Full transcript of the episode:
Welcome to Untangling Science, with me Darragh Ennis, a new podcast that aims to untangle and explain science in a way that everyone can understand. After more than twenty years working in science I am convinced that all of us can be fascinated by it. So, whether you have a passing interest in science or you’d like to but were rubbish at science in school, this podcast will explain it in a fun way without using too many confusing technical terms or jargon. Each new episode will focus on one major topic and will break it down so it makes sense before building it back up to include the latest research in the field and how this research has changed all of our lives through the years. This will be science for everyone and will range from tiny molecules to new technology and up to exploring the stars.
The first episode will be on that most famous of molecules, DNA. Watch out for it and be sure to subscribe so you don’t miss any episodes.
Episode 1: DNA
Welcome to the first episode of Untangling Science, with me Darragh Ennis. Many of you may know me as a professional quizzer from the ITV quiz show The Chase, but my day job is as a scientist. I work in the University of Oxford Biochemistry Department and I always want to encourage people to engage with and understand science. I decided to do this podcast for the large number of people who see science as being something they don’t understand, maybe because they didn’t like it at school or avoided science as it looks horrible and complicated. I think science is cool and fascinating and I really believe that, if it’s explained in the right way, that anyone can become interested in the science that plays such a huge part in all of our lives.
For this first episode I am going to cover a topic that everyone should be familiar with, even if they don’t know any in depth details. This is, after H2O, the most famous molecule in science and it has been called the blueprint for life. I am, of course, talking about DNA. Almost every cell in our body contains DNA and most people realise that it is important, but what exactly is it? What does it do? How does it work? How did we discover it? These are the questions I will try to answer over the course of this episode. But let’s start at the beginning. Our body is made up of a huge number of cells, most estimates have the total number around 15 trillion which is 15 million million. These cells are very different in their shape and what they do, but the vast majority have a control centre called the nucleus. Inside the nucleus is a very tightly packed bundle of DNA. If you were to take this bundle of DNA out and straighten it all out it would be somewhere around 3 metres or 10 feet in length. If you could somehow magnify it to see the structure (and we’ll talk more about how that was first done a bit later on) it would look a bit like you took a ladder and stood it up, then holding it at the top and bottom you twisted it so the ladder formed a spiral. So now that you’ve got that in your head, let’s look at the steps or rungs of the ladder. In DNA these are called the bases and they are what stores the actual information. There are 4 different kinds of base in DNA and they are called Adenine, cytosine, guanine and thymine. Now I know those are starting to sound like technical terms, but the only thing you need to take away from this is the first letter of each one – A, C, G and T as that’s what we’ll call them from now on. This is why when you see DNA code in a movie it’s always those four letters. There is a base on each side of the rung and they are bonded together which is what holds the two strands of DNA together, and in DNA A always bonds to T and C always bonds to G. This becomes important when we talk about how DNA copies itself, but more on that later.
The name DNA stands for deoxyribose nucleic acid. This sounds complicated but it is just a description of what it’s made of. If we think of the DNA as our spiral ladder, then the two sides of the ladder are made up of something called deoxyribose. The nucleic part is because it’s usually found in the nucleus of cells, and the acid is because it’s acidic. Now, that’s the last time we’ll use those words, from now on it’s simply DNA. So now that we know what it’s called, where to find it and sort of what it looks like the big question is, why should we care?
Well, in order for life to work as we know it our cells need a way to grow, react and adapt to situations as well as divide and make new cells to replace those that are damaged and worn out. And on a bigger scale, a species needs a way to create new generations of similar organisms to replace those that went before. We’ll look at those questions now, but to make it more understandable we will use an analogy to better understand what DNA does.
