Course description

DNA – The Key to Life
512px-Ishwar_Chandra_Vidyasagar.jpg (512×672)If your parents hadn’t had sex just when they did—possibly to the second, you wouldn’t be here. And if their parents hadn’t bonded in the same timely way, the same is true. Go back in time and your ancestors begin to add up. Look at just eight generations to about the time that Ishwar Chandra Vidyasagar was born, and already there are over 250 people on whose sexual habits your life depends. Go further, to the time of Shakespeare, and you have 16,384 ancestors. At twenty generations ago, the number of men and women making love just to create you is now 1,048,576. Five generations before that, there are 33,554,432 of them. By thirty generations ago, your total number of great great great great…. grandparents — remember, these aren’t cousins or aunts, but only parents and parents of parents in a line leading directly to you — is over one billion (1,073,741,824, to be precise). If you go back sixty-four generations, to the time of the Romans, the number has risen to about 1,000,000,000,000,000,000, which is several thousand times the total number of people who have ever lived.
Clearly something has gone wrong. The answer is you couldn’t be here without a little incest – actually quite a lot of it. In fact, if you’re married to another Bengali now, the chances are high that you are related. In fact, if you look around you on a bus or any crowded place, most people you see are very probably relatives. When someone claims he’s descended from Gopala, you should answer: “Me, too!” In the most fundamental sense, we are all family.
512px-Chemische_Struktur_der_DNA.svg.png (512×597)We are also strangely alike. Compare your genes with any other human being’s and, on average, they will be about 99.9% the same. That is what makes us a species. The tiny differences in that remaining 0.1% are what give us our individuality. In recent years, there’s been a lot of talk about the human genome. In fact, there is no such thing as “the” human genome. Every human genome is different. Otherwise we would all be identical. It is the endless combinations of our genomes—each nearly identical, but not quite—that make us what we are, both as individuals and as a species.
But what exactly is this thing we call the genome? And what are genes? Well, let’s start with a cell. Inside the cell is a nucleus, and inside each nucleus are the chromosomes – forty-six little packages of complexity. Twenty-three come from your mother and twenty-three from your father. With a very few exceptions, every cell in your body – 99.999% – carries the same chromosomes. Chromosomes are the set of instructions necessary to make you and are made of long strands of deoxyribonucleic acid or DNA.
DNA exists for just one reason—to create more DNA—and you have a lot of it inside you: about six feet of it crowded into almost every cell. Each length of DNA has 3.2 billion letters of coding, enough to provide 103,480,000,000possible combinations. That’s a lot of possibility – one followed by more than three billion zeroes. Altogether you may have as much as twenty million kilometers of DNA inside you.
512px-Friedrich_Miescher.jpg (512×700)Your body, in short, loves to make DNA and without it you couldn’t live. Yet DNA is not alive. DNA is actually especially unalive. It is among the most non-reactive, chemically inert molecules in the world. That’s why it can be recovered from long-dried blood in murder investigations and taken from the bones of Neanderthals and dinosaurs. That’s why it took scientists so long to believe a substance so lifeless could be at the heart of life itself.
The idea of DNA has been around longer than you think. It was discovered in 1869 by Johann Friedrich Miescher, a Swiss scientist at a university in Germany. While observing pus in bandages under a microscope, Miescher found a substance he didn’t recognize and called it nuclein (because it lived in the nuclei of cells). At the time, Miescher did little more than see it, but nuclein clearly remained on his mind. Twenty-three years later he raised the possibility that such molecules were the agents behind heredity. This was an extraordinary insight, but one so far in advance of the day’s science that it attracted no attention.
For most of the next half century the assumption was that the material, now called DNA, had a minor role in heredity. It was too simple. It had just four basic components, called nucleotides, like having an alphabet with four letters. How could you possibly write the story of life with it? (The answer is that you create the same complex messages as the simple dots and dashes of Morse code – you combine them.) DNA didn’t do anything at all, as far as anyone could tell. It just sat in the nucleus, possibly binding the chromosome in some way or adding a drop of acidity or doing some other minor task no-one had yet thought of.

