by Guy Murchie
Then in 1858 Mendel started his classic experiments with hundreds of plants in a section of his monastery garden, carefully labeling each with fertilization data as he played the part of a bee or butterfly in artificially breeding it to others by transferring pollen on a brush from male anthers to female stigmas in a planned and systematic pattern. With single-minded patience in minding his peas and cues and a combination of intuition and luck in his choices of plants and traits, he soon found extraordinary evidence that traits do not mix like stirred paint but rather like shuffled playing cards, always retaining discrete "factors" hidden somewhere inside every organism, including the organisms of animals, such as a few light and dark mice that he experimentally bred in addition to his plants.
In the case of the flower Mirabilis jalapa, commonly known as four-o'clock, to take a simple example, two of its many varieties come out in all-red and all-white petals. When pollen from either variety is used to fertilize the other, the resulting seeds grow into pink flowers with nothing visibly red or white about them, yet when these pink second-generation flowers are fertilized in turn, either with each other's pollen or their own, the third generation produces not only more pink flowers but also red and white varieties, just like their grandparents, in the proportion of 25 percent red, 50 percent pink and 25 percent white. It thus became clear that whatever factors initially made the flowers red and white were not all used up by being mixed into pink, for the pink flowers always kept their power to revert back to red and white in another generation. And not only that but, as the mathematically minded Mendel could readily see, they did so according to orderly rules, most obviously the well-known mathematical law of probability under which, if you flip two coins, each red on one face and white on the other, they will fall so as to show only their red faces 25 percent of the time, both a red and a white face 50 percent of the time and only their white faces the other 25 percent of the time.
This simple case involving red and white `factors" (which we now call "genes") was a lucky discovery, giving Mendel his main clue. But inheritance usually is more complicated than this and far less obvious because genes seldom are so evenly balanced and so clearly definable. In fact many genes go in pairs (each member of which is known as an allele) like the genes for roughness or smoothness in a guinea pig's fur, one allele or the other being apparent but not both, and one of them often being dominant over the other, so that when both are inherited only the dominant allele shows, like the black eyes of children begotten in the marriage of a blue-eyed Swede to a black-eyed Turk. When Mendel had hypothesized dominant and recessive alleles he was elated to discover he held the key to prediction of the way many traits will be inherited, including the occasional procreation of a blue-eyed child by black-eyed parents when both these parents have inherited hidden recessive blue-eyed alleles.
Genetics is a science that, ever since Mendel struck the light, has been rapidly developing into what is probably the most complex if not the most baffling of biology's many branches. Certainly it is beset with the mathematics of hard-to-visualize, submicroscopic factors and their seemingly infinite interrelationships. I cannot avoid mentioning a few main points, however, such as that Mendel, in working out his laws of inheritance, realized that every sexual coming together of two germ cells (pollen and ovule, sperm and ovum ...) must double (in the new combined cell) the number of genes that were in each old separate cell, and that this doubled number inevitably has to be halved again somewhere - presumably wherever germ cells are created by dividing the body's ordinary cells - in order to prevent each generation from inheriting twice as many genes as their parents did, which would make the gene number increase more than a thousandfold every ten generations, a manifest absurdity. Mendel did not work with a microscope and therefore could not see or count the chromosomes (as strings of genes are called) in cell nuclei, but he made a reasonable assumption of what happens both in mitosis, the normal reproduction of body cells by division into two complete new cells (page 106), and in meiosis, the more special production of germ cells from body cells, in which, as I have just suggested, the division separates the original chromosomes with their genes into two groups (not exactly alike but normally paired into alleles), each containing only half as many genes as the body cell they came from. While Mendel knew no way to check whether this genetic halving really happened, his logical surmise turned out to be remarkably accurate and eventually made him the acknowledged father of genetics - even though none of the few German-speaking scientists who glanced through his revolutionary article published in 1866 then had the independence of mind or imagination to realize its importance.
Furthermore, the two kinds of male germ cells (sperms) made by splitting their parental cell's chromosomes into the two groups (one containing so-called X and Y chromosomes, the other double X chromosomes) proved to be capable of fathering respectively only male or only female progeny, showing why the birth rates of boys and girls are so evenly balanced, each embryo's gender being determined entirely by which kind of these equally numerous sperms (XY = (m) XX = (f)) succeeds in penetrating the ovum first. From a mathematical or probability viewpoint meiosis thus shows itself comparable to halving a pack of cards (genes) at random, both half packs then forming germ cells (sperms if inside a male body and of two kinds; ova if inside a female, but of only one kind) - while sexual fertilization is like bringing two such complementary half packs (necessarily from different original packs) back together more or less by chance to form a new whole pack (an embryo) whose cards (genes) thus originated half from a random half of its father's cards and half from a random half of its mother's cards (genes). This constantly repeated shuffle indeed is nature's main way of varying the offspring of every generation of life to ensure that all their potential traits will ultimately be given their chance for a trial in the evolving world.
