How are teeth made?

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1:05I was having a procedure with a dentist, which was taking rather a long time and was quite painful. And I was desperate to try and think of something to take my mind off what was happening. But all I could think of was teeth. And then this question popped into my head. You're listening to CrowdScience from the BBC World Service, the show that drills down into your science questions, speaking to experts from around the world to extract answers. I'm Anand Jagatia, and our listener this week has been wondering about teeth. My name is John. I'm from the UK. My question is, how do we make teeth? What are they made from?

1:43How do we manage to make them whilst we're in the womb? And why do we only seem to have two sets when I believe that other animals have more than two sets? These are all really good questions. And I think if we had more than two sets of teeth, maybe we wouldn't have to go to the dentist as much, right? I believe that sharks have more than one set. I believe that sharks continually make teeth. But we don't. And it just seems a bit odd. Have we always been like that? Has that changed through evolution? I don't know. I'm really looking forward to looking into some of this stuff. A dental examination, I suppose, of your question.

2:20and we'll let you know what we dig up. Thank you. Thanks, John. So you want us to look into the origin story of teeth. How do they grow inside our mouths? And why don't we make more of them? By the time you're an adult, you have 32 pearly whites inside your skull, including wisdom teeth, which emerge during adolescence. These adult teeth replace the 20 milk teeth that carry you through early childhood until they fall out. But although your milk teeth begin to erupt during your first year of life, as listener John mentioned, they actually start developing when you're still in the womb. We actually start to develop our faces first, and that starts around the fourth week during the gestation period.

3:09This is Anna Angelova-Volponi, a specialist in regenerative dentistry at King's College London. Then the teeth, they start developing around six to eight weeks of the gestation period, which means just a month and a half that we started to develop, we start developing teeth as well. So really early on? Very early. So teeth obviously start, as you say, very early on in the womb, and then you can see them growing in baby's mouths, and then obviously they fall out, right? We have baby teeth, and then we have adult teeth. why do we have two sets of teeth? Like why do our teeth fall out in the first place?

3:48Like wouldn't it be better if they just were fixed to our jaws and they never fell out? Well that's one of the questions you know which is really interesting and fascinating for us. The teeth they are made of very different mineralised tissues heart tissues but within that it's encapsulated as soft tissue and if you just think we need them very hard And the anomaly is actually the hardest substance that we have within our body as humans. So if you imagine the root of the tooth is actually anchored to the bone with kind of elastic collagen fibers, which are taking on the pressure and really making it cushioned and nourished.

4:33And the balance is just amazing. Very often when I teach our students, I say the bone and the teeth, they really love and support each other. And when we lose a tooth, we lose the bone. And then consequently, when we lose the bone and the surrounding tissue, we actually lose that support for the tooth and the tooth can fall off. So it's really an amazing natural balance. So our teeth aren't made of the same stuff as our bones. and enamel, which makes up the surface of our teeth, is the hardest substance in the human body. We'll be looking a bit closer at what else teeth are made from in a moment but given that our teeth are so hard, there's a very good reason they aren't cemented into our mouths.

5:19If you clench your teeth together, you can feel the cushioning provided by your gums which dissipates the force of chewing. But that also makes your teeth more vulnerable to falling out. So listener John asked, why can't we simply regrow our teeth indefinitely, like some animals seem to do? The sharks, they have almost like rolling out new sets of teeth, while the crocodiles and the alligators, they actually come vertically. Or in elephants, elephants, they do not have continuous growth of their tasks, but on the other side, their molars can be replaced up to six times in their lifetime. And they do replace them like almost sliding horizontally.

6:03So it's really interesting how you can find different types of replacements and also how many times animals replace teeth. So if there are animals out there, like sharks or alligators or crocodiles and even elephants that can regrow multiple sets of teeth or have an endless supply of teeth, wouldn't that be better? Like, why do we only get two sets? If we could just replace them forever, then we'd never need to go to the dentist and you'd be out of a job. Yeah. So that's really an interesting question. And I'm trying to keep my job by, you know, studying how we can actually do that in humans. But the reason is that we do have two sets because we have changed our habits and because we have developed the way we did in a sense of the habit of eating.

6:56So we study a lot the reason behind the continuous replacement of teeth in animals and what we are missing in this sense. So the biological tooth replacement is actually the core of our research. And that means that we like to understand what are the genes, the signaling which happens between the different cells, which are triggered in animals and which are not triggered in humans. So can we wake up maybe some of those mechanisms? Can we actually switch on some of those pathways and some of those signals? So according to Anna, it might be possible for us to become a bit more like elephants or sharks and regrow multiple sets of teeth.

