The life-story of the red blood-corpuscles of mammals is one of the most fascinating that the histologist has to tell. He wishes that he could tell it with assurance; but, unfortunately, there are many uncertainties, due to conflicting testimony, in its earlier chapters. It is unlikely that a blood-corpuscle lives for long. A month or six weeks is probably the term of its existence. The rapidity with which the stock is replenished after bleeding shows that there must be ample provision in the body for making blood-corpuscles. The rate at which they disappear after they have been added in excess shows that there is an equally effective mechanism for destroying them. If half as many again as the animal already possesses be injected into its veins, the number is reduced to its normal limit in about ten days. It is clear that they can be made and can be destroyed with great facility, and it seems a legitimate inference that production and destruction are constantly taking place. Regarding the way in which they are destroyed there is no uncertainty. We shall refer to this subject when describing the functions of the spleen. But how are they made? We can sketch their history in outline, but the evidence is conflicting with regard to all matters of detail.
In early stages of embryonic life all red blood-corpuscles are nucleated, as they are permanently in birds and the other classes of vertebrates below mammals. In embryonic mammals they multiply by division whilst circulating in the blood, just as in the newt. But it is generally believed that this is not the most important source of new ones. During the earliest stages of growth they are being formed in enormous numbers. Such instances of division as can be seen in circulating blood appear to be all too infrequent to account for their rapid multiplication, and there can be no doubt but that a more complicated method of production is more important. Their formation is described as taking place “endogenously.” Certain cells termed “vaso-formative,” or “vaso-sanguiformative,” reach a considerable size, and become stellate in form, or branched. Their nuclei divide without the cell dividing. Each nucleus accumulates a little hæmoglobin round it. A space filled with fluid appears inside the cell. The nuclei project into this space. Then they drop off with their envelopes of hæmoglobin. The outer shell of the big vaso-formative cell becomes the wall of a capillary bloodvessel. By its branches it links up with other vaso-formative cells, making a network of vessels. The fluid inside it is the plasma of the blood. The nuclei and their envelopes are blood-corpuscles. This, if it be a true story, is a comprehensive way of making bloodvessels and blood at the same time. Doubts have been thrown upon its accuracy, but many leading histologists strenuously maintain that this description is correct.
At a certain period all nucleated red corpuscles disappear from mammalian blood. Non-nucleated corpuscles take their place. How are the latter formed? For a short stage of embryonic life nucleated cells containing blood-pigment are seen, or are supposed to be seen, in the liver—there is, unfortunately, great difficulty in distinguishing them with certainty from young liver-cells; later they are seen in the spleen; throughout the whole of life they are to be seen in the marrow of bone. The nucleated cells give origin to the non-nucleated corpuscles. It is hardly legitimate to call these cells persistent embryonic corpuscles. Yet the chain which connects the cells which in the embryo are capable of dividing into pairs of nucleated red blood-corpuscles, and the cells which, assuming the rôle of parent cells, do not accumulate hæmoglobin for their own purposes, but for the benefit of the red corpuscles which split off from them, is probably unbroken. In this sense they are persistent embryonic corpuscles which have deserted the blood-stream, and have taken shelter in certain tissues which are particularly favourable for cell division. The situations in which they hide themselves are singularly suggestive. In the liver there is an abundant supply of nutriment, more abundant than in any other part of the body of the embryo. Later, in the spleen, red blood-corpuscles are being destroyed. Materials available for making new ones must therefore be set free. The inside of a hollow bone is a peculiarly sheltered situation. The fat cells of marrow accumulate there after a time; but within some bones the marrow develops very little fat; hence it shows the red colour, which is due to its abundant bloodvessels. This “red marrow” is the most important seat of the manufacture of red blood-corpuscles