One in 700 US babies has a facial defect. Genetic therapy is offering them hope, reports Steve Farrar from the Amerucan Association for the Advancement of Science's annual meeting.
The British sea captain who arrived in the New England settlement of Brandywine almost 300 years ago was a charmer, but it was not his smile that caught the ladies' eyes. That the mouthful of gruesomely discoloured teeth he boasted did not hinder his pursuit of the opposite sex becomes tragically apparent to any visitor to Brandywine today.
Thanks to a faulty gene bequeathed to his descendants by the captain and three centuries of inter-marriage, one in 15 in the isolated Maryland community now suffers the same affliction. Their teeth are a deep amber colour. They also tend to wear down fast, sometimes right back to the gum, as the hard dentin "substance" of the tooth is malformed by a rare syndrome - dentinogenesis imperfecta, or DGI, a legacy of the sea captain.
To the scientists, this genetic legacy represents a chance to gain a remarkable insight into the biological rules for constructing the human face and mouth.
Mary MacDougall, associate dean for research at the University of Texas Health Science Center in the United States, has been working with two of Brandywine's extended families to identify the gene responsible for two related forms of DGI, types 2 and 3. While the hunt for the culprit is not over, it has already revealed a great deal about the chain of genetic and chemical dominoes that must fall in exactly the right order to result in the dentin being correctly deposited in each growing tooth in a child's mouth.
"This research is telling us a lot about the basic biology of how these genes and proteins work," MacDougall says. "And when we find the gene responsible for DGI, it will allow us to develop a gene therapy to correct sufferers' teeth prior to their growth."
The genetic symphony.
Behind every face is a set of basic genetic rules that were worked out 550 million years ago with the evolution of the first vertebrates.
Unlike most other animals, vertebrates sense the world from a set of organs - eyes, ears, nose and tongue - usually clustered near their brain. In essence, the face evolved to "house" those organs, but it has also become the principal means by which individual humans recognise each other.
In the foetus, the preliminary layout is set very early. Neural crest cells form in a pattern in the hindbrain and then move to the front of the foetus's head. There, they transform into a range of other cells that will go on to form the various elements of the face, such as teeth, skin and muscle. It takes just 24 hours and happens in a human foetus roughly 19 days after fertilisation.
The process is more or less the same for all vertebrates, although it seems that nature has added new rules in more complex organisms such as man. A whole orchestra of genes plays a part in this genetic symphony. Some create the necessary tissues or secrete tough substances such as dentin; others ensure the right bits form in the right places; and still others take the role of conductors, regulating and timing each movement.
It is a complex process. No single gene determines, for example, what your nose will look like. As with every part of your body, the interplay of a range of genes will dictate its development and eventual outcome.
Scientists in universities and institutes the world over are struggling to unravel how this genetic symphony is put together. At the University of California, San Francisco, Jill Helms has been investigating the central role that one genetically created chemical - vitamin A - plays in the development of the face.
It is emerging that the same molecular signals are needed to direct the early development of both the brain and the face, and Helms's work suggests that vitamin A is a key, though by no means the only, conductor.
Her experiments on chickens have shown that blocking vitamin A at a crucial moment in the brain's development has a catastrophic effect - other vital genes do not "switch on" when needed and, as a result, large parts of the face and forebrain do not form. When something as apparently minor as a single gene fails at a critical moment, the impact can be devastating.
In the US, one in every 700 newborn babies has some facial defect. They may develop with a single, cyclopean eye or have mouths filled with dagger-like teeth spread across their palates. More often, they suffer cleft lips or faces whose shape is distinctively distorted, such as in Down's syndrome.
Those who survive often face discrimination and social exclusion that prevents their leading a normal life. They are bullied as children, stared at or mocked in public, shut out of careers that involve meeting people and, in many cases, find themselves prevented from making normal networks of friends or finding partners. The social dilemmas they confront can be damaging. Science can help offer a way out of the impasse.
A look at the face of the future.
The face clinic of the future will be a place of gene therapy. It will be thronged not only by those who seek help with genetic disorders such as DGI and those who have suffered severe facial injuries, but also by those seeking to make themselves or their children more attractive.
Americans spend $100 billion a year on cosmetic surgery. But the new science holds the hope of far more sophisticated interventions that will make a huge difference to those whose lives have been blighted by genetic facial conditions. At the National Institute of Dental and Craniofacial Research in Bethesda, Maryland, such work receives $0 million of government money per year.
Harold Slavkin, director of the institute, says this is a legitimate use of public funds. "The people in Congress and the executive branch of government are extremely sensitive to quality-of-life issues such as this," he says. "When most people look in the mirror, they want to look good. The face is the card of acceptance in our society - why else would people spend so much on make-up?" And it makes all the difference to those trying to cope with debilitating facial conditions.
Research being carried out in universities and institutes in the US, the UK and elsewhere has already started to bear fruit. For those like the Brandywine villagers, it can help provide a diagnosis for their condition.
So far the distinctive molecular signatures of some 360 different facially disfiguring syndromes have been identified. This total will probably double by the end of this year.
"Many of these will lend themselves to single or multiple gene-mediated therapies," Slavkin says. The coming decades promise a far greater understanding of the genetic and chemical mechanisms that create the face, giving scientists new openings to find treatments for those ruined by nature as well as pushing forward the flourishing field of bioengineering to enhance and patch up the rest.
The Office for National Statistics recorded 5,607 babies with congenital anomalies of all types in England and Wales in 1998 - about one in 116 births. Of these, 583 had the most common craniofacial deformation - cleft lips and/or palates, where separate pieces of the face do not fuse together as they should. Corrective surgery is generally carried out when the infant is between two and six months of age. The ONS figures also recorded 76 babies with congenital eye anomalies and 245 with other face, ear or neck anomalies.
Down's syndrome affects more than one in 2,000.