Part 1: A Short History of Genetics
"Aug. 7, 1997. ABS Global here in DeForest, Wisconsin has just announced the successful cloning of a bull calf. His name is "Gene."
1998. Here in a US Dept of Agriculture laboratory they are using a new gene gun to permanently change the gene code that makes a barley plant.
2003. Automated laboratories around the world successfully completed the most ambitious biological project of all time, the complete sequencing of the human genome.
2004. Here in a closed laboratory at the University of Wisconsin James Thomson and his colleagues are busy, culturing human stem cells. Each of these stem cells, potentially immortal, has that complete human genome, a complete set of instructions, coded on all of its genes, instructions on how to make a human being.
"Coded on all its genes..." What does that mean? What exactly is a gene? How does it work?
To understand more about the revolution in biology (and in society) that many think will almost certainly make the 21st century the century of biotechnology, let's first take a look at the history of how we found out about genes.
From very early times people understood that sex was needed to produce offspring in the higher animals. They didn't think it was necessary for lower creatures, however.
Aristotle, the Greek philosopher and scientist, considered the greatest authority on science for over a thousand years, said that worms and flies and such were spontaneously generated out of muck and slime. No sex needed. No parents required.
Even when parents were obviously involved, no one had any idea what it was that made offspring resemble their parents. Nor what it was that made them a little different, too. In other words, no one had any idea how heredity worked.
Today we know how heredity works. We know what it is that makes offspring resemble their parents. It is genes. This is the story of how humans found out about genes. And the story of how genes work in our living world today.
The first real scientific insight into heredity came over one hundred thirty years ago-about the time of our American Civil War-in a now abandoned garden in Brno, Czechoslovakia. The breakthrough was made by an eccentric Catholic monk named Gregor Mendel.
Mendel was a busy man. He smoked twenty cigars a day, kept fifty hives of bees and many cages of mice, was regional weather correspondent for the Austrian empire, was elected abbot of his monastery, and carefully nurtured and studied thousands of garden pea plants. For this last task the world is forever in his debt.
Up until Mendel's time even educated people thought that inheritance was somehow carried by the blood. They thought that offspring were a blend of the qualities of their parents. They even thought that if a man had a tattoo on his right arm, his child might also be born with a tattoo on his right arm.
Mendel's work with garden peas proved all these beliefs to be mistaken. Inheritance, he showed, was not carried by blood or any other general body cells of plant or animal. Instead, it was carried by some kind of special something that was hidden in the sexual cells, the egg and sperm cells. These special somethings were later given the name of genes.
Here is how he did it. In his monastery garden he experimented. He took the male cells of peas that produced tall-stemmed plants, for instance, and crossed them with the female cells of peas that produced short-stemmed p!ants. To his surprise, from this cross Mendel ended up not with a blend of tall and short stems, but with all tall stems. One hundred percent tall stems! What had happened to the short stem trait?
It had not blended. Had it been lost? Mendel did another experiment. He took the tall plants that he got from crossing tall and short plants (called the hybrid first generation plants) and crossed them with each other.
Lo and behold, this time-the second generation-he did get some short-stemmed plants! In fact, on the average, one-fourth of the new pea plants turned out to be short-stemmed ones, and three-fourths turned out to be tall.
Mendel got these same ratios when he tried six other simple characteristics-wrinkled and smooth seeds, axial and terminal flower buds, green and yellow seeds, yellow and green cotyledons, inflated and constricted pod shapes, and gray and white seed coats.
Some thought Mendel was a little odd to spend so much time counting seeds. When he published his results in the Proceedings of the Brunn Society in 1866 it did not make much of a splash. It was not until some forty years later, long after Mendel was dead, that the scientific world did take notice.
Today all biologists agree that Mendel's discoveries are indeed basic laws of heredity, valid not only for garden peas, but for elephants, for worms, for swordfish, and for humans.
After Mendel, progress was still slow in learning more details of heredity. And there was backsliding as well. Despite Mendel's work, the great pioneer of evolution theory, Charles Darwin, still believed in blending. He also thought that traits picked up in the lifetime of plants and animals could be inherited through what he called "gemmules" in the body cells of plants and animals.