in adult life. Unfortunately, when we try to answer the question, How are they formed? we are obliged to speak with caution. Some histologists assert that the nucleated cells divide, and that one of the two daughter cells accumulates hæmoglobin, and loses—that is to say, extrudes—its nucleus. Others maintain that the nucleated cells become irregular in form; that hæmoglobin accumulates in the projecting portion of the cell; that this projecting portion breaks off as a non-nucleated corpuscle. It would be indiscreet at the present time to pronounce in favour of either of these reports, although the decision is of theoretical importance. If the former account be true, red blood-corpuscles are nucleated blood-cells which have lost their nuclei. If the latter account be in accordance with fact, it is hardly justifiable to regard them as cells. They are parts of cells which finish their existence independently of the cell body and nucleus to which they belong. As circumstantial evidence, favouring the theory that cell division is normal and the nucleus subsequently lost, may be pleaded the existence in marrow, and also in the embryonic liver and spleen, of certain very peculiar cells. These cells have long been known as giant cells, and all attempts at accounting for them have broken down. They are relatively of immense size: their diameter may be twenty times as great as that of a red blood-corpuscle. Each contains a huge irregular, bulging nucleus. Hence the cells are termed “megacaryocytes” (big-nucleus cells). They must not be confounded with the polycaryocytes (cells with several nuclei), which eat up degrading bone, although it must be confessed that megacaryocytes and polycaryocytes appear to be genetically connected. It is supposed that megacaryocytes consume the nuclei which red corpuscles extrude during the process of their conversion from nucleated cells. Traces of nuclei, or things which often look like nuclei, are found in their body-substance. Their own overgrown misformed nuclei appear to be the result of an excess of nuclear food. It is certainly remarkable that megacaryocytes are not found below mammals. They do not occur in any animal in which red blood-corpuscles retain their nuclei. Polycaryocytes are found in numbers in the bones of growing birds. They are evidently scooping out bone from situations in which it has to be displaced in order that the shape of the bone as a whole may be changed. But there are no megacaryocytes in birds. On the other hand, megacaryocytes are present in the liver, and later in the spleen, of mammals at the periods when blood-formation is occurring most actively in these organs. From the liver they disappear early. In most mammals they disappear from the spleen about the time of birth; but in some—the hedgehog, for example—they are found in the spleen throughout the whole of life.
Hæmoglobin is a substance which has the property of uniting with oxygen to form oxyhæmoglobin—a compound from which the oxygen is, again, very readily withdrawn. It is extremely soluble, but may be made to crystallize by adding alcohol to blood, after setting the hæmoglobin free from the corpuscles by freezing and thawing. From the blood of Man and most other animals it crystallizes in the form of rhombic prisms, whether in the oxidized (oxyhæmoglobin) or non-oxidized condition. The addition of oxygen does not affect its crystalline form; although crystalline, it is absolutely non-diffusible. This is due to the great size of its molecule, which is probably larger than that of any other substance which is capable of crystallizing.
The percentage composition of hæmoglobin conforms closely with that of albumin and other proteins, with this most important difference: it contains a definite proportion of iron—0·336 per cent. That the percentage of carbon, hydrogen, nitrogen, sulphur, and oxygen should agree with that commonly found in proteins is inevitable, since it may be split into a part which contains all the iron, hæmatin, and a proteid part resembling albumin; and the latter constitutes 96 per cent. of its weight.
There is no doubt but that its value as a vehicle of oxygen depends upon the presence of iron. In the matter of taking up and dropping oxygen, hæmatin behaves somewhat in the same manner as hæmoglobin; whereas if iron be removed from hæmatin the “iron-free hæmatin” loses its respiratory value. It is almost certain that a molecule of hæmoglobin contains a single atom of iron. On this supposition its molecular formula may be calculated. It is not quite the same for all animals, although the variations are slight. For the blood of the horse it is as follows:
C₇₁₂H₁₁₃₀N₂₁₄S₂FeO₂₄₅.
