Without a voicebox, people can't talk at all, they can only laugh and cry soundlessly, and they can't kiss, because no air passes the lips. These are all things that make us human. As a surgeon, Martin Birchall, Consultant Senior Lecturer in Head and Neck Surgery at the University of Bristol, has had to remove innumerable larynxes. Recently, however, larynx transplantation has emerged as a viable alternative to simple removal, and with Wellcome Trust funding, Mr Birchall aims to refine the procedure so patients can return to near normal lives.

Loss of the larynx can be highly traumatic. Although there are various ways in which patients can learn to talk again, such as the voice valve and electro-larynx, none of these devices sounds human or normal, or allows fluent communication. Some patients even opt to do without, leaving them unable to communicate vocally, socially excluded and, in the worst cases, prone to become social recluses. The desire not to be robbed of speech can provoke drastic action – as in the case of the Hollywood actor Jack Hawkins, who developed cancer of the larynx, underwent a laryngectomy, and died after an unsuccessful attempt to restore his speech.

In the past couple of years, exciting progress has been in an alternative approach, larynx transplantation. In 1998, the first human transplant was performed by Marshall Strome, head of the Cleveland Clinic, Ohio. Timothy Heidler was 40, and his larynx had been irreversibly damaged in a road accident two decades previously. The surgery seems to have been a great success, says Mr Birchall: "Five days after the operation, he said the word 'hello' – his first word for 20 years. He talks for a living now. He talks normally, he can intonate his voice and he can sing. A paper has just been published in the New England Journal of Medicine describing the three-year follow up of this patient, and he's doing really well, so that's fantastic."

The downside, however, is that Heidler has to breathe through a hole in his neck. There is thus substantial room for improvement in this emerging surgical technique.

Inside the larynx

The larynx is at the crossroads between swallowing and breathing. "It's primary role is that of a sphincter," says Mr Birchall, "it closes to let you talk and swallow, and opens to let you breathe. When the vocal cords are lying together you get an excellent voice, but there's not a big enough hole to breathe through. If you open it up you can breathe but you can't talk very well and your food goes down the wrong way."

Patients therefore need fine control over their larynx, opening it to breathe and then closing it again. Unfortunately, instead of growing back to the right muscles, the nerves that control the motion of the vocal cord grow back randomly after a transplant, leading to useless movement of the larynx.

Rather than simply repairing the laryngeal nerves, Mr Birchall and his team aim to use the phrenic nerve, which normally controls movements of the diaphragm during breathing, and re-route it to the larynx. "You take a deep breath, your diaphragm contracts, and your larynx opens up. This technique has been shown to work in animal work done by others. Our group is now assessing whether the same technique can be used in humans, and the first impressions are encouraging. Whether it's going to be sufficient we'll have to wait and see when we've completed a proper series of patients."

Lending a hand

Mr Birchall will also be seeing if nerve regrowth can be stimulated by the application of biological mediators, such as nerve growth factors. This work will be carried out in collaboration with neurologists at the Blond McIndoe Laboratories at the Royal Free and University College Medical School, London, headed by Dr Georgio Terenghi, the world leader in this field. There are other difficulties to be tackled, too, including the problems caused by oxygen deprivation before and during transplantation. As with all transplants, lack of oxygen to the larynx while it is being transported triggers changes in the walls of blood vessels within the organ. Ironically, these changes lead to significant tissue damage when bloodflow is restored – so-called ischaemic reperfusion injury.

"We don't know how much ischaemic damage the larynx suffers," says Mr Birchall. "We aim to develop a model to measure both 'cold' ischaemic damage (caused during transportation on ice) and 'warm' ischaemic damage (caused during the operation before blood starts to flow through the organ) – and then work out strategies for reducing this damage."

Another area of investigation is the amount of immunosuppressant drugs patients will have to be given to prevent rejection of their transplant. How closely matched do donor and recipient need to be for laryngeal transplants, and how does the closeness of the match affect the levels of immunosuppressants needed? "We need to determine the amount and duration of immunosuppression required across varying antigenic or immune barriers. Until there's been a series of people or animals who've had laryngeal transplants, we won't know what levels immunosuppressants a patient should take, which could mean that people like Timothy Heidler might be kept on unnecessarily high levels of drugs for the rest of their lives."

Mr Birchall is therefore underpinning his clinical work with laboratory work in collaboration with immunologists in Professor Chris Stokes's unit at the University of Bristol. Work to date has thrown up some interesting results. "It used to be assumed that the larynx was just a hollow tube of muscles and bones, with no or negligible immune features," explains Mr Birchall. "However, during pilot work we discovered something we've called LALT: laryngeal-associated lymphoid tissue. It appears, sadly from our point of view, that LALT is packed with dendritic cells – the cells that present foreign antigens to the immune system. These cells are going to be very efficient at presenting their own antigen to the recipient's immune system, so it looks as though the transplanted larynx is going to be attacked quite strongly."

There may be a silver lining to this discovery, however: "An exciting spin-off from this work, is that we found that LALT was most well developed in the trachea and the subglottic area of the larynx and least well developed in the vocal chord. By far the commonest of cancers in the airway are in the vocal chords. You never get cancers of the trachea, which is packed with LALT. This has made us think that perhaps a well-developed LALT system – and other lymphoid tissues, throughout the body – might protect people from cancer and tumours. This is the first indication that they might do so and may well be an insight into cancer."

Towards clinical trials

Mr Birchall's aims to conclude his research with a demonstration that a transplanted larynx can survive – maintaining normal functions and without developing complications – for eight months in pigs. The operation will incorporate knowledge gained from the previous experiments to minimise ischaemic injury and maximise nerve repair. The entire research programme will enable him to determine whether or not laryngeal transplantation can proceed to clinical trials.

The project has been made possible by a Wellcome Trust Research Leave Award for Clinical Academics, which releases Mr Birchall from his clinical and teaching duties and enables him to dedicate five years to this research. "The unique thing about my award is that the Trust have acknowledged that surgeons cannot stop operating for five years and they're allowing me to do an operating list and a clinic for a day each week. It's essential for surgeons to keep their skills going, so the Trust has shown great foresight. It's a milestone, a real move forwards, in terms of recognising the importance of surgeons doing research in this country."

At the end of the project, the technique should be nearer clinical application. "Whatever happens – even if we don't transplant, which I'm pretty sure we will – we will still have made huge strides in terms of immunology and neurology. If we understand how the larynx immune tissue works and in particular its roles in cancer and disease – and if we can also make a paralysed voicebox work again more effectively, either through the phrenic nerve or by using nerve growth factor – that will benefit enormous numbers of people."

External links

• Mr Martin Birchall at the University of Bristol: Research interests
• News release from the University of Bristol announcing the research award to Mr Martin Birchall
• Marshall Strome: Research details at the Cleveland Clinic Ohio, USA
• Laryngeal Transplantation and 40-Month Follow-up: Reference to Marshall Strome’s paper published in the New England Journal of Medicine
• Jack Hawkins: Brief biography details