Pushing the boundaries | Action Medical Research

Touching Lives - June 2004

Pushing the boundaries

Professor Nicholas Fisk is a driven man. When I met him in his laboratory in Queen Charlotte’s & Chelsea Hospital, London, he was fizzing with energy. He’d just got back from Dublin the previous weekend where he’d been attending a meeting of the International Society of Cell Therapy, and was later that evening to catch a flight to South Africa to lecture at their national conference on foetal medicine.

In between international flights Professor Fisk is a practising obstetrician — specialising in foetal medicine — and a research group leader at the largest obstetrics and gynaecological research facility in Europe. He’s a busy man, who is all set to get busier.

£139,000 project

Action Medical Research has just funded Professor Fisk to the tune of £139,000 to investigate the potential of stem cell therapy to help with a particularly nasty disease called Osteogenesis Imperfecta. The investigations will be carried out collaboratively with Professor Dame Julia Polak and her team working within the Tissue Engineering and Regenerative Medicine Centre based at London’s Chelsea & Westminster Hospital.

Osteogenesis Imperfecta (OI), also known as brittle bone disease, is a genetic disease that affects babies whilst they’re inside their mother’s womb. Collagen — the main building block for bone — fails to develop as it should, leading to a whole spectrum of problems. Professor Fisk explains, “With OI you can have some kids who just fracture an arm or a leg every couple of years. It’s a nuisance but it’s not the end of the world. That’s Type 1.

Bone fractures

“Then there’s Type 2. We saw a case of this just recently on ultrasound where the baby was already experiencing bone fractures inside the womb at 12 weeks of pregnancy. These children currently have no chance of survival. The baby’s chest will be misshapen, the skull is deformed, and they’ll have multiple fractures. Sadly, these babies will die shortly after birth because their chests are too small to allow them to breathe.

“Additionally there are the intermediate types of OI, 3 and 4. These are also more severe than Type 1. The child may well have fractures in the womb, but they’re more likely to survive past birth. But ^their growth will be stunted and they’ll have multiple, painful fractures throughout their lives, each one leading to a deformity. It’s a pretty awful existence for these children.^”

OI is serious, but, thankfully, rare. Professor Fisk has seen two families affected in the last year. Both were what you might call ‘low-risk’ families not expecting any problems. But then out of the blue at 20-25 weeks of pregnancy, increasingly sophisticated ultrasound scanning techniques picked up the telltale fractures of OI.

OI is an important disease to cure, not least for these children, their parents and families, but it also happens to be a good ‘model’ of a genetic disease for Professor Fisk and his team to work on, with the aim of developing therapies not just for OI but also for other genetic diseases of the muscle and brain, such as muscular dystrophy.

The big idea

Stem cells are the very building blocks of life. These primitive cells have the ability to turn themselves into a variety of body tissues, and in the laboratory scientists can stimulate them to turn into muscle, bone or fat cells. What Professor Fisk and his team have already discovered is a particular group of stem cells that circulate in very high numbers in the unborn baby’s bloodstream, and then only in the first four months of pregnancy.

“In an adult you won’t find any of these cells at all,” Professor Fisk says. “In a baby at birth it’s still very difficult to find any of these cells. But if I took a blood sample from a baby at three months of pregnancy, it’s got showers of them circulating all over its body because they are the building blocks of the baby’s development, and are going to go on and form bones, muscle and organs.

“We want to use these cells as a vehicle to give affected babies the correct gene at the very time when they are laying down their normal bones and muscles inside the womb.

“We think that we can take these stem cells from the unborn baby diagnosed as carrying the abnormal OI gene, genetically manipulate them to correct the errant gene, and then put them back into the foetus to allow it to develop properly.”

Stem cells

So far, so space age. But just how do you take microscopic stem cells from a baby at such an early stage of its development? “They are found in the baby’s blood,” Professor Fisk tells me. “We only need to collect 100 or 200 microlitres of blood from the foetus, which is a tiny amount, less than a fifth of a millilitre of blood, and from that we can grow literally buckets of stem cells in the laboratory. This is what stem cells do. They’re basic cells that are programmed to just keep on multiplying.”

