THE dentist takes a look inside the patient’s mouth and shakes her head, frowning. “I’m afraid that will have to come out. The decay has spread right through the tooth.”
“Gaaaargh,” replies the patient, gripping the arm-rests more tightly.
“Don’t worry. I see from your records you have a stem cell deposit with us. We’ll have a new tooth ready in no time. Make an appointment for the fitting on your way out. Let’s say 10 weeks.”
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Mention bioengineering and the last thing people think of is teeth. Vital organs, such as the liver, kidney and heart – the ones that kill if they stop working – are one thing. But teeth?
A few groups of researchers think that right now dentistry is producing some of the most exciting developments in bioengineering. And it might be only 10 years until some variation of the scene above is played out for real in the dentist’s chair, reckons Paul Sharpe, head of craniofacial development at King’s College London. “The aim is you go along to your dentist, we take cells from you and engineer them,” he says. “We replace them into the site you need the tooth and hey presto, the tooth would grow.”
In a knock-about world with no absolute cure for tooth decay, teeth are always going to need replacing. But let’s face it, the standard options are less than ideal. Dentures are uncomfortable, clumsy and inconvenient. State-of-the-art titanium implants mean gory, heavy-duty dental work, and they still don’t feel like the real thing. Better alternatives can’t come a moment too soon.
Bioengineering has moved on apace in the past few years and with it has come the possibility of growing organs from scratch. Teeth are a very attractive target for bioengineers. They don’t keep people alive like the liver and heart do, so if a tooth failed to grow correctly, the dentist could simply whip it out and start again – much less daunting than if an engineered liver were to stop working. Plus, getting to the implant site doesn’t mean major surgery – just the familiar “open wide”. Indeed, some researchers think teeth have been foolishly neglected compared with efforts to regrow more “glamorous” organs.
And there’s a good chance that human vanity will ensure a steady supply of cash for the necessary research. The huge US market for cosmetic dentistry is testament to at least one nation’s longing for the perfect smile. Biotech firms are already salivating at the thought of grabbing a piece of that multibillion-dollar pie.
The founders of Dentigenix, a US start-up founded last November, aim to buy licences for techniques developed by other researchers working on biological tooth repair and whole-tooth regeneration. Company CEO Christopher Somogyi, a former biotech venture capitalist, says: “The revolution of tissue engineering in medicine still has some way to go in dentistry. At conferences, when cardiology enters the room it kind of sucks all the oxygen out.” But, he adds, the “sheer number of potential procedures” makes the area ripe for investment.
And there are plenty of reasons to think tooth regeneration is feasible, according to Mary MacDougall, associate dean at Texas University Dental School. Many lower vertebrates constantly grow new teeth – with some shark species churning out a few thousand in a lifetime. Although mammals lost this ability long ago, people with certain inherited diseases do in fact grow extra teeth. And bone – which shares some basic building materials with teeth – can regenerate after injury, so why shouldn’t teeth do the same? “Every time we get a fracture our bones heal up – we’re just trying to augment the body’s ability in that respect,” MacDougall says.
It won’t be easy though. Teeth are made of several different tissue types, including tough dentine, and a thin layer of enamel – the hardest substance in the body. Their development is triggered by two-way molecular signalling between the skin, or epithelial, cells of the gums, and the underlying mesenchymal cells. It is the mesenchymal cells that give rise to dentine-producing cells, called odontoblasts, and the epithelial cells that become enamel-producing cells, or ameloblasts (see Diagram).
Inside every tooth is a small pocket called the pulp chamber, fed by blood vessels and nerves from the gum. And the tooth root is held in place by a thin layer of tough bone-like substance called cementum, and thousands of microscopic fibres known as the periodontal ligament. They anchor the tooth in the jaw while allowing some “give”. The development of all these different tissues is orchestrated by a complex sequence of chemical cues. You’d somehow have to replicate these signals to grow new teeth from scratch.