If Darwin could have seen Mendel's meticulous account of his genetic discoveries when it appeared in the Proceedings of the Natural History Society of Brunn, both men would surely have been stimulated by the contact, and the science of genetics would have hatched a third of a century earlier. As fate decreed it, however, Darwin's puzzlement about the mechanism of inheritance was matched by Mendel's frustration that other scientists thought he was only an eccentric bookkeeper indulging his whims with a new garden hobby - so Mendel' s work slept unrecognized until 1900, when, in one of those mystic historical coincidences that certainly spring from more than chance, three men (De Vries in Holland, Correns in Germany and Tschermak-Seysenegg in Austria) simultaneously but independently rediscovered Mendel's reports, repeated his experiments and confirmed his conclusions. By then Mendel had been dead for sixteen years.
With the Mendelian laws of inheritance now suddenly established, genetics blossomed spontaneously and attracted increasing numbers of imaginative pioneers, including Spemann. One of the earliest was Thomas Hunt Morgan, who discovered in experiments with fruit flies that genes can cross from one chromosome to another and that this appropriately happens when the chromosomes go into a kind of love dance just before meiosis, pairing and entwining each other in a kind of fond farewell as they separate to begin their new life as sperms or ova. Another pioneer, Archibald Garrod, correctly conceived that genes operate through enzymes, an idea almost as far ahead of its time in 1908 as Mendel's "factors" had been in 1866. And by 1913 accelerating research indicated that the chromosomes, familiar under the best optical microscopes as wormlike specks in cell nuclei, almost surely store their genes in one-dimensional order. No one yet had the faintest idea what genes looked like or how they worked, but a zoological count of chromosomes had been started which eventually revealed a curious hierarchy: the cells of a round worm, for instance, having 4 chromosomes, of a fruit fly 8, corn 20, a mouse 40, man 46, certain butterflies 62 and, curiously, the one-celled paramecium about 200.
But research has been accelerating ever since then, and by now not only have functioning genes been synthesized in the laboratory but literally hundreds of diffe
rent kinds have been identified by their exact function and labeled with a number. A single gene theoretically can control the creation and assembly of a 60-subunit icosahedron which, perhaps for that reason, is the most usual shape of small viruses, whose subunits seem as uniform as building tiles and so tenoned and mortised that they can only fit stably into one simple symmetry. The only one-gene "organism" so far discovered in nature seems to be a potato virus. Larger structures naturally need more genes, usually including a few for "nuts" and "bolts," or "buttons" and "zippers," not to mention those of temporary function like "hammers," "wrenches," "funnels" and "scaffolding." More than 100 genes have been mapped for the complex T4 virus, for example, of which gene no. 23 makes the major subunit or building "brick," gene no. 20 closes off the icosahedral shape, gene no. 27 is a key to the tail, no. 18 assembles the tail's sheath, no. 15 "sews" a kind of "button" to the core, no. 31 adds solubility, no. 66 is an elongation factor, etc. Although a few rare genes have been found that will function effectively at any stage in the development of an organism, like salt in cooking a stew, genes generally work only sequentially and must apply themselves in an exact order if they are to succeed. Thus they create protoplasm not in the simple way knitting needles knit socks (by starting at one end and adding similar stitches until they reach the other) but rather through an assembly-line process of assigning jobs to specialists, most of whom build essential parts for others to put together into complete, working wholes.
THE SECRET: DNA
After World War II, when the electron microscope suddenly made it possible to magnify a pinhead to the size of the Pentagon building and new x-ray equipment started "seeing" chromosomes as fibrous, twisted cords, the gene molecule at last came into focus, resolving itself into a beautiful and intricate spiral, now deservedly famous, if not exactly familiar, as DNA (page 105). In fact it proved (on close analysis) to be a double helix ladder, something like a spiral staircase with curving but parallel sides cross-linked every millimicron of the way by steplike rungs embedded at both ends. And the detailed order of these chemical rungs comprises the information actually dispensed by the cell's nuclear management as new cells are conceived and fabricated into all the specialized body materials of bone, blood, gut, nerve, hair, skin and sinew.
It is not easy to determine exactly where an individual gene begins and ends in the spiral stair - even the definition of a gene is in dispute - but it is generally understood that a gene is a continuous and complete sequence of DNA that, when active, progressively replicates either more DNA or a slightly different molecule called RNA (ribonucleic acid) out its side chains, as you can see in the illustration. DNA can contain anything from a few rungs to many thousand of them, depending on the complexity of the function involved. And a very simple chromosome, say in a bacterium, is a stair made up of several small genes strung in line like beads on a necklace. But a larger chromosome in a more complex creature like a paramecium would likely consist of several such strings wound around each other something in the way a large steel cable is twisted from smaller cables, and the larger and more complicated the organism, the larger the number of strands of DNA that are wound into its chromosomes.
