Earlier this year doctors made history, using their knowledge of the genome to treat a child with a congenital condition
James Meek
Last February an air of euphoria seeped into the corridors of the Necker hospital for sick children in the Montparnasse district of Paris. Wondrous cures, great courage and the heart-hollowing grief of parents left behind by children who could not be saved, make the Necker and its ilk emotionally charged places at any time, but this was different.
What was happening to the 11-month-old baby boy in the airtight bubble in a room in the hospital’s immunology and haematology unit was an incredible transformation, and more: it was history. For the first time, doctors had used mankind’s knowledge of the genes involved in a fatal disease to cure it. After more than eight years of inconclusive experiments, gene therapy’s promise to correct nature’s flaws was being realised. Now that humans’ genetic code has been cracked, more and more of those flaws will come within reach of repair.
When the boy was admitted to hospital, he was facing death within a year from a rare inherited disorder called X-linked SCID, one of a family of diseases that cause children to be born without a working immune system. The slightest infection can be deadly.
The boy lay in his bubble for several days while doctors Alain Fischer, Marina Cavazzana-Calvo and Salima Hacein-Bey took out a few million of his bone marrow cells and coaxed the healthy gene to enter them. Then they put them back – a single, simple infusion of 20 to 30ml of fluid. It took half an hour to buy the boy what they hope will be a lifetime of normal immunity.
Doctors knew in 15 days from tests that the new gene was working. But the marvel for the parents was watching the change in their sickly, underweight boy. Before their eyes, he began to thrive. The ugly red blotches on his skin faded away, his diarrhoea disappeared, he put on weight, his breathing became easier. Three months after the infusion, his astonished parents were told they could take him home. There he remains, a normal, healthy two-year-old boy.
“We lived three months of euphoria in the lab,” said Cavazzana-Calvo. “Everyone was so happy. For three to six months we talked about nothing else except the results.”
Three other children, one French, one Dutch and one American, have since been treated at the Necker hospital with similar success. A fifth boy, Shah Rayhman from London, has not done so well, because the disease had already caused serious complications, but the Necker is pressing ahead with further trials later this year, and simi-lar gene therapy is to be carried out in London and Maryland.
This first gene therapy success, formally announced in April’s issue of the journal Science, will have to be further proven over time and does not translate into working gene therapies for other, more common genetic diseases such as cystic fibrosis, muscular dystrophy or Down’s syndrome. But it is a stride forward after last year’s pessimism about gene therapy in the wake of the death of Jesse Gelsinger, the 18-year-old gene therapy guinea pig who died in a poorly designed trial in Pennsylvania.
Dr Cavazzana-Calvo said:”Curing is one thing. Correcting an illness for two or three years is another. We have not had enough follow-up time to claim that it’s a definitive treatment: it’s a success so far. But the importance of this work is to have made the proof of principle that this strategy can work.”
Seen through the eyes of the genetics researcher, the human body is a humblingly vast world made up of 75-trillion cells. In this world, each cell is like a city state in its own right. Each has walls bristling with communications equipment. Inside it has stockpiles of chemical raw materials; its own power plant; factories making products according to the city state’s own needs and the needs of its import-export operations; and an army of couriers carrying instructions to the factories.
At the centre of each of these city states (with the exception of the red blood cells) is the library where these couriers find their instructions. This is the genome. The tens of thousands of volumes in this library contain orders for the couriers, such as “tell the factory to make this much insulin, now”. Sometimes the couriers will bring instructions into the library from another city, telling them to seal or unseal this or that volume.
Now imagine that in each of these billions of libraries there is an identical mistake in one book. The couriers will do their best to fulfil the bad instructions, and something will go wrong. It may not do the cell much harm. It may make it seriously defective. In the worst case, the whole world goes dark and dies.
Looked at this way, it is possible to understand how hard the task facing gene therapy scientists is. First, they see that there is trouble in some of the cities: the walls are the wrong shape, for example, making them vulnerable to attack from outside. Then, scientists have to work out which of the volumes in the libraries is causing this by giving out false instructions about wall-building. To make it harder, several volumes, cross- referencing each other, could be involved.
Finally, they have to work out how to transport a correct replacement book on an often treacherous journey to the gates of millions of cities, smuggle it inside, and sneak it on to the library shelves in such a way that the couriers will read it and obey.
With X-linked SCID, researchers identified the flaw in 1993. It lay on the x-chromosome, which in boys is one of 46 sets of genes in the genome. (Girls have a spare set of x-chromosomes so are not affected by the disease.) The flaw, a tiny genetic mutation, is a tragic broken link in a vital sequence.
In every person’s bone marrow is a group of cells known as stem cells, which, when they receive the right chemical signals, evolve and multiply to become red and white blood cells. The white blood cells are central to the body’s daily fight against infection, identifying and killing alien organisms. In order to turn into white blood cells, the stem cells have to receive a signal from other cells in the body telling them to do so. In babies with X-linked SCID, the faulty gene fails to produce one of the proteins that enable the cells to receive the signals – so the cell does not hear, there are no white blood cells, and no immunity.
So how did Cavazzana-Calvo, Hacein-Bey and their 11 collaborators crack it? They took bone marrow from the little boy and isolated the cells most likely to be stem cells. Then they sent in mercenaries, in the form of a virus. Viruses do what the scientists cannot do themselves, break inside a cell with a set of genes and squeeze the genes into the host genome. It is possible to slip a human gene into a harmless virus and have it infect human cells, which can then be returned to the patient. That was what the Necker team did. The cells given the good gene entered the baby’s body and produced the missing component.
X-linked SCID is rare, afflicting 0,002% of the population. But when it threatens the lives of 100% of your children, as it did with Ann Vincent, the rarity is no comfort. For a mother to be told her baby has the disease, the shock is threefold. First, your son could die before his second birthday. Second, you are the carrier. Third, your mind flashes back over family history; the mysterious infant deaths of brothers generations back become mysteries no longer.
“I come from a family which has a history of losing baby boys when they were six months old. They all died of different things, so we never thought they were connected. But when my son became really, really ill, he was diagnosed with X-linked SCID.”
Mercifully, since 1968, there has been another treatment for SCID patients: a bone marrow transplant. A donor was found for Vincent’s first son, Owen, and he was saved. Later, she accidentally became pregnant again, with another son, Niall, who also had the defective gene. Doctors were able to save him using his older brother’s rejuvenated bone marrow.
But marrow transplants have severe limitations. Even patients with compatible donors have to endure months of chemotherapy, with all its ghastly side effects. Patients with non- compatible donors have only a 60% chance of survival, and many of those who do survive have only partially restored immune systems.
Many false hopes have been raised before, and bone marrow transplants will continue to save lives for the foreseeable future, but the signs look good that X-linked SCID, at least, can within a few years be held at bay by better means. Ultimately, children could be treated in the womb. As the human genome reveals its secrets, other inherited diseases, in children and in adults, should follow.