It might have been the Pope, it might have been Charles and Camilla, or even just election fever, but somehow a revolution in medicine went unnoticed this month. Scientists don’t often use the word “amazing” but they are using it of a new breakthrough in gene therapy.
Push to the back of your mind all the recent research identifying genes associated with disease. This landmark research is about actually re-writing genes. It opens up the prospect of making permanent repairs to any gene that is causing a disease or disability.
The new technique, dubbed “gene editing”, overcomes many of the problems associated with current techniques of gene therapy by harnessing the DNA’s own repair system to correct the fault in the gene. The key is something called zinc finger proteins. Remember the name — you’ll be hearing a lot more about them.
Even a tiny error in a gene — one unit in the chemical instruction manual that is the DNA in our cells — can alter the sense of an important instruction. Imagine, for instance, getting a message that said “Sit on the cat” instead of “Sit on the mat”. These errors, called single gene defects, can cause devastating inherited diseases such as muscular dystrophy, sickle cell anaemia or Huntington’s disease. And mistakes in genes that occur later in life, particularly in those that control how fast cells divide, are the cause of many forms of cancer.
Professor Adrian Thrasher, of Great Ormond Street Hospital, the man who in 2002 successfully treated “bubble boy” Rhys Evans, is very excited about the new gene editing technique. For Rhys, a tiny difference in a gene carrying instructions for one bit of his immune system caused a disease called “X-linked SCID”. As a result, he had no resistance at all to infection and spent the early part of his life in a plastic bubble at Great Ormond Street. But, in 2002, Rhys became one of the first people to be cured of his genetic disease using gene therapy.
Not everyone is so lucky. Conventional gene therapy, which has been around for 20 years, has distinct drawbacks. It compensates for a genetic fault rather than correcting it, adding working copies of the gene to cells. It exploits the cunning way in which viruses blag their way into cells, and then get their genetic material incorporated into that of their host. Gene therapy uses a virus delivery system to smuggle new genes into cells — typically, a retrovirus engineered so that its genetic material contains the correct version of a faulty human gene.
People undergoing gene therapy have some of their cells “infected” with these manipulated viruses. But the process isn’t very efficient. Only a small number of the cells that are infected actually take up the gene. The change may not be permanent and it’s difficult to be sure that the right cells have been targeted. More worryingly, the new gene can insert itself anywhere in the person’s DNA. Genes inserted too close to cancer-regulating ones are thought to be behind the cases of leukaemia that developed after children in France had been treated with gene therapy. It has meant trials have been delayed.
“Only a tiny number of people have been helped by gene therapy,” says Alastair Kent, the director of the Genetic Interest Group, which represents those affected by genetic disease.
Zinc finger proteins could provide the answer. They are finger-like projections of protein, held in this shape thanks to an atom of zinc. Found naturally in all cells, the “fingertips” are configured to match one particular gene sequence.
Although there are some 30,000 genes in our DNA, they aren’t all working at the same time. The normal job of zinc finger proteins (ZFPs) is to find the genes that need activating or turning off. For example, in stomach cells, the genes that control digestive enzyme production are only switched on when food is on its way. When ZFPs locate a gene sequence that matches their fingertips, they lock on to it. Once the fingers are locked on, a switch molecule trailing behind the ZFP becomes activated, with the gene then being switched on or off.
What scientists at Sangamo BioSciences, a gene research lab in California, have done is attach a specially made zinc finger protein not to a switch, but to a molecule that can cut DNA. The result, called a ZFN, not only finds a specific sequence, but replaces it too. When introduced to a cell, the zinc fingers look for “their” gene and attach themselves. The DNA-cutter then snips out this faulty gene. The cutting of DNA triggers the cell to repair the damage. The cell needs an undamaged bit of DNA with which to make a repair. Handily, sent in along with the zinc fingers, are fresh copies of the correct gene.
The cell uses these as templates for repair, swapping the duff version for the right one.
In an experiment reported this month in the journal Nature, the Sangamo scientists showed that a faulty gene could be corrected in about 20 per cent of cells using a ZFN. This may not sound much, but even if only 1 per cent of cells have the right gene, it may be enough for the patient to remain well.
This was an experiment on cultured cells rather than on people, but as proof of the principle it is breathtaking. Not only is it very specific, opening up the prospect of a tailored correction service for any faulty gene, but it’s also permanent. Once the gene has been repaired, the cell divides as normal, with all the new cells formed having the correct gene, too. The Nobel prize winner Sir Aaron Klug, who discovered zinc finger proteins in 1982, called it a landmark study. “It provides the foundation for gene modification without the safety issues that have plagued many gene therapy applications,” he says.
Sangamo are currently developing ZFNs to treat sickle cell anaemia and other blood disorders. They are even considering their use for treatment of HIV. As yet, the technology is a long way from being proved. But it is one of the most fascinating genetic developments of the past two decades — and the one with perhaps the greatest promise.
What is a gene?
Within each cell is its control centre — the nucleus. Our genetic material, which contains the entire set of instructions to make and run our bodies, is contained in the nucleus, in the form of 23 pairs of chromosomes. Each chromosome contains one long strand of DNA (deoxyribonucleic acid), and it is within this that genes, the individual units of information, are housed.
