The Secret of Life

(See Cover)

Where did you come from, baby dear?

Out of the everywhere into the here.

Where did you get those eyes so blue?

Out of the sky as I came through.

--George MacDonald

The origin of baby dear, and the reasons for "eyes so blue" are the concern of genetics, the comparatively young, fast-developing science of heredity that is trying to solve the mystery of life, as physics works at solving the mystery of matter. Genetics has already accounted scientifically for blue eyes (even in a strictly dark-eyed family). It is working toward an explanation of how the first life appeared on earth. It is offering knowledge that may lead to the cure of cancer. And it came along just in time to warn against misuse of another young science: nuclear physics. The comparative "cleanness" (low fallout) of the test bombs that the U.S. was exploding in the Pacific last week was in large part a response to the warnings of the geneticists.

So young is the modern science of genetics that some of its grand old men are still alive, and some who gave it form are still only middleaged. Outstanding among them: Professor George Wells Beadle of Caltech, who did most to put modern genetics on its chemical basis. Geneticist Beadle is a mere 54. In his working lifetime he has seen genetics grow from a small, rather baffled specialty into a central, exciting science that is drawing the rapt attention of chemists, physicists, mathematicians, even astronomers, as well as nearly every type of biologist.

Monk & Peas. Genetics got its recognizable start, along with relativity, quantum theory and nuclear physics, during the scientific revolution of the early 1900s, but it had a strange, unpublicized start more than 40 years earlier when Gregor Mendel, an Augustinian monk and natural-history teacher in Bruenn (now Brno, Czechoslovakia), began experimenting with peas in the monastery garden. Mendel found that the parent plants transmitted their characteristics to their descendants in a predictable, mathematical way. When purebred red-flowered peas, for instance, are crossed with white-flowered ones, all the seeds grow into plants with red flowers. But when these red hybrid plants are crossed with each other, one-fourth of their offspring bear white flowers.

Mendel concluded that the reproductive cells of peas contain factors (now called genes) of two kinds: dominant and recessive. The gene for red-floweredness is dominant; the gene for white-floweredness is recessive. When red-and white-flowered plants are mated, the seeds produced get both genes, but the dominant red gene suppresses the recessive white gene. Result: red flowers in the first generation (see diagram).

The white-flowered gene, though suppressed, is still in existence. When red hybrid flowers are mated together, each seed in the second generation has a one-in-four chance of inheriting nothing but white-flowered genes. It will then bear white flowers, just as if its parents were of pure, white-flowered stock.* The other three-fourths of the seeds will bear red flowers.

Here was one of those extraordinary simplicities that can revolutionize a whole field of science. Mendel's observations proved that inside the cells of plants--and presumably animals too--is a mysterious mechanism, incredibly small, that rules heredity in accordance with precise mathematical laws. In 1866 Mendel published a paper to this effect in the proceedings of the Bruenn Natural Science Society, but nothing happened. The world was not ripe for his ideas. In 1868, when he was appointed abbot of his monastery, his scientific career came to an end.

At the turn of the century, three scientists (Hugo De Vries in The Netherlands, Karl Correns in Germany, and Erich Tschermak in Austria) independently rediscovered Mendel's principles. They also rediscovered his long-forgotten paper, and gave him full credit; the basic principles of genetics are still known as Mendel's laws. Genetics, born at last to science's estate, went to work on the interwoven mysteries of life and heredity.

Key Chromosomes. For a while, as often happens after a scientific breakthrough, additional discoveries came easily. Several biologists, notably Walter S. Sutton in the U.S., connected Mendelian inheritance with the known behavior of chromosomes, which are threadlike bodies in the nuclei of cells. When a cell divides nonsexually, as in a growing plant or animal tissue, the chromosomes replicate (make copies of) themselves. Each daughter cell gets a full set, and unless something has gone wrong, it is exactly like the chromosome set of the parent cell (see diagram).

In sexual reproduction, the chromosomes behave differently. The sex cells (sperm and egg) are the end results of a complicated process (meiosis or reduction division) that gives each of them half as many chromosomes as in the nonsexual cells. This reduction is necessary because the sex cells join during fertilization of the egg, and if each contributed a full set of chromosomes, the fertilized egg would have twice the normal number. But if both sperm and egg contribute half as many chromosomes, the fertilized egg gets just the right number.