Some researchers feel the entire process is far too complicated to copy. Irma Thesleff, research director at Helsinki University in Finland, who has created a huge database of all the known genes involved in tooth development, is pessimistic. “It’s such a delicate process and such a complicated organ,” she says. “It could be possible but it’s a long time in the future.”
Lined up against Thesleff, however, are many more optimists, each with different lines of attack. MacDougall says: “It’s that mix that’s going to lead to the solution.”
The case for the optimists got a boost when the existence of tooth stem cells was confirmed. Stem cells have the incredibly valuable ability to develop into many different kinds of tissue. Once thought to exist only in the embryo, they actually persist in many tissues right into adulthood. If – and it is still a big if – these cells can be isolated from people and manipulated, they could be turned into whatever tissues are needed.
Two years ago Songtau Shi and colleagues at the National Institutes of 91ɫƬ near Washington DC showed that the tiny pulp chamber inside every tooth contains stem cells capable of becoming dentine-producing odontoblasts. The researchers took dental pulp from extracted human wisdom teeth, broke it down with enzymes then incubated it on Petri dishes. Most of the cells died, but a few kept growing and dividing – a sure sign that they were stem cells. The researchers worked out that out of the millions of cells in a tooth’s pulp chamber, about 80 of them are stem cells.
The next challenge was to see whether they could encourage these cells to develop into odontoblasts. Shi’s team mixed the dental pulp stem cells with hydroxyapatite, the mineral part of dentine, and implanted them below the skin of mice, to simulate their normal position underneath gum epithelial cells. Two months later, some of the cells had turned into odontoblasts, and had begun secreting dentine, with its telltale crystalline structure. And some had formed a pulp-like substance containing blood vessels and nerve tissue. “Everybody was excited when we saw it under the microscope,” recalls Shi. “It showed that tooth regeneration was theoretically possible.”
But turning mice into tooth factories is an unattractive option. Other researchers are trying to deliver the vital epithelial signal in a more authentic manner. Finding epithelial stem cells was never going to be as easy as getting dental pulp stem cells. During development, enamel-producing cells (ameloblasts) lie on top of the enamel they secrete. As soon as a tooth erupts through the gum, the surface layer of ameloblasts is quickly worn away and lost forever – or so people had always thought.
MacDougall, however, says her team has discovered a source of epithelial cells inside adult mouse teeth – although for commercial reasons she won’t say exactly which part. When these cells are grown in the lab alongside dental pulp stem cells, dentine-enamel structures form. MacDougall says it’s “not 100 per cent of a tooth”, but it’s getting there. Her next step will be to implant the teeth into animal jaws, allowing them to fuse slowly into the bone over several months. In clinics, such a long timescale would be a drawback, but it’s no worse than that for the titanium implants used today, she points out.
MacDougall’s is not the only approach, however. Others favour growing a tooth within the gum itself, allowing the cementum and ligament to develop in a more natural manner. They plan to insert a tooth into the gum at a much earlier point in its development, when it’s merely a clump of cells, a “tooth bud” only a few millimetres long.
One of those planning to use this approach is Jay Vacanti, based at Massachusetts General Hospital in Boston. Vacanti is an early pioneer of tissue engineering – five years ago he helped to create the famous artificial “ear” transplanted so freakishly onto the back of a mouse. In work submitted for publication, he and Pam Yelick of the Forsyth Institute in Boston are growing teeth inside rats, on their intestines. This is a tried and tested technique in tissue engineering that exploits the gut’s rich blood supply.
“We’ve successfully generated little teeth that contain both epithelial and mesenchyme structures,” Yelick says. “Now we’re learning how to grow larger teeth by playing with the culture conditions.” For now, Vacanti and Yelick are getting their cells from developing teeth in rat embryos, an impractical technique for human dentistry. Yelick says the next hurdle will be to grow teeth from adult stem cells.