7:50We'll be returning to Anna's research later in the show. But before that, although you, like listener John, might be feeling a bit short-changed that sharks have an infinite supply of new teeth while we only get two sets, our teeth do have some rather unique properties. In fact, they're a big part of our incredible success as a species. Our teeth are extraordinary because they are so generalised. Peter Ungar is a professor at the University of Arkansas in the US. He studies the evolution and development of teeth. They pretty much allow us to break down whatever food that we come into contact with, especially when you have tools and fire and things of that nature that sort of pre-process our foods before our teeth even get to them.

8:38But basically, teeth are there for one purpose and one purpose alone, and that is to fracture or fragment foods so that the digestive enzymes in our stomachs can extract more energy from them. That gives an animal an incredible advantage. In fact, it was the energy-unlocking power of teeth that helped mammals to develop one of their greatest innovations. It's only with the mammals that we start to get this warm-bloodedness, this endothermy. And endothermy means we can be active at night when there's no sun to warm our bodies. We've got more energy and endurance. but it comes at a cost. Because if you are creating your own body heat, that requires a lot of fuel for the furnace.

9:28The metabolic rate, the basal metabolic rate, which is the rate at which your body burns energy, is actually 10 times that of a similar sized animal that is cold-blooded. And so mammals have had to come up with ways of extracting more energy from a given bite of food. And that's where our teeth come in. By slicing and cutting food into tinier and tinier chunks, the digestive enzymes in our stomach have much more surface area to work with. And that allows our bodies to extract the energy we need to be warm-blooded, which, again, gives us a tremendous advantage. but it puts a lot of pressure on our teeth to give us the fuel we need for our internal fire.

10:14So how does the structure and the composition of teeth enable them to do this job that's so important for us? Teeth are really wonderful and unique tools. In fact, I work with a number of engineers who are using them as bio-inspired designs for creating stronger materials for human use. What makes teeth unique and exceptionally strong is there's this combination of a very, very hard outer shell called enamel and a still hard but a little bit tougher internal structure called dentin. And it's the combination of this hard, brittle structure, the enamel, and the dentin inside, which has a little bit of give.

11:01It's much tougher. That gives teeth their unique strength. So enamel is like the hardest structure in the human body. So what makes it so hard? What gives enamel its hardness and what gives dentine its toughness? Enamel is hard because it's 95 % mineral. It's calcium phosphate, something we call hydroxyapatite, which is effectively rock. And not only that, but if you look at the microscopic structure of the enamel, it's laid out in these long rods that we call prisms. And these rods sort of undulate back and forth. They wiggle back and forth. And so it's kind of like if you've got a whole stack of pencils, right, and you put pressure on the top of those pencils, you're not going to break those pencils.

11:56And so having this enamel structure, these rods or prisms, gives teeth extra strength to prevent them from starting and spreading cracks through them. Both enamel and dentin are predominantly hard mineral, but dentin contains a higher percentage of collagen, the protein that also makes your skin supple and your tendons elastic. This gives dentin its ability to absorb energy without cracking. And it's the combination of enamel and dentin, both hard and tough, that makes teeth so useful. They are the hardware that help us extract maximum energy from our food, so that we can run further and function in the cold or at night.

12:40In fact, because we can eat pretty much anything anywhere, our teeth have helped to make us the most dominant species on the planet. But what about before the rise of the toothy, hot-blooded mammals? How did teeth evolve in the first place? That's what we'll be finding out next.

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14:01You're listening to CrowdScience from the BBC World Service. I'm Anand Jagatia, and this is the show that answers your science questions. You know, the kind that just pop into your head in the shower, or, as happened to listener John this week, in the dentist's chair. So where do our teeth actually come from? Well, to answer that, you have to go back a very long way, to where we come from. We all came from fish. We all came from ocean-dwelling animals that eventually came on land. This is Yara Haridi. She's an evolutionary biologist and paleontologist at Chicago University in the US. Yara has been researching the origins of our teeth, and to begin with, they didn't have anything to do with eating.