Many years before the birth of the science of genetics, the chromosomes had been observed behaving in this way, but no one knew why they did. Genetics supplied the answer. Reduction division is a kind of lottery that deals the fertilized egg half a set of chromosomes from each parent, like cards dealt out to players in a two-handed card game. When maternal and paternal chromosomes are slightly different, which is generally the case, their dominant genes (units of heredity) suppress recessive genes, as Mendel's red-flowered peas suppressed white-floweredness. Each recessive gene is still riding its chromosome, and biding its time in obscurity. It can assert itself only when the corresponding gene from the other parent is also recessive. It may have to wait for many generations (in the case of humans, for hundreds of years) before it gets its innings. Then, free of suppression by a dominant gene, it produces a white-flowered plant or a blue-eyed baby. Or, if it is a bad gene, it may produce a deformed baby or a plant that bears no flowers.

Nebraska Farm Boy. These basic facts of genetics were becoming known about the time Geneticist George Beadle was born in 1903. His father ran a small, progressive farm near Wahoo, Neb. (1900 pop. 900). His mother died when he was four, leaving him, his brother and sister to be mothered, after a fashion, by a succession of hired housekeepers. He remembers farm life in general with pleasure, but he still dislikes cream because he had to skim it off endless milk pans.

Wahoo was not noted for learning half a century ago, but its less-than-perfect school system did not slow or discourage Beadle's active mind. He made his own lunch, generally jelly sandwiches (he still hates jelly sandwiches) and walked the three-mile round trip to school. When he earned a little money by such rural operations as keeping bees and trapping muskrats, he bought garlic bolognas (two for 5-c-) at the Bohemian butcher shop.

Beadle might be a farmer today if the Wahoo high school had not had a teacher, Miss Bess McDonald, with the gift of infectious enthusiasm. She taught physics and chemistry, and young George fell in love with both her and her sciences. He spent long evenings at her house, wrapped in his schoolboy crush, and listened to her attempts to convert him to an unusual religious sect whose name he does not remember. He never hit the sawdust trail, but when Miss McDonald's religious appeals failed, she started persuading him to go to college. His father expected him to take over the farm, but Bess McDonald headed him for the University of Nebraska's College of Agriculture at Lincoln. A small inheritance helped, and father Beadle made no objection.

The Fruit Flies. Beadle entered college in 1922. At the time, genetics was still a small, specialized field, but it was growing in both importance and intellectual vogue. Its great man was Professor Thomas Hunt Morgan of Columbia University, founder of the "fly school'' of genetics. He worked with Drosophila melanogaster, the small fly that congregates around fruit stands and garbage pails. As living instruments of genetics they were a happy choice. They are only 1/12 in. long, so their board bill is low. They produce new generations in about two weeks, multiplying rapidly in cream bottles stoppered with wads of gauze. They are easily come by; when a geneticist wants wild "genotype" flies, he puts a banana on the windowsill, and the genotypes come unbidden.

In large populations of fruit flies, a few are apt to be naturally defective, with stunted wings or misshapen limbs. In some cases these defects are inherited in a Mendelian manner, like the color of Mendel's flowers. Some traits are dominant, others recessive. They are caused by mutations (damaged genes) in the flies' chromosomes (they have only four pairs), and Morgan's method was to study every possible way that mutations could be passed from generation to generation.

Thomas Hunt Morgan's work won a Nobel Prize, and his laboratory was probably the first in the U.S. to which European scientists and students made serious pilgrimages. Genetic knowledge dredged out of fruit flies had an enormous effect on plant and animal breeding. Geneticists believe that a great bronze statue of a Drosophila. suitably mutated, should be erected in some such place as Iowa, where farm production has been greatly expanded by genetically sophisticated corn.

The gospel of fruit-fly genetics and its many practical applications reached young Student Beadle at the University of Nebraska, mostly through Professor Franklin D. Keim, who was working on hybrid wheat. Beadle helped Keim in summers, and when he graduated from college in 1926, Keim got him a graduate assistantship at Cornell at $750 a year. George Beadle still intended to become some sort of agricultural expert, but when he started working at Cornell with Professor Rollins Adams Emerson, founder of the ''corn school'' of genetics, he found the work so fascinating that he could not leave it. He never returned to agriculture above the backyard garden level.

Enter Radiation. About this time a new thing happened to genetics. Since the beginning, geneticists had regretted the scarcity of mutated flies, corn. etc.. to work with. The scarcity ended in 1926 when Professor Hermann J. Muller. now of Indiana University, discovered that X rays applied to fruit flies or any other living organism, create a wealth of mutations, apparently by damaging the genes in their chromosomes. Muller, too, won a Nobel Prize, and soon most genetics laboratories had X-ray machines and were buzzing with dwarfed, twisted, crippled or half-alive fruit flies whose ancestors had been Xrayed.