To get a grip on what the mysterious molecule of DNA is, it can be helpful to think of it like a book. It’s not a storybook however, it’s more like a book of instructions and our DNA book would be titled something like “How to make a human”. A key concept of this instruction book is that each page of the book tells your cells how to do one key thing, and that is to make a protein. We all know the term protein, it’s a key dietary requirement and people trying to build muscle can often be obsessed with it. Whether eating high protein actually works is also fascinating, but that’s for a later episode. Anyway, proteins…. So in our cells proteins are super important. Proteins do a lot of the work in our cells, they carry things, are major structural parts of the cell, are catalysts for reactions among many other functions. Each of our cells needs to produce a very large number of them on an almost constant basis in order to function properly. The cells in the human body require around 30,000 different types of protein at one time or another, but how does it know how to make them? Well it consults it’s book of DNA instructions of course. For each of these approx. 30,000 proteins there is a page in our DNA book called a gene. And if you’re ever wondering what a gene is, that’s pretty much it. It’s mostly a set of DNA instructions on how to make a particular protein. So when your cells need to do something, it makes the proteins needed to do it by consulting the relevant page in our DNA instruction book, which can be translated from the DNA code to a list of the building blocks needed to make a protein, amino acids. To make an amino acid our cells open up the page of our DNA book and make a copy of the page that’s needed. This copy is called an RNA, we will have to do a whole other episode on that, and this copy is brought to the part of the cell where proteins are made. So the page is just a list of 4 different bases, how is that used for instructions to make a protein? Well as it turns out, there’s lots of combinations of these 4 bases and your cell reads them in sets of three. Your cell selects an amino acid depending on which three are next in the sequence. So a sequence of CAC would cause your cell to put one amino acid in place, while CGC would mean it selects a different one and so on. These amino acids are then assembled into a chain which then folds into shape and forms the protein. In most cells this is a pretty constant process, with genes being used to make new proteins across the cell and the DNA instructions are at the heart of it.
But going back to our question from earlier, how does DNA work on a species level? If humans all have their 30,000-page instruction book why are we all different? Well the easy answer is that everyone’s book is a little bit different, unless you’re an identical twin but I’m guessing most of you are not one of those very rare people. But for most of us if we have a sibling they are not exact genetic copies, and our DNA books are different. This is because any organism with parents gets part of its DNA instructions from both parents. This is not set for all of the children of those parents, they each get different pages from their mother and father. So this means that brothers and sisters often have a jumbled mix of features of their parents, but if we think of the bigger picture it becomes a lot more significant than understanding why you have brown eyes and your sister has blue eyes. In the species across the world this mixing and jumbling of features can be a driving force behind evolution. To add to the mixing caused by having two parents, there is also a random mixing between the pages donated from each parent, so some of your DNA book is like a scrapbook of segments from your mother and father. If one of these random mixing events could cause that individual to have an advantage over others in the species then it is more likely to survive and produce the next generation. If the advantage is large enough this can then become the dominant form of the species. As an example, let’s say this happens in a plant. That plant produces lots of seeds and one of them happens to have a random DNA change that causes it’s leaves to taste disgusting to the local insects. This plant is then much more successful and is more likely to survive. Now let’s suppose this change makes it taste disgusting only to certain insects, and insects in another area think it’s delicious. So, what does that mean for our plant? It might well cause it to be become localised to one area where the insects don’t like eating it and this can, over time cause it to separate as a new species. And to add to the fun it can impact on the insect that doesn’t like eating it as well. If the plant really does well and becomes very abundant, then any DNA change that would allow that insect to go back to eating it would mean the insect is itself more likely to survive and then that new adapted insect would become dominant in the population. This competitive edge that gives one individual an advantage over others has become known by the famous phrase “survival of the fittest.” Now while the word fittest might conjure up visions of people on a treadmill in the gym, in biology fitness is really about how likely an individual is to reproduce. So “survival of the fittest” doesn’t necessarily mean the one with the biggest teeth or the fastest, it’s all about which one is best suited to their environment in order to survive and pass on what makes them the fittest, their DNA.
So I hope everyone now has a handle on what DNA actually is, and what it’s used for by our cells. I thought now we could move on to the story of how DNA was discovered and then we could talk a little bit about modern DNA research.