Of course, you would only treat babies if you knew they had a genetic disease. Tests can currently be done for genetic diseases through amniocentesis, where a needle is inserted into the mother’s womb to withdraw a small amount of fluid from the sac surrounding the foetus, or through Chorionic Villus Sampling, where a small sample is removed from the wisps of tissue that connect the pregnancy sac to the womb.

But medicine is advancing in this area too and Professor Fisk hopes to see in the not too distant future “clever ways of doing the tests through ‘free DNA’ from the baby which exist in the mother’s blood.” This would remove the risks associated with amniocentesis.

Genetic testing

However, there are good and bad things about using Osteogenesis Imperfecta as a model to test techniques which might have applications in other genetic diseases. One drawback is that OI tends to appear out of the blue in families not thought to be at risk. Another is that instead of the usual chance of a genetic disease recurring in a second child of 1 in 4, with Type 3 OI the chances are 1 in 14. This means that it is difficult to identify babies with OI through traditional genetic testing.

What’s more likely to happen is that OI will continue to be detected primarily through ultrasound scanning. But OI does have its advantages as a model to work on. It is the only genetic disease for which stem cells have already been used successfully to treat children after birth.

“In trials in Tennessee, ^children with Type 3 OI have been given stem cells in a bone marrow transplant and have gone on to show a reduction in fractures and improvement in growth^,” he says. “When implanted the bone marrow with stem cells has gone on to form normal bone, which is hugely exciting, and clearly shows us that OI is a genetic disease which responds positively to stem cell therapy.

“A fantastic property of these stem cells is that they’re non-immunogenic,” continues Professor Fisk. “We want to put genetically altered stem cells back into the foetus, and you might be concerned as to the fact that these stem cells will go everywhere and might lead to other effects in the body. But we’re only putting in normal stem cells so this shouldn’t be a problem.

“If I give you some of my blood cells, if we’re of different blood types you might drop dead. But these particular stem cells are interchangeable between people, and moreover they suppress the immune response. They’re fantastic in that you don’t have to worry about triggering immune reactions in the same way as you do when giving a child a bone marrow transplant. The challenge will be to see just how readily the stem cells circulate in the foetus to prevent and repair damage.”

Forward thinking

There’s no doubt that Professor Fisk has the ideas and vision to pull off such a huge undertaking. But it is as much about perspiration as inspiration. A typical day sees the Professor rise at 4.30am and quite often he won’t get away from the hospital until 9.30 at night. His Centre for Foetal Care which operates within Queen Charlotte’s & Chelsea Hospital sees some 5,000 patients a year from all over the world, and deals with the most complex foetal problems.

Professor Fisk believes that this marriage of the hands-on clinical work and the lab-based research work really complement each other. “The clinical problems we see inform what we’ll do in the laboratory — we’ll often know if this or that won’t work from our experiences on ward. Very few people in the world have the skills to collect such early blood samples with the needling techniques we use. And not only that, but we have the lab group on site to make use of them. ^You need both the clinical and research sides^, but it makes for a busy life! It doesn’t give you much sleep or many weekends off!”

Hard work

It’s good for the rest of us that researchers like Professor Fisk are willing to make sacrifices in their pursuit of new treatments for these chronic disabling and often lethal diseases. And Professor Fisk is hopeful that the hard work will pay off.

“You have to be cautious. However, in OI there’s already a clinical trial showing benefit from using stem cells in children. We would argue that you’re far more likely to see benefit by using stem cells at an earlier stage before the foetus is damaged by OI.

“The laboratory side is enthralling, but the clinical side of foetal medicine can often be depressing — there are many disabling genetic diseases and for almost all of them there is no treatment. I’ve worked in this field for 20 years, so for me this Action Medical Research project is highly exciting. The prospects for the future are really quite good.”

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