Ribbon representation of a protein in its normal (left) and prion (right) forms

Ribbon representations of a protein in its normal (left) and prion (right) forms

Humans long believed that disease was caused by witchcraft, the moon, or the humors. In 1890 Robert Koch postulated that infectious disease is caused not by evil eyes or evil woman, but by microorganisms that live in our water and homes. For the next eighty years, biologists held that infectious disease is caused by the spread of nucleic acids (DNA or RNA) in the form of viruses or single-celled organisms that contain DNA as their genetic material, such as bacteria like streptococcus. In 1960 the infectious disease paradigm was again smashed when a biologist and a mathematician proposed that DNA isn’t the only offender — protein can also act as an infectious agent. Their idea is revolutionary in more than one way — proteins are the building blocks of life, but they do not contain the information for life, so how can a protein, without any instructions, spread disease?

Just like your hand needs a certain conformation to undertake a task, such as picking up a teacup, so must a protein take a specific conformation to perform its task in the cell. Sometimes though, like a hand with a broken finger that can’t pick up a teacup, a protein “breaks”  by becoming misfolded and is no longer helpful to the cell — it cannot do its task. Even worse, it can hurt the cell. These deleterious infectious misfolded proteins, called prions, propagate not by creating more of themselves de novo such as the case with replicating viruses or spreading bacteria, but instead convert healthy protein in the cell to the misfolded and harmful form. Misfolded proteins expose unstable surfaces to the cell, and to minimize that instability, will convert and aggregate with other proteins like itself. These aggregations themselves are harmful, and they are the current explanation for Alzheimer’s Disease, although that link remains tenuous.

Now you might ask, “How does a protein become misfolded in the first place?” No one knows for sure, but once a protein misfolds, its unstable state is literally infectious. Prions are responsible for Mad Cow Disease, Crutzfield-Jackob Disease, Scrapie, Kuru, among others. Scientists are taking several approaches to study prions diseases. One such approach is the model organism approach, where an animal (or worm, fungus, fly) is used in environmental and genetic studies for which we can’t use humans — plus model organisms tend to be simpler than humans, so using model organisms is like learning addition before moving on to algebra.

Recently one of my favorite biologists Eric Kandel postulated that some prions may occur naturally in the body, where they to help the body function normally. Our brain cells have billions of connections, and part of what makes us unique (and helps us learn) is the strength and identity of these connections. One brain cell talks chemically to multitudes of others, and each of these connections is distinct. But how are these connections, called synapses, made distinct? One hypothesis is that the protein composition at each synapse is unique. However, molecules diffuse to areas of lower concentration, thus destroying the heterogeneity of synapses. A possible solution: prions — prions accumulate into non-diffusable aggregates, thereby maintaining unique synapses, allowing memory, personality and unique, beautiful snowflakes.

On a personal note, I used to work in a lipids (e.g. fatty acids) lab that studies membrane structure, and my Nobel Prize-winning idea was infectious lipids. Believe me, they’re out there. Making us sick. Making us fat. Tasting delicious.

Finally, a cautionary reminder: Prions, prions everywhere and not a brain to eat!