Psych! Prions and Ice Nine

3D structure of amyloid fibrils

I saw this post about the possibility that Alzheimer’s is an infectious disease at Derek Lowe’s blog, In the Pipeline.  There’s a new paper out that reports that animals whose brains were exposed to misfolded amyloid-β protein extracted from patients with Alzheimer’s disease will go on to also develop amyloid plaques while control animals do not.  While there is a reputed genetic component to the development of Alzheimer’s disease, this study suggests that it can be induced by the transmission of a prion from one animal to another.  Prions are infectious bits of protein.  They’re teensier than viruses even.  In the case of amyloid disease, the protein under investigation is about 42 amino acids long, which is tiny.

The principle is this: in order to function properly, proteins need to fold into distinct secondary patterns and then a specific 3D shape.  If the protein is misfolded, it doesn’t work properly or it can aggregate, ie form clumps.  The sneaky think about prions is that they can induce other proteins to misfold.  The misfolded protein is in a lower energy state than the properly folded state so the protein can’t unfold itself and refold properly.  It’s stuck.

If any of you have read Kurt Vonnegut’s novel, Cat’s Cradle, and can remember anything beyond spritual footrubs and Bokononism, you may recall that one of the characters created a substance called Ice-9.  A single crystal of Ice-9 had the potential to freeze all contiguous bodies of water.  Throw it into a bathtub, the bath water freezes.  Throw it into an ocean, the ocean freezes.  I can’t recall if it stayed that way permanently but after Ice-9 was released, the world started to die of thirst.

The introduction of amyloid-β prions into a healthy brain may be doing an analogous thing by inducing newly formed amyloid protein to misfold.  And an excess of misfolded protein tends to aggregate, triggering inflammation and, down the road, dementia.  Mad cow disease is also a prion disease that in sheep manifests itself as scrapies.

Er, no one knows how to fix it yet.  One of the problems with developing a drug for Alzheimer’s disease is that the enzyme that normally would be targeted for inhibition, γ-secretase, is also used to cleave a protein called Notch, which the cell can’t really do without.  So, there’s that.  Drug discovery is much harder than it sounds, as Derek says in this recent podcast that he did with Paul Howard from the Manhattan Institute.

The frustrations of the drug discovery process that Derek describes reminds me of the central tenet of Bokononism:

“Beware of the man who works hard to learn something, learns it, and finds himself no wiser than before. He is full of murderous resentment of people who are ignorant without having come by their ignorance the hard way.“

Well, we *are* learning but the truth comes slowly and the answers to the questions are frequently accompanied by a whole new set of questions that must be answered.  This is in part why the pressures of the financial industry have been particularly harmful to the pharmaceutical industry and may have contributed to the high price of drugs.  Drug discovery is a long term process.  It can’t be sped up just to meet the numbers on a spreadsheet for the bean counters.  Cost controls that are intended to whip researchers to pick up the pace are bloody useless and counterproductive when applied to the complexity of the cell, something that the guys with executive hair may just now be realizing.  There’s not a whole lot more of mergering, cutting and restructuring that can be done at this point.  And the patent cliff still looms.  It’s going to be a rough ride for the drug industry for the next couple of years.

Derek also points out that the drugs that are now being approved were probably first discovered or synthesized in the mid 1990’s.  That means the patent clock has been running down for some of them and if there’s not a lot of time left to recoup the costs of discovery, it gets passed on to the consumer as higher prices.  There are other contributing factors to the cost of drugs but the length of the process is a significant one.

I encourage readers to check out the podcast.  Derek also discusses a new therapy for cancer that involves harnessing the immune system.  Fascinating and promising.