Throughout history it’s been observed that animals and plants produce offspring that share characteristics with the parent generation, but how this happened was not actually known until pretty recently. From ancient times it was believed that inherited traits were carried in the blood, which we still see in phrases such as bloodline and bloodstock. In ancient Greece philosophers such as Aristotle suggested that it was a mixing of blood from both the parents that led to a baby’s development and explained the mixture of traits handed down by the mother and father of the child. Another Greek philosopher, Anaxagorus, suggested that humans were actually in miniature in the egg and merely unfolded and grew in the womb. This idea resurfaced in the 17th century where it was believed that the sperm or egg were actually preformed humans waiting to grow. Amazingly, this idea was the accepted one for almost two hundred years. The change to a more modern understanding didn’t come from studying animals, but instead was made by looking at traits passed through the generations in plants.
In the 1860s, a German monk called Gregor Mendel carried out a series of experiments using pea plants. He noticed that certain characteristics of the plants including things like seed and flower colour, were not only passed on to later generations but if you cross-bred plants with different characteristics then the traits were passed on in mathematically predictable ways. These mathematical rules of how organisms inherit traits are now named Mendelian inheritance after him. One of his key findings was that some of these traits are more likely to be shown in later generations than others, in what he called dominant and recessive traits. Mendel noticed something interesting if you crossed a plant with purple flowers that always produced purple flowered seeds with a white flowered plant that always produced white flowered seeds. Instead of getting a mix of purple and white plants from those seeds all of the plants produced purple flowers. If however you then allowed these plants to produce a next generation there would be some white and some purple flowers and this was always in a ratio of about three purple flowers to every one white flower. He called the traits that showed in more individuals in his crosses the dominant trait while the others were recessive. This pattern was found across all the traits that he examined, and he suggested that there were unknown factors causing these predictable outcomes and those factors are now known to be genes. Because we get two copies of our genetic instructions, one from each parent, it is whether one or both of these is recessive or dominant that causes the dominant feature to be shown. I’m aware this got a bit technical, so just in case I lost you I’ll give another example and slow it down a bit. Let’s say we have two parents, one with brown eyes and one with blue eyes. Now in humans, brown eyes are dominant over blue eyes. So if you have one or two copies of the brown eyed gene then you will have brown eyes. Blue eyes are recessive, so you need both of them to be the recessive blue eyed gene to have blue eyes. With me so far? Now let’s suppose the father has brown eyes and he has two brown eyed copies of the gene. The mother has blue eyes, so she HAS to have two copies of the blue eyed gene, otherwise her eyes would be brown. For this couple any children they have would have brown eyes and all of them would have one copy of each gene, a dominant brown eyed from their father and a recessive blue eyed from their mother. If these children were then to have children with another person who has one copy of each, then about 75% of those children would have brown eyes, with the other quarter being blue eyed. This ratio is because there are four different combinations of the gene they can get: two copies of dominant, two copies of recessive, dominant from their father and recessive from their mother and finally recessive from their father and dominant from their mother. Of those four outcomes, only one results in blue eyes, so they will account for about one quarter of children in that generation.
Now just in case this has become too much to keep in your head, there is a website for this podcast (https://www.podpage.com/untangling-science/) and in the section for this episode I’ve drawn a diagram to explain it and you might find that easier to follow along with.
So, the main outcome from Mendel’s work that is of interest to us for this podcast, is that there are what we now call genes and these impact traits or characteristics down through the generations in a fairly predictable manner. The big missing part at this stage was what exactly was passing these traits between generations. For a long time it was believed that the proteins themselves were what was passed along similarities from parent to offspring. This included a Swiss scientist Friedrich Miescher, who first discovered DNA in white blood cell nuclei, calling it nuclein. It wasn’t until the 1940s that Oswald Avery showed that DNA was able to cause changes in the structure of bacteria that caused pneumonia while protein was not. Further experiments in later years added more evidence, particularly in viruses by Martha Chase and Alfred Hershey showing that DNA alone could lead to production of more viruses. This clearly showed DNA was able to transmit information and led it to be recognised as the only real candidate for heritability between generations.
Now I’d like to introduce another concept that I’m sure most of you have heard of at some point, chromosomes. What exactly are they and what do they do? In our DNA instruction book it’s helpful to think of chromosomes as chapters. Chromosomes are made up of genes all bundled together and the human instruction book is made of 46 chapters, 23 from each parent. Like the number of genes, the number of chromosomes varies an awful lot from one species to the next. In the lab we work with fruit flies who have 4 pairs, while pigeons have eighty pairs and some ferns have more than 1000. But to keep things simple, we will stick with humans and fruit flies for the moment. And don’t complain about the fruit flies, they’re awesome to work with and have some super cool history in chromosome research that we’ll get to in a minute. So on to the obvious question first, what actually is a chromosome?