As late as 1899 a student of biology at Brunn found Mendel's 1866 paper and eagerly showed it to his professor. "Oh, I know all about that paper, it is of no importance," said the professor. "It is pure Pythagorean stuff; don't waste your time on it."
One of the problems was that investigators were too ambitious. People like Francis Galton in England, for instance, carried out scores of ingenious studies on the inheritance of complex human traits like intelligence, size, and bodily strength. Galton even tried to develop numerical scales for beauty and love, and once did a statistical study of disasters on ships that carried missionaries versus those that did not.
All of these complex traits and happenings, we know today, are due to a bewildering combination of thousands of genes and even more thousands of environmental factors.
Around the turn of the century, botanists were independently finding Mendel's laws to be true. One far-seeing German scientist, August Weismann, was already predicting in 1885 that heredity would eventually be found to be carried by "definite chemical, and above all, molecular structures." It remained for the twentieth century to discover just what that molecular structure is.
The most dramatic breakthrough in heredity since Mendel's garden happened on the banks of the Cam River in Cambridge, England in the 1950's. A quiet young American biologist (and former Quiz Kid from Chicago) James Watson, used to stroll along the river path with an English biologist in his mid 30's, famous for his loud voice and even louder laugh-Francis Crick. Crick said of Watson, "He was the first person I had met who thought the same way about biology as I did." Watson said of Crick, "He was the brightest person I had ever worked with."
Along this path, in a tiny office at nearby Cavendish Lab, and over long luncheons at the Eagle Pub, Crick and Watson puzzled about what genes were and how they worked. The place, the time, the spirit-all were ready-and the sparks from the combination led to the greatest revolution in biology since that of Charles Darwin's theory of natural selection a hundred years before.
You see, by the 1950's much more was known about cells and about the Mendelian laws of heredity. T. H. Morgan at Columbia University and Hermann Muller at Indiana University had used fruit flies to locate genes on the chromosome. They had shown how Mendelian laws still apply, but in a more sophisticated way than Mendel had imagined.
Muller, in particular, had shown how x rays can cause mutations-that is, permanent changes on a chromosome, on a gene. He was able to construct full-scale maps of the genes on the chromosomes of the fruit fly. A few decades later geneticists would be able to do the same with human genes and chromosomes.
One of the most important keys in this progress was new and better scientific equipment. Microscopes, for instance, had become much more powerful. Using new x-ray diffraction techniques scientists could peek into the actual molecular structure of large molecules. New chemical techniques were invented-chromatography, electrophoresis, radioactive tracing-that could separate and identify unbelievably tiny amounts of complex chemicals.
Each one of these advances required the thought and work of many hundreds of researchers, so that it is misleading and unfair to single out one or two people to get all the credit. So too with the discovery of the molecular structure of genes that is now usually credited to the famous Crick and Watson team.
The particular tools that Watson and Crick used to make the breakthrough were model building, some recent x ray data, and inspired guesswork. The principles needed for the model building had been worked out across an ocean and a continent by the chemist Linus Pauling at the California Institute of Technology at Pasadena. The x ray data had come from the work of two scientists in London, Rosalind Franklin and Maurice Wilkens. The guesswork was their own.
Later, three of the four received the Nobel Prize for the brilliant answer they gave to the question of what a gene is and how it works. Sadly, the fourth, Rosalind Franklin, died a premature death from cancer in 1964, two years before the Nobel Prizes were awarded.
What exactly did Crick and Watson do?
They figured out the architecture of a very large molecule-deoxyribonucleic acid-DNA for short. This molecular structure was so important because it is DNA in the nucleus of all cells that is the actual physical thing that carries the all-important information of heredity. The special something that Mendel had assumed in pea plants. The molecule that Weismann had predicted in 1885. The gene hat Muller had mapped on fruit fly chromosomes.
