The Organism as a Whole, from a Physicochemical Viewpoint

by Jacques Loeb

CHAPTER IX

MENDELIAN HEREDITY AND ITS MECHANISM[200]

I

1. The scientific era of the investiga­tion of heredity begins with Mendel’s paper on plant hybridiza­tion which was not appreciated by his contemporaries. Mendel invented a method for the quantitative study of heredity which consisted essentially in crossing two forms of peas differing only in one well-defined hereditary character; and in following statistically and separately the results of this crossing and that of the inbreeding of the second and third genera­tions of hybrids. This led him to the recogni­tion of one essential feature of heredity; namely, that while the hybrids of the first genera­tion are all alike, each hybrid produces two types of sex cells in equal numbers, one for each of the pure breeds which has been used for the crossing. This takes place not only when the forms used for the crossing differ in regard to one character only but also if they differ for two or more characters. The statement made is Mendel’s law of heredity, or, more correctly, Mendel’s law of the segrega­tion of the hereditary characters of the parents in the sex cells of the hybrids.[201] Mendel’s law allows us to tabulate and calculate beforehand the relative number of different forms which appear if the offspring of a mating of two varieties are bred among themselves.

In order to do this it must be remembered also that while in some cases the hybrid is an intermediate between the two parent forms, in other cases it cannot be discriminated from one of the two parent forms. In such cases the character which appears in the hybrid was called by Mendel the dominant character and the one which disappeared the recessive character. According to Bateson, who was the first to systematize the phenomena of Mendelian heredity, recessiveness means generally the absence of a character which is present in the dominant type. When, e. g., the cross between a tall and a dwarf form of pea gives in the first genera­tion only tall peas, on the basis of the presence and absence theory the dominant form contains a factor for growth which is lacking in the dwarf form. While this theory fits many cases it meets with difficulties in others. Thus the presence of a factor for pigment should be dominant over the absence of such a factor, which is usually the case, inasmuch as the cross of a coloured rat or rabbit with an albino is black or coloured. There is, however, also a case where whiteness is dominant over colour, as we shall see later. This fact does not necessarily contradict the presence and absence theory.[202]

When two pure breeds of parents differ in one character, e. g., two varieties of beans, one with a violet the other with a white flower, the cross between the two species (the F₁ genera­tion) has pale violet flowers, approximately intermediate between the two parents. If these hybrids are bred among themselves the offspring is called the F₂ genera­tion. According to Mendel’s law the hybrids of the first F₁ genera­tion all have two kinds of eggs in equal numbers, one kind representing the pure breed of the parents with violet, the other of the pure breed with white flowers. The same is true for the pollen cells. Hence the following possible combina­tions must appear in the offspring when the pale violet hybrids are inbred:

The four possible combina­tions are: (1) violet—violet; (2) violet—white; (3) violet—white; (4) white—white. The first will result in pure violet flowers, the fourth in pure white, and the second and third in pale violet flowers. Since all four combina­tions will appear in equal numbers when the number of crossings is sufficiently large the numerical result will be:

violet : pale violet : white = 1 : 2 : 1

Fifty per cent. of the F₂ genera­tion will be pale violet, 25 per cent. violet, and 25 per cent. white. The violets and whites each will breed true when bred among themselves since they are pure, and produce only one type of eggs and pollen. The pale violets are hybrids and will again produce the two types of eggs and pollen, that is, if bred among themselves will again give violets, pale violets, and whites in the ratio 1:2:1. This the experi­ment confirms.

As has been stated, it not infrequently happens that all the hybrids of the first genera­tion are alike. In such cases the one character is “recessive,” i. e., overshadowed or covered by the other the “dominant” character, which alone appears in the hybrids. Thus when Mendel crossed peas having round seeds with peas having angular seeds all the hybrids had round seeds. The round form is dominant, the angular recessive, i. e., all the hybrids have round seeds. When these hybrids were bred among themselves the next genera­tion produced round and angular seeds in the ratio of 3:1 (5474 round to 1850 angular). The explana­tion is as follows. Let R denote round, A angular character; the pure breeds of parents have the gametic constitu­tion RR and AA respectively. When crossed, all the offsprings have the constitu­tion RA and since A is recessive this hybrid genera­tion resembles the pure RR parents. The F₁ genera­tion produces two kinds of eggs R and A and two kinds of pollen R and A in equal numbers, and these if inbred give the following four combina­tions in equal numbers:

RR, RA, AR, AA.