14:44The fish that were in the water that looked closer to us, these lobe-finned fish, our watery relatives, they were covered in little tooth-like projections on their scales. And these little projections, they're called odontodes, and they're made of the same tissues that our teeth are made of. So these early scales and the teeth in our mouth share the same tissues and came from the same structures. And we secondarily proved this by seeing that the same genes that make odontodes on modern fish, like sharks and certain catfish, are the same genes that make your teeth and mine. That's really cool. So basically, what, over evolutionary time, these structures that were on the outside of fish, on the outside of their scales, they've been co-opted by evolution and they've kind of come inside the body and then we've been able to use them to eat and bite.

15:37Yeah, that's exactly right. So what do we think that they were used for? Why did fish have these structures on their bodies? I mean, that is the question, right? Well, teeth on the outside might have protected you from other things that wanted to eat you, but also might have aided in understanding your environment. Because as you know, and as I know, teeth are very sensitive. If you bite into an ice cream or, you know, if you have a toothache or this is why people don't like the dentist, usually. It's just not a fun time to have your teeth drilled into. Why are these things that we chew with so sensitive?

16:14And so that was kind of one of the questions we tried to answer. and look at, well, could they be sensitive on the outside? Or did the sensation evolve when they came inside of the mouth as part of our chewing mechanism? When you say sensitive, what does that mean? So they've got like blood vessels and nerve fibers and stuff? So at the base level, sensitivity needs a receptor and a nerve. And so that's what we looked for. We obviously can't ask fossils if they still have a nerve inside them. So that's why we used modern fish. and we saw that the nerves in modern fish, like sharks, which are covered in little teeth, and certain catfish, which are covered in little teeth, have nerves going inside the pulp cavities of all these little odontodes on the outside.

16:57And then the last thing we need to look at is if the dentine itself, the tissue that makes up the bulk of our teeth, looked the same in these early fish. Because dentine has all these little tubules, it has all these little canals inside that allow for the reception of sensation. So basically, that's why when you bite into something cold, your dentine has all these little holes in it that transmits that sensation to the inside of your tooth. And we found that in fossils. So that gave us the two pieces that are absolutely critical for sensation. So we knew that probably the earliest odontodes on the outside were also sensitive.

17:35So do we know anything about the process that led these structures to end up inside the mouth in, other animals and in other types of fish as well. Right. So how did things on the outside actually end up in the mouth is a great question. And unfortunately, the fossil record at that time period is very sparse. So there's a couple of hypotheses that are floating around. Generally, it's the outside in hypothesis, as in like the structures that started on the outside, they eventually migrated on the inside. So there's two ways that happens. One is that you kind of evolved the toolbox of making a tooth in your genes and that can be expressed in different places.

18:18So you can express it in the mouth, you can express it on the tail, you could express it all over the body and that doesn't necessarily mean that the physical structures have to move, right? It's just you're turning on this switch in one place versus another. Okay and that's then what determines where they end up. So that's the first hypothesis you mentioned. What's the second one? The other is that it was actually useful for certain fish to be covered in these scales all over their face. And at certain point, some of them have had it on the margins of their mouth. And that helped them catch better prey.

18:52And of course, we know through evolution, the ones who are eating more, more successful are the ones that pass on their genes. And so therefore, this became a more successful lineage, the ones that had it on the margins of their jaws, and then eventually moving into the jaw and whichever one became the most successful was selected for and over time that's what we end up with. So you can blame your ancestors fish for your toothache. Your teeth weren't initially used for eating at all in fact they weren't really teeth. They originally evolved to protect fish like a kind of armour as well as helping them sense their environment and over millions of years that structure incredibly ended up inside our jaws.

19:35And given how useful they are, you've probably got a lot to thank those ancient fish for too. So far, we've looked at where teeth come from, what they're made from, and how they propelled mammals and our species to all corners of the globe. But listener John also wanted to know how teeth are formed in our bodies. For that, let's go back to Anna Angelova-Volponi's lab at Guy's Hospital in London. So we make our teeth in a very similar way as we do other organs, such as, for example, hair or salivary glands, all those which we call ectodermal organs. And in order to form these organs, we need two different types of cells.

20:18Earlier, Anna was explaining how our teeth develop in the womb, and it turns out they come from two key cell types. We need those cells which we call epithelial and another type of cells which are called mesenchymal. But we don't need only cells. We actually need these types of cells that they start really talking to each other. Anna says that to understand how teeth form, you have to understand how these two cell types behave. Epithelial cells form the outer layer of our body, like our skin and the lining of our mouth. Under the microscope, they look a bit like tightly packed bricks, making walls.

