The doctor

Name: Ron Crystal
Institution: New York Presbyterian Hospital
Field: gene therapy

Ron Crystal is an American pulmonary specialist, an expert in the lungs and heart, which is one of the reasons that he likes to break off from work to exercise - he knows it's good for him. It was while running one afternoon that he had a crucial idea about using a genetically modified cold virus to carry genes into the damaged organs of his patients.

On the day of the run in April 1989, Dr Crystal had received a call from a medical research team in France with whom he had been collaborating on lung diseases. They told him they'd adapted an adenovirus - a cold virus - to include a gene which prompted the production of a naturally occurring protein (Alpha 1 antitrypsin).

'They said they didn't know what to do with the virus,' said Crystal. 'I told them, let me think about it and I'll get back to you. Then I went running and suddenly got this idea. I said to myself, gee, adenoviruses are the cause of the common cold. That means they must like the cells which line the airways. Why don't we use the cold virus to cure cystic fibrosis?' He ran back to the lab to tell his colleagues, and over the next few days made arrangements for one of his team to travel to France to learn the techniques involved in modifying the cold virus. The bigger problem was that no one had yet identified the gene which causes cystic fibrosis, which meant that the virus could not be loaded with any new instructions for the lungs. Crystal knew he had to launch a search for the gene, a process which at that time might have taken years. But first he decided to see if any other researchers were pursuing the gene. Eventually he approached Francis Collins, a famous geneticist who now leads the Human Genome Project.

'I talked to Francis and figured that he was holding something back from me. I realised that he'd got the gene but wasn't telling me,' Crystal said, glancing out of the window of the Starr Building in New York Presbyterian Hospital.

He was right about Collins. Within a few months, Collins's team announced that they'd found the gene, which enabled Crystal and his colleagues to begin work to modify the virus so that it could carry instructions to the lung tissues of cystic fibrosis sufferers. Several years passed, which were to prove exciting but also rather frustrating. Crystal's original hope of finding a cure for cystic fibrosis did not work out. They found that gene therapy could only relieve sufferers for three or four days at a time because of what is called low gene expression.

It wasn't the idea that was at fault because the virus turned out to be the perfect vehicle. 'We had this robust gene transfer system, and we began to ask what else could we use this for? How could we help people? It became obvious to me that we had a reasonable chance of rebuilding blood vessels, so we started thinking of the heart and peripheral vascular disease,' he said.

Crystal experimented with the idea by injecting a gene into a pig's heart and observed new blood vessels being formed. Tests on humans followed in December 1997, by which time he was working closely with the Todd Rosengart, a cardiologist at the Presbyterian Hospital. The first 15 patients received the gene therapy while also undergoing conventional bypass surgery. A further 10 patients have now received gene therapy in a minor operation that involves tiny holes being bored in the chest through which a syringe and video camera are passed. It is, of course, much less traumatic for the patient and it is hoped that this amazingly ingenious operation will eventually replace a lot of open heart surgery.

The interesting thing about Crystal's progress over the last decade is that he had the right idea for the wrong illness. The notion of using a cold virus which would taxi in genes then be rejected by the immune system is neat. It's best application has been to persuade an old heart to think young and create the blood vessels. But a great panorama of possibilities opens up. And as the analytical work is done on the human genome, more and more ideas will occur to men like Crystal. The protocol may yet prove to be a new line of attack on cancer.
