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THE BIOLOGICAL CODES R.L. Beard The Connecticut Agricultural Experiment Station New Haven, Connecticut
134 The present development of biological codes is the result of cooperative effort on the part of the staff at the Chemical-Biological Coordination Center, the Biological Codification Panel, and the several subcommittees interested in the biological phases of the Center's activities. The purpose of the biological codes is to classify biological information in a manner per- mitting the representation of data by punched cards. Such a classification needs to be of sufficient detail to permit correlations, particularly those relating to chemical structure and biological response, but not so detailed that each bit of information becomes unique. It needs to be an indexing system, but one permitting a multiplicity of cross referencing. A system of this kind, embracing physiology, pharmacology, toxicology, and enzymology, and considering all organisms, is not easy to construct with logical and consistent patterns. The adaptation of the system to punched cards imposes some limitations, but the program has been pursued on the premise that only by the use of mechanical aids will it be possible to handle efficiently the mass of information which ultimately will be in the files at the Center. Because no previous system applicable to the punched-card machines and all fields of biology was available to serve as a model, development proceeded in an experimental manner. As a result, several coding systems have been tested at the Center for their application to the problem. At the outset it seemed desirable to devise a general code, chiefly for utilitarian purposes, to describe the broad fundamental actions of many compounds and to indicate the extent to which the compounds had been tested on biological systems. Impetus to this was given by the accumula- tion of data resulting from the war-stimulated screening programs particularly for anti-malanals, insecticides, rodenticides, fungicides, and plant growth regulators. The General Biological Code was thus developed to meet the practical needs of the moment. It was designed to occupy the space on a punched card not occupied by the code which describes the chemistry of the test compound and was to be used in conjunction with this chemical description. This space amounts to twenty-three columns each of which contains twelve punching positions, or a total of two hundred and seventy-six. The General Biological Code is based on the principle of direct coding, in which each punch designates a single unique concept which is independent of all other concepts. Thus there is opportunity for expressing two hundred and seventy-six different ideas. Of these, two hundred and eleven have been utilized, which represent subdivisions of the following major considerations: Taxonomic groups of microorganisms and plants Physiologic actions on plants Taxonomic groups of invertebrates Physiologic action on invertebrates Population control of microorganisms Population control of invertebrates Chemotherapeutic action against parasitic infections Enzymes Carcinogenic and carcinoclastic action General physiologic actions pertaining to microorganisms, plants, and animals Taxonomic groups of vertebrates Morphology and pharmacology of vertebrates The unit represented by the punched card is the chemical compound. All the biological information, classified according to the code, is indicated on the one card together with the chemical information. This code provides for recording positive or negative activity, but the degree of activity is not expressed. The usefulness of this code is largely limited to providing a general summary of the actions of a compound and to designating the fields of study in which the compound has been investigated. Many desired correlations cannot be made because of the lack of specificity in many of the categories and because the degree of activity is not indicated. Moreover, the application of direct coding introduces difficulties in machine operation which require special handling in entering new information, in maintaining useful files, and in seeking answers to questions put to the system.