Since RA, AR, and RR all give round seeds the F₂ genera­tion produces round seeds to angular seeds in the ratio of 3:1. The two organisms with the gametic constitu­tion RR and RA look alike, yet they are different in regard to heredity. The gametically pure form RR is called homo­zygous, the impure form RA hetero­zygous.

2. W. S. Sutton[203] was the first to show that the behaviour of the chromo­somes furnishes an adequate basis on which to account for Mendel’s law of the segrega­tion of the characters in the sex cells of the hybrids. If we disregard the cases of parthenogenesis and the X chromo­somes, we may state that each species is characterized by a definite number of chromo­somes, e. g.[204]

man (probably)	24	corn	20
mouse	20	evening primrose	7
snail (Helix hortensis)	22	nightshade	36
potato beetle	18	tobacco	24
cotton	28	tomato	12
four o’clock	16	wheat	8
garden pea	7

In the fertiliza­tion of the egg the number of chromo­somes is doubled (if we disregard for the moment the complica­tion caused by the X and Y chromo­somes which was considered in the previous chapter). It was noticed by Montgomery that each chromo­some had a definite size and individuality, and he suggested that homologous chromo­somes existed in sperm and egg and that in fertiliza­tion the homologous chromo­somes of egg and sperm always joined and fused in the special stage designated as synapsis, which will interest us later. On the basis of this sugges­tion Sutton developed the chromo­some theory of the mechanism of Mendelian heredity or segrega­tion.

According to this theory, all the cells of an individual (inclusive of the egg cells and sperm cells) have two sets of homologous chromo­somes, one from the father, the other from the mother. Before the egg and sperm are ready for the produc­tion of a new individual, each loses one set of homologous chromo­somes in the so-called reduc­tion division, but the lost set is made up indiscriminately of maternal as well as paternal chromo­somes, so that while one egg retains the maternal chromo­some A the other will retain the paternal one, and so on. If before the reduc­tion division all the eggs had the chromo­some constitu­tion AA₁, BB₁, CC₁, DD₁ (where A B C D are the paternal and A₁ B₁ C₁ D₁ the maternal chromo­somes), after the reduc­tion division each daughter cell has a full set of four chromo­somes, but maternal and paternal mixed. Thus the one cell may have AB₁CD₁, the other A₁B₁C₁D₁, etc. This, according to Sutton, is the basis of the Mendelian heredity. Suppose the determiner of a certain character (violet colour of flower in the bean) is located in a chromo­some A of this species. The homologous chromo­some in beans with white colour may be designated as a. According to the chromo­some theory of Mendelian heredity a differs from A in one point, though this difference is probably only of a chemical character and not visible.

If an egg with A is fertilized by a pollen with a (or vice versa), after fertiliza­tion the chromo­some constitu­tion of the fertilized egg is Aa. All the other homologous chromo­somes are identical and therefore need not be considered. All the nuclei of the F₁ genera­tion have the chromo­some constitu­tion Aa. All will form eggs and pollen with nuclei of the same chromo­some constitu­tion Aa, but all these sex cells will go through the matura­tion division before they are fertilized; and this reduc­tion division leads to the existence of two kinds of eggs in equal numbers, one containing only the A, the other only the a chromo­some; and the same happens in the pollen. When therefore the hybrids F₁ are mated among themselves, the following four chromo­some combina­tions will be produced:

Possible combina­tions in fertilized eggs AA, Aa, aa, in the ratio 1:2:1.

Now this is exactly the ratio of Mendelian heredity in the F₂ genera­tion. The plant with the chromo­some constitu­tion AA will form violet flowers, those with the chromo­some constitu­tion Aa will form pale violet flowers, and those with the chromo­some constitu­tion aa will form white flowers.