When Muller made this discovery, he may have heard a roll of distant thunder, but he could not have known what it meant. In the year 1926, long before Hiroshima, no man-made radioactivity was at large on earth outside the range of X-ray machines and radium capsules, and none was expected. No one suspected that in less than 20 years the mutation-producing effects of radiation would be a worldwide worry.

The new wealth supplied by Mullers X rays gave genetics a big boost, and Beadle felt the benefit along with his colleagues. After getting his doctorate (in genetics) at Cornell in 1931, he went to the California Institute of Technology on a National Research Council fellowship. Dr. Morgan, grand maestro of the fruit flies, had moved there in 1928 to head the biology section, and several of his keenest disciples had come with him. Young Dr. Beadle found himself in the best genetic society.

Teaming up with Alfred H. Sturtevant, one of Morgan's men, Beadle worked for three years on corn and fruit-fly genetics. But he felt vaguely that something was wrong, that perhaps corn and fruit-fly chromosomes were almost worked out. His friend Professor Boris Ephrussi, a visiting embryologist from the University of Paris, agreed. Both decided that genetics had become too isolated; what it needed was ideas from other sciences.

Taking a leave from Caltech, Beadle went to Paris to work with Ephrussi. Their first joint experiment was the delicate feat of transplanting an eye from one minuscule fruit-fly larva to another. After many attempts, an eye took hold and lived, and the two young scientists spent a whole day of celebration at a sidewalk cafe.

This was no mere stunt; it had a purpose--to find out whether the chemicals in one larva's body would affect the color of an eye transplanted from another larva. It did not work, but Beadle remained convinced that the innermost secrets of genetics and of life itself must be approached from the chemical angle.

Skilled Cell. The idea was not original with Beadle. Every biologist marvels at the chemical virtuosity of living cells. Under the eye of the microscope they seem placid things. The slimy protoplasm inside them sometimes streams slowly, but little other action is visible. This quietude is an illusion. The typical cell, which may be only one twenty-five-thousandth of an inch long, is aboil with chemical action. It is building thousands of complex compounds and tearing other thousands to bits. It selects nutrients that it wants, and in some mysterious way absorbs them selectively through its outer wall. Tiny, mysterious bodies move through its protoplasm, and inside the nucleus reside the powerful chromosomes, which most geneticists believe are like a chemical oligarchy controlling the activities of a chemical nation. If the cell is a fertilized egg, the chromosomes possess all the information needed to build the cell into a bug or a whale or a man.

Beadle believed that the easiest way into the chromosomes' citadel would be by finding mutations with single, simple effects on an organism's chemical behavior. This is the chemical approach that revolutionized genetics. Beadle did not really get to work on it until he went to Stanford in 1937 as a full professor, and he wasted several years more before he concluded that fruit flies (almost sacred animals with geneticists) are not the best subjects for chemical genetics.

In 1940 Beadle teamed up with Dr. Edward L. Tatum, a chemist now of the Rockefeller Institute, and selected a new laboratory victim, the so-called red bread mold (Neurospora crassa), which is really a beautiful coral pink in its natural state, unmolested by geneticists. Neurospora is a geneticist's dream. When properly introduced, it mates and reproduces sexually. It also grows nonsexually, so a truckload of mold with the same heredity can be grown, if desirable, from a single spore. But the best thing about Neurospora is that it asks for so little. It thrives on a medium containing nothing but mineral salts, sugar and a single vitamin, biotin. Everything else that it needs it can make out of these simple foods.

Mutated Mold. The Beadle and Tatum plan for Neurospora was to try to create strains that differ from the normal mold in simple, chemical ways. Their method was simple, too. They irradiated mold with X rays to induce mutations. Then they gathered spores formed by sexual reproduction and laid them out on a sheet of agar jelly containing the minimum nutrients that natural wild mold requires. Some of the spores sprouted and grew normally, showing that they had not been mutated in any obvious way. Some were dead, perhaps mutated too much.

A few sprouted hopefully but did not grow. These were the interesting spores. They acted as if they were trying to grow, but needed something that they could not get from the agar or produce for themselves. So when a microscope showed such a spore, it was tenderly fed with vitamins, amino acids and other growth-fostering chemicals in hope of making it perk up and grow normally.

At the start of the experiment, Beadle and Tatum resolved to make at least 1,000 tries before giving up. Such perseverence was not necessary. On the 299th try they found an ailing spore that needed only vitamin B-6 (pyridoxine) to make it grow lustily. When it had mated with a normal mold, it transmitted its need for vitamin B-6 to its descendants in the proper Mendelian manner for a single mutated gene.

