The Fitness of the Environment

If the water be pure, the concentrations of hydrogen and hydroxyl ions are necessarily the same, for water is electrically neutral. A variety of independent methods of estimation have shown that at 25° (centigrade) this concentration amounts almost precisely to O.OOOOOOIN, in the ordinary units.^ This corresponds to 0.0000001 gram of ionized hydrogen and 0.0000017 gram of ionized hydroxyl in 1000 grams of water. Further, the theory of solution explains acidity in water by the occurrence of hydrogen ions, formed from dissolved electrolytes, in excess of hydroxyl ions ; and alkalinity by a similar excess of hydroxyl over hydrogen ions. Neu- trality is then the condition when, as in pure water, the two concentrations are equal. In short, expressing the concentration of ionized

* Concentrations are expressed in terms of claemieal equivalents, gram-molecules, or moles. N (normal) is the symbol for tUs unit. The values of the concentration of ionized hydrogen at neutrality as estimated by different investigators are as follows : — It remains to point out that implicit in these definitions is the well-founded hypothesis that in water the concentrations of hydrogen and hydroxyl ions vary inversely, so that with constant temperature under all circum- stances their product is constant: ^ —

Substituting in this equation the value 0.0000001 of the concentrations at neutral- ity, we obtain the value Now there is a certain characteristic prop- erty of an acid, its ionization constant, h, which measures its tendency to dissociate in aqueous solution, thereby to produce hydro- gen ions, and hence to increase the intensity of acidity. Strong acids have ionization con- stants which are of the order of magnitude of 1.0, weak acids of the order of magnitude of 0.0001, the weakest acids, 0.00000001, or less.

It has been discovered that in the general case above discussed the concentration of ionized hydrogen is always almost exactly proportional to the ratio of free acid to salt, and is equal, in very close approximation, to the product of this ratio by the ionization constant of the acid. That is to say, repre- senting free acid by HA and salt by BA, From this relationship, therefore, follows the conclusion, fully established by experiment, that whenever in such a solution the excess of acid, HA, is chemically equivalent to the quantity of salt, BA, the hydrogen ion concen- tration is almost exactly equal to the ioniza- tion constant of the acid. But the ionization constant of carbonic acid (first hydrogen atom) is 0.0000003. Hence in a solution containing exactly equivalent quantities of free carbonic acid and, for example, sodium bicarbonate, the hydrogen ion concentration must be 0.0000003 N. Further, since

if the amount of acid be ten times the amount of salt i^^-r = 10 ], the hydrogen ion concentra- tion must be 0.000003 N, and if the reverse The range of variation of concentration of hydrogen ions in the usual solutions of the chemical laboratory considerably surpasses the limits 1.0 N and 0.00000000000001 N. In comparison with such enormous differences those between 0.000003 N and 0.00000003 N are phoric acid (after its first hydrogen has been neutralized by base), has the remarkable property of preserving a neutral reaction whenever it exists in solution with its salts, provided there be an excess of acid. All acids whose strength is even a little either greater or less than carbonic acid lack the property.^

This characteristic of carbonic acid is of the utmost significance, first by regulating one of the most fundamental of physico- chemical conditions, and secondly by pre- serving throughout nature the characteristic chemical inactivity of water, which disappears whenever the reaction becomes either appre- ciably acid or appreciably alkaline. Almost the only case of important geological action due to acidity or alkalinity of water is the action of fresh water, containing carbonic acid itself, to weather the rocks. This process is, however, self -limited, for the dissolved material forms bicarbonates, and thus at once pro- vides permanently inactive balanced solutions.

It is impossible to understand the eflSciency with which neutrality is preserved by carbonic acid, without the actual discussion of a par- ticular case. Let us therefore consider a solu- * Henderson, "The Relation between the Strengths of Acids and their Capacity to Preserve Neutrality," American Journal o/ Physiology, XXI, 173, 1908. tion of 1 kilogram of carbon dioxide in 100 liters of water, to which sodium hydrate is being added. At the beginning of the experi- ment the hydrogen ion concentration will be approximately 0.0001 N, almost exactly one thousand times that at neutrality, and the hydroxyl ion concentration 0.0000000001 N, one one-thousandth that at neutrality. If, now, the sodium hydrate be added to the solution in successive portions, the change of reaction will be as indicated in the following table: —

From the table it appears that the first 50 grams of alkali reduce the hydrogen ion concentration to but 50 times that of neutral solutions, and 200 grams of alkali have made it only about 10 times that of pure water, in spite of the fact that there are more than 750 grams of free carbonic acid still present in the solution. So much acidity can at once be obtained by dissolving merely 0.004 gram of hydrochloric acid in 100 liters of water. Thereafter neither acidity nor alkalinity sur- passes this intensity until 450 grams more of sodium hydrate have been added to the solu- tion. Yet in 'pure water 0.005 gram of sodium hydrate would make the reaction more alka- line than that.