To quote Sutton’s words:

The result would be expressed by the formula AA: Aa: aa which is the same as that given for any character in a Mendelian case. Thus the phenomena of germ cell division and of heredity are seen to have the same essential features viz., purity of units (chromo­somes, characters) and the independent transmission of the same; while as a corollary it follows in each case that each of the two antagonistic units (chromo­somes, characters) is contained by exactly half the gametes produced.

It is obvious that Sutton by this idea did for heredity in general what McClung had done for sex determina­tion or sex heredity, that is, he showed that the numerical results obtained in Mendelian heredity can be accounted for on the basis that factors for hereditary characters are carried by definite chromo­somes. The cytological basis of sex determina­tion becomes only a special case of the cytological basis of Mendelian heredity. In the examples quoted the plants giving rise to violet and to white flowers are homo­zygous for the colour of flower having the chromo­some constitu­tion AA and aa respectively; while the plants with pale violet flowers are hetero­zygous, having the chromo­some constitu­tion Aa in their nuclei. The former give rise to identical sex cells A and A or a and a; while the hetero­zygous plants give rise to different sex cells A and a.

From this point of view in Drosophila (and very probably also in man) the female is homo­zygous for sex having in all its cells the critical chromo­some constitu­tion XX and giving rise to one type of eggs only, each with one X chromo­some; while the male in these forms is hetero­zygous for sex having in all its cells the chromo­some constitu­tion XY and forming two different types of spermatozoa in equal numbers X and Y. In Abraxas and in the fowl the female is hetero­zygous for sex and the male homo­zygous.

3. If the chromo­somes are the vehicle for Mendelian heredity it should be possible to show that the various hereditary characters which follow Mendel’s law must be distributed over the various chromo­somes; and it should be possible to find out which characters are contained in the same chromo­some. It has already been stated that sex-linked heredity is intelligible on the assump­tion that the X chromo­some carries the sex-linked characters. T. H. Morgan and his pupils have shown with the greatest degree of probability that corresponding linkages occur in the other chromo­somes and that there are in Drosophila exactly as many groups of linkage as there are different chromo­somes, namely four.[205]

Mendel had found that when he crossed two species of peas differing in regard to two pairs of characters, he obtained in the F₂ genera­tion results which he calculated on the assump­tion that the segrega­tion of the two pairs of characters in the sex cells of the hybrids took place independently of each other. To illustrate by an example: When crossing a yellow round pea with a green wrinkled variety in which the characters round and yellow are dominant, green and wrinkled recessive, all the hybrids of the F₁ genera­tion had the characters round and yellow. When these were inbred the F₂ genera­tion produced four types of seed in the ratio 9: 3: 3: 1, namely:

(1) yellow round (315 seeds)
(2) yellow wrinkled (101 seeds)
(3) green round (108 seeds)
(4) green wrinkled (32 seeds)

The explana­tion according to Mendel’s theory is as follows: Since the segrega­tion of each pair of characters occurs independently, there must be 3 yellow to 1 green and also 3 round to 1 wrinkled in the F₂ genera­tion. The yellow will, therefore, be round and wrinkled in the ratio of 3:1, which will give 9 yellow round to 3 yellow wrinkled. The green will also be round and wrinkled in the ratio of 3:1, which will give 3 green round to 1 green wrinkled, which is the ratio of 9: 3: 3: 1 found by Mendel.

On the basis of the chromo­some theory the following explana­tion could be given of this numerical rela­tion. The peas with yellow round seeds have sex cells with a factor for both yellow and for round in two different chromo­somes; these two different chromo­somes we will designate with Y and R. The peas with green and wrinkled seeds will have in their sex cells factors for these characters in two homologous chromo­somes g and w, where g is the homologue of Y and w of R. The cells of the hybrids of the F₁ genera­tion will have the chromo­some constitu­tion Yg Rw, where Y and g and R and w are homologous chromo­somes which will lie alongside each other YRgw. In the forma­tion of sex cells a reduc­tion of these four chromo­somes to two takes place whereby, according to the theory of Sutton, the following two types of separa­tion can take place: YR and gw, or gR and Yw. (A separa­tion into Yg and Rw is impossible since the division takes place only between homologous chromo­somes.) Hence there will be four types of eggs, YR, gw, gR, and Yw and the same four types of pollen cells. The F₂ genera­tion will produce the sixteen possible combina­tions in equal numbers: namely,

YRYR YRgw YRgR YRYw
gwYR gwgw gwgR gwYw
gRYR gRgw gRgR gRYw
YwYR Ywgw YwgR YwYw

Since w and g are recessives and therefore disappear when in combina­tion with their respective dominants Y and R the result will be 9 YR (yellow round), 3 Yw (yellow wrinkled), 3 Rg (round green), and 1 gw (green wrinkled) as Mendel actually observed and as all investigators since have confirmed.