21:01Mesenchymal cells, on the other hand, are found underneath. These are more loosely organised and can move around, a bit like builders doing the construction work below the brick walls. These cells together act like a team, exchanging signals that will ultimately create a tooth. So they're sending signals and it's a very, very well-orchestrated process. So for example, in our case for teeth, the epithelial cells will be sending the first signal then the mesenchymal cells will be responding, they will be changing, they will be moving, they will be reacting to each other and all of that happens in a certain environment.

21:41And also our research which is trying to mimic all of that what happens during our embryonic life when we're making teeth, we try to mimic that in the lab. The environment that Anna is talking about is a kind of gloop of nutrients that supports the cells and allows them to communicate. Anna and her team at Guy's and Imperial College have artificially recreated this environment using cells from mice embryos. The aim is that by putting those epithelial and mesenchymal cells into it, they'll start acting out the same processes that happen in our body and form a tooth in the lab. We use a kind of material which is a collagen-based hydrogel.

22:23Shuechen Zhang is a PhD student on the research team. We use this hydrogel to inject the cells inside. And in this environment, the two different kind of cells can communicate with each other very well. Wow. So you've basically created like a kind of jelly substance that you put the cells in. It's the medium in which they can communicate with each other. Yes, yes, yes. So have you been able to basically grow a tooth in the lab, a whole tooth? So currently we grow the progenitor tooth. It's like the tooth germ. because in the lab environment, we cannot make the tooth germ to become a real tooth.

23:01But for now, we already create like the tooth germ. It's like a kind of structure before tooth going to form. Okay, so you've been able to create the kind of the precursor cells that would, in theory, if you put them into a living organism, turn into a tooth. Yes, yes. Okay, can you show us anything? Yes.

23:23Shuechan and the team inject the cells into the hydrogel where the mouse embryo cells can interact just like they would in the body of a mouse Looking at the image projected from Shuechan's microscope I can see some purplish shapes made up of lots of cells which, if you squint, look a bit like teeth So from the screen, there's 1, 2, 3, 4, 5, 6 like around six tooths they are going to form. So they're all teeth? Yes, they're all teeth. Or pre-teeth? Yes, pre-teeth, like tooth germ. But we cannot control how many tooths they are going to form because we just mix the two kind of cells together and inject them in the jelly directly.

24:04So they are going to communicate with each other and they are going to form the tooth. Cool. So what's the next step then? For the next step, what we are trying to do is use some stem cells. Everyone has the stem cells. so we can use the stem cells to induce them to differentiate to the specific type of cells, and we can use those cells to make a real teeth. So you could in theory in the future maybe take stem cells from me, push them in this direction so they turn into mesenchymal and what was the other one? Epithelial. Epithelial cells, give them this signaling pathway, and then get them to form this proto-tooth and then put the proto-tooth back into my mouth and it would maybe turn into a real tooth.

24:46That's the whole picture of what we want. Cool. How far away is that from happening? It's really hard to say, actually. Researchers hate that question. Yeah, yes. But currently we are focused on how to study the signaling pathway. So, yeah, it's really hard to say how far away.

25:08So scientists like Anna Angelova-Volponi and Shuechan Zhang could revolutionize dental care by growing teeth in the lab. which would mean less painful drilling for people like John. Being able to biologically replace teeth, rather than relying on fillings or crowns, is a hot topic in dental research right now. And in Japan, they're attempting to do this another way, by tapping into the body's hidden ability to grow extra sets of teeth. We've always had the potential to grow third teeth. They've mostly vanished, but in some people, around 0.3%, they actually grow extra teeth. This is Dr Katsu Takahashi, a dentist and molecular biologist at the Medical Research Institute at Kitano Hospital in Osaka, Japan.

26:0020 years ago, he made a breakthrough when looking at the teeth of mice. Now, mice don't usually have milk teeth, but Dr Takahashi found that some of them did, and those mice were also missing a gene for a protein called USAG1. I was able to verify the formation of fully formed teeth in a mouse that was missing the USAG1 protein. That means that by removing a single gene, it was possible to grow fully formed new teeth. The original biological medical function of this protein that was missing was to suppress the growth of teeth.

26:44Wow. So your aim as a dentist, obviously, is not to edit the genes of your patients, but if you could produce some sort of protein or some sort of medicine that would do the same thing and get rid of this protein in other animals, then it might enable you to regrow teeth. It's a very simple concept, a simple idea, but you can't treat patients by removing their genes. So we came up with the idea of developing an antibody that would suppress the function of this protein. And eventually, we succeeded in producing this antibody called a neutralising antibody that suppressed that function. In addition to mice, we also used ferrets.