Well in our cells there’s a lot of DNA, billions of bases that all need to be packaged up and kept safe. If you have a vital instruction book like your DNA you would obviously need to keep it safe, and if it’s 30,000 pages long you don’t want those pages lying around loose. So it would make sense that it’s divided into chapters and that it’s properly bound and covered. This is kind of like what happens with chromosomes in your cell nucleus. Chromosomes mean that the long DNA thread is condensed down into tightly packed structures around proteins that help hold it all together. But where chromosomes really get noticed is when a cell needs to make another cell. For very simple cells without a nucleus, like many bacteria, this means that the cell just splits in half. But for our cells and other organisms with a nucleus it’s a little bit more complicated. One of the key challenges is to make sure that when the cell divides into two, that both have a full copy of their DNA instructions. If this doesn’t happen properly it can lead to the cell dying or even worse malfunctioning. That might sound weird but a broken cell with unusual DNA has the possibility of causing cancer or other diseases. Luckily this is a very rare occurrence in our cells and chromosomes themselves play a large part in successful cell division. When most of our cells are going to divide, it duplicates our DNA so it doubles our chromosomes. They then condense so much that they can be easily seen with a standard microscope and line up across the middle of the cell. If we think of the cell as a sphere then they are lined up along the equator. Special fibres called spindles then grow from the poles of the cellular sphere and they pull one set of chromosomes into each half of the cell, which then divides into two identical cells with the right number of chromosomes. This means that both cells can then function normally.
So how did we figure out that chromosomes carried genes on them? Well believe it or not, the answer lies in fruit flies and some experiments done a little over 100 years ago. Thomas Hunt Morgan was working on fruit flies, when he noticed one had white eyes. He carried out some crosses in the same way Mendel had with his pea plants and found a similar 3:1 ratio of red to white eyes in the third generation, with one extra thing. The white eyes were overwhelmingly in the males. So something was linked to sex determination and white eyes. Hunt Morgan figured out the most likely explanation, which was later proven to be correct, was that the gene for eye colour was on what is called the X chromosome. When an embryo is first formed and it gets one copy of chromosomes from its parents, the particular chromosomes they get determine what sex they are. Female flies both have two X chromosomes while males have one X and one Y. So if the recessive white eyed gene is on the X in males, and it’s not on the Y that means the recessive males will still have white eyes. Females however have two X chromosomes so they can have a dominant red eyed copy of the gene and will mostly be red eyed. This is true in humans of some traits and diseases, most notably Haemophilia which is famously present in males of European royal families. From this and other similar discoveries it became clear that genes are carried on chromosomes and they seemed to be on specific chromosomes even across many generations.
The next key step was to find out the exact structure of the DNA molecule. Even people with very little experience of science would recognise the double helix of DNA. Whether it’s from slightly suspect science bits of beauty product adverts, or the animated DNA strand at the start of Jurassic Park we’ve all seen the shape somewhere. But that shape was not always known and the breakthrough happened in Cambridge in 1953. But before we get to that, a slight digression to talk about the nature of scientific discoveries.
As humans, we like to have defined things, we like to say this thing happened on this date and that was the breakthrough, the turning point the key moment. It makes things easier to remember and think about but it is very rarely like that. In science this is also true and a very important thing to think about, is that each discovery works using the knowledge that someone else discovered before that point. The great English scientist Isaac Newton (who we’ll have to talk about in some future episode) famously said “If I can see further than you, it is because I stand on the shoulders of giants,” giving credit to all the scientists that went before him. In the case of the discovery of the structure of DNA this is famously the case and in my mind, three scientists who did not share the credit played a huge role. So before we head to Cambridge in 1953 we will quickly mention them.
