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Wednesday, March 24, 1999 Published at 18:20 GMT


Shark therapy for bizarre bone disease

A new bone fused Harry Eastlack's skull to his neck

Harry Eastlack's bizarre skeleton is on display in a glass case in the Mutter Museum in Pennsylvannia.

Sheets of bone cover Harry's back like a crab's shell.

Ribbons of bone lock his skull to his spine and weld his shoulder and hip joints solid.

The skeleton is almost completely fused into a single rigid piece.

Harry died in his late 30s from a rare disease known as Fibrodysplasia Ossificans Progressiva (FOP). The condition is examined on BBC Two's Horizon programme on Thursday.

[ image: FOP can cause terrible disability]
FOP can cause terrible disability
FOP causes the muscle and ligaments of sufferers to turn into solid bone.

Scientists have been striving for 15 years to try to understand and cure the condition which affects one in two million people.

Many FOP patients are children or teenagers.

Any injury to muscle or connective tissue can kick-start a flare up of the condition during which the body produces a new piece of bone around the damaged site.

The bone that is formed can grow, repair itself and even harbour marrow in the same way that normal bones do.

The new bone rapidly becomes permanent, and can eventually join up with the normal skeleton, leading to devastating mobility problems.

Sufferers can end up fused in a standing poisition, so rigid that they must sleep leaning in a corner.

They may eventually die from starvation, when their jaw fuses shut, or suffocate as new bone crushes their lungs.

Scientific discovery

[ image: Michael Zasloff has studied FOP]
Michael Zasloff has studied FOP
US doctor Michael Zasloff has been attempting to solve why the body should suddenly start to transform one tissue into another in this way for many years.

He realised early in his work that surgery to help FOP patients was out of the question, as every time an incision was made, it led to the formation of new bone at the site of the injury.

Dr Zasloff also discovered that in some instances FOP would strike without warning, leading to the formation of new bone, even when no injury had occurred.

It was this discovery that led Dr Zasloff to get a real understanding of the disease. He noticed that the new bone formed in a predictable pattern, mirroring the normal way the skeleton develops prior to birth.

Dr Zasloff realised that FOP patients have a genetic fault that means that their bodies cannot switch off the mechanism that grows the skeleton in the womb.

Dr Zasloff found it difficult to secure funding to carry out further research because the disease was so rare.

After a decade of struggling he was on the point of abandoning his FOP research completely.

Then he met orthopaedic surgeon, Dr Fred Kaplan, who was interested in FOP. The two joined forces almost immediately.

The first thing they decided to tackle was the general ignorance among other doctors about the disease.

Many FOP patients are wrongly diagosed.

[ image: Ashley Kurpiel's shoulder was amputated]
Ashley Kurpiel's shoulder was amputated
Doctors told Ashley Kurpiel's mother that her daughter was suffering from cancer, and amputated her arm at the shoulder when she was just three years old.

In fact, the FOP swelling that she had developed would have impaired her mobility only very slowly.

The two doctors published more than 20 papers about FOP in an attempt to educate other doctors.

Two years later the number of cases referred to their Philadelphia Hospital had more than doubled.

Fly breakthrough

However, the speed at which the condition spread through the body constantly impressed upon the doctors that the need for a treatment breakthrough was urgent.

In order to unlock the mystery of FOP, Dr Kaplan realised he had to isolate the faulty gene.

He said: "It's like launching a military operation. Before you attack the enemy, you need to know exactly where it is, and then to use that to develop medications and treatments that will be truly beneficial to the children."

A breakthrough came when the doctors heard about the work of Boston scientist Dr John Wozney, who had isolated a bone protein - Bone Morphogenetic Protein (BMP) - which has the ability to stimulate the production of new bone.

BMP stimulates the creation of the skeleton prior to birth, but artificially implanted in living tissue it produces an effect similar to FOP.

The scientists discovered the BMP gene was almost identical to a gene isolated in a fly - a creature with no bones, but an external supporting skeleton.

They mutated the fly gene, and found that it produced anatomical quirks in the creatures which paralleled those in FOP patients. It seemed that the BMP gene must be responsible for the disease.

A further piece in the jigsaw came with the discovery in mice of another gene, Noggin, which stopped the deposition of bone.

Mice bred without the Noggin gene demonstrated FOP-like symptoms.

The scientists hope that Noggin can be used to stop BMP laying down excessive amounts of bone in FOP patients.

Noggin cannot prevent FOP from creating bones, but it might allow surgery to remove excess bone to become possible.

Immune system

Zasloff and Kaplan then discovered that in FOP patients lymphocyte cells from the immune system, instead of attacking foreign invaders when the body is injured, actually attack the body's muscle cells instead.

The lymphocytes were also found to transport the BMP protein to the site of the wound, which triggers the formation of bone.

Knowing how FOP bone formed, the scientists developed a theory about how to attack the disease.

It led them to study another creature without bones - the shark.

[ image: Sharks could hold the key to a treatment]
Sharks could hold the key to a treatment
Sharks have a unique way of forming cartilage but preventing it from ossifying into bone by restricting blood supply to the tissues.

From the shark, the scientists have isolated a new drug which they hope will arrest bone growth growth in FOP patients.

Dr Kaplan said: "When you look at a child who has an FOP flare up, you see a painful swelling lump, and very often you can see blood vessels just below the surface of the skin.

"The blood vessels are critical at a very early stage of bone formation. The thought is that if we could somehow stop the blood vessels from forming and delivering nutrients to the lump that we would be able to slow down, perhaps even stop, the bone formation at that stage."

"Skeleton Key" will be broadcast on Horizon on BBC One on Thursday 25 March. 21:30 GMT.

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