DNA is the physical molecule that carries the computer like code that tells your cells how to make an eye, an arm, a brain. And not just any eye, any arm, any brain, but your eye, your arm, your brain. And not just you, but your dog, your goldfish, your poison ivy, your earthworm, the largest whale in our ocean, the smallest virus in our blood stream.
All living things, in other words, are built and operated following instructions from the DNA in their cells. Crick and Watson could now diagram and make models of the very most-secret heart of life itself!
Here is the actual diagram Crick and Watson drew for their famous paper, "A Structure of Deoxyribose Nucleic Acid" in the scientific journal Nature of April 25, 1953.
DNA, they guessed correctly, was a double helix structure. The helix backbone was always the same, a well-known chemical group called phosphate sugar. Connecting the two phosphate sugar ribbons are pairs of four well-known chemical bases called adenine, cytosine, guanine, and thymine. To a chemist it was simplicity itself. And an elegant, beautiful simplicity! Especially when they saw that guanine can only connect to cytosine and adenine can only connect to thymine. Yet despite that limitation, the helix is long enough so that an almost infinite number of possible sequences is possible. Which means that an almost infinite variety of life forms is possible.
And finally, as Crick and Watson said in their paper, "It has not escaped our attention that this double helix structure provides powerful hints as to methods of replication within the cell." In Part 2 we will show how simply that replication works. Again, an elegant, beautiful solution to an age-old puzzle.
Just finding the actual molecular structure of DNA did not in itself solve all the problems of genetics. It did provide, however, the most powerful tool yet found to investigate these problems. Now scientists could isolate the parts of the cell that were the sites of the actual physical genes. They could proceed to take these genes apart and put them back together again. In old ways, and in new ways.
And today in laboratories all over the world geneticists and biochemists are making rapid progress in deciphering life's codes in many plants and animals, including humans. Synthetic genes have been made. Genes have been spliced from one organism into another. Genes have been repaired. Genes have been mutated.
Genetic surgery is now widely used commercially as hundreds of new biotech companies are launched. Whole new kinds of life forms-especially new strains of bacteria-are being designed and made in the laboratory. New kinds of life forms engineered to do specific tasks like create hormones, antibiotics, vaccines. Mine metals, clean up pollution, even build computers.
And in one of the biggest scientific projects of all time, geneticists and chemists have now completed the job of mapping all the DNA sequences--that is, all of the genes-- of the human species! This project was first led, fittingly enough, by James Watson himself. It was successfully completed almost exactly fifty years after that first breakthrough. The past fifty years have indeed started a revolution in biology. The next fifty years will have their own surprises.
Part 2: What Is a Gene and How Does It Work?
Well, now that you have seen how the gene was discovered, let's look in Part Two at how the gene works and how this knowledge can help unlock some of life's secrets today and benefit all life on earth, including human beings.
"Alice laughed, 'There's no use trying," she said. "One cannot believe impossible things."
"I daresay you haven't had much practice," said the Queen. "When I was your age, I always did it for half an hour a day. Why, sometimes I've believed in as many as six impossible things before breakfast."
And if Alice could wander through the wonderland of modern genetics she would need even more practice. For here, at the heart of life, the impossible is an everyday thing.
Today, in the 21st century, we can transfer a gene from one plant to another and from one animal to another. We can make a synthetic gene for rabbit hemoglobin. We can create new kinds of living bacteria. Some of these bacteria can mine copper for us, can make insulin and other hormones, can produce new antibiotics, can fix nitrogen into fertilizers, and someday soon may even be able to produce and reproduce living computers!
Researchers have been able to make exact duplicates, clones, of sheep, pigs, mice, cows, and many other common mammals. No one has yet cloned a human being though this is probably possible. In fact, if we look only at the possible, less than a teaspoon of a chemical called DNA, deoxyribonucleic acid, would be enough to re-create all the people now living in this world?
All of this is not science fiction. Scores of hardnosed business people have invested millions of dollars in new high-tech companies springing up all over the world to make these impossibles everyday realities.
Let's look at the basic science that makes all this possible. Just as knowledge of the atom is the most important key to understanding physics and chemistry, so knowledge of the gene is the most important key to biology today.