This means a molecular weight of 16708. We give the figures, because the properties of hæmoglobin will be better understood if its prodigious molecular weight is borne in mind. In a sense, the reason for the great size of its molecule is not far to seek. The atomic weight of iron (Fe = 56) is much greater than that of either of the other elements contained in hæmoglobin. The molecule needs to be very great to float an atom of iron. As it is, the corpuscles are heavier than the plasma which surrounds them, in the proportion of about 13 to 12. Although hæmoglobin is a crystallizable substance, its immense molecule is absolutely non-diffusible. It cannot pass through a membrane. This is of no consequence as regards the relation of hæmoglobin to the walls of the capillary bloodvessels, since it is contained in corpuscles; but it is of great importance as regards its relation to the discs which carry it. A very small quantity of enveloping substance suffices to prevent it from diffusing into the plasma of the blood. The great molecules are held together and isolated from the fluid in which they float by a minimal amount of insoluble globin.
The iron needed for the making of hæmoglobin is obtained both from meat and vegetables. The constituents of an ordinary diet provide from 2 to 3 centigrammes of iron a day. The whole of the blood contains about 4·5 grammes. When corpuscles are being destroyed in the spleen, the iron which their pigment contains is largely reabsorbed and rendered available for further use. The iron in a mixed diet is more than sufficient to counterbalance any loss. Milk contains extremely little iron. Before birth the liver and spleen accumulate a store of iron which lasts until the end of the nursing period, unless this be unduly prolonged. If it be prolonged, the child is apt to become anæmic. Iron has been administered in the treatment of anæmia ever since its presence in the red clot of blood was recognized a hundred and fifty years ago. Physicians are agreed that in the anæmia of young people it is of value; but observations made with a view to obtaining definite data as to the increase in number of blood-corpuscles which results from the administration of iron, without any other alteration in the diet or the habits of the patient, have not given accordant results. Some observers have obtained an increase with organic compounds of iron, others with inorganic compounds; some are in favour of small doses, others of very large ones. As in the treatment by drugs of other abnormal conditions, it is difficult to isolate the effect of the drug from the effects of improvements in the general regimen. Yet physicians agree that iron accentuates the beneficial effects of fresh air and improved diet.
When the surface of the body is struck, the effect of the blow is marked at first by redness. There is nothing to show that small bloodvessels have been ruptured and blood effused beneath the skin. Next day the injured area is reddish-purple. The bruise turns blue, green, yellow, and eventually disappears. In the process of absorption, oxyhæmoglobin undergoes decomposition. First its proteid constituent is removed, leaving a coloured pigment containing iron, termed “hæmatin”; soon reduced by loss of oxygen to hæmochromogen. When Sir George Stokes first described the spectrum of blood ([cf. p. 185]), he showed that as hæmoglobin may exist in an oxidized and in a non-oxidized condition, distinguished by their spectra, so also may the coloured residue which is left after the proteid constituent has been removed from hæmoglobin. This coloured residue he termed, when oxidized, “hæmatin”; when not oxidized, “reduced hæmatin.” Stokes’s reduced hæmatin is now termed “hæmochromogen.” Hæmochromogen stands for the coloured nucleus of hæmoglobin. Although it is not present in hæmoglobin as hæmochromogen—hence we must not speak of hæmoglobin as made of a protein, x, plus hæmochromogen, y—it is to its coloured residue that hæmoglobin owes its value as a carrier of oxygen. Later, iron is removed from hæmochromogen, leaving hæmatoidin, a substance often found at the seat of old hæmorrhages, where it may remain unchanged for a very long time. Hæmatoidin is apparently identical with the yellow pigment of bile, bilirubin. The green colour which shows itself in the bruise seems to indicate that the more oxidized bile-pigment, biliverdin, is formed in the first instance. Red corpuscles, when destroyed in the spleen, pass through transformations similar to those which blood undergoes when effused beneath the skin. Their protein is used by the phagocytes which eat them. Their iron is reserved for the use of the blood-forming cells of the red marrow of bone. The pigment which remains as the residue of hæmoglobin is carried by the splenic vein to the liver, which secretes it as bile-pigment. So much of the bile-pigment as is reabsorbed by the wall of the alimentary canal is eventually excreted as the pigment of urine.