Bateson made the discovery that these Mendelian ratios 9: 3: 3: 1 did not always occur when forms differing in two characters were crossed. He found typical and very constant devia­tions from this ratio in definite cases and these cases he interpreted as being due to “gametic coupling.”

These phenomena demonstrate the existence of a complex interrela­tion between the factorial units. This interrela­tion is such that certain combina­tions between factors may be more frequent than others. The circumstances in which this interrela­tion is developed and takes effect we cannot as yet distinguish, still less can we offer with confidence any positive concep­tion as to the mode in which it is exerted.[206]

Morgan has given an ingenious explana­tion of these devia­tions on the basis of the chromo­some theory of Mendelian heredity. He assumes that they occur in those cases where the two or more characters are contained in the same chromo­some. In that case the two factors lying in the same chromo­some should generally be found together. Such was the case for instance in the experi­ments with flies having red eyes and yellow body colour versus white eyes and grey body colour, the character for white eyes and yellow body being located in the X chromo­some (see preceding chapter), or in the experi­ments on Abraxas. These phenomena are called linkage, and the numerical results of linkage were given in the preceding chapter in connec­tion with the crossing of sex-linked characters.

We have already mentioned that before the matura­tion division occurs the homologous maternal and paternal chromo­somes fuse—the so-called synapsis of the cytologists—and afterward separate again. It had been observed by Janssens that in this stage of fusion and subsequent separa­tion a partial twisting and a partial exchange between two chromo­somes may take place. Morgan assumes that this exchange accounts for certain devia­tions in the ratio of linkage. If in Fig. 40 the white and black signify two homologous chromo­somes I and I₁ containing the two pairs of homologous factors AB and ab respectively, the synapsis state would be as in Fig. 41. If the separa­tion were complete, either I or its homologue I₁ might be lost in the matura­tion division of the egg. If, however, the synapsis is slightly irregular, as in Fig. 42, where the chromo­somes are slightly twisted, I and I₁ will not separate completely but an exchange will take place, part of I₁ and I becoming exchanged. This would result in the forma­tion of two mixed chromo­somes Ab and aB (Fig. 42). This partial exchange of homologous chromo­somes, which Morgan calls “crossing over,” occurs, as he found in Drosophila, in the egg only, not in the matura­tion division of the sperm. He informs me that in the silkworm moth Tanaka found that it occurs only in the male, while in Primula it takes place both in the ovules and in the pollen as shown by Gregory.

Fig. 40

Fig. 41

Fig. 42

Morgan and his fellow-workers have put this theory to numerous tests by breeding experi­ments and the results have fully supported it. According to the chromo­some theory linkage should occur only when factors lie in the same chromo­some. Hence it should be possible, on the basis of this linkage theory, to foretell how many linkage groups there may occur in a species; namely, as many as there are chromo­somes. In Drosophila there are four pairs of chromo­somes, and Morgan and his fellow-workers found only four groups of linked characters.[207] This agreement can be no mere accident.

Carrying the assump­tion still farther, these authors were able to show that each individual character has in all probability a definite loca­tion in the chromo­some, so that it seems as if each individual chromo­some consisted of a series of smaller chromo­somes, each of which may be a factor in the determina­tion of a hereditary character which is transmitted according to Mendel’s law of segrega­tion. Biology has thus reached in the chromo­some theory of Mendelian heredity an atomistic concep­tion, according to which independent material determiners for hereditary characters exist in a linear arrangement in the chromo­somes.