What is a gene?
The gene, we now know, is a molecular structure that carries the code needed to govern life functions. Just as a computer needs a program, so a cell (and a complex combination of cells called an organism) needs a program. That program is in code. The code is on a spiralling molecular structure called deoxyribonucleic acid, DNA for short.
A molecule of DNA actually carries more than one instruction, more than one gene. Along this spiralling DNA molecule, for instance, one section might be part of the code that (in interaction with other genes) governs eye color. Another section could have a code needed to produce the hormone insulin. Another section would have a code for hemoglobin in your red blood cells.
Obviously, in order to create an entire person you need a lot of genes. How many is an active research question today. It used to be thought humans had 100,000 or more genes. The most recent estimate is much smaller, probably on the order of 25 to 30,000. But this relatively small number of genes (not that many more genes than a fruit fly!) has complex interactions that multiply into billions! In fact, the possible combinations get astronomical. How else could we have such a rich variety of living things in our world?
Think of all the possible combinations of magnetic pulses on a tape, grooves on a record, words in a book. DNA is like that, only more so. More information, more power.
The DNA is surrounded by protective protein coats and is strung like beads along structures called chromosomes. These chromosomes wind around in every cell's nucleus.
The DNA in each chromosome has thousands of genes. One surprise is that much of the DNA does not seem to carry any coded messages at all. We don't know at this time just why this should be so. Perhaps nature, like human beings, can be redundant and wasteful, as well as efficient and powerful.
Just about every cell in the living body of every organism has a store of DNA in its nucleus. The same store as in every other cell of the same individual organism. This is why cloning is possible.
Cloning has been known and practiced for many years by gardeners. Recently it has been done experimentally with animals, too, including mammals.
Cloning is a way to use the coded instructions of a general body cell to reproduce the whole organism without sexual recombination. Thus, the cloned individual turns out to be exactly like the parent in every respect-since he or she has exactly the same genetic instructions within each and every cell.
Normally, of course, this is not the way organisms reproduce.
Normally, the genes that are going to be used to create a new organism are, very early along, segregated from other body cells. They are kept separate in the ovaries of the female (the eggs) and in the testes of the male (the sperms). Because they are segregated so early, experience of the adult organism has nothing to do with the heredity given to the offspring. Thus, inheritance of acquired characteristics is not possible.
When it comes time to reproduce, cells in the testes and in the ovaries go through a special kind of division called meiosis. In the diagram you see a microscopic view of what happens to the chromosomes in meiosis. They divide in two. Each sperm and each egg thus gets only one-half the regular number of chromosomes and genes. In your case, for instance, this means you got one half of your inheritance from your mother and one-half from your father.
When your parents had sexual intercourse, these half-number cells joined together to make a new whole-number cell-a fertilized egg. The egg from your mother and the sperm from your father, in other words, fused together to make one complete cell, a fertilized egg cell that in a few short months was born as a unique new person-you.
In those "few short months" came the impossible part, the part we still know so little about it does seem near miraculous.
The single fertilized egg cell had all the codes needed to create you. To let these codes do their job, the fertilized egg cell needs the right environment. Your mother's uterus provides this environment. It provides the right temperature and the right chemicals. It provides a saltwater world (very similar to the ancient ocean) where amino acids, sugars, salts and fatty acids are abundant and ready for use.
When all is right, the process unfolds like the most dramatic motion picture you have ever seen. The single fertilized egg cell quivers, doubles its chromosomes, and divides into two. This is called mitosis. Notice, it is different from meiosis in that the chromosomes (and thus the DNA and the genes) doubled before the cell divided into two. Thus each new cell has a full set of chromosomes, DNA and genes.
Let's look at this doubling more closely. Remember how Crick and Watson put it in their 1953 article in Nature magazine, "It has not escaped our attention that this double helix structure provides powerful hints as to methods of replication within the cell." Here is what they meant and here is how it does work.