The universality of this extraordinary material is quite beyond comprehension, but a slight idea of its scope may be gleaned if you can realize that on Earth alone DNA is widely presumed to have existed since "life" began some three billion years ago, and it now directs in detail all cellular growth in every kind of organism, from viruses to mold to houseflies to trees to whales. In your own body, for example, DNA is distributed into your fifty-trillion-odd cells and, as suggested earlier, it remains uniquely your own and identical in atomic arrangement from head to toe, whether in bone, nerve, muscle or other tissue. The only cells that don't have it are red blood cells which, without nuclei, are impersonally exchangeable between all members of your blood group. If all the tightly wound DNA in even a single cell nucleus of your body were uncoiled and the pieces laid end to end, it has been estimated the invisible genetic thread would extend five feet, which would make the DNA in all your 50 trillion cells stretch out 50 billion miles or enough to reach to the moon and back 100,000 times.
In Chapter 3 I likened DNA to magnetic tape of a mystic origin, which seems an apt analogy for this extraordinary "one-imensional" molecule that holds all the essential data of a lifetime. Yet, amazingly, DNA is made of nothing but common elements put together as twin backbones of repeating groups of sugar and phosphate with crossrungs of nitrogen compounds whose numerous variations spell out the ineffable code of life. You might think that the four standard chemical rungs of adenine, thymine, cytosine and uanine (usually abbreviated A, T, C and G) would be much too simple to convey all the sophisticated information and intricate instructions needed to assemble an entire organism, but a leading geneticist has calculated that if we were to translate the coded messages of a single human cell into English, they would fill a thousand-volume library. So the four rungs somehow seem to manage to express themselves. And increasingly overwhelming evidence shows that they do it in stages, even as do the simpler dots and dashes of Morse code compose letters that make words that write books that fill libraries. It is significant, moreover, that all phonetic alphabets contain about twenty letters, which, not by chance, is the number of different amino acids that surge through protoplasm and its genes. And the very A, T, C and G rungs in those genes, operating like linotype machines, are what pick up the amino molecules, one by one, to mold from each the equivalent of letter type, whose sequences spell out words in the 20-letter amino alphabet. Indeed this is the source of the long polypeptide chains that stream from DNA like ticker tape, the hundreds of amino words in a typical one composing a complete genetic paragraph that exactly delineates a particular protein molecule so it can be assembled and sent forth to live a few weeks or months as part of an arm, a liver or an eye.
When the genes are asleep or dormant (which they are perhaps 90 percent of the time) it is noted that the chromosomes embedding them in their cables of DNA remain slim and inconspicuous, but when they are awake and "turned on" - that is, actively replicating themselves into more protoplasm in the cell's protein factories (called ribosomes) - the chromosomes puff out in noticeable swellings at all their busy points. For decades geneticists could not figure out what was going on inside these chromosome puffs but, now that DNA's genetic code has been cracked, they realize that the DNA chains in these spots (either genes or small groups of genes) somehow have "got the word" that they are to produce and they respond by suddenly stiffening and straightening out their coils, literally untwisting themselves so the twin strands of the DNA double helix can come apart. This stretching and undoing inevitably takes extra room and is what creates the puff (as the illustration shows), the full beauty of which we have scarcely begun to appreciate.
What we have learned, however, is that this is the first stage of cell growth, of reproduction of a new cell that is usually a replica of the old one, but also often modified, more specialized or, in the particular cases of meiosis and mutation, fundamentally different. What happens is that, as the two strands of the DNA separate, each is bereft of part of itself, leaving it feeling incomplete, like a bride-to-be at the church door. But it has been unzipped down the middle of each rung, so to speak, precisely between the two letters that form the rung (these being always either AT or CG, or their reverse orders of TA or GC, a total of four alternatives) so that each A is now yearning for another T and each C for another G and vice versa. Moreover, since the medium surrounding the DNA in the cell's nucleus is full of millions of identical nitrogen compounds (A, T, C and G) and many other chemical fragments, all milling freely about in the unbelievably rapid hurly-burly of molecular turbulence, each lovelorn "letter" almost instantly finds a new partner that fits or suits it just like the old one. It is probably an almost automatic process of high-speed high-pressure trial and error, but it results in each strand of the separated DNA replacing its missing twin out of their common su
rroundings, including not only the amputated rungs but the whole absent strand, so that the DNA chain has been completely duplicated and each half of the next cell division can be assured of having exactly the same DNA as its fellow in the new generation.
Alternatively when DNA is not just reproducing but is serving as chief administrator for its cell, directing internal growth and other cellular activities, it creates (instead of more DNA) the aforementioned different kind of molecule called RNA (ribonucleic acid) that serves as a sort of lieutenant to which it delegates specific responsibilities. RNA is thus a special breed of genetic catalyst or enzyme (page 104), and it assumes various forms depending on the task at hand, mostly doing errands outside the DNA boss's office, presumably so that the vital DNA itself need never risk venturing abroad.