Counter-intuitive #1: The Shape That Kills

Chris Lawson

Sébastian is two years old. It is the early 1980s. He lives in Canada. He has a brain tumour.

To get at Sébastian’s cancer, the surgeon has to cut a hole in the fibrous layer covering the brain called the dura mater. After the tumour is removed, the hole has to be patched. The surgeon uses a product called Lyodura to cover the hole.

Sébastian pulls through. The tumour is gone. His brain is scanned every two years and there is no sign of recurrence. Sébastian grows up like any normal boy, except for the six-inch scar that he carefully combs his hair over every morning.

Fast forward >>>

Sébastian is eighteen. While driving to volleyball practice, he runs his car off the road and wraps it around a pole. He is not hurt, but he is shaken by the accident and cannot explain how it happened.

His parents notice that his walk has changed. His balance deteriorates over the next few weeks. He is having trouble concentrating on his college exams. Sébastian is terrified that his tumour is growing back, but repeated brain scans show nothing abnormal.

Sébastian starts to lose his train of thought. His right hand trembles. He gets stuck in the Riven computer game and can’t find his way out. He has trouble lining up a hot dog with his mouth. He has more brain scans, spinal taps, blood tests, and electro-encephalograms. Nothing indicates the cause of his problem. Meanwhile, his tremors turn into spasms and uncontrollable jerks.

Finally a neurologist makes the diagnosis. Sébastian has a rare condition called Creutzfeldt–Jakob Disease.

A shape is eating his brain.

Creutzfeldt–Jakob Disease, or CJD, is the human equivalent of mad cow disease in cattle and scrapie in sheep. Less than twenty years ago, these diseases were called “slow viruses” because they took years and sometimes decades to incubate. Other human “slow viruses” include Kuru, which affected the Fore people of New Guinea, Gerstmann–Sträussler–Scheinker disease (GSS), and the self-descriptive Fatal Familial Insomnia. But nobody could identify the viruses, and it was not for a lack of searching.

Thanks to clever research by Stanley Prusiner, we now have very good evidence that “slow viruses” are infectious despite having no genetic material, which if true means they can’t be viruses. Prusiner won the Nobel Prize for his work, but only after a bitter struggle against the prevailing “slow virus” orthodoxy that nearly cost him his funding and his career several times over.

Prusiner called the new agents prions, a contraction of “proteinaceous infectious particles”. Prions are not viruses. Prions are not bacteria. Prions are not yeasts, fungi, protozoa, or helminthic worms. Outside the most liberal definitions of life, a prion is not a living thing.

A prion is a shape, a self-replicating shape. It is a folded form of a protein found in the brain, and the most extraordinary of its properties is that it catalyses the conversion of normal protein into a copy of itself.

All the human prions diseases, CJD, Kuru, GSS, and Familial Fatal Insomnia, are caused by subtly different foldings of a protein called PrPc. The PrPc protein is found in nerve cells throughout the body, and also in the tonsils, kidneys, heart, lungs, and spleen. The function of the protein is not well understood — there are five competing theories — but it may be of critical importance because the gene that codes for PrPc is almost the same across all mammalian species. (As a general rule, the more critical the function of a gene, the less evolutionary variation there is across divergent species; although just to complicate matters, there is a strain of lab mice that lacks PrPc from birth and they seem to get along fine.) Because the PrPc protein is highly conserved across all mammals, prions can cross the species barrier with relative ease.

If a biochemist were to draw the reaction, it would look like this:

Prions act as enzymes that accelerate the transformation from normal protein to prion. In other words, prions create copies of themselves from the raw material of the PrPc protein in our brains, just by folding it over.

The normal PrPc protein looks like a key ring with three keys, and a chain holding it all together. The prion is the same key ring, the same three keys, and the same chain, but all tangled up in a solid mess and one of the keys bent in half. Anyone who has carried a large set of keys will know how easily the keys can lock themselves into a tight knot of metal. The prion is like the knotted key ring: it has all the same components, but it is folded into a tight, stable configuration, plus it has the unusual property of making other key chains it touches tangle themselves up as well. A prion is a contagious knot.

Like the knotted key ring, the prion is much tougher to pull apart than the unknotted protein. The normal PrPc protein is soluble in water and easily degraded by the cellular machines that break down unwanted debris and excess proteins. The prion form is not soluble, and it is knotted so tightly that it cannot easily degrade. The result is a nasty reaction that turns normal functional proteins into fibrous tangles that clog up nerve cells. The reaction starts slowly, taking decades to become noticeable, but it is a form of compound interest and once it reaches a critical point, the growth is spectacular and terrible…

Sébastian, the college student from Montreal, is probably infected by prions he received from the Lyodura graft when he was two. Lyodura is harvested from the dura mater of cadavers, followed by irradiation and then freeze-drying to kill bacteria and viruses. The prions survive. It can take up to twenty years to incubate CJD, but progression can be rapid once symptoms appear.

Sébastian is admitted to hospital. His seizures are quelled only by large doses of sedative. He loses control of his bladder. He stops eating. His mental capacity deteriorates on a daily basis. Soon he cannot speak. Then he slides into unconsciousness. His father speaks to Sébastian, hoping to penetrate the fog of coma by telling him he is very brave, but also because he wants to be honest, telling him that there is no way out.

Four months after the accident he could not explain, Sébastian dies.

That was 1998. There has been a wealth of research since then, but there is still no cure, still no way to slow progression, and still no diagnostic test except autopsy or brain biopsy.

Prions will remain a difficult challenge to medical science. Prions are not invaders, like bacteria or viruses. They do not have a metabolism to attack. They have no cell walls to break down. They do not evoke an immune response, the basis of vaccination. They construct themselves out of our own brain matter.

It is one thing to fight an invading microbe. Our immune systems have evolved to be very adept at that, and modern technology has made us even stronger. But how do you fight a topological nightmare? How do you fight a contagious knot? How do you fight a shape?

I would like to thank Robert Roussel, father of Sébastian, and others who made their stories public. Several personal accounts can be found at
The Many Faces of CJD. (http://www.fortunecity.com/healthclub/cpr/798/cjd.htm)

Chris Lawson is a doctor and writer from Melbourne, Australia. Written in Blood is his first collection of short stories and essays and is available through MirrorDanse Books and Slow Glass Books.

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