135 In order to augment the General Biological Code and to answer questions on biological actions more specifically, detailed codes have been worked upon concurrently, and an integrated Detailed Biological Code is in use at the present time. This represents an expansion of the ideas cataloged by the General Biological Code as well as additional concepts and details. As applied to punched cards, the two codes differ fundamentally in what the cards represent. Used with the General Biological Code, the punched card describes the chemical compound and all its actions. Used with the Detailed Code, the punched card contains a coded description of one observation on the effect of a compound on a biological system, with details of the particular system affected, technique of application, and type and degree of response. This card is designated as the Biological Card in distinction to the Chemical Card which, in code form, describes the chemical structure of the compound tested. A third card, designated as the Chemical-Biological Card, combines the chemical information with certain of the more fundamental biological information. This card permits direct correlation of those elements expressed on it. In addition, because of the information common to it and to the Biological Card, correlation is possible between any of the details expressed on the Biological Card and those of the Chemical Card. Replicas of the three basic cards are filed in such a way as to facilitate the search for cards having one or more characteristics in common. In such a search, hand selection and machine sorting are used for the greatest economy of time and effort. As used with the Detailed Code, the punched card is divided into fields each of which consists of the space required for the code number expressing a given idea. The various fields of immediate interest are as follows: Test chemical Organism Test organism Host organism (or non-living test environment) Sex and stage of development of the test organism Primary organ system (organ system responding to test chemical) Secondary organ system (organ system experimentally modified, or site of application when organ is not responding) Tissues, cells, fluid (concerned with action and/or primary organ system) State of organism, organ, or tissue tested (experimental condition) Action Direction of action (increases, decreases, inhibits, etc.) Specific action General action (includes ". . . cidal" actions (i.e. fungicidal), terms embracing more than one specific action, conditions of ill-defined origin) Estimate of effectiveness (quantitative summary expressing effectiveness in one of five ranges) Secondary chemical (chemical which may be affected, antagonized, synergized, produced, or which serves as a standard for comparison) Technique Size of inoculum in chemotherapeutic studies Route and manner of administration of inoculum Route and manner of administration of test chemical Route and manner of administration of secondary chemical Part treated Method of expressing dosage Concentration component of dosage Quantity component of dosage Time component of dosage Frequency of dose Duration of action Time of evaluation Criterion of response Slope of the dosage-response curve Physical state of the compound when applied Physical state of the compound when response is read Presence of conditioning agents Properties of the compound studied; indication of additional information
136 All of the quantitative data are expressed in ranges rather than in absolute values. Although the above outline seems to give undue emphasis to technique, this is actually subordinate to the more fundamental information and serves merely to give additional information and to qualify the estimate of the chemical's effectiveness in producing the recorded action. Of chief interest are the test organism, the organ system responding, and the biological response, and it is upon the basis of these three components that the card files are established. Some of the concepts expressed, or the way in which they are expressed, are incorporated in the code on a trial basis. Experience in use will determine whether or not they become permanent features of the code. A few examples will serve to illustrate the use of the code and the language employed in expressing data. The observation that "Indole-butyric acid induces root formation in branch cuttings of Atrocarpus communis" would be represented, according to the General Biological Code, on the punched card for indole-butyric acid by two concepts: (1) Growth modification and (2) Information available relative to Angiosperms. It should be pointed out that these two items are added to any other concepts which may have been recorded for this compound, and the several items bear no relationship to each other. On the other hand, this observation would be represented according to the Detailed Code by a punched card recording the information as follows: Indole-butyric acid Induces Tissue development (in the) Shoot (as an) Isolated structure (of) Atrocarpus communis (test chemical) (direction of action) (specific action) (primary organ system) (state of organ) (test organism) This illustrates that the language of the report has to be "translated" into the code language. In developing the code an attempt was made to use the common terminology of a given discipline. In some cases, however, different disciplines use different phraseology to express similar concepts, and compromises were required. The important thing is the coding of ideas and not words. The observations that "Parathion causes 50 per cent inhibition of bee brain cholinesterase at 1 x 10"Â° molar concentration; its 1 .Oso to the honeybee is 3. 5,Â«g/g" are indexed according to the General Biological Code by three categories on the punched card for diethyl p-nitrophenyl thiophosphate (- parathion). These are (1) Information available relative to Insecta (2) Esterases, phosphatases, sulfatases, and (3) Insecticide. These items are so general that almost all the details are lost. As described by the Detailed Code, these observations might reai as follows: (1) Diethyl p-nitrophenyl thiophosphate (-parathion) Inhibits Cholineste rases (in the) Brain (of) Apis mellifera (=honeybee) (being) Highly effective (ln50 = 1 x 10"Â° or less) (2) Apis mellifera ( = honeybee) Acute toxicity Insecticide Effective (LD5o = . 2 - 3. 5 ft g/g1 (test chemical) (direction of action) (action) (primary organ system) (test organism) (estimate of effectiveness) (test organism) (specific action) (general action) (estimate of effectiveness)