II

4. We are not concerned in this volume with the many applica­tions of the theory of heredity to the breeding of plants, animals, and man; the reader will find a discussion of these topics in the numerous writings of the special workers on genetics.[208] We are, however, interested in the bearing this work has on the concep­tion of the organism. Two ques­tions present themselves: Is the organism nothing but a mosaic of hereditary characters determined essentially by definite elements located in the chromo­somes; and if this be true, what makes a harmonious whole organism out of this kaleidoscopic assortment? We call it a kaleidoscopic assortment since a glance at the list of hereditary characters found in one chromo­some, according to Morgan, shows that there is apparently no physio­logical or chemical connec­tion between them, and second: How can a factor contained in the chromo­some determine a hereditary character of the organism? To the first ques­tion we venture to offer the answer which has been already suggested in various chapters of this book, that the cytoplasm of the egg is the future embryo in the rough; and that the factors of heredity in the sperm only act by impressing the details upon the rough block. This metaphor will receive a more definite meaning by the answer to the second ques­tion. The characters which follow Mendelian heredity are morpho­logical features as well as instincts. For the former we have already had occasion to show in previous chapters to what extent they depend upon the internal secre­tions or the existence of specific compounds in the circula­tion, and the same is true for the instincts (Chapters VIII and X). This then leads us to the sugges­tion that these determiners contained in the chromo­somes give rise each to the forma­tion of one or more specific substances which influence various parts of the body. We probably do not notice all the effects in each case, but when a special organ is affected in a conspicuous way, we connect the factor with this organ or the special feature of the organ which is altered, and speak of a determiner or factor for that organ, or for one of its characters. We also understand in this way why outside condi­tions should be able to overcome the hereditary tendency in certain cases, for instance why the influence of certain hereditary factors for pigmenta­tion should depend upon temperature as E. Baur observed.

The view, according to which the determiners in the chromo­somes only tend to give special characters to the embryo or to the adult while the cytoplasm of the egg may be considered the real embryo, receives some support from the fact that the first development of the egg is purely maternal, even if the egg nucleus has been replaced by sperm of a different species. If an egg of a sea urchin be cut into two pieces, one with and one without a nucleus, and the enucleated piece be fertilized with the sperm of a different species of sea urchin, the blastula and gastrula stages are purely maternal and only the skeleton of the pluteus stage begins to betray the influence of the foreign sperm inasmuch as this skeleton is purely paternal, according to Boveri. In all experi­ments on hybridiza­tion it has been found that the rate of cell division of the egg is a purely maternal character. Thus when fish eggs of a species, in which the rate of first segmenta­tion of the egg is about eight hours, are fertilized with sperm of a species for which the same process requires about thirty minutes or less at the same temperature, the rate of segmenta­tion is again about eight hours. There is then no chromo­some influence noticeable in the early development.

When two forms of sea urchins, Strongylo­centrotus franciscanus and purpuratus,[209] are crossed, certain features of the skeleton of the embryo, e. g., the so-called cross-bars, are a dominant, inasmuch as they are found in purpuratus and both the crosses, while they are absent in franciscanus. The development prior to the forma­tion of the skeleton is purely maternal. These observa­tions again lend support to the idea that the Mendelian factors of heredity must have the embryo to work on and that the organism is not to be considered a mere mosaic of Mendelian factors. This is further supported by the idea that the species specificity resides in the proteins of the unfertilized egg (see Chapter III), and it is quite likely that this species specificity decides which type of animal should arise from an egg.

The idea had been suggested that the factors which determine the future character might be ferments or enzymes, or substances from which such ferments develop. A. R. Moore[210] pointed out that the cross-bars in the skeleton of the hybrid between S. purpuratus and franciscanus develop more slowly than in the pure breed and that this should be expected if the determiners were enzymes. Since the pure purpuratus has two determiners for the development of the cross-bars (from both egg and sperm), the hybrids only one (from either egg or sperm), the pure purpuratus should have twice the enzyme mass of the hybrid. It is known that the velocity of a chemical reac­tion increases in propor­tion with the mass (or in some cases in propor­tion with the square root of the mass) of the enzyme; the cross-bars should therefore develop faster in the pure than in the hybrid breeds, as was observed by Moore. It was, however, not possible to obtain quantitative data.