Such is the case when the equilibrium is homogeneous, i.e. in an isolated solution. But when, in similar cases, an atmosphere containing carbon dioxide is present, the con- ditions are still more striking. Suppose, for example, a solution of 100 liters containing 1 kilogram of sodium bicarbonate in equilib- rium with an atmosphere containing 1 gram of carbon dioxide per liter. Let hydrochloric acid be added in successive small portions to the solution. Further let the solution be constantly stirred and shaken, and let the experiment be conducted slowly, so that there

shall always be equilibrium between the car- bonic acid in the solution and in the atmos- phere. Further^ let the temperature be such that the absorption coefficient of carbon dioxide shall be 1.000. Then the successive states of the solution will be approximately as recorded in the following table: — From the beginning of the experiment until almost 250 grams of hydrochloric acid have been added, neither alkalinity nor acidity is double in intensity the values which obtain in a perfectly neutral solution. This amounts to a constancy of reaction which, until a few years ago, was scarcely known to the chemist at all. Such close approach to neutrality

can be attained with pure water only after elaborate and very difficult purification, yet in the presence of carbonic acid it is the natural condition. Of course the case above dis- cussed is an extreme one. In nature the con- centrations of dissolved substances are less, the mixing less efficient, and the variations of reaction a little greater. There is also, in nature, likely to be a considerable excess of bicarbonate over free carbonic acid present. The cause of the greater constancy of re- action in the "case of the heterogeneous equi- librium is simple enough. At the beginning of the experiment the free carbonic acid of the solution is exactly in equilibrium with that of the atmosphere. Accordingly, when hydro- chloric acid is poured in and reacts with so- dium bicarbonate to form sodium chloride and more carbonic acid,

every bit of the latter escapes to the atmos- phere, and the total amount of acid is just what it was before. But a certain amount of carbonic acid has been replaced by the equiv- alent amount of hydrochloric acid. This latter substance, however, is wholly in union with sodium, as its salt. Thus the addition of the strong acid diminishes the amount of alkaline salt (sodium bicarbonate), but does not increase the amount of free acid. Not until the bicarbonate is entirely decomposed (318 grams HCl) does the hydrochloric acid begin to exert its own action as an acid, and then 2 grams cause about as much rise in acidity as 318 grams have previously caused, or nineteen times the rise effected by the first 300 grams, or about two hundred times the rise caused by one hundred times the quantity of hydrochloric acid at the beginning of the experiment.

These statements all rest upon facts which have been accurately established by experi- ment and are brought forward in company with the theoretical treatment, based upon the Mass Law, only for the sake of complete- ness of statement and because brief exposition is otherwise scarcely possible. The extraor- dinary capacity of carbonic acid to preserve neutrality in aqueous solution, which is ex- ' plained by its ^rength and solubility in water, is a well-established experimental fact, and no other known substance shares this power. ^ Hydrogen sulphide might perhaps be thought of as an exception. But while its solubility

1 Henderson, "The Theory of Neutrality Regulation in the Animal Organism," American Journal of Physiology, XXI, in water is not favorable for the best results, its instability is a fatal obstacle. Such are the physico-chemical facts re- garding neutrality regulation in heterogeneous systems by means of carbonic acid and bicar- bonates, and, though the exposition is diflScult, it has seemed necessary to make them clear. For there is, I believe, except in celestial me- chanics, no other case of such accuracy in a natural regulation of the environment. More- over, the chemist has discovered no means of rivaling the efficiency and delicacy of adjust- ment of the process. Finally, acidity and alkalinity surpass all other conditions, even temperature and concentration of reacting substances, in the influence which they exert upon many chemical processes.^

Almost wholly through this mechanism the oceans are always nearly neutral. Chiefly with its aid protoplasm and blood possess an unvarying reaction. Quite recently the con- centration of hydrogen ions in the ocean has been very carefully studied by Palitzsch,^ * Of all catalytic agents these ions are by far the mo^ important. In their influence upon the stability of colloidal systems they are also unapproached by other substances. ^ " Etant donne que I'eau de mer a un contact is jntime avec les organismes de la mer et que non seulement elle les entoure de ses flots, mais qu'eUe traverse leurs branchies et impregne en partie les corp des invertebres, il semble assez

