杏吧原创

THE dentist takes a look inside the patient鈥檚 mouth and shakes her head, frowning. 鈥淚鈥檓 afraid that will have to come out. The decay has spread right through the tooth.鈥�

鈥淕aaaargh,鈥� replies the patient, gripping the arm-rests more tightly.

鈥淒on鈥檛 worry. I see from your records you have a stem cell deposit with us. We鈥檒l have a new tooth ready in no time. Make an appointment for the fitting on your way out. Let鈥檚 say 10 weeks.鈥�

Mention bioengineering and the last thing people think of is teeth. Vital organs, such as the liver, kidney and heart 鈥� the ones that kill if they stop working 鈥� 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鈥檚 chair, reckons Paul Sharpe, head of craniofacial development at King鈥檚 College London. 鈥淭he aim is you go along to your dentist, we take cells from you and engineer them,鈥� he says. 鈥淲e replace them into the site you need the tooth and hey presto, the tooth would grow.鈥�

In a knock-about world with no absolute cure for tooth decay, teeth are always going to need replacing. But let鈥檚 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鈥檛 feel like the real thing. Better alternatives can鈥檛 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鈥檛 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 鈥� much less daunting than if an engineered liver were to stop working. Plus, getting to the implant site doesn鈥檛 mean major surgery 鈥� just the familiar 鈥渙pen wide鈥�. Indeed, some researchers think teeth have been foolishly neglected compared with efforts to regrow more 鈥済lamorous鈥� organs.

And there鈥檚 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鈥檚 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: 鈥淭he 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.鈥� But, he adds, the 鈥渟heer number of potential procedures鈥� 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 鈥� 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 鈥� which shares some basic building materials with teeth 鈥� can regenerate after injury, so why shouldn鈥檛 teeth do the same? 鈥淓very time we get a fracture our bones heal up 鈥� we鈥檙e just trying to augment the body鈥檚 ability in that respect,鈥� MacDougall says.

It won鈥檛 be easy though. Teeth are made of several different tissue types, including tough dentine, and a thin layer of enamel 鈥� 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 鈥済ive鈥�. The development of all these different tissues is orchestrated by a complex sequence of chemical cues. You鈥檇 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. 鈥淚t鈥檚 such a delicate process and such a complicated organ,鈥� she says. 鈥淚t could be possible but it鈥檚 a long time in the future.鈥�

Lined up against Thesleff, however, are many more optimists, each with different lines of attack. MacDougall says: 鈥淚t鈥檚 that mix that鈥檚 going to lead to the solution.鈥�

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 鈥� and it is still a big if 鈥� 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 Health 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 鈥� a sure sign that they were stem cells. The researchers worked out that out of the millions of cells in a tooth鈥檚 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鈥檚 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. 鈥淓verybody was excited when we saw it under the microscope,鈥� recalls Shi. 鈥淚t showed that tooth regeneration was theoretically possible.鈥�

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 鈥� or so people had always thought.

MacDougall, however, says her team has discovered a source of epithelial cells inside adult mouse teeth 鈥� although for commercial reasons she won鈥檛 say exactly which part. When these cells are grown in the lab alongside dental pulp stem cells, dentine-enamel structures form. MacDougall says it鈥檚 鈥渘ot 100 per cent of a tooth鈥�, but it鈥檚 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鈥檚 no worse than that for the titanium implants used today, she points out.

MacDougall鈥檚 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鈥檚 merely a clump of cells, a 鈥渢ooth bud鈥� 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 鈥� five years ago he helped to create the famous artificial 鈥渆ar鈥� 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鈥檚 rich blood supply.

鈥淲e鈥檝e successfully generated little teeth that contain both epithelial and mesenchyme structures,鈥� Yelick says. 鈥淣ow we鈥檙e learning how to grow larger teeth by playing with the culture conditions.鈥� 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鈥檛 say which ones. And he鈥檚 growing teeth in culture rather than inside an animal. By finding the right signalling molecules, he鈥檚 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鈥� jaws. He reckons the developing tooth bud will attract its own nerve and blood supply, and develop its own cementum and ligament. 鈥淥nce you start them off, they will go on their own,鈥� 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. 鈥淵es, it鈥檚 complicated,鈥� he says. 鈥淏ut we are letting the natural embryonic developmental pathways do the work for us.鈥�

Such tooth-bud implants would be almost like the real thing鈥�but not quite. MacDougall has an even more ambitious goal 鈥� persuading teeth to grow from scratch inside the gum. She believes her team鈥檚 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 鈥渄ownstream鈥�, says MacDougall. Her lab is trying to work out which downstream gene triggers new tooth development, and how to switch it on. 鈥淭he body has the capability of doing it. We just have to learn more about that process and be able to control it,鈥� 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鈥檚 tooth-bud implants may look most promising at the moment, MacDougall鈥檚 longer-term goal may prove the simplest for patients. MacDougall admits, however, that this treatment would have its own price to pay. There鈥檚 another name for the process of a tooth emerging through the gum 鈥� teething. The last time that happened, when we were about six months old, most of us weren鈥檛 too happy about it. 鈥淲e had never thought about tooth eruption as being a problem before, until recently,鈥� she says. 鈥淎 journalist from a men鈥檚 health magazine asked me whether men would be prepared to put up with basically going through teething. That鈥檚 a potential problem.鈥� Most people, she believes, would be able to bear the discomfort without being too babyish about it, though. 鈥淚 suppose we could just give them painkillers,鈥� she muses. 鈥淥r a teething ring.鈥