The double backbone of the helix is made of phosphate sugar groups. These are connected-like rungs on a twisted ladder-by four different kinds of chemical bases-guanine, thymine, cytosine and adenine. Guanine, it turns out, can only hook itself to cytosine, and adenine can only bond with thymine. That is sufficient to create an intricate code, and to provide an ingenious way of replicating.
With the help of other important chemical molecules called enzymes, the two backbone parts of the DNA molecule untwist, and then the whole '' molecule unzips. This gives two half-DNA molecules. But two halves with highly active base parts.
Here is where the environment comes in again. Floating in the saltwater soup of the cell are plenty of guanine, thymine, cytosine and adenine groups. Where did they come from? From the food the mother ate and supplied to the uterine environment.
With the help of still other important enzymes, each half of DNA hooks onto the base group as needed. That is, every guanine hooks onto a cytosine, every adenine to a thymine, every cytosine to a guanine, and every thymine to an adenine. Phosphate sugars are also nearby and so we zip back up and now we have two DNA's where there was only one before. Two identical DNA's.
The cell now divides, the chromosomes divide, the DNA's divide and you have two complete cells with two complete sets of code. Each cell identical to the one it came from.
The process continues. Two become four, four become eight, eight become sixteen, sixteen, thirty-two, etc. etc. etc. And we get millions and billions of cells, all with the complete set of chromosomes, DNA and codes to make you you.
But wait! How come the cells are not all alike then? The cells in your eye, for example, are not like the cells in your ear. The cells in your lungs are not like the cells in your biceps. How did they all become different?
For the most part, that is still a great mystery! No one knows. Not yet. This great mystery is given a name. It is called differentiation. There is a lot we don't know about differentiation. One thing we know is that it is governed by the genetic code on the DNA molecules. We also know a little about how the DNA code tells the rest of the cell what to do.
The DNA is able to pass along its coded messages to a very similar single chain molecule called ribonucleic acid, RNA. This smaller RNA molecule is able to slip out of the nucleus into the rest of the cell. There it takes charge of the building of new enzymes and proteins.
And finally, it is these enzymes and proteins that do the actual work of the cell. Carrying oxygen, for instance, if they happen to be in a red blood cell. Carrying electrochemical pulses if they happen to be in a nerve cell. Contracting if they happen to be in a muscle cell.
Amazing! Amazing that it does work and even more amazing that scientists have been able to decipher as much as they already have about how it does work. Of course, it is one thing to read about this, and another to actually figure it out in practice. Today there are many genetics laboratories all over the world cooperating and competing to push forward our basic knowledge of the gene.
The tools of all these scientists are similar. Some of the most basic are as old and common as any in science-test tubes, beakers, sterile culture dishes, pipettes, colored tapes, a variety of chemical reagents, bunsen burners and refrigerators.
Others are newer and more sophisticated. Electron microscopes, electrophoresis set-ups, scintillation counters, ultra-high-speed centrifuges and, of course, ultrafast computers.
The techniques worked out to probe these submicroscopic genes are ingenious to say the least. For instance, suppose you want to cut a strand of DNA at a particular spot, say where the gene for eye color is located. No problem. Today there is a large variety of chemicals called restriction enzymes that can act as sharp and ever-so-accurate chemical scissors. You can buy these restriction enzymes off the shelf.
Other chemicals, usually radioactive tracers, are used to mark the points of cutting. Then various gels can be used in combination with electrical charges to separate the DNA fragments. Once separated on a piece of paper or on a gel, a computer is brought in to help interpret the patterns found. The final result is a kind of photographic record of the sequences of thymine, guanine, cytosine and adenine pairs.
Whether on film or reprinted on paper, the sequences are very long. Geneticists today are a little like a child just beginning to read. They are still at the primer level. What will it be like when we reach the length and sophistication of a War and Peace-length novel?
It's time to summarize the basic facts before we take a final look at the controversial future.
One. The gene is the biological unit that carries heredity in every cell of every living organism, from viruses to fruit flies, from pea plants to people.
Two. The gene itself is a molecular structure, a group of atoms that are part of a large molecule called deoxyribonucleic acid, DNA.