There were, however, two problems with dismissing DNA. First, there was so much of it. Also, it kept turning up in experiments. In two studies in particular, one involving the Pneumonococcus bacterium and another with viruses that infect bacteria, DNA’s role was central. It was making proteins, a process vital to life. Yet, it was also clear that proteins were made outside the nucleus, well away from the DNA.
512px-Thomas_Hunt_Morgan.jpg (512×683)No-one could understand how DNA could get messages to proteins. The answer, we now know, was RNA, or ribonucleic acid, which acts as an interpreter between the two. It is an oddity of biology that DNA and proteins don’t speak the same language. For almost four billion years they have been the living world’s great double act, and yet they speak incompatible codes. However, in the early 1900s, we were still far from understanding that, or anything else about heredity. Clearly we needed some inspired experimentation, and happily the age produced just the right person to do it, Thomas Hunt Morgan. In 1904, four years after the re-discovery of Mendel’s experiments with peas and a decade before gene became a word, he began to do remarkable things with chromosomes.
Chromosomes were discovered by chance in 1888. By 1900, it was suspected that they were somehow involved in passing on traits, but no-one knew how, or even whether, they did this.
512px-Fruit_fly_Sri_Lanka.jpg (512×512)Morgan chose a tiny fly, the fruit fly, as his subject. We all know it as that colorless insect that seems to need to drown in our drinks. As laboratory specimens, fruit flies had attractive advantages: they cost almost nothing, could be bred by the millions in milk bottles, went from egg to reproduction in ten days or less, and had just four chromosomes, which kept things simple.
Working out of a small lab at Columbia University in New York, Morgan and his team started a program of breeding and crossbreeding, involving millions of flies. For six years they tried to produce mutations any way they could think of: zapping the flies with radiation and X-rays, growing them in bright light and darkness, spinning them crazily in centrifuges - but nothing worked. Morgan was about to give up when a sudden and repeatable mutation happened – a fly with white eyes rather than the usual red ones. With this breakthrough, Morgan could generate useful deformities, allowing him to follow a trait through generations. In this way, he could work out correlations between characteristics and individual chromosomes, eventually proving that chromosomes were at the heart of inheritance. The problem, however, remained the next level of biological complexity: the genes and the DNA that made them. These were trickier to isolate and understand. As late as 1933, many researchers still weren’t convinced that genes even existed. The idea that you could pick one from your body and take it away for study was ridiculous.
What was certainly true was that something connected with chromosomes was directing cell replication. Finally, in 1944, after fifteen years of effort, a team at the Rockefeller Institute in Manhattan, led by a brilliant Canadian named Oswald Avery, succeeded with an extremely hard experiment in which a strain of bacteria was made permanently infectious by crossing it with alien DNA, proving that DNA was far more than a passive molecule and almost certainly the active agent in heredity.
512px-James_D_Watson.jpg (512×513)If you’d been a gambler in the early 1950s, you’d almost certainly have bet on Linus Pauling of Caltech, America’s leading chemist, to discover the structure of DNA. Pauling had been a pioneer in X-ray crystallography, a technique vital to looking into DNA. He would win two Nobel Prizes (for chemistry in 1954 and peace in 1962), but with DNA he became convinced that the structure was a triple helix, not a double one, and never corrected this idea. Instead, four unlikely scientists in England who didn’t work as a team, often weren’t on speaking terms, and were amateurs, managed it.
Of the four, Maurice Wilkins, who spent the Second World War designing the atom bomb, was the most academic. The most unconventional was James Watson, an American, who entered the University of Chicago aged just fifteen. He had his Ph.D. by twenty-two and was now with the famous Cavendish Laboratory in Cambridge. In 1951, he was twenty-three. Francis Crick, twelve years older and still without a doctorate, was nosy, cheerfully argumentative and impatient with anyone slow to share his ideas. Neither was trained in biochemistry.