This was what Beadle had been hoping for. His explanation is that the gene damaged by X-ray violence was originally responsible for producing an enzyme (organic catalyst) needed in the mold's process of making vitamin B-6 out of simpler nutrients. With the gene out of action, the process stopped, and the mold could not grow without help. It was like a human diabetic who needs an external source of the insulin that his body cannot make.

New Attitude. When Beadle and Tatum reported their success in 1941, they had quite a collection of defective molds, each needing some extra nutrient or having some other gene-controlled chemical ailment. In a few years their imitators filled their own laboratories with molds as unnatural as the most monstrous fruit flies. The coral fluffs of normal Neurospora are rare in the test tubes and Petri dishes. In their place are blackish warts, lichenlike incrustations, or sick-looking globules. One horrible kind of mold grown in a moving liquid floats in bunches with limp limbs like soft, dead crabs.

An immediate, practical result of Neurospora genetics was the application of mold irradiation to wartime penicillin production. Much more important were the long-range scientific results. The success with Neurospora yielded new techniques for using molds and other small organisms as genetic tools. Out of its use flowed a new attitude toward genetics. No longer were genes considered abstract units of heredity. They became actual things, not entirely understood but known to be concerned with definite chemical actions. Professor Joshua Lederberg, 33, of the University of Wisconsin, probably the world's leading young geneticist, says that the Neurospora work at Stanford clinched the whole idea that genes control enzymes, and enzymes control the chemistry of life.

In 1946 Caltech needed a new head for its now famous Division of Biology. Professor Morgan had retired. Beadle was tapped for the job and accepted, knowing well that he would have to curtail, perhaps abandon, his personal research. Some of his friends felt that a great scientist was being wasted on a routine administrative job, and there was a precedent for their fears in the history of genetics. Mendel himself did nothing of note after he was made abbot.

But Beadle was not wasted. Since becoming chief of Caltech's biologists, he has revealed unexpected talents, including fund raising and speechmaking. His colleagues agree that his greatest talent is his way of encouraging and enhancing his division without visibly running it. He tries to function as a catalyst rather than as organizer, encouraging scientists from different disciplines to take a lively interest in each other's fields. Caltech's Division of Biology is equal to any in the world, and it operates in an atmosphere of amiability spiced with high intellectual excitement. These are Beadle's personal qualities, and he makes them infectious.

Morgan's House. In 1953 Beadle married young, handsome Muriel Barnett, a feature writer who still works at her newspaper job on the Los Angeles Mirror-News. She has a teen-age son, Redmond Barnett, whom Beadle has legally adopted. They live on Pasadena's San Pasqual Street near the Caltech campus in a charming, rambling house that once belonged to Dr. Morgan and was sold by his widow to Caltech. The grounds glow with flowers, some of them experiments in genetics but still attractive, and a patrol of eight Siamese cats keeps watch on everything interesting. Beadle is fond of all cats, but Siamese cats are his favorites. He explains that they would be dark all over except for a mutated gene that permits dark pigments to be formed only in places (ears, tail, nose, etc.) that have a low temperature.

Magic DMA. Since the Neurospora breakthrough, chemical genetics has made startling progress. Its most important movement has been down the scale of size toward the actual chemical molecules that control life and reproduction.

Never far from the geneticist's mind is the three-letter symbol DNA, which stands for deoxyribonucleic acid. It is a giant molecule of slightly variable composition that is found in chromosomes, and it is believed to be the substance that determines heredity and governs all cells (and therefore all life) from the stronghold of the nucleus. DNA has been known to exist for years, but until postwar years little was known about it. Now it is being attacked from many angles by nearly every breed of scientist.

In 1953 Caltech's Chemist Linus Pauling, who won a Nobel Prize for his work on molecular structure, reported that the DNA molecule has a helical (spiral-staircase) structure. Later that year, James D. Watson and Francis H.C. Crick in England went a step farther. DNA, they said, is a double helix with two spirally rising chains of linked atomic groups and a series of horizontal members, like steps, connecting the two spirals. This molecular model, deduced mostly from X-ray diffraction photos, seemed complex and unlikely, but geneticists rejoiced when they heard about it. It was just what they" needed to explain many perplexing things that they had been observing for years (see diagram).

In the Watson-Crick model of DNA, the two spirals are made of five-carbon sugar molecules (deoxyribose), alternating with phosphate groups. The "steps" connecting the two spirals are made of four "bases" (adenine, guanine, thymine, cytosine) linked in pairs. The pairs can point in either direction, but adenine must always be joined to thymine and guanine to cytosine.