First was a scientist working in Columbia University in New York, Erwin Chargraff. Chargraff’s research into DNA found that the components of the bases were always in the same ratio to each other. There was always the same amount of A’s as there were T’s and the same went for C’s and G’s. He was the first to realise that these bases were bonded to each other to form pairs, a truly vital finding for figuring out the structure of DNA. The other two worked in Cambridge at the time of the discovery of the structure and conducted key experiments towards the discovery, but were not fully credited at the time. They were Raymond Gosling, a student and his lab supervisor Rosalind Franklin and they took the most famous picture in biology, photo 51. This was taken using x-rays instead of normal light allowing the structure of the double-helix shape of DNA to be discovered as well as information about the size of the molecule. Franklin in particular was a brilliant scientist and her contribution was never given the credit it deserved during her lifetime and she died tragically young of cancer.
But back in Cambridge in 1953, two scientists Watson and Crick walked into the Eagle Pub proclaiming their breakthrough as “the secret of life.” In their paper published on the subject they were deliberately understating the significance by saying it had “novel features of considerable biological interest”. They later shared a Nobel prize with Maurice Wilkins, Gosling and Franklin’s supervisor at Kings College London. While I’m not a fan of labelling things “breakthrough moments” this is one that is hard to argue with. The structure of the molecule at the heart of our cells was figured out and scientist took this information and ran with it, the new science of molecular biology expanded at a ferocious rate.
So, we’ve got the history of how we figured out what DNA is, where it is, what it does and what it looks like. What else is there? Well in this podcast I want people to know what it is that scientists working in labs across the world actually do, so now that we know a bit about the molecule let’s talk a bit about modern genetic methods that look at and use DNA in research.
One interesting use of DNA technology is in forensics, and a very famous technique called DNA fingerprinting was first used to catch a criminal in the UK thanks to a brilliant scientist based in the University of Leicester, Alec Jeffreys. But how exactly does DNA fingerprinting work? Well if we go back to our DNA book, where each page is a gene with instructions on how to make a protein. Across all humans the vast majority of our DNA books are exactly the same, in fact it’s about 99.9% the same as every other human on the planet. There small remaining difference is mostly from parts of the DNA that don’t seem to have much function and so this 0.1% varies quite a lot from person to person. Some of these, called microsatellite regions, are so variable that in anything other than a close relative it is quite easy to match a sample found on a crime scene to a person. Unless they have an identical twin of course, but we’re going to pretend that isn’t the case to make things easier. But what exactly do they do to get this fingerprint?
First of all, “fingerprint” is only used as a catchy name, it’s more properly called DNA profiling. To generate a profile a sample is taken, usually from the inside of the person’s cheek. The cells on the swab are isolated and the DNA is extracted. The DNA is then broken into little sections by using special proteins called enzymes that cut the DNA strands into pieces. We will need a whole episode on enzymes at some point, so for now just believe me that they can cut up the DNA into smaller pieces and those pieces are cut at specific parts of the DNA. Now, DNA has an overall slightly negative electric charge and so do these fragments. So, to separate out the DNA fragments they are put into what scientists call a gel. In this context, a gel is a block of jelly like substance with some small wells cut into it at one end. The DNA samples are loaded into these wells and the gel is submerged in a liquid that can conduct electricity. An electrical current is then passed through the gel running from a negative charge to a positive one. Because our DNA is negatively charged it moves through the gel towards the positive end. The gel means that larger bits of DNA move more slowly, while smaller fragments are able to move more easily and so they go faster and further. This means that after a while the fragments are separated out by size. The scientists also load a standard DNA mix in one of the wells with known size fragments in it, that works like a ruler to see how big the fragments in the sample are.
In the early days of DNA profiling the 0.1% of DNA that was unique to the person would be found by then exposing the separated fragments to radioactive probes that can only bind to the unique DNA sequence found in those particular fragments. They are specific to those particular fragments because of how we know the two strands in the DNA helix bind to each other. If you remember we talked about how A & T and G & C always bind to each other? Well if you make a strand of those bases in the right sequence that will bind to the particular section of DNA you’re interested in, and if you make it long enough then no other part of your DNA will have the exact same sequence. This means that it can only find one place that matches and it will bind there. The gel with these probes would then be imaged using x-ray film which would show the radioactive labelled DNA fragments from the gel as fluorescent bands on the film. The pattern these bands make are completely unique to that person and could be used to identify or rule out a suspect from an investigation. Today the radio labelling technique has been replaced by using something called PCR, which many of you will recognise from it’s use in virus testing but PCR is definitely a whole episode to itself. This kind of technique is also used by people for things like paternity tests and companies offer genetic ancestry services using similar methods.