In London, after many years of work with embryonic stem cells, Sharpe is now also using adult stem cells, although he won’t say which ones. And he’s growing teeth in culture rather than inside an animal. By finding the right signalling molecules, he’s persuaded several types of stem cell from adult mice to develop into tooth progenitor cells and immature teeth.
Next, he plans to implant the tooth buds into animals’ jaws. He reckons the developing tooth bud will attract its own nerve and blood supply, and develop its own cementum and ligament. “Once you start them off, they will go on their own,” he says.
Although he has published few details of his techniques, several researchers in this field believe Sharpe is one to watch. Sharpe himself is confident his technique will reach the clinic, and has set up a firm, Odontis, to exploit it. He has little time for criticisms that tooth development is too complex to emulate. “Yes, it’s complicated,” he says. “But we are letting the natural embryonic developmental pathways do the work for us.”
Such tooth-bud implants would be almost like the real thing…but not quite. MacDougall has an even more ambitious goal – persuading teeth to grow from scratch inside the gum. She believes her team’s research on a bizarre genetic disorder called cleidocranial dysplasia, will point the way. People affected have a range of abnormalities, including misshapen heads, missing collar bones and, intriguingly, extra teeth.
All the problems stem from a mutation in a single gene, called RUNX2. It has so many effects that it must play a key role early on in skeletal development, switching on many different genes “downstream”, says MacDougall. Her lab is trying to work out which downstream gene triggers new tooth development, and how to switch it on. “The body has the capability of doing it. We just have to learn more about that process and be able to control it,” she says. MacDougall wants to be able to trigger the growth of a new tooth with just one or two injections into the gum, so that a few months later, a fully formed tooth emerges.
While Sharpe’s tooth-bud implants may look most promising at the moment, MacDougall’s longer-term goal may prove the simplest for patients. MacDougall admits, however, that this treatment would have its own price to pay. There’s another name for the process of a tooth emerging through the gum – teething. The last time that happened, when we were about six months old, most of us weren’t too happy about it. “We had never thought about tooth eruption as being a problem before, until recently,” she says. “A journalist from a men’s health magazine asked me whether men would be prepared to put up with basically going through teething. That’s a potential problem.” Most people, she believes, would be able to bear the discomfort without being too babyish about it, though. “I suppose we could just give them painkillers,” she muses. “Or a teething ring.”
Bank on it
Forget umbilical cord blood banks – the next big thing in stem cell stockpiling could be tooth banking.
Stem cells, with their valuable ability to develop into many different kinds of specialised tissue, are widely seen as one of medicine’s greatest hopes for curing disease. Trouble is, they’re not easy to get hold of. They’re there for just a few days in developing embryos before specialising into skin cells, bone cells, and so on. Once on their fixed course they’re believed to lose their precious versatility. A few semi-specialised types of stem cell have been discovered in some adult tissues such as bone marrow, but we haven’t yet unlocked all their secrets.
Blood from newborn babies’ umbilical cords has been found to contain stem cells capable of developing into blood cells, and is increasingly being used to treat illnesses such as leukaemia and inherited immune disorders. These transplants usually involve altruistic donations coordinated by national blood banks. But several firms offer private umbilical blood storage, for about £600 plus annual fees. These mainly American companies, which have lately started targeting other countries, claim it is a “once-in-a-lifetime opportunity” to “freeze a spare immune system”. And while some doctors frown on the hard sell, many parents are starting to feel it’s better to be safe than sorry.
But don’t forget your tooth stem cells. If tooth regeneration becomes a reality, dental pulp stem cells could be in great demand. These cells, present in tiny numbers inside mature teeth, are central to several groups’ efforts to regrow new gnashers to order. If tooth stem cells do prove crucial, wisdom teeth are one obvious source, particularly in the US, where they’re often extracted at the first hint of trouble. And Songtau Shi at the National Institutes of 91ɫƬ near Washington DC is investigating whether baby teeth also contain stem cells – putting a whole new spin on the tooth fairy myth. No company is yet offering a tooth-banking service, but what’s the betting it won’t be long?