Electronics

Of late the emphasis has been more on transducers whose output is related to some electrical property such as voltage, resistance, capacity, or inductance. This permits the bulk of the instrument to be placed at some distance from the transducer, and through the use of electronics i t is possible to attain almost any degree of speed and sensitivity commensurate w i t h the transducer, and to perform such operations as multiplication, integration, differentiation, and many others. Electronics has also made i t possible to apply many of the discoveries that were made long ago but remained i n a state of academic interest. F o r example, i n 1880 the brothers Curie observed that when certain crystals were subjected to pres sure or tension electric charges were developed on definite crystal surfaces. The piezoelectric effect is now used i n microphones, accelerometers, pressure gages, and vibration pickups. Electronics has also stimulated study of other materials, and today the same effect can be induced i n certain types of ceramics that do not ex hibit this phenomenon naturally. In biology, the fact that a principle of measurement is available does not guar antee that the measurement can be performed on a l i v i n g system. The problem of measuring blood flow, which was mentioned earlier, is exceed ingly important whenever studies are undertaken on circulation, circulatory diseases, or the effect of drugs on circulation. There are many principles available for the measurement of liquid flow i n pipes and tubes. Without exception, a l l of these have been applied and new ones have been devised by workers i n the field. How ever, every method used so f a r has certain inherent disadvantages and the choice depends more or less on the problem at hand and the liberties one can take w i t h the system being measured. Thus, i f the vessel is accessible and can be cut, the blood can be by-passed through a flowmeter, such as a rotameter, and the flow read directly. There are also methods for measuring flow i n the intact vessel; the first one was devised by Rein i n Germany. The measurement is effected by placing two fine thermocouples on the vessel about 1 cm. apart and heating the vessel slightly i n proximity to one thermocouple. Movement of the blood w i l l produce a temperature gradient across the two points which can be related to the rate of flow. However, none of these methods can be used to measure instantaneous flow, since the response time is slow. To measure pulsating flow an electromagnetic flow meter is generally used. A c t u a l l y the instrument measures the velocity of flow i n a short length of tubing of fixed diameter inserted i n the vessel, and the readings are then translated into flow. The principle itself is rather unique. Two small, nonpolarizable electrodes are mounted diametrically opposite each other i n the tubing. A strong magnetic field is made to traverse the tube, and as the blood moves through this field a minute voltage is generated i n that cross-sectional segment of blood that is perpendicular to the magnetic field. The resultant voltage is then amplified and recorded. More recently a method was developed at the National Bureau of Standards for measuring the flow of liquids i n pipes by measuring the difference i n the velocity of propagation of ultrasonic sound w i t h , and against, the direction of flow. It has been suggested that this technique may be used for measuring blood flow. If i t can be applied, the method may have some added advantages, but like the others, it is basically a velocity measurement and spontaneous changes i n vessel diameter ruin the quantitative accuracy. So f a r there is no direct physical method which does not A Key to PHARMACEUTICAL AND MEDICINAL CHEMISTRY LITERATURE Advances in Chemistry; American Chemical Society: Washington, DC, 1956.

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require a surgical procedure, or which w i l l permit repeated readings to be made i n any size of vessel, i n any part of the body under normal conditions.