Something else that you have probably heard of is cloning, most likely from the case of Dolly the sheep. (fun fact: She’s named after Dolly Parton due to the starting material coming from the sheeps udder. Also, I won’t have a word said against Dolly Parton, that woman is a hero). Anyway, back to cloning. So, what exactly is cloning? Those of you who are into sci-fi may have visions of giant glass tubes with identical people floating in blue or green liquid, but in reality, that’s not how it works. Simply put, a clone is a biological thing made with an exact copy of the genetic information of another. Lots of things in the world are in fact naturally clones. Many bacteria and other single-celled creatures reproduce clonally as do quite a few plants. Indeed the heaviest known organism is a giant clonal colony of Aspen trees in Utah that weighs about 6 million tons and covers over 40 hectares. And technically our old friends, identical twins could be considered clones of each other. But in terms of scientists in the lab, and our old friend Dolly the sheep, clones are created artificially. There are three main types of cloning and we will quickly go through them.
The first is gene cloning, and this is pretty routinely used by scientists to study a particular gene they are interested in. They first isolate the DNA of the gene, then it is inserted into the DNA of a bacteria or yeast. This can then be easily grown and multiplied to a large scale and used to study the function of the gene or to make large concentrations of the protein that gene codes for. This is particularly useful for medicinal protein products and the first one to be done using this technology on a commercial scale was insulin. So a very useful technique that is known in biotechnology as recombinant DNA technology.
The second type of cloning is where Dolly came in, reproductive cloning. This is done by taking a cell such as a skin cell from an animal and inserting it’s DNA into an egg cell that has had it’s own DNA removed. Once a viable embryo has been formed it is then inserted into an animals womb to develop. If successful the animal when born will be an exact genetic copy of the animal that the donor cell was taken from. This has been successfully done in several animal species including horses, cats and rabbits. In theory it is possible to do the same with humans, but the ethical considerations are extremely complex and not something I want to get into here. It should be noted that cloning doesn’t necessarily give physically identical animals. There are lots of factors other than genetics that determine how organisms develop through their life so some clones can and do look quite different.
The third type of cloning is one most people have never heard of, and that’s therapeutic cloning. This type of cloning works on the principle of stem cells. Most cells when they divide produce exact copies of themselves. Stem cells are different in that they are able to produce cells of different types and function to themselves. When an egg is first fertilised there is only one cell, and this divides into all the cells in our body, so the stem cells from the early embryo are potentially able to produce any cell type you would need to treat an illness. In theory this could mean growing tissue or organs in the lab that would never be rejected as they could be made using stem cells that are clones of the patient’s own cells. While this is amazing in its potential for therapeutics there are several issues to be considered, chief among which are the ethical issues of creating human embryos to be used in the process.
There are so many different applications using DNA in modern genetics research that we could keep talking about them for days. But unfortunately, I don’t have the time. So we will finish off with a quick summary of what we’ve covered today. We’ve learned that DNA is the vital molecule in most of our cells and have come to think of it as the instruction book that allows our cells to function and for species to evolve and flourish. We’ve learned that learning what it is and what it looks like was a long process, in which generations of scientists built on what others had done before. We’ve learned that it’s vital to a range of fields of research from forensics to covid tests and cloning. And I hope you’ve learned that science isn’t scary and can be interesting and engaging. If you have enjoyed this episode please subscribe on whatever platform you use to listen to podcasts and let people know it exists. I will only keep doing these if it generates some interest, so spread the word.
Next time we will talk about viruses, what they are, how they were discovered, how they cause disease and ask the very controversial question “Are they even alive?” Until then I just want to thank you for listening and ask that you subscribe wherever you listen to podcasts, and leave any comments or questions on the website (www.untanglingscience.com) or follow the pod on twitter @UntanglingS . The show was edited by Neal Veglio at Podknows Productions and many thanks to Paul Farrer for the funky theme tune.