They believed if you could discover the shape of a DNA molecule, you could see how it did what it did. They hoped to achieve this by doing as little work as possible apart from thinking. As Watson remarked, “It was my hope that the gene might be solved without my learning any chemistry.” They weren’t asked to work on DNA, and at one point were ordered to stop it. 512px-Francis_Crick_1981.jpg (512×502)Although Crick and Watson enjoy all the credit for solving the mystery of DNA, their breakthrough depended on experimental work done by their competitors, Wilkins and Franklin. The New Zealand–born Wilkins was an almost invisible figure. The strangest character was Franklin. In a very impolite portrait, Watson in The Double Helix portrayed her as a woman who was unreasonable, secretive, uncooperative, and – this seemed especially to irritate him – deliberately unsexy. He complained that she was attractive but didn’t even use lipstick. However, she did have the best images of the possible structure of DNA, from Linus Pauling’s X-ray crystallography. Crystallography was used to map atoms in crystals (hence ‘crystallography’), but DNA molecules were a much more difficult business. Only Franklin could get good results from the process, but to Wilkins’s annoyance, she refused to share her findings. She cannot really be blamed. Female academics in the 1950s were treated with contempt. However senior, they were not allowed into the college’s faculty room. She was harassed to share her results with three men who showed her no respect. No surprise, then, that she kept her results locked away. Watson and Crick exploited Wilkins’ and Franklin’s poor relationship. Franklin was beginning to act in a very strange way. Although her results showed that DNA definitely was a helix, for instance, she insisted it was not. The outcome of all this was that, in January 1953, Wilkins showed Watson Franklin’s images, without her knowledge. It was a huge help. Years later, Watson agreed it was the key event that mobilized them. Everything now seemed to go their way. At one point, Pauling was going to a conference in England where he’d have met Wilkins and learned enough to correct the misunderstanding that put him on the wrong track, but Pauling was stopped at New York Airport, his passport confiscated, because the US government thought he was a Communist. Crick and Watson also knew Pauling’s son, who was working at the Cavendish and innocently updated them on news of his father’s scientific developments at home. Still facing the possibility of losing the race at any moment, Watson and Crick focused on the problem. DNA had four chemical components – adenine, guanine, cytosine, and thiamine – which paired up in particular ways. By playing with pieces of cardboard cut into the shapes of molecules, Watson and Crick worked out how the pieces fitted together. From this they made a model of metal plates bolted together in a spiral, and invited Wilkins, Franklin, and the rest of the world to have a look. Anyone could see they’d solved the problem. It was a brilliant piece of detective work. 512px-Rosalind_Franklin.jpg (512×615)The April 25, 1953, edition of Nature had a 900-word article by Watson and Crick, ‘A Structure for Deoxyribose Nucleic Acid.’ There were separate articles by Wilkins and Franklin. However, it was an exciting time in the world: Edmund Hillary was about to climb to the top of Everest and Elizabeth II was crowned queen and, so, the discovery of the secret of life was overlooked. But progress in genetics was now very fast and, by 1968, it looked like the work of genetics was nearly at an end. In fact, of course, it was only just beginning. Even now there is a great deal about DNA that we scarcely understand, not least why so much of it doesn’t seem to do anything. 97% of your DNA is nothing but meaningless “junk,” or “non-coding DNA,” as biochemists call it. Only here and there do you find sections that control and organize vital functions. Genes are instructions to make proteins. This they do with boring certainty. They are like piano keys, each playing a single note and nothing else. But combine the genes, like piano keys, and you can create an infinite variety of music. Put all these genes together, and you have the human genome. The genome is a kind of instruction manual for the body. Chromosomes can be seen as the book’s chapters and genes as individual instructions for making proteins. The words in which the instructions are written are called codons. The bases, or the letters of the genetic alphabet, are adenine, thiamine, guanine, and cytosine. Despite the importance of what they do, these substances are not made of anything exotic. Guanine is the same stuff that makes bat shit and gives it the name, guano.
The shape of a DNA molecule is rather like a spiral staircase: the double helix. The uprights of this structure are made of a type of sugar called deoxyribose, and the whole of the helix is a nucleic acid —hence the name “deoxyribonucleic acid.” The steps are formed by two bases joining across the space between, and they can combine in only two ways: guanine is always paired with cytosine and thiamine always with adenine. The order these letters appear in as you move up or down the ladder is the DNA code; logging it has been the job of the Human Genome Project.