who finds very great constancy, the extreme variations (with the exception of the Black Sea) being 0.000000011 N to 0.0000000045 N. Allowing for the change • of the ionization constant of water with the temperature, and the fact that in siich systems the hydrogen ionization is nearly independent of the tem- perature, these values roughly correspond to hydroxyl ion concentrations 0.000002 N and 0.000005 N respectively at the lower temper- atures and slightly higher values at the higher temperatures of sea water. This is a sufficient excess of hydroxyl ions properly to be termed faint alkalinity, though it amounts to but about 0.00005 gram per liter, or 0.000005 per cent. It is in part due to the fact that the quantity of carbonic acid in the air is now very small, while in the ocean the concentra- tion of bicarbonates is great. Indeed, the ocean has unquestionably grown alkaline;

justifie de la placer dans la m^me categorie que les autres- liquides physiologiques. Des determinations exposes dans ce qui precede jl ressort que, de mgme que ces liquides, I'eau de mer est douee d'une grande capacit6 de r6gler sa concentra- tion en ions liydrogene, bien que cette capacity soit moins prononcee que celle constatee par example dans le sang." — S. Palitzsch, " Siu' le mesurage et la grandeur de la concen- tration en ions hydrogene de I'eau salee," Comptes-rendus des travaux du Laboratoire de Carlsberg, lOme Volume, Ire Livraison, 1911, p. 93,

for its origin must have been acid from the presence of carbonic acid unbalanced by base. The present ratio between bicarbonates and carbonic acid in sea water has not been accu- rately estimated, but it is perhaps 50 : 1 or 100 : 1. The conditions are complicated by flora and fauna, and such influences have not yet been determined. Turning to the acid-base equilibrium of blood and protoplasm, we encounter a subject which is better understood, though not more significant in the present discussion. The alkalinity of the blood is one of the familiar subjects of physiological investigation, and its clinical importance has long been clear. Not until the introduction of the ionization hypothesis, however, was it possible to explain the conditions. The outcome of these studies has been to assign to the equilibrium between carbonic acid and bicarbonates a first place in the regulation of the reaction of blood ;^ and since such substances are invariably constitu- ents of all protoplasm, to make evident the universal biological importance of this equi-

* Friedenthal, "Arcliiv fiir Physiologie, Verhandlungen der Physiologischen Gesellschaft Berlin," May 8, 1903. Hen- derson, American Journal of Physiology, XV, 257, 1906, "Ergebnisse der Physiologie," VHI, 254-325, 1909 (the last a review of the equilibrium between acids and bases in the organism). librium. The process is complicated by the intervention of all the other acids and bases of the body. Of these, however, only phos- phates, and in lesser degree proteins, are im- portant. Thus it is certain that in the one universal chemical equilibrium of protoplasm which has thus far been defined and quantita- tively described the carbonates take a prin- cipal part.

It is not possible to explain the significance of carbonic acid in this physiological process as chiefly an adaptation ; for natural selection can have nothing to do with the occurrence of carbonic acid in the living organism, or, pre- sumably, with the nature of the original living things upon the earth.^ The presence of carbonic acid is inevitable, and whatever the first forms of terrestrial life may have been, certain it is that carbonic acid was one of the constituent substances. From that day to this it has steadily fulfilled the function of regulating the reaction of protoplasm, and of body tissues and fluids.

The recent studies of Hasselbach and Lunds- gaard^ indicate that the hydrogen ion concen- tration of normal blood at body temperature 1 It was this obvious fact which originally led me to a re- consideration of fitness. is about 0.000000044 N. This value is sub- ject to constant slight variations, diminish- ing as the blood passes through the lungs, increasing during the greater circulation; but variations of this kind are certainly very- slight in the healthy organism. The value corresponds to a concentration of bicarbonates about ten times as great as that of free car- bonic acid. Together the acid and its salts make up the larger part of all the carbonic acid, and a very considerable fraction of all the dissolved molecules of the blood. In disease, especially diabetic coma, the hydro- gen ion concentration may rise to 0.0000001 N, or perhaps higher ; when acid is injected into the blood the value may be greater still, but death speedily ensues, and it is certainly im- possible during life that there should be any considerable permanent variation.

Increase in acidity of the blood can occur only in association with marked diminution in the concentration of bicarbonates, which may fall to less than one third of their normal amount, greatly impoverishing the blood in respect to carbonic acid, and interfering with its excretion. This is due to the fact that the amount of free carbonic acid in the blood is under the independent control of the respira- tory center, and when acids decompose bicar-

bonates the carbonic acid which is hberated escapes through the lungs into the air. This action is analogous to the simple heterogeneous equilibrium explained above, and calls for no special discussion. The importance of this physiological equi- librium is to be sought in part in one of the primary characteristics of the metabolic process, — the chiefly oxidative formation of acid. In the main the foodstuffs are neutral substances, but their principal end products, except water, are almost exclusively acid compounds, — carbonic acid, phosphoric acid, sulphuric acid, uric acid. Moreover, there is a well marked tendency, at least in man and the vertebrates, under very many pathological conditions, to form other acids, such as lactic acid, )8-oxybutyric acid, acetoacetic acid, etc. This tendency toward acidity of reaction and the accumulation of acid in the body is one of the inevitable characteristics of metabo- Usm ; the constant resistance of the organism one of the fundamental regulatory processes. Now it comes about through the carbonate equilibrium that the stronger acids, as soon as they are formed, and wherever they are formed, normally find an ample supply of bicarbonates at their disposal, and accordingly react as follows: —