The charm of this structure for geneticists comes from its variability. Each step between the helices can be made of either pair of bases pointing in either direction. If the spirals should be pulled apart (the chemical bonds between bases are weak), each spiral would be left with the four bases arranged in any sequence. If arranged meaningfully along the spiral, the bases could carry information in a four-symbol code, much like digits on the magnetic tape of an electronic computer.

Here, the geneticists now believe, lies the high command of growth and reproduction. Double-helix DNA molecules, thousands of turns long and arranged by thousands in each chromosome, can carry a vast amount of coded information. They may very likely carry enough to determine whether a fertilized egg grows into a clam or an elephant. When chromosomes replicate during cell division, the DNA molecules that they contain presumably replicate too.

Stealthy Viruses. This concept of the DNA molecule has started a vast amount of excited work. Mathematicians are trying to break its four-symbol code. Chemists are trying to dig deeper into its structure. All sorts of biologists are looking for effects of DNA on the behavior of living organisms, and they are finding a wealth of strange things. Loose DNA can penetrate certain bacteria, changing them permanently into a new strain. Many viruses are packets of DNA wrapped in a coat of protein. When a virus infects a living cell, it leaves its coat outside. The DNA enters the cell and takes charge of its activities, issuing chemical orders as if it owned the place. Its orders are simple: "Stop everything and make more virus particles packed with DNA." The cell obeys helplessly, turns its contents into virus particles, bursts and dies.

Sometimes a virus enters a cell and makes it multiply over and over, even if its unruly growth kills the animal of which the cell is a part. Several kinds of animal cancer are caused by such viruses, whose DNA presumably takes command and makes the cells multiply wildly.

Anticancer Orders. Some geneticists think that many if not all kinds of cancer are caused by invading viruses. Others think not. But all agree that the genetics of cancer-causing viruses and cells that are their victims is a promising road toward the cure or prevention of cancer. If cancer cells multiply wildly because the DNA of a virus is giving them orders, it may be possible to countermand those orders with another kind of DNA. Knowledge about DNA may also help prevent some kinds of radiation damage.

If DNA can change bacteria from one true-breeding strain to another, it may have some similar effect on higher animals, including humans. If such a process is discovered, not much DNA will be needed. The entire supply of DNA that could control the heredity of the next generation of the human species (several billion individuals) could be put in a cube one twenty-fifth of an inch on a side.

Geneticists are so confident of their new science these days that most of them do not dodge questions about the origin of life on earth. The first living things, they say, were probably crude, simple versions of DNA. They floated in an ocean, or perhaps some smaller body of water, and floating around them were all sorts of organic molecules that had been formed by chemical chance. At long intervals the crude ancestral DNA found and seized some molecule that it wanted. When it had caught enough smaller molecules, it was ready to divide into two identical parts.

This would be true growth, say the geneticists, and evolution would soon improve the original breed. DNA would eventually wrap itself in cells and retire to their nuclei to give orders. Cells would later band together into multicelled animals, but they would not escape the commands of the DNA within them. Samuel Butler wrote: "A hen is only an egg's way of making another egg." Geneticists like to make this remark more general: "All plants, and animals and humans," they say, "are DNA's way of making more DNA."

Genetics & Bomb Tests. A part of the public seems to think that the chief concern of genetics is the hereditary damage that may or may not be done by the radioactive fallout from nuclear bombs and bomb tests. Geneticists insist that this matter is not a central part of their science, but none of them takes the potential effects of fallout lightly. They have spent their working lives with experimental organisms deliberately deformed by radiation. They know how recessive damaged genes persist unnoticed for many generations, only to appear (and perhaps to kill or cripple) when two of them meet in the same fertilized egg. They know that some damaged genes in humans have bad effects so subtle that they are hard to measure or count. They suspect that radiation damage to genetic material may have many unknown relations to cancer. Most of them say emphatically that the less radiation on the loose, the better it is for the world.

Beadle does not take an extreme position. "As a geneticist," he says, "I am prepared to say that fallout is biologically harmful and that we must therefore recognize a moral responsibility to humanity to reduce it to the lowest possible level." He is not sure "whether nuclear-weapons testing has a military or other benefit that outweighs the biological harm." But, like other geneticists, he knows too much to be indifferent to the problem.

* Blue eyes in humans are also commonly due to a single recessive gene. Dark-eyed people may have this gene in its suppressed state, obtaining it from an ancestor so remote that his blue eyes have been forgotten. When two such people marry, one-fourth of their children (statistically) will have blue eyes.

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