Now the brilliance of DNA is its way of replicating: two strands part down the middle, like a zip on a jacket, and each half goes off to form a new partnership. Because each nucleotide pairs up with a specific other nucleotide, we can easily reconstruct the matching side by working out the necessary partnerships: if the top is made of guanine, then the top on the matching strand must be cytosine. Work your way down the ladder through all the nucleotide pairings, and eventually you have the code for a new molecule. That is just what happens in nature. Single_nucleotide_polymorphism_substitution_mutation_diagram_-_cytosine_to_thymine.png (711×483)Most of the time our DNA replicates accurately, but just occasionally – about one time in a million – a letter goes in the wrong place. This is known as a single nucleotide polymorphism, or SNP, known by the nickname, “Snip.” Generally these Snips are in stretches of non-coding DNA and have no importance for the body. But occasionally they make a difference. They might leave you predisposed to some disease, but they might also give you some advantage — more protective pigmentation, for instance, or increased red blood cells for someone living at altitude. Over time, these slight modifications gather in both individuals and in populations.
The balance between accuracy and errors in replication is a fine one. Too many errors and the organism can’t function, but too few and it loses adaptability. A similar balance must exist in an organism. An increase in red blood cells helps a person or group living high up to move and breathe because more red cells can carry more oxygen. But additional red cells also thicken the blood. That’s hard on the heart. So, those designed to live at high altitude get better breathing ability, but pay for it with higher risk of heart attacks. The 0.1% difference between your genes and mine is because of our Snips. Now if you compared your DNA with a third person’s, there would also be 99.9% correspondence, but the Snips would, for the most part, be in different places. Add more people and you will get yet more Snips in yet more places. So not only is it wrong to refer to “the” human genome, but in a sense we don’t even have “a” human genome. We have seven billion of them.
But we must still explain why so little DNA has any obvious purpose. It really seems that the purpose of life is to perpetuate DNA. The 97% of our DNA commonly called junk is largely made of clumps of letters that exist as they are good at getting duplicated. Most DNA, in other words, is not devoted to you but to itself: you are a machine for reproducing. Life just wants to be, and DNA is what makes it happen. Even when DNA includes instructions for coding genes, it’s not always to help us function. One of the commonest genes is for a protein called reverse transcriptase, with no beneficial function at all. The one thing it does is make it possible for retroviruses, such as Covid 19, to slip unnoticed into our system. All organisms are slaves to their genes. That’s why salmon, spiders and uncountable creatures are prepared to die while mating. The desire to pass on one’s genes is the most powerful impulse in nature. Sex is just a reward to encourage us to do this. Scientists had only just learnt the surprising news that most DNA doesn’t do anything when even more unexpected findings began to turn up. First in Germany and then Switzerland, researchers performed bizarre experiments producing unbizarre outcomes. In one, they took the gene that controlled the development of a mouse’s eye and put it into the larva of a fruit fly. The mouse-eye gene not only made an eye in the fruit fly, it made a fly’s eye. Here were two creatures that hadn’t shared a common ancestor for 500 million years, yet could swap genetic material as if they were sisters.
lossy-page1-800px-Hox_gene_expression_in_bones_from_tetrapod_limbs.tif.jpg (800×455)The story was the same wherever researchers looked. They found that they could insert human DNA into certain cells of flies, and the flies would accept it as their own. Over 60% human genes, it turns out, are the same as in fruit flies. At least 90% correlate to those in mice. (We even have the same genes for making a tail.) In field after field, researchers found whatever organism they were working on – worms or humans – they were studying the same genes. Life was drawn from one set of blueprints. There was a group of master control genes, each directing the development of a section of the body, which were dubbed homeotic or hox genes. Hox genes answered the question of how billions of embryonic cells, all from a single fertilized egg and carrying identical DNA, know where to go and what to do — that this one should become a liver cell, this one a bubble of blood. It is the hox genes that instruct them, and they do it for all organisms in the same way.