This reaction corresponds exactly to the simple case first discussed, and so causes an inconsiderable change in the concentration of ionized hydrogen. The free carbonic acid then passes out through the lungs, and the salt is excreted in the urine. Other processes are involved, including a device for final re- tention of a part of the alkali which has neutral- ized acidj^^ but in the whole complex function nothing is more important than the simple reaction written above.

The hydrogen ion concentration exerts a marked influence upon the rate of progress of chemical reactions. Thus, for example, the so-called inversion of cane sugar by a proc- ess of hydrolytic cleavage into glucose and fructose, is commonly accomplished by warming a solu- tion of sugar to which a little acid has been added. It was shown by the classical investi- gation of Wilhelmi that the velocity of this process depends upon the strength of the acid, or, according to the modern view, upon

the concentration of hydrogen ions. Indeed, these ions are the efifective agents in the process. Reactions of this type, in which carbohy- drates, fats, proteins, and other substances take part, make up a very large, if not the largest fraction of all the processes of metabo- lism, and there can be no doubt that for their regulation very accurate adjustment of acidity and alkalinity is essential. In the body, to be sure, such reactions are under the control of enzymes, but the concentration of hydrogen and hydroxyl ions is not less, rather more important for that reason. Beside retaining their direct influence upon the reaction, the ions also exert an influence upon the enzymes themselves. Moreover, not only enzymes, but almost all colloidal bodies, especially such unstable structures as the colloids of proto- plasm, are profoundly affected by changes of reaction, and for the preservation of their' stability they also are absolutely dependent upon constancy of acidity and alkalinity.

Finally, it is to be noted that glucose, which is the principal source of energy in physiolog- ical processes, is very unstable in even faintly alkaline solutions, and that its stability varies in most marked degree with the slightest change in the concentration of hydroxyl ions.^ Further, there is also reason to be- heve that the concentration of hydrogen and hydroxy! ions may sometimes be concerned in adjustments of great magnitude, which involve the distribution of water between the tissues and the body fluids, or at least be- tween red blood corpuscles and the plasma.^ Recently, for example, a theory has been sug- gested which seeks to account for certain forms of oedema as the result of local or general increase in the acidity of the organism.^ In any case, whatever the fate of these latter

^ The changing distribution of material between red blood corpuscles and plasma as the tension of carbonic acid changes has, since its discovery by Zuntz, been investigated by a series of physiologists. (See Spire and Henderson, Biochemische Zeitschrift, 15, 114, 1908.) In each complete cycle of the circulation there occurs a complete cycle of changes between the constituents of the corpuscles and of the plasma. As the blood passes through the tissues and receives carbonic acid the volume of the red corpuscles increases from the entrance of water coming from the plasma; chlorine simul- taneously passes in the same direction; and various other changes occur. In the lungs, with the escape of carbonic acid, the process is reversed. There seems to be no doubt that this process is largely dependent upon changes in re- action accompanying changes in the concentration of carbonic acid.

' M. H. Fischer, "(Edema," New York, 1910. It is impos- sible to judge of the correctness of many of the views set forth in this work. At present they appear to be in part ill- founded. views may be, the common physiological processes, and the structural conditions which depend for their integrity upon constancy of the concentration of hydrogen and hydroxyl ions are certainly manifold. The principal conditions and processes, both inorganic and organic, which rest upon the acid nature of carbonic acid and its char- acteristic distribution between the atmos- phere and aqueous solutions have now been indicated. In their origin at least they are nowise due to the agency of organic evolution. Yet directly, because of the nature of carbon dioxide as a gas, because of its solubility in water, and on account of the precise degree of its weakness as an acid, they possess the highest possible efficiency. This conclusion might be established with rigorous accuracy by means of a mathematical analysis, but the above discussion is sufficient for the present purpose.^

In this manner carbonic acid shows itself in its physico-chemical traits variously fitted for the organic mechanism. Less various, to be sure, and less obvious than those of water, such fitnesses as it does possess are quite as genuine. But they are dependent upon water ; secondary in their nature ; resting upon solu- bihty and ionization ; upon interactions be- tween the two substances. So they lead us to a consideration of the most intricate of all mutual relations, to a purely chemical study of the compounds of carbon, hydrogen, and oxygen, into which water and carbonic acid can be transformed.