Three. It is the pattern of base sequences on the DNA that is the code which, when translated by living cells, makes a virus a virus, a fruit fly a fruit fly, a pea plant a pea plant and a human a human. Not only in general, but a particular virus, a particular fruit fly, a particular pea plant, a particular human being.
Four. When you change the structure of the DNA sequence, you change the code, you change the living tissue, you change the living organism. It's like changing the computer program, or the words in a book. You end up with a new program, a new book. Maybe better, maybe worse. In the case of genes in nature, the new living organism that results from a change in the gene (called a mutation) is usually worse off than its parent.
Five. Very occasionally a mutation may lead to a new trait in the offspring that is to its advantage. That offspring will have a better chance to survive and pass on that new mutant gene to its offspring. In this way change and natural selection will occur.
What does all this mean in practical life today?
For one thing, humans are trying to engineer genetic changes for the good. They do this using what is called recombinant DNA technology.
Say you find a gene that is capable of some desired task-cleaning up oil spills, producing insulin, gobbling up some nasty toxic waste, fixing nitrogen into fertilizer or making a life saving drug. Using one of the new restriction enzymes, you snip it out of the cell it is found in normally. Then you "paste" it into an opened-up cell in a fast-reproducing bacteria.
You give the newly enhanced bacteria enough food and living space and let it reproduce. Within a very short time you have billions on billions of these powerful new living things-living factories.
You purify the substances they have produced, bottle them and sell them to people who need them.
Similar techniques are also being developed to "cut and paste" genes from one organism into another-say from a bean plant into a corn plant, or from a bacteria into a rabbit.
Here at a US Dept of Agriculture laboratory in Wisconsin they are using a newly invented gene gun to transfer genes that resist mold into a barley plant. If successful these experiments will lead to new varieties of barley that can themselves resist the mold epidemic that threatens barley crops all across the northern hemisphere today.
In one of the most dramatic breakthroughs of the late 20th century, biologists in Scotland cloned Dolly, the first mammal created from a cell taken from an adult of the same species.
This feat was quickly followed by the successful cloning of three bull calves in DeForest, Wisconsin in the summer of 1997. "GENE 1, 2 and 3" were all cloned from differentiated cells taken from a donor cow embryo.
In cloning experiments, researchers take a nucleus from a cell in an embryo or in an adult animal. This nucleus, no matter what cell it comes from-skin, muscle, gland -- contains all the genes of an organism. They then take an egg cell from the same species of animal. They take out the nucleus of this egg cell and insert the nucleus of the donor animal in its place. Now they implant the new egg cell into a female surrogate mother. If all has been successful in the transfer, the single egg cell will now develop in the normal way inside the surrogate mother's uterus, and when born the baby will be an exact duplicate of the adult sheep, cow -- or human! -- from which the original cell was taken.
One of the most promising as well as most controversial of the new genetic advances is in what is called stem cell research. Stem cells are blank cells. They are cells that have the complete set of genes but genes that have not as yet received instructions as to what they are supposed to do in the growing organism. Some of the most potentially useful stem cells are human embryonic cells, that is, the cells that come from the very early divisions of the human fertilized egg.
Researchers led by James Thomson at the University of Wisconsin succeeded a few years ago in culturing these embryonic human stem cells. These cultured human stem cells are potentially immortal. That is, they can be reproduced indefinitely in culture dishes. The hope is that researchers can use these cultured stem cells to learn what are the signals that make them turn into blood cells, or liver cells, or muscle cells or nerve cells. Once they can find these signals biologists could use this knowledge to find ways to treat Parkinson's, Alzheimer's, heart disease and many other diseases and defects of the human species.
All of these new technologies are helping us to understand life at its most basic molecular level. They are also challenging some of our oldest and most basic beliefs. Theory, evidence and technology that can change basic life structures and behaviors bring up serious ethical and social problems. These issues are being studied and debated today. Now that you understand the basic principles of this new genetics, you too can take a role in this debate. For in the long run, in a democracy like ours, how this immense new power will be used is up the most important people in the democracy -- you and me.
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