Interestingly, the amount of genetic material and its organization don’t generally reflect the complexity of the creature that contains it. We have forty-six chromosomes, but some plants have more than six hundred. The lungfish, one of the least evolved animals, has forty times as much DNA as we have. Clearly, it is not the number of genes you have, but what you do with them. The Human Genome Project has suggested we have 35,000 or 40,000 genes — about the same number as grass. 512px-Genomes_and_proteomes_of_nidoviruses.png (512×290)Genes have been commonly implicated in many human characteristics. Scientists have declared at various times that they have found genes responsible for obesity, schizophrenia, homosexuality, criminality, violence, alcoholism, even shoplifting. In fact, we now know, almost nothing about you is simple.
This is a pity in one important sense, because if you had individual genes that determined height or diabetes or baldness, then it would be easy to isolate and play with them. Unfortunately, thirty-five thousand genes functioning independently is not enough to produce the kind of physical complexity that makes a satisfactory human being. Genes clearly therefore must cooperate. A few disorders (like haemophilia and Parkinson’s disease, for example) are caused by a single dysfunctional gene, but as a rule, disruptive genes are eliminated by natural selection before they become troublesome to a species. In fact, our fate and comfort – and even our eye color – are decided not by individual genes but by complexes of them working together. That’s why it is so hard to work out how it all fits together and why we won’t be producing designer babies anytime soon. In fact, the more we learn, the more complicated matters become. Even thinking affects the ways genes work. How fast a man’s beard grows, for instance, is partly a function of how much he thinks about sex (because thinking about sex produces testosterone). In the early 1990s, scientists made an even more profound discovery when they found they could knock out supposedly vital genes from embryonic mice, and the mice were not only often born healthy, but sometimes were actually fitter than their brothers and sisters who had not been tampered with. When certain important genes were destroyed, it turned out, others were stepping in to fill the gap. This was excellent news for us as organisms, but not so good for our understanding of how cells work. It is because of these complicating factors that solving the human genome is seen as only a beginning. The genome tells us what we are made of, but says nothing about how we work. What’s needed now is the operating manual. We’re not close to that point yet. 512px-Difference_DNA_RNA.svg.png (512×410)So now the quest is to solve the human proteome – an idea so new that the term proteome didn’t even exist in the year 2000. The proteome is the library of information that creates proteins. Proteins, you will remember, are the workhorses of all living systems; as many as a hundred million of them may be busy in any cell at any moment. That’s a lot of activity to try to figure out. Worse, proteins’ behaviour and functions are based not simply on their chemistry, as with genes, but also on their shapes. To function, a protein must have the necessary chemical components, properly assembled, and then must also be folded into an extremely specific shape. It can all seem impossibly complicated, and it is impossibly complicated. But there is an underlying simplicity, too, owing to an underlying unity in the way life works. All the tiny, deft chemical processes that animate cells — the cooperative efforts of nucleotides, the transcription of DNA into RNA — evolved just once and have stayed fixed ever since across the whole of nature. Every living thing is based on a single original plan. Remarkably, we are even quite closely related to fruit. About half the chemical functions that take place in a banana are fundamentally the same as yours. It cannot be said too often: all life is one. If you want to watch some videos on this topic, you can click on the links to YouTube videos below. If you want to answer questions on this article to test how much you understand, you can click on the green box: Finished Reading? Videos: 1. DNA and Genes (4:00) 2. Human Genome (5:00) 3. DNA, Chromosomes, Genes (5:00) 4. Heredity (10:00) 5. Friedrich Miescher (1:00) 6. RNA (3:00) 7. Thomas Hunt Morgan (12:00) 8. Oswald Avery (7:00) 9. Linus Pauling (6:00) 10. Maurice Wilkins & DNA (5:00) 11. James Watson, Francis Crick, Rosalind Franklin and Maurice Wilkins (11:00) 12. James Watson (20:00) 13. Francis Crick (3:00) 14. Rosalind Franklin (4:00) 15. Codons (3:30) 16. Organism (2:00) 17. Red Blood Cells (1:00) 18. Hox Genes (2:00) 19. Human Proteome (8:00)

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