137 In these cases, the details are preserved except for the exact quantitative data, which are placed in ranges instead of being reported in absolute values. A third example involves vertebrate pharmacology. "Dimercaprol (12.5 mg./kg. injected intramuscularly after intravenous injection of lead acetate) increases the excretion of lead in the bile of anesthetized rabbits. " By the General Biological Code this would be indexed on the card for 1-propanol, 2, 3-dimercapto- (= dimercaprol) as (1) Information available relative to rodents other than rats or mice, (2) Elimination, (3) Liver function. By the Detailed Code the information is coded quite literally: 1 -propanol, 2, 3-dimercapto ( dimercaprol) (test chemical) 5. 1-25 mg/kg (range of dose administered) Intramuscular injection (route of administration) Test drug given after secondary chemical (signa) Lead acetate (secondary chemical) Intravenous injection (route of admin, of second chemical) Rabbit (test organism) Anesthetized (state of test organism) Biliary elimination of secondary chemical (action) Increased (direction of action) To understand how the cards can be used as an aid in answering questions it should be explained that data sheets, on which may be found information abstracted from original papers, are filed according to the test chemical. As mentioned before, the punched cards describing the chemistry of test chemicals (Chemical Cards) are filed in one series according to the serial numbers assigned to the chemicals and in another series according to the code designations for the structural groups for each compound. The latter file is the "rotated" file in which for a given compound there are as many cards as there are structural groups present. The Biological Cards and the Chemical-Biological Cards are replicated and filed under "test organism", primary organ system", and "action". In many respects the simplest type of question to answer is that involving information on a single compound, as "Has Â£-chlorophenoxyacetonitrile been tested as a plant growth regulator?". This can be found by referring directly to the data sheet file under the serial number of this compound, which happens to be 900,249. Other types of questions require the use of the punched cards and the aid of the machines. It is beyond the scope of this paper to explain the use of machines, but some idea of the procedures followed in answering questions can be obtained from a few examples. One type of question involves a primary search among the biological data. "What structural relationship is exhibited by compounds known to be C.N.S. depressants in cats and dogs and which also are known to interfere with succinic acid dehydrogenase metabolism in the liver?" In answering this, cards dealing with the Nervous System can be hand-selected from the file based on Primary organ system, and cards dealing with Succinic dehydrogenase can be hand- selected from the file based on Action. These cards then can be handled by machine according to the following scheme:
138 Hand select Sort Sort Sort Collate Nervous system i (organ system) Nervous activity (action) Succinic dehydrogenase (action) Sort Depresses Cats (direction of action) Dogs organism) Liver (organ system) Examine chemistry for structural relationships (Sorting, tabulating, visual inspection) Another type of question calls for use of the Chemical-Biological Card file, which permits direct correlation between chemical and biological information. "Which compounds possessing the thiocyanate or the isothiocyanate groups have been tested as fungicides and what is their relative effectiveness ?" In answering this question, Hand select cards dealing with Sort for Sort for (action) Thiocyanates Isothiocyanates Relative effectiveness A still different procedure can be followed in answering these questions: "Which compounds having 5-membered rings containing N in the ring have been studied for their effects on the nervous system of insects? Which of these compounds have similar effects on mammalian nervous tissue?" From the Biological Card file based on the Primary organ system those cards dealing with the Nervous System can be hand selected, and from the Chemical rotated file those cards dealing with the desired structural groups can be hand selected. These groups of cards then can be handled as follows: Hand select Collate Sort Collate Nervous system C4N C3NS C3NO CN(Z) Examine for similar effects (Sorting, tabulating, visual inspection)
139 These suggested procedures are not the only way in which these questions can be answered. A skilled machine operator, familiar with the files, can outline procedures which require the minimum number of cards to be handled and the minimum nuVnber of machine operations. The systems outlined above were not designed to replace the thinking process, nor can they be expected to yield a completed manuscript ready for publication. They were designed to serve as a research tool to facilitate experimental work and to provide leads toward new investigations. Note: Since the above was presented, certain modifications of detail in card arrangement and filing procedures have been made at the Coordination Center. The principles, however, remain the same.