Special Applications

Frequently, neither the biologist nor the instrumentation specialist has a well defined notion of the underlying factors of the phenomena which are amenable to measurement. A n illustration is a sequence of developments that took place i n the author's laboratory. D u r i n g the course of work on vitamins the question arose, whether the lack of a specific vitamin would inhibit the ability of an animal to perform a prescribed task. The r a t was the animal of choice and the task was swimming, as i t was possible to elicit a f a i r degree of cooperation from the animal without recourse to any secondary stimuli. The first measurement was merely of the length of time the animal could swim with a given fixed weight. In such a procedure, the end point is difficult to de fine because the rats are clever, and as they attempt to rest or swim under water one may overestimate their ability and inadvertently lose valuable animals. To over come these difficulties and provide greater versatility i n application and reading, an apparatus was built that resembled a heavy-duty balance. The animal was sus pended from one a r m of this balance i n a special harness, and the other a r m sup ported a mechanism which automatically adjusted a counterweight depending on the animal's efforts. A continuous record of the weight changes was made during the course of the experiment. The results were encouraging, especially as i t was pos sible to rate the individual animals on the basis of their gradually diminishing effort, eliminating the need for continuing the experiment to complete exhaustion. How ever, the system had a great deal of inertia and it was felt that a better insight would be had into the manner i n which the animal behaved i f rapid changes i n effort could be sensed, as lack of coord-nation might bear some relation to the onset of fatigue. A t about that time efforts were diverted to a seemingly unrelated problem—viz., development of a rapid-reading device for an analytical balance. Although differ ing i n application, the problem was basically the same—namely, measuring sudden changes i n weight, taking into account the effect of inertia on the deflection of the balance. To satisfy every possible set of circumstances, it became evident that it was necessary to solve the differential equation decribing the motion of a balance. To be practical, this calculation had to be performed as soon as the balance gave any indication of motion, so that the information could be transmitted to the indica tor or controller. This was finally accomplished by designing a suitable electronic analog computer. W i t h this new technique, an instrument could be designed which would not only determine the total energy expended by the swimming animal, but also follow the effort associated w i t h each individual swimming stroke. In biological instrumentation examples such as the above are the rule rather than the exception. However, instrumentation can also serve i n many other capaci ties, not the least of which is relieving the investigator of routine chores, thereby allowing h i m more time for designing new experiments and testing new theories. The biologist is dealing with an exceedingly complex system and until he can account for a l l the variables and constants that he now must approximate, he is w o r k i n g w i t h averages necessitating numerous observations. E v e n at this early stage of development, scientific instruments have much to offer i n terms of automatic features, reliability, and reproducibility as contrasted to the errors inherent i n human observa tion. Obviously the situation can be solved only through cooperative effort. How ever, such cooperative effort is impeded not only by the normal restraints of time, money, and availability, but also by lack of understanding between the workers i n the various fields and indeed by the lack of contact between them. A t the present time, as with a l l new ventures, we are going through a period of adjustment. The situation is somewhat chaotic, particularly i n the difficulty of finding a l l the latest information on new measuring techniques. Publication

Today only one journal i n the United States is devoted solely to the field of i n strumentation, and thp funds available to it from affiliated societies are wholly i n A Key to PHARMACEUTICAL AND MEDICINAL CHEMISTRY LITERATURE Advances in Chemistry; American Chemical Society: Washington, DC, 1956.

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commensurate w i t h the activity i n the field. However, certain journals such as the Review of Scientific Instruments and the Journal of Laboratory and Clinical Medicine are devoting sections to methods, techniques, and physical instruments for the biologist. Much valuable scientific information is being disseminated through publi cations, bulletins, and house organs of manufacturers; they contain bibliographies, special hints and unusual uses, and other guides of value i n the application of the instrument to special problems. O n the other hand, reports of physicists, electronic specialists, and other nonbiologists who have been interested i n the application of their findings to biology are scattered throughout the literature i n various branches of physics, electronics, and biology. I n an effort to provide a common meeting ground for the exchange of just such information, the Institute of Radio Engineers recently formed a professional group on medical electronics and at present this group is providing the only organized activity of its k i n d i n this v i t a l field.


Biophysics

To bridge the gap between physics and biology, a new science is gradually coming into its own—biophysics. A t the present time this science does not have an estab lished domain nor a generally accepted curriculum of prescribed education, because physics borders on practically every field of biological specialization. The biophysicist may be expected to be better versed i n instrumentation, but i t is no more his i n tent to devise his own instruments than i t would be for a biochemist or a physical chemist. However, i f the science of biophysics can find expression through its own journal, i t may provide a more logical central repository for information on i n strumentation than any other branch of biology. Communication

Problem

A t the moment, there is perhaps no real solution available and a l l that one can do is to explore the nature and the magnitude of the communications problem. This problem is vast, and of a somewhat different nature than that of communications within a single science or specialty. More technical bulletins, papers, journals, etc., are not an adequate solution. A f t e r a l l , communication is dependent, i n the last analysis, on the interest of the recipient and on his ability to understand. The biologist interested i n blood flow, for example, has no interest i n , nor understanding of, the necessary instrumentation and has neither time nor inclination to read i n strumentation journals, nor would they help h i m much i f he did, as the language and approach are quite foreign to his field. The problem of communication between the biologist and the instrumentation worker is one of increasing importance and growing priority. L a c k of means of b r i n g i n g a l l the scattered information together w i l l defeat the ultimate purpose of scientific w r i t i n g , as was so well p u t by MacDonald, who said, " B y the interchange of information today's work can begin where yesterday's ended; one need not do again today what was well done yesterday." RECEIVED

N o v e m b e r 5,

1954.

A Key to PHARMACEUTICAL AND MEDICINAL CHEMISTRY LITERATURE Advances in Chemistry; American Chemical Society: Washington, DC, 1956.

Instrumentation Applied to the Biological Sciences - Advances in

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