On the other hand, it is obvious that this reasoning would not hold for all cases. Thus when beans with violet flowers are crossed with white-flowered beans the hybrids are pale blue, which indicates that the hybrids have less pigment than the pure violet. Now we know that the mass of enzyme does not influence the chemical equilibrium but only the velocity of the reac­tion. The hybrids and pure violets differ, however, in the mass of violet pigment formed, that is to say, in regard to the equilibrium. Hence the idea that the determiners are enzymes or give rise to enzymes is probably not applicable to cases of this type.

The experi­ments on the heredity of pigments are at present almost the only ones which can be used for an analysis of the chemical nature of the character and its possible determiner. The important work of G. Bertrand[211] and of Chodat[212] on the produc­tion of black pigment in the cells of animals and plants with the aid of enzymes has paved the way for such work. Bertrand has shown that tyrosine (p-oxy­phenyl­amino­propionic acid) is trans­formed into a black pigment by an enzyme tyrosinase which occurs in numerous organisms and is obviously the cause of pigment and coloura­tion in a great number of species. This discovery was utilized in the study of the heredity of pigments by Miss Durham, Gortner,[213] and very recently by Onslow.[214] The latter showed that from the skins of certain coloured rabbits and mice a peroxidase can be extracted which behaves like a tyrosinase toward tyrosine in the presence of hydrogen peroxide. This peroxidase was found in the skins of black agouti, chocolate and blue rabbits, but not in yellow or orange rabbits. The recessive whiteness in rabbits and mice according to this author is due to the lack of the peroxydase. There exists a dominant whiteness in the English rabbit which is due to a tyrosinase inhibitor which destroys the activity of the tyrosinase “and the dominant white bellies of yellow and agouti rabbits are due to the same cause.” “Varia­tions in coat colour are probably due to a quantitative rather than to a qualitative difference in the pigment present.”

One point might still be mentioned since it may help to overcome a difficulty in visualizing the connec­tion between the localiza­tion of a factor in the chromo­some and the produc­tion of a comparatively large quantity of a specific chemical compound, e. g., a chromogen or a tyrosinase. We must remember that all the cells of an organism have identical chromo­somes, so that a factor for an enzyme like tyrosinase is contained in every cell throughout the whole body. It is likely, however, that the same factor (which we may conceive to be a definite chemical compound) will find a different chemical substrate to work on in the cells of different organs of the body, since the different organs differ in their chemical composi­tion. Thus it is conceivable that in the produc­tion of tyrosinase or of tyrosine not a single chromomere of one single cell is engaged, but the sum total of all these individual chromomeres of all the cells in one or several organs of the body. The writer has added this remark especially in considera­tion of the fact that some authors seem to feel that the chromo­some concep­tion of heredity is incompatible with a physico­chemical view of this process.

Since we have mentioned this difficulty which some writers seem to find in the chromo­some theory of Mendelian heredity, it may be added that a single factor may suffice to determine a series of complicated reflexes. Thus the helio­tropic reac­tions of animals are due to the presence of photo­sensitive substances, and it suffices for the hereditary transmission of the complicated purposeful reac­tions based on these tropisms that a factor for the forma­tion of the photo­sensitive substance should exist.[215]

5. Another point should be emphasized, namely that for Mendelian heredity it is immaterial whether the character is introduced by the spermato­zoön or by the egg. This fact which Mendel himself already recognized is in full harmony with the conclusion that the chromo­somes and not the cytoplasm are the bearers of Mendelian heredity, since only in respect to the chromo­some constitu­tion are egg and sperm alike, while they differ enormously in regard to the mass of protoplasm they carry. We can, therefore, be tolerably sure that wherever we deal with a hereditary factor which is determined by the egg alone the cytoplasm of the latter is partly or exclusively responsible for the result.

We have already mentioned the fact that the rate of segmenta­tion of the egg is such a character. Yet this character is as definite as any Mendelian character, and it would be as easy to discriminate two species of eggs by the time required from insemina­tion to the beginning of cell division as it would be by any Mendelian character of their parents.

The applica­tion of our modern knowledge of heredity to human affairs has been discussed in a very original way by Bateson in his address before the British Associa­tion in Sydney to which the reader may be referred.[216]

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